Encyclopedia of Biomedical Gerontology 9780128160756, 3313383513, 0128160756

Table of contents :
Front Cover......Page 1
ENCYCLOPEDIA OF BIOMEDICAL GERONTOLOGY......Page 2
ENCYCLOPEDIA OF BIOMEDICAL GERONTOLOGY......Page 4
Copyright......Page 5
CONTENTS OF ALL VOLUMES......Page 6
CONTRIBUTORS TO VOLUME 1......Page 14
EDITOR BIOGRAPHIES......Page 20
PREFACE......Page 24
PERMISSIONS ACKNOWLEDGEMENT......Page 26
A......Page 27
B......Page 279
C......Page 341
CARF and Cell Proliferation Decisions......Page 387
D......Page 494
Front Cover......Page 555
ENCYCLOPEDIA OF BIOMEDICAL GERONTOLOGY......Page 556
ENCYCLOPEDIA OF BIOMEDICAL GERONTOLOGY......Page 558
Copyright......Page 559
EDITOR BIOGRAPHIES......Page 574
PREFACE......Page 578
PERMISSIONS ACKNOWLEDGEMENT......Page 580
Epigenetic Biomarkers of Biological Age......Page 581
F......Page 658
G......Page 708
H......Page 790
I......Page 851
L......Page 893
M......Page 943
N......Page 1059
O......Page 1082
Front Cover......Page 1143
ENCYCLOPEDIA OF BIOMEDICAL GERONTOLOGY......Page 1144
ENCYCLOPEDIA OF BIOMEDICAL GERONTOLOGY......Page 1146
Copyright......Page 1147
CONTENTS OF ALL VOLUMES......Page 1148
CONTRIBUTORS TO VOLUME 3......Page 1156
EDITOR BIOGRAPHIES......Page 1162
PREFACE......Page 1166
PERMISSIONS ACKNOWLEDGEMENT......Page 1168
P......Page 1169
R......Page 1288
S......Page 1353
T......Page 1514
U......Page 1550
V......Page 1569
W......Page 1594
Y......Page 1611

Citation preview

ENCYCLOPEDIA OF BIOMEDICAL GERONTOLOGY

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ENCYCLOPEDIA OF BIOMEDICAL GERONTOLOGY EDITOR-IN-CHIEF

Suresh I. S. Rattan Aarhus University, Denmark ASSOCIATE EDITORS

Mario Barbagallo Università degli Studi di Palermo, Italy

Éric Le Bourg Université Paul-Sabatier, France SECTION EDITORS

Gustavo Duque The University of Melbourne, Australia

José Jauregui Ciudad Autónoma de Buenos Aires, Argentina

Dimitris Kletsas NCSR "Demokritos", Greece

Jan Nehlin Copenhagen University Hospital, Hvidovre, Denmark

Jean-Marie Robine INSERM, France

Katarzyna Szczerbinska Uniwersytet Jagiello nski, Krakow, Poland

Alexander Vaiserman Institute of Gerontology, Kiev, Ukraine

Nicola Veronese University of Padova, Italy

Academic Press Academic Press is an imprint of Elsevier 125, London Wall, EC2Y, 5AS 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright Ó 2020 Elsevier Inc. All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers may always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-816075-6 For information on all publications visit our website at http://store.elsevier.com

Publisher: Oliver Walter Senior Content Project Manager: Richard Berryman Associate Content Project Manager: Fizza Fathima Designer: Christian Bilbow

CONTENTS OF ALL VOLUMES Editor Biographies Preface

xix xxiii

VOLUME 1 Abuse and Neglect of Older Adults Lynn McDonald

1

Acute Kidney Injury in the Aged Marco Ostuni and Carlos G Musso

9

Advanced Glycation End Products: Origins and Role in Aging Mohammad Nadeem Khan

16

Age Determination and Lifespan of Marine Animal Species Baptiste Le Bourg and Eric Le Bourg

26

Aging and Entropy Alvaro Macieira-Coelho

37

Aging and Skeletal Muscle Gordon S Lynch

41

Aging Bone, Osteoporosis and Fragility Fracture J Zanker, SL Brennan-Olsen, and G Duque

48

Aging in Drosophila melanogaster Sentiljana Gumeni and Ioannis P Trougakos

60

Aging in Rodents Herminia González-Navarro, Soner Dogan, Bilge G Tuna, Paul K Potter, Gea Koks, and Sulev Koks

73

Aging in the Nematode Caenorhabditis elegans Ioanna Daskalaki, Maria Markaki, and Nektarios Tavernarakis

88

Aging in Zebrafish Dimitris Beis and Adamantia Agalou

104

Aging Lung Fatmanur Karakose Okyaltırık

114

v

vi

Contents of All Volumes

Aging Muscle and Sarcopenia Ben Kirk, Steven Phu, Danielle A Debruin, Alan Hayes, and Gustavo Duque

120

Aging of Bone Marrow Kornelia Ke˛ dziora-Kornatowska, Katarzyna Ma˛ dra-Gackowska, and Marcin Gackowski

132

Aging of Cells In Vitro Maria Cavinato, Sophia Wedel, and Pidder Jansen-Dürr

138

Aging of the Brain Sweta Srivas and Mahendra K Thakur

149

Aging of the Endocrine System Banteiskhem Kharwanlang and Ramesh Sharma

159

Aging of the Heart and Cardiovascular System Mingyi Wang, Robert E Monticone, and Kimberly Raginski McGraw

173

Aging of the Skin Christos C Zouboulis

183

Aging of the Tardigrades Simon Galas and Myriam Richaud

198

Air Pollution, Aging and Lifespan: Air Pollution Inside and Out Accelerates Aging Joseph Saenz and Caleb E Finch

203

Anatomical Changes in the Aging Kidney Joaquin Antonio Alvarez-Gregori and Juan Florencio Macías Nuñez

214

Anemia Kornelia Ke˛ dziora-Kornatowska, Katarzyna Ma˛ dra-Gackowska, and Marcin Gackowski

222

Anorexia in Older People Ozge Dokuzlar and Ahmet Turan Isik

229

Anti-aging: Myth or Reality Ligia J Dominguez and Mario Barbagallo

236

Artificial Feeding in Older People Nicola Veronese

249

Behavioral, Psychotic and Affective Disorders in Dementia (BPSD) Wojciech Rachel, Dominika Dudek, and Katarzyna Cyranka

253

Biodemography of Aging and Longevity Leonid A Gavrilov and Natalia S Gavrilova

260

Biology of the Aging Process Juan-Florencio Macías-Núñez, Joaquin-Antonio Alvarez Gregori, and José-Miguel López-Novoa

272

Blue Zones Michel Poulain, Dan Buettner, and Gianni Pes

296

Breast Cancer Elif Atag Akyurek

306

Calorie Restriction Guillermo López-Lluch and Plácido Navas

315

Calorie Restriction Mimetics Donald K Ingram

322

Contents of All Volumes

vii

Calorie Restriction, Health and Longevity Lee Smith, Justin Roberts, James Johnstone, Sarah E Jackson, Nicola Veronese, and Lin Yang

331

Cancer in Older Adults Hüseyin Salih Semiz

338

Cardiovascular System Wibert S Aronow

351

CARF: A Stress, Senescence, and Cancer Regulator Caroline TY Cheung, Rajkumar S Kalra, Sunil C Kaul, and Renu Wadhwa

357

Cellular Signal Transduction Amrita Kamat and Michael S Katz

371

Centenarians (Blue Zones?) Francesco Bolzetta and Alberto Cester

380

Chance Events in Aging David Steinsaltz, Maria D Christodoulou, Alan A Cohen, and Ulrich K Steiner

386

Chromatin Remodeling During Aging Teimuraz Lezhava

395

Chronic Lymphocytic Leukemia Agnieszka Szymczyk, Monika Długosz-Danecka, and Iwona Hus

400

Chronic Renal Disease in the Elderly and Senescent Nephropathy Mercedes Capotondo and Carlos G Musso

407

Claims for Extraordinary Human Lifespans Bernard Jeune

413

Clinical Overview of Osteoarthritis (OA) and the Challenges Faced for Future Management Dawn Aitken, Graeme Jones, and Tania Winzenberg

420

Constipation Ferhat Arık, Ugur Kalan, and Pinar Soysal

431

COPD: A Disease of Aging Andrea Corsonello and Raffaele Antonelli Incalzi

438

Cosmetics and Cosmeceuticals Maria Cavinato

446

Cross-Sectional and Longitudinal Designs in Animal Models Eric Le Bourg

462

Death and Longevity, Causes of France Meslé and Jacques Vallin

468

Delirium Eva Topinkova

484

Dementia M Cristina Polidori

493

Depression in Older People Dominika Dudek, Wojciech Rachel, and Katarzyna Cyranka

500

Diabetes Mellitus in Elderly Damiano Pizzol

506

viii

Contents of All Volumes

Dialysis in the Elderly Nada Dimkovi
c

511

Dose-Response Revolution: How Hormesis Became Significant Edward J Calabrese

519

VOLUME 2 Epigenetic Biomarkers of Biological Age Lidia Daimiel and Victor Micó

1

Epigenetic Drugs Elena G Pasyukova, Alexander V Symonenko, and Olga Y Rybina

11

Erythrocyte as a Cellular Model of Aging Research Geetika Garg, Sandeep Singh, Abhishek Kumar Singh, and Syed Ibrahim Rizvi

27

Ethics of Antiaging Intervention Ilia Stambler

36

Evolution of the Human Life Cycle Samuel Pavard and Christophe FD Coste

46

Evolutionary Theories of Aging Martin Reichard

57

Exercise and Physical Activity Recommendations for Optimizing Musculoskeletal Health in Older Adults Benjamin K Weeks and Belinda R Beck

68

Falls in Older Persons Maysa Seabra Cendoroglo and Neide Alessandra Perigo Nascimento

78

First Demographic Transition, From the Pleistocene to the 18th Century Paul L Hooper and Hillard S Kaplan

85

First to the Second Demographic Transition Jacques Véron

99

Food–Drug Interactions Among the Elderly: Risk Assessment and Recommendations for Patients Paweł Pa
sko

107

Freshwater Cnidarian Hydra: A Long-lived Model for Aging Studies Quentin Schenkelaars, Salima Boukerch, and Brigitte Galliot

115

Gastrointestinal Cancer Igor Grabovac, Lee Smith, Sarah E Jackson, and Lin Yang

128

Gene Therapy Olga Maslova, Alexander Koliada, and Alexander Vaiserman

136

Geriatric Emergency and Prehospital Care Esra Ates Bulut and Ahmet Turan Isik

147

Geroscience Alexander Vaiserman and Oleh Lushchak

154

Gluten Intolerance and Sensitivity in the Elderly Antonio Carroccio, Francesco La Blasca, and Pasquale Mansueto

160

Contents of All Volumes

ix

Growth Hormone and Mammalian Aging Diana Van Heemst, Evie van der Spoel, and Andrzej Bartke

171

Gut Microbiota and Aging: Targets and Anti-aging Interventions B Singh, R Catanzaro, G Mal, SK Gautam, Mohania, F He, H Yadav, L Bissi, and F Marotta

185

Gut Microbiota and Healthy Aging Léa Siegwald and Harald Brüssow

199

Health and Social Care Services Organization for Older Adults Natalie McNeela, Amit Arora, and Peter Crome

210

Heart Failure in Older Patients Krzysztof Rewiuk and Tomasz Grodzicki

223

History of Life-Extensionism Ilia Stambler

228

Homeostasis, Homeodynamics and Aging Suresh IS Rattan

238

Hormesis and Hormetins in Aging Suresh IS Rattan

242

Hunting, Predation and Senescence in Boars Marlène Gamelon

251

Hypertension in the Elderly José Alfie and Paula Edit Cuffaro

258

Inflammaging Targets Miriam Capri, Claudio Franceschi, and Stefano Salvioli

271

Intermittent Fasting Oleh Lushchak, Olha Strilbyska, Veronika Piskovatska, Alexander Koliada, and Kenneth B Storey

279

iPSCs-Induced Cellular Reprogramming Khachik K Muradian and Vadim E Fraifeld

291

Ischemic Heart Disease in Older Adults FM Trotta, D Caraceni, R Antonicelli, and A Cherubini

299

Life Expectancy and Health Expectancy Yuan S Zhang, Hyunju Shim, and Eileen M Crimmins

313

Loneliness in Old Age Javier Yanguas, Amaya Cilveti, and Cristina Segura

326

Long-Term Care Finbarr C Martin and Katie Robinson

332

Lung Cancer Rafael Lucas Costa de Carvalho, Pedro Henrique Cunha Leite, Flávio Pola dos Reis, Eserval Rocha Júnior, and Ricardo Mingarini Terra

348

Malabsorption Syndrome in the Elderly Murat Akarsu and Mehmet Hursitoglu

363

Malnutrıtıon ın Older People Ugur Kalan, Ferhat Arık, and Pinar Soysal

372

x

Contents of All Volumes

Maximal Human Lifespan Jean-Marie Robine and François R Herrmann

385

Mediterranean Diet and Longevity Ligia J Dominguez and Mario Barbagallo

400

Melatonin Rüdiger Hardeland

414

Metformin Jared M Campbell

424

Mitophagy Modulators Konstantinos Palikaras, Andrea Princz, and Nektarios Tavernarakis

433

mTOR Pharmacology Veronika Piskovatska, Olha Strilbyska, Kenneth B Storey, Alexander M Vaiserman, and Oleh Lushchak

447

Multimorbidity: Definition, Assessment, Measurement and Impact Pauline Boeckxstaens and Mirko Petrovic

455

Multiple Myeloma Artur Jurczyszyn and Anna Suska

461

New Ages of LifedEmergence of the Oldest-Old Marja Jylhä

479

Nutrition, Inflammation, and Infection in the Genomics of Lifespan Caleb E Finch

489

Obstructive Nephropathy Periklis Dousdampanis, Konstantina Trigka, and Ioannis Stefanidis

502

Oral Care Joanna Zarzecka, Gra_zyna Wyszy
nska-Pawelec, Jan Zapała, Tomasz Kaczmarzyk, Małgorzata Pihut, Janusz Czekaj, Justyna Hajto-Bryk, Karolina Babiuch, and Maciej Le
sków

512

Osteosarcopenia: The Modern Geriatric Giant J Zanker, SL Brennan-Olsen, and G Duque

537

Overweight and Obesity Lee Smith, Justin Roberts, James Johnstone, and Lin Yang

554

VOLUME 3 Pain in Older Age Pinar Soysal, Ugur Kalan, and Ferhat Arik

1

Palliative Care for Older People Danni Collingridge Moore and Sheila Payne

8

Paradoxes in Old Age Timo E Strandberg

18

Physical Exercise A Hernández-Vicente, G Vicente-Rodríguez, A Gómez-Cabello, J Alcazar, I Ara, and N Garatachea

24

Phytochemicals Shin-Hae Lee and Kyung-Jin Min

35

Contents of All Volumes

xi

Pneumonia Buyukaydin Banu

48

Postural InstabilitydBalance, Posture and Gait Steven Phu, Ben Kirk, and Gustavo Duque

64

Pressure Injury Suleyman Emre Kocyigit and Ahmet Turan Isik

77

Proteasome Modulation: A Way to Delay Aging? Niki Chondrogianni, Mary A Vasilopoulou, Marianna Kapetanou, and Efstathios S Gonos

92

Psoriatic Arthritis: A Current Vision Rubén Queiro, Andrés Lorenzo, Estefanía Pardo, and Juan D Cañete

105

Regulation of Metabolism and Longevity Mateusz Moło
n

120

Rehabilitation and Physical Therapy in Older Adults Pushpa Suriyaarachchi, Laurence Chu, Neeta Menon, Oddom Demontiero, Anuka Parapuram, and Piumali Gunawardene

127

Renal Cystic Disease in the Elderly Mónica Furlano and Roser Torra Balcells

148

Rheumatoid Arthritis Keith Lim, Matthew Jiang, and Thilinie De Silva

162

Role of Altered Extracellular Signalling in Cellular Senescence Masaki Takasugi

178

Senescence in the Wild: Theory and Physiology Jean-François Lemaître and Jean-Michel Gaillard

185

Senescence-Associated Beta-Galactosidase Marker of Cellular Senescence Manjari Dimri and Goberdhan P Dimri

193

Sexuality, Sensuality and Intimacy Michael John Stones, Katie Lemmetty, and Lee Stones

199

Sirtuin Activators Alice E Kane and David A Sinclair

210

Sleep Disorders Adam Wichniak, Katarzyna Gustavsson, Aleksandra Wierzbicka, and Wojciech Jernajczyk

220

Social Determinants of Life Expectancy and Inequality in Lifespan Alyson A van Raalte and Rosie Seaman

239

Social Participation in the Second Half of Life Marja Aartsen and Thomas Hansen

247

Social Security Systems and Life Expectancy Domantas Jasilionis

256

Stem Cell Therapy Elena De Falco, Antonella Bordin, Eleonora Scaccia, and Carmela Rita Balistreri

262

Stochastic Nature of Cellular Aging: The Role of Telomeres  Nikolina Skrobot Vidacek and Ivica Rubelj

271

xii

Contents of All Volumes

Stress Response Pathways Sumangala Bhattacharya and Suresh IS Rattan

282

Stroke Muhammad U Farooq, Christopher Goshgarian, Bradley Haveman Gould, Amy Groenhout, and Philip B Gorelick

290

Suicide Annalisa Anastasia, Marco Solmi, and Michele Fornaro

307

Supplements (Vitamins, Minerals, and Micronutrients) Joanna Chłopicka and Paweł Pa
sko

313

Syncope Ahmet Turan Isik and Ali Ekrem Aydin

326

Systems-Based Mechanisms of Aging Carole J Proctor, Amy E Morgan, and Mark T Mc Auley

332

Telomere Targeting Virginia Boccardi, Giuseppe Paolisso, and Patrizia Mecocci

346

Thyroid Disorders in Old Age Ligia J Dominguez and Mario Barbagallo

354

Trade-Offs Jean-François Lemaître, Louise Cheynel, Mathieu Douhard, Victor Ronget, and Jean-Michel Gaillard

367

Transhumanism Catherine Déchamp-Le Roux

376

Understanding the Importance of Proteostasis in Maximizing Healthspan: Challenges and Connections With the Other Pillars of Aging Qian Zhang, Maureen A Walsh, Melissa A Linden, and Karyn L Hamilton

382

Urinary Infections in Older Adults Laura Barcán

390

Vaccination (Prophylaxis) in the Elderly Fiona Ecarnot, Stefania Maggi, and Jean-Pierre Michel

401

Vision Disorders in Older People Agnieszka Kubicka-Trza˛ ska

412

Water and Electrolytes Disorders in the Elderly Pilar Domenech, Agustina Saldarini, and Carlos G Musso

426

What’s New on Alzheimer’s Disease? Insights From AD Mouse Models Christophe C Rey, Vanessa Cattaud, Claire Rampon, and Laure Verret

431

Yeast Models in Biogerontological Studies Anna Lewinska and Maciej Wnuk

443

Index

453

CONTRIBUTORS TO VOLUME 1 Adamantia Agalou Biomedical Research Foundation Academy of Athens, Athens, Greece Dawn Aitken Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia Joaquin Antonio Alvarez-Gregori Hospital Nuestra Señora del Prado, Talavera de la Reina, Spain; and University of Salamanca, Salamanca, Spain Ferhat Arık Kayseri, Education and Research Hospital, Kayseri, Turkey; and Tomarza Yasar Karayel State Hospital, Kayseri, Turkey Wibert S Aronow New York Medical College, Valhalla, NY, United States Elif Atag Akyurek Mehmet Akif Inan Research and Education Hospital, Sanliurfa, Turkey Mario Barbagallo University of Palermo, Palermo, Italy Dimitris Beis Biomedical Research Foundation Academy of Athens, Athens, Greece Francesco Bolzetta Azienda ULSS (Unità Locale Socio Sanitaria), DoloMirano, Italy SL Brennan-Olsen Department of Medicine-Western Health, The University of Melbourne, St Albans, VIC, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St Albans, VIC, Australia Dan Buettner Blue Zones, LLC, Minneapolis, MN, United States

Edward J Calabrese Department of Environmental Health Sciences, University of Massachusetts, Amherst, MA, United States Mercedes Capotondo Italian Hospital of Buenos Aires, Buenos Aires, Argentina Maria Cavinato Research Institute for Biomedical Aging Research, Innsbruck, Austria Alberto Cester Azienda ULSS (Unità Locale Socio Sanitaria), DoloMirano, Italy Caroline TY Cheung DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan Maria D Christodoulou University of Oxford, Oxford, United Kingdom Alan A Cohen University of Sherbrooke, Sherbrooke, QC, Canada Andrea Corsonello Unit of Geriatric Pharmacoepidemiology, IRCCSINRCA, Cosenza, Italy Katarzyna Cyranka Department of Psychiatry, Adult Psychiatry Clinic, Jagiellonian University Medical College, Kraków, Poland; and Jagiellonian University Medical College, Kraków, Poland Ioanna Daskalaki Foundation for Research and Technology-Hellas, Heraklion, Greece; and Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Greece

xiii

xiv

Contributors to Volume 1

Danielle A Debruin Department of Medicine, Melbourne Medical SchooldWestern Health, The University of Melbourne, St. Albans, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia; and Institute of Sport and Health, Victoria University, Melbourne, VIC, Australia Nada Dimkovi
c Zvezdara University Medical Center, Belgrade, Serbia; and Medical Faculty, Belgrade University, Belgrade, Serbia Monika D1ugosz-Danecka Department of Hematology, Jagiellonian University, Krakow, Poland Soner Dogan Department of Medical Biology, Faculty of Medicine, Yeditepe Universty, Istanbul, Turkey Ozge Dokuzlar Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey Ligia J Dominguez University of Palermo, Palermo, Italy Dominika Dudek Department of Psychiatry, Adult Psychiatry Clinic, Jagiellonian University Medical College, Kraków, Poland; and Jagiellonian University Medical College, Kraków, Poland Gustavo Duque Department of Medicine, Melbourne Medical SchooldWestern Health, The University of Melbourne, St. Albans, VIC, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia Caleb E Finch Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States Marcin Gackowski Collegium Medicum of Nicolaus Copernicus University, Bydgoszcz, Poland

Natalia S Gavrilova Academic Research Centers, NORC at the University of Chicago, Chicago, IL, United States Herminia González-Navarro INCLIVA Health Research Institute, Valencia, Spain; CIBER Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain; and Department of Didactics of Experimental and Social Sciences, University of Valencia, Valencia, Spain Sentiljana Gumeni National and Kapodistrian University of Athens, Athens, Greece Alan Hayes Department of Medicine, Melbourne Medical SchooldWestern Health, The University of Melbourne, St. Albans, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia; and Institute of Sport and Health, Victoria University, Melbourne, VIC, Australia Iwona Hus Department of Clinical Transplantology, Medical University of Lublin, Lublin, Poland; and Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland Raffaele Antonelli Incalzi University Camups Biomedico, Rome, Italy Donald K Ingram Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, United States Ahmet Turan Isik Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey Sarah E Jackson UCL, London, United Kingdom Pidder Jansen-Dürr Research Institute for Biomedical Aging Research, Innsbruck, Austria Bernard Jeune University of Southern Denmark, Odense, Denmark James Johnstone Anglia Ruskin University, Cambridge, United Kingdom

Simon Galas Faculty of Pharmacy, University of Montpellier, Montpellier, France

Graeme Jones Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia

Leonid A Gavrilov Academic Research Centers, NORC at the University of Chicago, Chicago, IL, United States

Ugur Kalan Kayseri Education and Research Hospital, Kayseri, Turkey; and Ermenek State Hospital, Karaman, Turkey

Contributors to Volume 1

Rajkumar S Kalra DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan Amrita Kamat Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System and University of Texas Health Science Center, San Antonio, TX, United States Michael S Katz Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System and University of Texas Health Science Center, San Antonio, TX, United States Sunil C Kaul DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan Kornelia Kędziora-Kornatowska Collegium Medicum of Nicolaus Copernicus University, Bydgoszcz, Poland Mohammad Nadeem Khan School of Studies in Biotechnology, Bastar University, Jagdalpur, India Banteiskhem Kharwanlang St. Edmund’s College, Shillong, India Ben Kirk Department of Medicine, Melbourne Medical SchooldWestern Health, The University of Melbourne, St. Albans, VIC, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia Gea Koks Prion Ltd., Tartu, Estonia Sulev Koks Prion Ltd., Tartu, Estonia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA, Australia; and The Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia

xv

Teimuraz Lezhava Department of Genetics, Tbilisi State University, Tbilisi, Georgia Guillermo López-Lluch Universidad Pablo de Olavide, Sevilla, Spain José-Miguel López-Novoa University of Salamanca, Salamanca, Spain Gordon S Lynch Centre for Muscle Research, Department of Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia Juan-Florencio Macías-Núñez University of Salamanca, Salamanca, Spain Alvaro Macieira-Coelho INSERM, Versailles, France Katarzyna Mądra-Gackowska Collegium Medicum of Nicolaus Copernicus University, Bydgoszcz, Poland Maria Markaki Foundation for Research and Technology-Hellas, Heraklion, Greece Lynn McDonald University of Toronto, Toronto, ON, Canada Kimberly Raginski McGraw National Institutes of Health, Biomedical Research Centre (BRC), Baltimore, MD, United States France Meslé French Institute for Demographic Studies, Paris, France Robert E Monticone National Institutes of Health, Biomedical Research Centre (BRC), Baltimore, MD, United States Carlos G Musso Italian Hospital of Buenos Aires, Buenos Aires, Argentina; and University Institute of Italian Hospital of Buenos Aires, Buenos Aires, Argentina

Baptiste Le Bourg University of Liège, Liège, Belgium

Plácido Navas Universidad Pablo de Olavide, Sevilla, Spain

Eric Le Bourg Université de Toulouse, CNRS, UPS, Toulouse, France

Fatmanur Karakose Okyaltırık Bezmialem Vakif University Medical School Pulmonology Department, Istanbul, Turkey

xvi

Contributors to Volume 1

Marco Ostuni University Institute of Italian Hospital of Buenos Aires, Buenos Aires, Argentina Gianni Pes University of Sassari, Sassari, Italy Steven Phu Department of Medicine, Melbourne Medical SchooldWestern Health, The University of Melbourne, St. Albans, VIC, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia Damiano Pizzol Doctors with Africa CUAMM, Beira, Mozambique M Cristina Polidori University of Cologne, Cologne, Germany Paul K Potter Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom Michel Poulain UCLouvain, Ottignies-Louvain-la-Neuve, Belgium; and Tallinn University, Tallinn, Estonia Wojciech Rachel Department of Psychiatry, Adult Psychiatry Clinic, Jagiellonian University Medical College, Kraków, Poland; and Jagiellonian University Medical College, Kraków, Poland

Sweta Srivas Banaras Hindu University, Varanasi, India Ulrich K Steiner University of Southern Denmark, Odense, Denmark David Steinsaltz University of Oxford, Oxford, United Kingdom Agnieszka Szymczyk Department of Clinical Transplantology, Medical University of Lublin, Lublin, Poland Nektarios Tavernarakis Foundation for Research and Technology-Hellas, Heraklion, Greece; and Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Greece Mahendra K Thakur Banaras Hindu University, Varanasi, India Eva Topinkova Charles University, Prague, Czech Republic Ioannis P Trougakos National and Kapodistrian University of Athens, Athens, Greece Bilge G Tuna Department of Biophysics, Faculty of Medicine, Yeditepe Universty, Istanbul, Turkey Jacques Vallin French Institute for Demographic Studies, Paris, France

Myriam Richaud Faculty of Pharmacy, University of Montpellier, Montpellier, France

Nicola Veronese National Research Council, Neuroscience Institute, Padova, Italy

Justin Roberts Anglia Ruskin University, Cambridge, United Kingdom

Renu Wadhwa DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan

Joseph Saenz Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States Hüseyin Salih Semiz _ T. C. Health Sciences University Izmir Tepecik Training _ and Research Hospital, Izmir, Turkey

Mingyi Wang National Institutes of Health, Biomedical Research Centre (BRC), Baltimore, MD, United States

Ramesh Sharma North Eastern Hill University, Shillong, India

Sophia Wedel Research Institute for Biomedical Aging Research, Innsbruck, Austria

Lee Smith Anglia Ruskin University, Cambridge, United Kingdom

Tania Winzenberg Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia

Pinar Soysal Bezmialem Vakif University, Istanbul, Turkey

Lin Yang Medical University Vienna, Wien, Austria

Contributors to Volume 1

J Zanker Department of Medicine-Western Health, The University of Melbourne, St Albans, VIC, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St Albans, VIC, Australia

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Christos C Zouboulis Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany

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EDITOR BIOGRAPHIES EDITOR-IN-CHIEF Suresh I.S. Rattan, PhD, DSc, is a biogerontologist, and leads the Laboratory of Cellular Ageing at the Department of Molecular Biology and Genetics, Aarhus University, Denmark. His research areas, expertise, and interests include aging of human cells and application of the concept of mild stress– induced hormesis and hormetins as a modulator of health and aging. He is the discoverer of the human cellular aging-modulatory effects of the plant growth factors kinetin and zeatin. He is the recipient of the Lord Cohen Medal in Gerontology from the British Society for Research on Ageing (BSRA), and an Honorary Doctorate from the Russian Academy of Medical Sciences. He is the present Chairman of the Biology Section of the International Association of Gerontology and Geriatrics-European Region (IAGG-ER). He has published more than 250 peer-reviewed scientific articles, and has edited/coedited 15 books, including professional books for research scientists, for children, and for the general public. Some of his popular science books are translated into Danish, Polish, Romanian, Hindi, and Punjabi languages. He is also the founder and continuing Editor-inChief of the journal Biogerontology, and serves on the editorial board of several international journals on aging. His official email is: [email protected] and his personal website is: www. sureshrattan.com.

ASSOCIATE EDITORS Mario Barbagallo, MD, PhD, is Professor of Geriatrics and Director of the Geriatric Unit, University Hospital of Palermo, and Director of Post-graduate program in Geriatrics, Director of the Department of DIPECA, University Hospital, University of Palermo, Italy. He is President of IAGG-ER (International Association of Geriatrics-European Region) for the years 2019–23 and Past Chairman of the Clinical Section of IAGG-ER (International Association of Geriatrics-European Region) for the years 2015–19. He is a Member of the Superior Council of the Italian Minister of Health. He is included in the list of the Top Italian Scientists (www.topitalianscientists.org). Born in Palermo, Italy, he obtained his medical degree in 1983. He worked in Parma and Rome where he obtained PhD in 1989. From 1989 to 1992, he worked at the Cornell University Medical Center, New York, NY, USA, and from 1993 to 1995, as a Fulbright Scholar and Visiting Professor at Wayne State University, Detroit, MI, USA. He is an expert of problems related to the prevention and treatment of diseases associated with aging. He is a member of several national and international scientific societies and appreciated speaker in Italy and abroad. He is author of about 500 publications in national and international scientific journals. Éric Le Bourg, PhD, DSc, is a researcher in biogerontology at the French National Center for Scientific Research (CNRS), Université Paul Sabatier, Toulouse, France. He has performed many studies on the effects of mild stress in the fruit fly Drosophila melanogaster, but he has also worked or is currently working on its learning and behavior, and on human demography matters linked to aging. Beside his numerous papers in journals or books, he has written four books in French for the lay public and academics on biology, demographic, and social matters linked to the aging process, and he has edited or coedited three books, as well as special issues. He often writes papers dealing with the aging process and related issues for the French press.

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Editor Biographies

SECTION EDITORS Prof. Gustavo Duque, MD, PhD, FRACP, FGSA, is a geriatrician and a clinical and biomedical researcher with special interest in the mechanisms and treatment of osteoporosis, sarcopenia, and frailty in older persons. His initial training included Internal Medicine at Javeriana University (Colombia) and Geriatric Medicine, which he completed at McGill University in Montreal (Canada). Subsequently, he obtained his PhD at McGill University in 2003 with a thesis entitled “Molecular Changes of the Aging Osteoblast” under the supervision of Dr. Richard Kremer. Prof. Duque’s major research interests include the elucidation of the mechanisms and potential new treatments for age-related bone loss, osteoporosis, sarcopenia, and frailty. He is also looking at the effect of vitamin D, exercise, and proteins on bone and muscle mass. He is currently Chair of Medicine and Director of the Australian Institute for Musculoskeletal Science (AIMSS) at the University of Melbourne and Western Health. He is also Director of the Fracture Care and Prevention Program at Western Health (Melbourne). As part of this Program, Prof. Duque implemented a Falls and Fractures clinic at Sunshine Hospital where patients are assessed for falls and fractures risk in a comprehensive manner.

José R. Jauregui, MD, PhD, received with honors from the University of Buenos Aires, School of Medicine on December 23, 1986. He completed full residency in Internal Medicine at the Hospital for Acute Carlos G. Durand, City of Buenos Aires (1987–91) and Annual Course of Geriatrics and Gerontology of the Argentina Society of Gerontology and Geriatrics (1990). He was University Career Specialist in Geriatrics and Gerontology at the University of Buenos Aires (1992–94); Postgraduate degree Fellow, Department of Geriatrics, University of Wales, UK; Professor Ken Woodhouse holder; and Prof. Antony Bayer acceptor. He was Senior Lecturer (March–May 1995). He completed Doctor of Medicine, University of Salamanca, Spain (March 2012). He has been rated “Outstanding CUM LAUDE” Academic graduate of the Latin American Academy of Medicine for the Elderly, ALMA (April 2012). Resident Internal Medicine, “Hospital Carlos G. Durand,” City of Buenos Aires (June 1987 to May 1991). He was invited lecturer in Geriatrics, Faculty of Medicine, Occupational Therapy and Psychology at the University of Salamanca, Spain (December 2007); Chief of Geriatrics Programme at Family and Community Medicine department, Hospital Italiano de Buenos Aires (1995–2012); and Deputy Medical Director in charge of the Italian Hospital of San Justo, Agustín Rocca (2001–12). He is Director of the Career College Specialist in Gerontology and Geriatrics, University of Buenos Aires; Director and Founder of “Biology Research Unit on Aging” certified facility and a member of the international network of research centers in geriatricsdGarndby “IAGG” (International Association of Gerontology and Geriatrics), located in the Italian Hospital of San Justo, Argentina; Past President of Argentinean Society of Gerontology and Geriatrics; Past President of Latin American & Caribbean Committee of IAGG; and IAGG President elect for the period 2021–25.

Dr. Dimitris Kletsas holds a BSc in Biology from the University of Thessaloniki and a PhD in Biochemistry, Cell and Molecular Biology from the Biology Department of the University of Athens (thesis accomplished in National Centre of Scientific Research “Demokritos”dNCSRD). He then worked in EMBL (Heidelberg), NCSRD (Athens), Imperial College (London), and Georgetown University (Washington, DC). Currently, he is Research Director, Head of the Laboratory of Cell Proliferation and Ageing, of the Laboratory of Cell Systems and Bioactive Compounds, and of the Animal House of the Institute of Biosciences & Applications (IBA), NCSRD. Since 2017 he is the Director of the Institute and Member of the Board of NCSRD. His research interests include: mechanisms of aging and longevity, cellular senescence and age-related pathologies, cancer, intervertebral disc degeneration, wound healing, growth factors and signaling pathways, stress response, extracellular matrix and cell–matrix interactions, bioactive compounds (synthetic or from natural sources) with anticancer, antioxidant/anti-aging or wound healing action, biomaterials, stem cells, and cell replacement therapies. His work has produced more than 180 peer-reviewed articles, 16 book chapters, 2 patents, and has attracted more than 10500 citations and an h-factor of 49 (Google Scholar). He served as President of the Hellenic Society of Biochemistry and Molecular Biology and of the European Tissue Repair Society (ETRS), and he is Member of the National Council of Research and Innovation, Sector of Biosciences.

Editor Biographies

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Jan O. Nehlin, Dr. Med. Sci., Cand. scient., is a senior researcher, Associate Professor, at the Clinical Research Centre, Copenhagen University Hospital, Amager-Hvidovre hospital, Copenhagen, Denmark, and specialist in biogerontology, immunology, stem cell biology, and cellular and molecular biology. His research focuses on the validation and clinical use of biomarkers of aging in chronic, elderly multimorbidity patients, mechanisms of senescence, preventive health, and therapeutic interventions. He is a member of a Clinical Academic Group dealing with prognostication of acute recovery capacity in an aging population (ACUTE-CAG). He has published more than 50 peer-reviewed articles including several book chapters. He has held positions in Denmark at the University of Southern Denmark and Odense University hospital, Novo Nordisk Pharmaceuticals, Rigshospitalet and Copenhagen University, in the United States at National Institute on Aging, Baltimore, Berkeley National Lab and University of California, Berkeley, and in Sweden at the Ludwig Institute for Cancer Research and Uppsala University, Sweden. He did undergraduate studies at Simon Bolivar University, Venezuela; graduate studies in Sweden; and postdoctoral studies in Sweden and United States. He has taught numerous students and technical staff at all levels, supervised more than 14 graduate and undergraduate student theses, participated at more than 100 scientific conferences, and invited speaker in more than 30 occasions. He is assistant editor of the journal Biogerontology and serves as reviewer for numerous journals. Jean-Marie Robine is an Emeritus Research Professor at INSERM, the French National Institute of Health and Medical Research (http://www.inserm.fr), within the CERMES3 Research group in Paris and the Unit 1198 in Montpellier where he heads the research team Biodemography of Longevity and Vitality. He is also an Emeritus Professor at the advanced school Ecole pratique des hautes études (http://www.ephe.sorbonne.fr) in Paris. He studies human longevity, with the aim of understanding the relations between health and longevity. In particular, he measures the impact that the increase in adult life durations may have on the health status of the elderly population. In his most recent work, he takes into accounting the climate changes. Since its creation in 1989, he has been the coordinator of the International Network on Health Expectancy (REVES), which brings together more some 200 researchers worldwide (www.revesnetwork.org). He is co-responsible for the development of the International Database on Longevity (IDL) in association with the Max Planck Institute for Demographic Research (Rostock) and INED (Paris). He is the project leader of the healthy longevity project granted by AXA Research Fund: the Five-Country Oldest Old Project (5-COOP). He is also advisor to the Director of INED, the French National Institute on Demographic Studies (https://www.ined.fr) on longevity and aging issues. He was the project leader of the European Joint Action EHLEIS (2011–14) which provided analysis of disability-free life expectancies in the European Union (www.eurohex.eu) and part of the BRIDGE-Health project (2015–17) which aimed to prepare the transition toward a sustainable and integrated EU health information system (www.bridge-health.eu). He was one of the Directors of the French Research Consortium on aging and longevity (GDR CNRS 3662, 2014–17) which prepared the way for ILVV, the French Institut de la Longévité, des Vieillesses et du Vieillissement (https://ilvv.site.ined.fr). Publications: http://www.researcherid.com/rid/F-5439-2011 Katarzyna Szczerbi nska, MD, PhD, is Professor of Geriatrics at Jagiellonian University Medical College (JUMC, Kraków, Poland), and the Head of the Unit for Research on Ageing Society at Chair of Epidemiology and Preventive Medicine, at Medical Faculty at JUMC. She is a physician, specialist in geriatric medicine with long practice experience in nursing homes, and expertise in public health and long-term care. For several years she has been appointed in the Health Promotion Department at the Institute of Public Health in JUMC, and since 2012 at the Epidemiology Department and Preventive Medicine. Her areas of expertise are geriatrics, long-term care, health promotion, and healthy aging. She is an author of over 200 scientific papers, including 50 chapters in books, the editor of 3 books and a member of editorial board of other 20 manuals, and an author of more than 80 conference presentations. Most of her publications are result of 16 international projects funded by European Commission (EC) in which she participated as a researcher and principal investigator (in 12 of them) leading Polish team. She is a very active researcher in the field of gerontology and geriatrics in Europe. She was a World Bank consultant for analysis of long-term care resources in Poland. Since 2004 she is a representative for Poland in the InterRAIda Consortium for the Cross-National Assessment of Elderly and Disabled Persons. Since 2015 she is a member of the Executive Committee, and since 2019, a General Secretary of the International Association of Geriatrics and Gerontology for the European Region. She also plays important role in Polish gerontology leading the Cracovian Branch section of Polish Society of Gerontology (since 2014). In the period 2013–17 she was a Vice-President, and now is a Treasurer in the Executive Committee of the College of Geriatric Specialists in Poland, belonging to the European Geriatric Medicine Society (EuGMS). She was an expert at the Ministry of Health for elaboration of geriatric care standards (2007–15), and for conducting the educational project funded by EC: Support for life-long learning system for medical professionals in geriatric care (2011–14). Since 2012 she is also a member of Experts’ Committee for Older People at Ombudsman Council in Poland.

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Editor Biographies Alexander Vaiserman was born in Kyiv, Ukraine, in 1957. His research interests comprise epigenetics, epidemiology, and experimental gerontology. He earned his MSc Degree in cytology and developmental biology from Kyiv State University in 1984, and his DSc in normal physiology from Institute of Gerontology (Kyiv, Ukraine) in 1991 and 2004, respectively. Since 1978, he has had a permanent position in the Institute of Gerontology (Kyiv, Ukraine). Since 2010 to present, he is the head of the Laboratory of Epigenetics in the Institute of Gerontology (Kyiv, Ukraine). He is the member of the Editorial Boards of the journals Biogerontology, Frontiers in Genetics of Aging, Journal of Genomic Medicine and Pharmacogenomics, and Journal of Gerontology & Geriatric Research.

Dr. Nicola Veronese was born on February 1, 1983, in Adria, Rovigo, Italy. During his specialization in Geriatrics, he worked as Research Fellow at the Washington University in Saint Louis, MO, USA. During this period, he attended on several projects regarding the effect of healthy lifestyle, calorie restriction, and intermittent fasting on metabolism of obese and overweight subjects. Moreover, he worked as research fellow with Stefania Maggi, Neuroscience Institute, National Research Council, Padua, Italy, regarding the positive effects of Mediterranean diet on several medical conditions typical of older people, such as neurodegenerative diseases. After these experiences, he obtained the position of community-based geriatrician in ULSS 3 Serenissima, Venice, Italy. His research is mainly epidemiological and focused on the most common diseases present in older people. In particular, areas of his interest are osteoarticular, metabolic (including obesity and diabetes), and cardiovascular diseases, as well as nutrition. He is an expert in meta-analyses and systematic reviews, being the leader of the Special Interest group of the European Society of Geriatric Medicine (EuGMS). He is also involved as expert in the Scientific Committee of National Societies interested in Geriatrics. He won the ESCEO-MSD Fellowship (March 2016), given to a young investigator for his future contributions in the field of bone and mineral research, one of the areas of his interest. He is author of more than 300 articles published in national and international scientific journals and of numerous abstracts accepted in national and international congresses. Finally, he is an Editorial Member of American Journal of Therapeutics, Geriatric Care, and Associate Editor of Aging Clinical and Experimental Research.

PREFACE This edition of the Encyclopedia of Biomedical Gerontology (EBMG) represents both the continuity and a reincarnation of the previous two editions of the Encyclopedia of Gerontology, published in 1996 and 2007. The focus of EBMG is the biomedical aspects of aging research and interventions. Thus, EBMG may be considered a totally independent and fresh compilation of almost 150 articles with less than 10% articles updated or rewritten by the authors from the previous editions. The biological aspects of aging covered in the EBMG can be categorized into four sections: evolutionary and demographic aspects; phenotypic and descriptive aspects; mechanistic aspects; and interventionary aspects. Similarly, on the medical and clinical side of gerontology, the topics covering a wide range of issues can be categorized into diagnostic aspects; comorbidities; public health aspects; and prevention and treatment of agerelated diseases. Biomedical gerontology has made tremendous advances in recent times. Explaining aging and longevity in evolutionary and demographic scenarios; describing what happens during aging in molecules, cells, tissues, organs, bodies, groups, populations, and species; and what may be the public (universal) and the private (individualistic) mechanisms of aging and age-related diseases are the common, and sometimes overlapping, threads of discussion in this encyclopedia. Understanding, accepting, and realizing both the universal and the individualistic heterogenous nature of aging is crucial to “do something” about aging, age-related diseases, and lifespan. Such an understanding also helps in evaluating and sorting out what is fact, fiction, and a wishful thinking. This challenging task of compiling a comprehensive and up-to-date encyclopedia was successfully taken up and completed by the efforts of the whole editorial team comprised of eight section editors, two coeditors, and myself as the editor-in-chief. Each one of them brought in his/her academic and professional expertise and credibility, international network, and their perseverance to get the best possible contributors to the EBMG. We are confident that the readers will find this encyclopedia a highly useful source of the latest and accurate information in biomedical gerontology. Suresh I. S. Rattan Editor-in-Chief

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PERMISSIONS ACKNOWLEDGEMENT The following material is reproduced with kind permission of Oxford University press Figure 3. Lifespan of marine organisms (excluding tortoises) Table 1. Ischaemic heart disease in elderly Table 2. Ischaemic heart disease in elderly Table 4. Osteosarcopenia www.oup.com

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Abuse and Neglect of Older Adultsq Lynn McDonald, University of Toronto, Toronto, ON, Canada © 2020 Elsevier Inc. All rights reserved. This is an update of L. McDonald. Abuse and Neglect of Elders. Encyclopedia of Gerontology, 2nd Edition, 2007, Pages 1–9.

Introduction The Extent of Elder Abuse Elder Abuse and Neglect in Community Settings Elder Abuse in the Institution Risk Factors for Elder Mistreatment Theoretical Explanations The Situational Model Social Learning Model Social Exchange Perspective Routine Activity Theory The Ecological Model The Life Course Perspective Responses to Abuse and Neglect National Responses to Mistreatment Legal Responses to Mistreatment of Older Adults Community Interventions Residential Care Facilities Services References

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Glossary Community elder abuse Generally refers to any of the above types of mistreatment that are committed by someone with whom the older person has a special relationship. The abuse usually occurs within the home of the older adult or in the home of the perpetrator (for example, a spouse, sibling, child, friend, or caregiver who they trust). Elder abuse Elder abuse is a single or repeated act, or lack of appropriate action, occurring within any relationship where there is an expectation of trust, which causes harm or distress to an older person. This type of violence constitutes a violation of human rights and includes physical, sexual, psychological, and emotional abuse; financial abuse; abandonment; neglect; and serious loss of dignity and respect. Institutional abuse Refers to any of the above-mentioned forms of abuse that occur in residential facilities for older persons (e.g., nursing homes, assisted living, hospitals). Perpetrators of institutional abuse usually are persons who have a legal or contractual obligation to provide older victims with care and protection (e.g., staff, and professionals). Perpetrators may also be other residents in the same facility, who appear to have no apparent intent to harm fellow residents. They may be cognitively impaired as could be the victim. Resident-to-resident harmful behavior is sometimes labeled as a form of abuse, aggression or mistreatment. The definition includes aggressive and intrusive physical, sexual, verbal, and material interactions between longterm care residents that may cause physical or emotional or other harm to the victim. Resident-to-resident aggression remains difficult to classify because of little research and because it does not fit comfortably into typical definitions of elder abuse, which tend to include an expectation of trust on the part of the victim in relation to the perpetrator. Mistreatment/maltreatment Refers to all forms of abuse (psychological, physical, sexual and financial) and neglect; ‘abuse’ is used to refer to all forms of abuse, excluding neglect. Neglect Intentional or unintentional harmful behavior on the part of an informal or formal caregiver in whom the older person has placed his or her trust. Unintentional neglect is a failure to fulfill a caretaking responsibility, but the caregiver does not intend to harm the older person; intentional neglect occurs when the caregiver consciously and purposely fails to meet the needs of the older person, resulting in psychological, physical or material injury to the older person. Self-neglect An act of omission on the part of the older person, such as the failure to take care of personal needs, which may result in psychological, physical, or material injury. The problem can often be attributed to the older person’s diminished physical or mental capabilities to care for themselves. There is some question as to whether self-neglect should be included in a consideration of elder neglect and abuse, since no abusive perpetrators are involved.

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Change History: May 2019. L. McDonald, updated the text and references.

Encyclopedia of Biomedical Gerontology, Volume 1

https://doi.org/10.1016/B978-0-12-801238-3.11354-6

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Abuse and Neglect of Older Adults

Introduction There is growing world agreement that the mistreatment or older adults is an extensive and costly public health problem often fatal to older adults. Older adults who experience mistreatment and neglect are twice as likely to be hospitalized as those who are not abused and have more than threefold increased likelihood of mortality compared to those not abused (Lachs et al., 1998). The direct medical costs of elder abuse injuries in the United States are estimated to contribute more than $5.3 billion to the nation’s annual health expenditures (Dong, 2005). Historically, there has been no generally accepted definition of elder abuse but there is a growing international consensus about the types of actions to be included in the definition. There are usually five agreed upon categories of abuse with some disagreement around whether self-neglect or abandonment are forms of older adult mistreatment. Physical abuse includes any act that involves the intentional infliction of physical discomfort, pain, or injury. Examples of physical abuse include such behaviors as restraining, slapping, kicking, cutting, or burning. Medical maltreatment is sometimes considered an example of physical abuse such as withholding or inappropriate use of medications. Sexual abuse or assault covers non-consensual sexual contact of any kind with an older person such as unwanted touching, all types of sexual battery like rape or coerced nudity. Psychological abuse, sometimes referred to as verbal or emotional abuse, involves the intentional infliction of mental anguish or the provocation of fear of violence or isolation in the older person. Psychological abuse can take various forms, such as name-calling, humiliation, intimidation or threats of placement in a nursing home. Financial abuse, sometimes referred to as material abuse, involves the intentional, illegal, or improper exploitation of the older person’s material property or financial resources by the abuser. Financial abuse can include fraud, theft or use of money or property without the older person’s consent. Neglect generally refers to the intended or unintended failure of a formal or informal caregiver to fulfill any part of a caregiving obligation. Examples include failure to provide an older person with the necessities of life such as food, water, clothing, shelter, medicine or comfort. Acts such as theft, physical assault, rape and burglary by a person outside of a trusting or contractual relationship with the older person usually would not be classified as elder abuse but rather as crimes. Crimes against older persons include some, but not all, forms of elder abuse. Older adults living in institutional care facilities may experience abuse that is a single incident of poor professional practice or part of a larger pattern of ill treatment. This may include inadequate care and nutrition, poor standards of nursing care, substandard or unsanitary living conditions, misuse of physical restraints or medicine and low levels of supervision. Resident-to-resident maltreatment may also represent a single occurrence or on-going behavior. Resident-to-resident aggression has physical and psychological consequences for residents by increasing their morbidity and mortality (e.g., lacerations, fractures, depression, anxiety). These categories of abuse have been strongly influenced by research in Canada, the United Kingdom, Europe, Asia and the United States. Studies conducted in other countries such as China, India or South Africa have used different definitions that reflect the values within their societies. In China, where harmony and respect are core societal values, neglecting the care of an older person is considered elder abuse. In one of the first attempts to classify abuse in a developing country, focus groups held in South Africa added to western definitions such categories as accusations of witchcraft, loss of respect for older adults and mistreatment by systems such as health clinics and pension offices. The mistreatment of older people by family members never came to light until after child and wife abuse had entered the public domain in the mid 1960s. Mistreatment of older persons was first described as late as 1975 in British scientific journals as “granny battering” but rapidly came to be regarded a significant health and social problem in developed countries in the 1980s. With the realization of the dramatic increases in the aging populations in developing countries in the 1990s, elder mistreatment became a global health and welfare issue. This article will review the extent of older adult mistreatment in community and institutional settings, the risk factors for mistreatment, the theoretical frameworks used to explain abuse and neglect and global responses to the problem.

The Extent of Elder Abuse Elder Abuse and Neglect in Community Settings Progress has been made in establishing the prevalence of elder mistreatment worldwide with the introduction of many new studies in the research literature. Analyses of investigations have suggested that aggregate prevalence varies widely between countries (e.g., 2.2% in Ireland vs. 8.2 in Canada) and within countries, as is the case for the United States where Acierno et al. (2010) found an aggregate national prevalence rate of 11.4% compared to 7.6% found in the New York State study (Life Span of Greater Rochester Inc., Weil Cornell Medical Centre, New York Dept. for the Study of Aging, 2011). Most recently, three attempts have been made to synthesize global prevalence estimates of elder mistreatment (Yon et al., 2017; Pillemer et al., 2016; Dong, 2015). The first study by Dong (2015) highlighted the global epidemiology of elder abuse according to its prevalence and risk factors in community populations. The second study, originally prepared for the World Health Organization (WHO), provided a synthesis of prevalence in the community in 18 countries (Pillemer et al., 2016). The last study used metaanalysis of 44 countries between 2002 and 2015 (Yon et al., 2017). The first study organized the world into broad regions. Accordingly, in North and South America, the prevalence ranged from 10% in cognitively intact older adults to 47.3% in older adults with cognitive impairments. In Europe, the prevalence varied from 2.2% in Ireland to 61.1% in Croatia. In Asia, the highest 1 year prevalence in older adults was in mainland China (36.2%) and lowest in India (14.0%). In the only two studies conducted in Africa the prevalence ranged from 30% to 43.7% (Dong, 2015).

Abuse and Neglect of Older Adults

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The second synthesis reviewed 18 countries. The highest aggregate prevalence was is in China (36.2%) followed by Nigeria (30.0%), Israel (18.4%), India (14.0%), Europe (10.8%), Mexico (11.4%), and the United States (9.5%). The mean was 14.3% across all countries (Pillemer et al., 2016). When substantive threshold criteria were included (i.e., emotional abuse frequency vs. any emotional abuse), aggregate prevalence was lower, and ranged from 2.2% to 14.0%, with a mean of 7.1% (Pillemer et al., 2016). The same study estimated each type of elder mistreatment, for 1 year prevalence. Physical abuse was 0.2% in the United States to 4.9% in China with a mean of 2.8% internationally. In the case of sexual abuse, prevalence ranged from 0.04% in Nigeria to 1.0% in Europe. Psychological abuse ranged from 0.7% in the United Kingdom and rose to 27.3% in China with an international mean of 8.8% (Pillemer et al., 2016). In terms of financial abuse, the range for 1 year prevalence was 1.0% in the United Kingdom and extended to 9.2% in five combined European countries, but only for women. The United States and European 1 year prevalence of 4.5% and 3.8%, respectively for financial abuse, was close to the average of 4.2% (Pillemer et al., 2016). Lastly, the 1 year prevalence for neglect was estimated to range from 0.2% in the Netherlands to 5.5% in five combined European countries but only for women. The mean neglect prevalence was estimated to be 3.1% across countries (Pillemer et al., 2016). The third synthesis used different countries and investigations of variable quality but had a comparable 1 year prevalence to the Pillemer et al. (2016) analyses. Pooled data from 44 studies between 2002 and 2015, set the global prevalence of older adult mistreatment at 15.7%, or about one in six older adults. The rate approximated 141 million global victims of elder mistreatment annually. Pooled prevalence estimates for each of the mistreatment types, was 11.6% for psychological abuse, 6.8% for financial abuse, 4.2%, for neglect, 2.6% for physical abuse, and 0.9% for sexual abuse. When geographical variations in prevalence estimates were calculated, the rates for Asia were 20.2%, Europe 5.4%, and the Americas at 11.7% (Yon et al., 2017). Unlike any other study of elder mistreatment, meta-analytical analyses assessed how the methodological characteristics of the various investigations affected mistreatment prevalence. It is not unexpected that large sample sizes, random sampling, and high-income countries were associated with lower prevalence estimates, although only sample size differences were independently statistically significant (Yon et al., 2017). These data of international prevalence rates have to be interpreted with some caution since they used different data files of varying quality, were all cross-sectional, made few distinctions between high and low-income countries or age and gender or in the diversity of culturally specific forms of older adult mistreatment. Although abuse prevalence investigations continue to progress with the addition of a life course perspective, improvements in measurements through “caseness” (severity and frequency of abuse), larger samples allowing more reliable analyses and an attempt to understand international diversity, the same problems linger. The discrepancies in findings can still be attributed to methodological issues such as age when abused, definitions of mistreatment, type of sampling, different measurement instruments, varying severity and frequency indicators of mistreatment and geographical region. The gap between older adults’ own definitions of elder mistreatment and the standardized measures used by researchers adds to the inconsistencies in findings (McDonald, 2018). More than likely, the studies provide low estimates because the cognitively or hearing impaired are excluded from much of the research. For example, studies suggest that prevalence ranges anywhere from 3.2–27.5% for those with normal cognition compared to 27.9–62.3% for those with cognitive issues (Kim et al., 2018). In a population-based study, a representative sample of only family carers in Ireland found that one in six engaged in harmful behavior toward their care recipients (Lafferty et al., 2016), a rate that, at best, falls within reported ranges for aggregate mistreatment. Nevertheless, these studies represent the best prevalence studies currently available and underscore the global extent of elder mistreatment.

Elder Abuse in the Institution Institutional abuse is the mistreatment of older persons living in facilities such as nursing homes, hospitals or long-term care institutions; it is perpetrated by the formal caregiving staff, and by other patients or sometimes, visitors. There is also some indication that an abusive relationship at home may not necessarily end once an older person has entered institutional care. Elder abuse and neglect in institutions falls into the same categories as that committed in the community, but the victims are likely to be more vulnerable to abuse by virtue of the fact that they require the protective environment of the facility. Some researchers have added violations of basic rights to the list of abuses that can occur in institutions. Such violations include, denying older people the right to make personal decisions or the right to privacy. Another form of abuse that has been considered is systemic abuse which refers to abuses resulting from unquestioning regimentation like routine use of incontinence briefs instead of helping the person to the bathroom. There is little reliable data on the prevalence of maltreatment or neglect in residential long-term care facilities. There are, however, a few rigorous studies coupled with enough anecdotal evidence in every country where these institutions exist, to suggest that abusive behavior is a widespread, regular aspect of institutional life. There have been reports of material abuse including the theft of patient’s funds and fraudulent therapy and pharmaceutical charges; physical abuse including rough handling, hitting and slapping, inappropriate medical treatment such as chemical and physical restraint; and psychological abuse including social isolation, yelling in anger and threats. Neglect often reflects deficiencies in the provision of nursing care such as inadequate nutrition and hydration, and poor oral and physical hygiene. The estimates of institutional abuse are generally higher than for the community and are widely diverse. There is only one current synthesis and partial meta-analysis of mistreatment investigations in institutions where only nine studies surfaced according to the inclusion criteria. Three were self-reports by older adults or proxies and 6 self-reported studies by staff and both were statistically treated separately (Yon et al., 2019). The investigations of staff were geographically dispersed extending from the Czech Republic,

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Germany, Ireland, Israel to the United States. An average prevalence for the previous 12 months was 64.2% admitted by staff as perpetrators of elder mistreatment. The prevalence studies based on self-report by older adults and their proxies, were from the Czech Republic, Israel, Slovenia and the United States (the Czech study used both staff and residents). One year prevalence estimates for overall abuse could not be calculated, only mistreatment subtypes were reported by older residents which were highest for psychological abuse at 33.4%, physical at 14.1%, financial abuse at 13.8%, and neglect at 11.6%, and the lowest prevalence, sexual abuse, at 1.9% of victims (Yon et al., 2019). The most robust institutional study to date was completed in Ireland. A national survey was used to measure the maltreatment of older people committed by and observed by staff from the perspective of staff working in residential care settings (Drennan et al., 2012). While there was no aggregate prevalence reported, a total of 27.4% of staff reported that they had been involved in at least one neglectful act within the preceding 12 months. The most frequently reported acts by staff were ignoring a resident when they called (22.6%) followed by not taking a resident to the bathroom when requested (13.3%). Close to 3.2% of staff reported that they had committed one or more acts of physical abuse of a resident in the preceding year. In terms of psychological abuse, 7.5% of staff reported they committed this type of abuse, usually by shouting at a resident in anger. Both financial (stealing from resident) and sexual abuse (inappropriate touching) perpetrated by staff was very small at .02% in the preceding year. Resident-to-resident aggression (RRA), also referred to as resident-to-resident elder mistreatment, or resident-to-resident aggression, resident-to-resident violence, resident-to-resident relational aggression, and resident-to-resident abuse, is a common occurrence in long-term care facilities that has only recently gained attention. Although the outcomes can be devastating, there is a lack of scientific evidence about the prevalence, the contributing factors or prevention and intervention strategies. A recent synthesis review of RRA (McDonald et al., 2015) concluded that individual studies could not produce a prevalence rate on the basis of their design, nor could the results be meaningfully pooled because of heterogeneity. In short, age and prevalence periods varied, definitions, the methods and the units of analyses were different or not randomly sampled and the residents themselves were rarely interviewed. The most rigorous study to date, addressed some of these flaws by using a standardized and validated case-finding methodology expressly developed for estimating RRA prevalence in nursing homes (Lachs et al., 2016). The results indicated that 20.2% of 2011 residents experienced at least one RRA event during the observation period of 1 month. Results suggested that older persons in dementia units suffered higher rates of resident to resident abuse (Lachs et al., 2016).

Risk Factors for Elder Mistreatment Accurate research on risk factors for abuse is critical for the development of effective screening tools and intervention protocols, for reducing or eliminating contributing factors to deter mistreatment and for the development of policy for those populations at heightened risk of mistreatment. As is the case with prevalence rates, the risk factor research on elder mistreatment is both limited, inconsistent and sometimes in conflict. The way in which risk factors affect the likelihood of mistreatment is not well known. The impact of risk factors may be altered by the presence of other modifying factors. Most researchers use varying predictive models to evaluate risk factors so the risk factors found to be significant may be artifacts of whatever variables were chosen. For example, a variety of factors have been included in regression models such as gender, income, level of education, ethnicity, marital status, health, mental health, etc. but no two models include the same factors so results emphasize different influences. This problem goes beyond the problems already noted above with definitions, measurement and design. Following the National Research Council framework (Bonnie and Wallace, 2003), the distinction between risk factors/risk indicators, have been divided into three categories based on available evidence, namely risk factors validated by substantial evidence for which there is near-unanimous support from a number of studies; possible risk factors, for which the evidence is mixed or limited and contested risk factors, for which potential for increased risk has been hypothesized, but for which there is a lack of evidence. Ultimately, nearly all international, population-based research of community-dwelling older persons has identified elder mistreatment as a family affair perpetrated by informal family caregivers. The main exception is instances of sexual abuse which is usually perpetrated by an outside party like a friend, work colleague or neighbor (McDonald, 2018). Some evidence has suggested that perpetrators of physical and psychological abuse in Asian countries are children and children-in-laws, while in the United States, Israel, Europe and Canada, the most likely perpetrator is reportedly a spouse/partner. In those countries that study community dwelling older persons, older adult functional dependence and/or physical disability are factors repeatedly associated with greater risk of elder mistreatment. Psychological and financial mistreatment in the United States and China are explicitly related to functional dependence while physical mistreatment is related to functional dependency and/or disability in the United States and Canada. Poor physical health of the victim has been regularly associated with adult mistreatment involving financial abuse in the United States and the United Kingdom, physical, sexual, and emotional abuse in Israel and neglect in the United States and Israel (Pillemer et al., 2016). In the case of cognitive impairment, physical abuse has been related to a non-Alzheimer dementia diagnosis and to moderate to severe behavioral and psychological problems related to the dementia (Kim et al., 2018). Some studies have found a strong link between abuse and poor mental health in the United Kingdom, China and Canada, specifically with depression symptomology in the aggregate, and for each type of abuse (McDonald, 2018). Whether the depression causes or is the result of the mistreatment, is a moot question in wait of longitudinal analyses. The most recent population-based research and the largest investigation globally, was a national study in Canada that used a life course

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perspective and found that abuse earlier in life was a constant risk factor across aggregate and all subtypes of mistreatment (McDonald, 2018). To date, there is only mixed research support for age, gender, race/ethnicity, financial dependence and low socioeconomic status of the older person, although there is disagreement about the latter as a predictor (Pillemer et al., 2016). The risk factors representing the perpetrator which garner strong support are poor psychological health sometimes requiring treatment, (usually for depression); a drug or substance misuse problem and a dependency on their victims for psychological support, financial help, and housing. For caregivers of the cognitively impaired, perpetrator characteristics associated with low income, inadequate knowledge about dementia and severe perceived care burden led to mistreatment. Only three relationship factors between the older person and the perpetrator have been found with mixed results, namely marital status, type of family relationship, and possibly social norms that normalize mistreatment of older persons. Finally, the strongest risk factors for mistreatment in institutional care were identified as high levels of burnout among staff, the frequency of resident related stressors, staff experiences of mistreatment by residents, and staff suffering psychological distress (Drennan et al., 2012). When it comes to resident-to-resident abuse the only available research suggests severe levels of cognitive impairment, residing on a dementia unit, and higher nurse aide caseload as risk factors for mistreatment (Lachs et al., 2016).

Theoretical Explanations Much of the literature on elder mistreatment of community-dwelling older persons does not make an important distinction between theoretical explanations and the individual factors related to mistreatment. A theory provides a general, systematic explanation for observed facts; in the elder abuse literature, particular factors, such as stress or dependency, are often treated as complete theoretical explanations even though they are only factors and could be incorporated into any of a number of theories. The specific relationships between the various factors and mistreatment form propositions upon which theories are built. Over the course of the brief history of older adult mistreatment, different accounts of the relationships among the factors have led to at least four distinct theoretical perspectives. Their variations are of particular import, since each theory determines what actions should be taken to ameliorate the abuse and neglect.

The Situational Model The situational model posits that caregivers can be overburdened, unable to satisfy the demands of their care recipients, and consequently perpetrate abuse and neglect. Borrowed from systems theory, this approach not only blames the victim for the abuse but has received little evidentiary support (Gaugler, 2016). The problem is that the majority of caregivers are not abusive or neglectful. Gerontologists are mystified as to why this approach still has any traction at all in the research (Anetzberger, 2012).

Social Learning Model Social learning, or modeling, is part of the symbolic interaction perspective. The theory posits that abusers learn how to be violent from witnessing or suffering from violence, and the victims, in suffering abuse and neglect, learn to be more accepting of it. This perspective also blames the victim and has been shown to be highly questionable. It seems that young victims of abuse grow up to be victims of elder mistreatment (McDonald, 2018), the exact opposite of the theory.

Social Exchange Perspective In the social exchange perspective, it is argued that as people age, they become more powerless, vulnerable, and dependent on their caregivers, and it is these characteristics that place them at risk for abuse (Chappell et al., 2007). There are many problems with this perspective, not the least of which is its basic ageist assumption: people do not automatically become dependent and vulnerable as they age. As already noted, it is the perpetrator’s sense of powerlessness that leads to maltreatment. There is no empirical evidence to support this theory.

Routine Activity Theory The criminalization of elder abuse is a recent addition to the literature and has had at least one new accompanying theory. Goergen and Beaulieu (2010) have proposed routine activity theory (RAT), which essentially hypothesizes that when an offender has an opportunity and ability to mistreat an older adult, who happens to be a suitable target with little or no likelihood of legal oversight, an illegal activity will occur. RAT has been mainly applied to financial abuse in nursing homes, but Goergen and Beaulieu (2010) argue that it could be applied to caregiving where aggression is involved and no one else would know.

The Ecological Model The applied ecological theory (Barboza, 2016) has been popular among gerontologists because it focuses on four concentric and interconnected systems as found in Bronfenbrenner’s ecological systems theory (1997). The microsystem includes the interpersonal

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relations between the older adult abuser, the meso-system, social relationships like family and friends, and the effect of the community as context in the exo-system that includes ideologies, values and polices at the time. A number of researchers have attempted to develop theory in elder mistreatment using this perspective. Some have framed caregiving and potential mistreatment using this approach and filled in the risk factors at the various levels based on the literature. Other versions of ecological theory have been used to describe a conceptual model for financial abuse, also drawing on potential and known risk factors detailed in the literature. Others have used a critical ecological model to frame family violence and elder mistreatment, with a note that ageism would likely intersect with patriarchy in the abuse and neglect of older women. Indeed, the fact that almost any subtype of elder mistreatment and known predictors could be inserted into the theory testifies to the flexibility of the model.

The Life Course Perspective The objective of life course studies was to develop a conceptual framework of social pathways and their relation to sociohistorical conditions with an emphasis on human development and aging (Settersten, 2003). The main architect of the approach, Glen Elder, developed five paradigmatic principles that provided a concise, conceptual map of the life course: development and aging as lifelong processes, lives in historical time and place, social timing, linked lives, and human agency (Elder, 2006). The life course is composed of a set of multiple, interdependent trajectories. similar to that of careers at school, work, and in the family (Settersten, 2003). What happens along one trajectory will have consequences for other trajectories, such as when living situations reflect risks for mistreatment (Settersten, 2003). Trajectories are punctuated with events, transitions, and turning points. An event is usually conceptualized as an abrupt change, such as being slapped once, while a transition is seen as a more gradual shift, such as becoming a victim of psychological abuse that research has suggested occurs over time (Taylor et al., 2014). A turning point is seen as a major directional change or discontinuity in a trajectory such as calling the police on an adult perpetrator to save one’s life. Several studies have indicated relationships between childhood violence and mental health problems in adulthood and issues with emotional closeness with family in later life. It has now been shown that abuse and neglect during different stages of the life course are highly correlated with elder mistreatment after age 55 and that different stages affect subtypes of abuse differently (McDonald, 2018). Overall, most scholars have realized that there is a broad diversity in the manifestations of elder abuse and neglect and have abandoned their search for a comprehensive, all-inclusive explanation of the phenomena. In the future, new theories of elder abuse may explain different dimensions of elder abuse and neglect, and theoreticians will probably cast their net wider including gerontological theories alongside the family violence theories that have been, so far, the mainstay of the elder mistreatment literature. As a consequence, practitioners will have a wider array of interventions at their disposal, which will facilitate the provision of more effective care for mistreated elders.

Responses to Abuse and Neglect National Responses to Mistreatment Efforts to spur social action to eradicate elder mistreatment at a national level and to develop national polices and legislation are at varying stages of growth around the world. While the United States has developed a full-blown national response to elder abuse at the state level that allows for the funding and reporting of elder abuse and has instituted at least three national organizations, other countries have been less proactive. The latest appraisal of responses to the mistreatment of older persons world-wide was conducted by the World Health Organization and the United Nations in 2014 (WHO, 2014). The report included 133 countries representing 88% of the world’s population, six major regions and covers only government responses to mistreatment. At the outset, only 41% of all countries had a national plan for elder mistreatment with the region of the Americas, the most likely to have such a national plan (51%) and the African Region the least likely to have a plan (33%). The European Region was somewhat low with only 39% of countries committed to a national plan compared to the South East Asia Region where 50% of the countries had a national plan. It is informative that although only 17% of all countries had a national data file on mistreatment of older persons, 41% still had a national plan indicating that many plans were not informed by data. In short, elder mistreatment was one of the least investigated types of violence in national surveys, and one of the least addressed in national action plans.

Legal Responses to Mistreatment of Older Adults Many countries have not introduced specific legislation on maltreatment of older persons. Abuse may be covered under criminal law, or by laws dealing with property rights, civil rights and family violence or mental health, and varies widely from country to country. Still, specific legislation is a key component of some violence prevention polices but laws against the mistreatment of older adults was the least evident among all global violence legislation. The WHO (2014) study found that 40% of countries enacted legislation to prevent elder mistreatment but only 20% enforced the law, highlighting a serious gap between enactment and enforcement (see WHO, 2014, for overview of legislation).

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In most countries, a number of common issues have emerged that continue to be legally challenging in many jurisdictions. One key issue has been whether and under what circumstances criminal charges should be filed against alleged perpetrators. There is a concern that appropriate assistance and support services will not be available after authorities have intervened in a mistreatment case and considerable concern as to whether the older person will lay charges, especially against a family member. When the problem of cognitive impairment is added to the equation, the complexity intensifies and further laws have to be introduced like substitute decision-making, powers of attorney and guardianship, which again, depend on jurisdiction. Even though every state in the United States has mandatory reporting it too, raises issues. The few research studies on mandatory provisions have cast doubts on the contribution the process can make to the prevention of mistreatment. There have been problems of reporting cases already known to authorities, statutes that sometimes have failed to ensure the consistent collection of data that would aid in the tracking of mistreatment and some confusion as to what types of cases mandatory reporting would likely uncover. Several studies have found that mandatory reporting is more likely to be associated with cases of neglect and self-neglect, others, however, established that reporting is more likely to be associated with cases of physical abuse. The few studies that examined the relationship between mandatory reporting and institutionalization of the older victim indicated that mandatory reporting could result in increased rates of institutionalization of the mistreated, although contact with protective services was the more plausible explanation. Finally, the passage of a mandatory reporting law does not mean that those who are required to report will be aware of the law or be motivated to comply. The general conclusion in the research literature is that the effectiveness of mandatory reporting systems in existing jurisdictions needs further investigation as to effectiveness. In recent years, there have been significant advocacy efforts calling for enhanced international action on the human rights of older persons. Various stakeholders have called for more visibility and increased use of international human rights standards to address elder mistreatment around the world. The Open-ended Working Group on Aging, formulated in 2010 at the United Nations, is currently working on an international framework of human rights and the feasibility of further instruments and measures (United Nations, 2010).

Community Interventions The most urgent need in the mistreatment of older adults is for evidence-based interventions that can prevent or contain mistreatment. Unfortunately, choosing intervention possibilities creates huge challenges, because reliable evaluation data do not exist on most intervention models. Faced with the dire situation of mistreatment, practitioners still must respond, especially in critical situations. From a global perspective the most common strategies used are efforts to raise professional awareness and train practitioners (40%); inform the public about how to identify the signs and symptoms of mistreatment and where help can be obtained (34%); caregiver support programs (33%), and improving policies and practices in residential care facilities for older people (37%). Based on limited evidence from multiple case studies, program descriptions, rare random clinical trials and surveys, the better intervention strategies at this point in time include knowledge mobilization about mistreatment directed at professionals and the public; multidisciplinary teams (MDT) across most service systems in the community and health sectors; national and regional telephone support lines; targeted emergency shelters for older persons and caregiver support programs (NICE, 2018; Pillemer et al., 2016). For example, the National Initiative for the Care of the Elderly (NICE) has developed evidence-based “pocket tools” (digital and paper) about elder mistreatment from assessment through intervention for professionals to family caregivers, while there are telephone “hotlines” such as ALMA in France that provides both immediate counseling and longer term follow-up to older adults (Sethi et al., 2011). The Israeli program entitled, Specialized Unit for the Prevention and Treatment of Elder Abuse, includes an advisory MDT of professionals (geriatric medicine, law, social work, etc.) and a welfare officer for the court and has shown significant success. Although temporary emergency shelters dedicated to older mistreatment victims are few and far between, they do have the potential to prevent permanent relocation to a nursing home through providing security while allowing planning for safety at home. Some of these “shelters,” however, may be housed in nursing homes which could be confusing although they have not been rigorously evaluated. Interventions for caregivers were among the first models used to prevent or manage older adult mistreatment. These interventions, then and now, have relied on services such as personal care, shopping, housekeeping and meal preparation, respite care, education, support groups online and in person, and day and night hospitals. As an example, ECARE (eliciting change in at-risk elders) is a United States program delivered to mistreatment victims and/or vulnerable older people, and caregivers to minimize the risk of elder abuse. This program uses motivational interviewing skills to reduce uncertainty related to making life changes. Research evaluation found a significant reduction in older adult mistreatment (Mariam et al., 2015). A cautionary note that these interventions only meet minimally acceptable methodological standards is important as is the recognition that they have been developed primarily in higher-income countries and may or may not have applicability to other jurisdictions because of fewer resources and cultural differences in the manifestation of the mistreatment of older adults.

Residential Care Facilities While residential care settings in most countries are subject to different regulations and enforcement strategies such as unannounced regulatory visits, video recorders in key locations and ombudsmen, several avenues for intervention have been identified to prevent institutional maltreatment. Interventions that address hiring and the supervision of staff, staff training and skill development,

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including the problems of burnout and the creation of specialized treatment programs for the abused could serve as the basis for managerial initiatives. Hiring a sufficient number of staff per older person, at the correct level of training, would be fundamental to any intervention but often conflicts with the need for the institution to make a profit. To date there are few programs and even less research as to what is effective.

Services It is evident from the literature that the services already available to older persons provide the bulk of the resources used in response to older adult mistreatment, regardless of what approach is utilized, and that new or uniquely designed services are not always required. Most mistreatment practitioners face difficulties in accessing limited resources, especially in critical emergency contexts, and they must deal with the challenges of coordination and collaboration in the existing patchwork of services. They also must deal with the reality that there is a paucity of well-researched intervention studies to inform the identification and management of elder mistreatment.

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Acute Kidney Injury in the Aged Marco Ostuni, University Institute of Italian Hospital of Buenos Aires, Buenos Aires, Argentina Carlos G Musso, University Institute of Italian Hospital of Buenos Aires, Buenos Aires, Argentina; and Italian Hospital of Buenos Aires, Buenos Aires, Argentina © 2020 Elsevier Inc. All rights reserved.

Introduction AKI Pathophysiology in the Elderly Prerenal Renal/Intrinsic Postrenal Diagnosis AKI Treatment Prophylaxis Rehydration Dialysis Conclusion References

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Introduction Several factors are associated with an increased risk of developing acute kidney injury (AKI) in the elderly population. For instance, comorbid conditions such as hypertension, diabetes, congestive heart failure and renovascular disease are highly prevalent among elderly individuals, and can lead directly or indirectly to an increased susceptibility to AKI. Moreover, many of these conditions may necessitate surgery, procedures or drugs that could be nephrotoxic (Stallone et al., 2012; Coca, 2010). Polypharmacy is particularly frequent in adults older than 60 years and it is strongly associated with AKI. Prolonged duration of polypharmacy and the use of cardiovascular medications are factors that increase the risk of renal dysfunction (Hain and Paixao, 2015; Rosner, 2013). This association may be the result of changes in baseline kidney function and pharmacokinetics, with increased exposure to drugs and risk for toxicity (Anderson et al., 2011). Older patients are more likely to suffer obstructive AKI given the higher incidence of prostate disease in men and pelvic malignancies in women, retroperitoneal adenopathies or neoplasms and neurologic bladder (Del Giudice and Aucella, 2012; Lautrette et al., 2012; Abdel-Kader and Palevsky, 2009). The use of anticholinergic medications may also promote acute urinary retention with the subsequent development of AKI (Rosner, 2013). The elderly population is especially prone to real or effective hypovolemia. This is the result of primary hypodipsia and impairment in sodium and water reabsorption by renal tubules, in addition to the high prevalence of comorbidities such as heart failure which promote effective volume depletion (Lautrette et al., 2012; Commereuc et al., 2014; Musso, 2005). Furthermore, immunosenescence alterations make older adults more vulnerable to infections, another relevant cause of kidney damage (Chronopoulos et al., 2010a). Several changes that take place in the aging kidney can make older adults more susceptible to AKI (Table 1). Structural changes include the presence of simple cysts and a reduction of total renal mass, which can be around 30% in patients between 50 and 80 years and affects both glomeruli and tubules (Lautrette et al., 2012). Arteriosclerosis of renal vasculature, intimal and medial hypertrophy and fibrointimal hyperplasia lead to cortical glomerulosclerosis, tubular atrophy and interstitial fibrosis, with compensatory hypertrophy and mesangial expansion (Coca, 2010; Lautrette et al., 2012; Chronopoulos et al., 2010a). This promotes injurious hyperfiltration of the glomeruli, eventually resulting in hyperfiltration injury and global glomerulosclerosis (Hain and Paixao, 2015; Rosner, 2013; Anderson et al., 2011; Lautrette et al., 2012; Chronopoulos et al., 2010a). Tubular atrophy is characterized by a reduction in number and shortening of the proximal portion. The distal tubules are notable for the presence of diverticula, which may potentially generate new cysts (Coca, 2010; Lautrette et al., 2012). Functional changes include a reduction in glomerular filtration rate (GFR) and alterations in electrolyte homeostasis. Structural changes described above lead to a reduced filtration surface, with a decline in GFR of approximately 0.75–1 mL/min/year (Coca, 2010; Hain and Paixao, 2015; Anderson et al., 2011; Commereuc et al., 2014). Tubular function is deteriorated, with notable impairment in urine concentration capacity and partial insensibility to vasopressin (Lautrette et al., 2012; Commereuc et al., 2014). The ability to reabsorb electrolytes in the proximal tubule is usually preserved, while the urine dilution-concentration capability is reduced in the collecting tubules (Hain and Paixao, 2015; Rosner, 2013; Chronopoulos et al., 2010a). Additionally, sodium reabsorption is diminished in the thick ascending limb of the loop of Henle, as well as in the distal tubules probably due to partial insensitivity to aldosterone (Lautrette et al., 2012; Commereuc et al., 2014). These alterations in water and sodium conservation may lead to urine sodium levels > 20 mmol/L and urinary osmolality < 500 mOsm/kg despite effective intravascular volume

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Acute Kidney Injury in the Aged Table 1

Renal aging changes

•

Structural changes

•

Functional changes

•

Hemodynamic changes

•

Cellular/molecular changes

               

Reduction in renal mass Less functioning glomeruli Tubular atrophy Mesangial expansion Interstitial fibrosis Reduction in glomerular filtration rate Altered tubular water, sodium and urea reabsorption Altered tubular potassium secretion Reduction in blood flow and renal blood flow reserve Increased vascular resistance Increased vasoconstriction and impaired vasodilation Reduced oxide nitric production Impaired autoregulation Increased oxidative stress Impaired cell proliferation Augmented expression of antiproliferation genes, with increased susceptibility to apoptosis  Increased expression of senescent genes  Reduced expression of renal growth factors

depletion, with a theoretical maximal osmolality of 900 mOsm/kg in the elderly (Del Giudice and Aucella, 2012; Lautrette et al., 2012). Moreover, decline in GFR, increased glomerular capillary pressure, and an imbalance between vasoconstrictors (angiotensin II) and vasodilators (nitric oxide) ultimately favor vasoconstriction, reduce autoregulatory capacity and decrease functional reserve (Rosner, 2013; Anderson et al., 2011; Commereuc et al., 2014; Chronopoulos et al., 2010a). The aged kidney also exhibits various cellular and molecular differences which are associated with AKI. Older kidneys show a higher expression of the senescence marker p16 (INK4A) compared to younger ones, and there is a decreased expression of renal growth factors (EGF, IGF-1, VEGF) (Coca, 2010; Anderson et al., 2011). Telomere shortening, Dicer-associated microRNAs and heme oxygenase–regulated autophagy are also important new modulators for risk for AKI (Anderson et al., 2011). It is possible that the senescent cells are more susceptible to apoptosis and that fewer tubular epithelial cells are available to de-differentiate and proliferate in response to injury, resulting in defective repair and decreased likelihood of recovery from AKI. (Coca, 2010; Rosner, 2013; Anderson et al., 2011; Chronopoulos et al., 2010a). Aging alone constitutes a chronic oxidative condition in which reactive oxygen species (ROS) and advanced glycation end products (AGEs) are unable to be cleared due to a reduction in oxidative stress defenses, including lower levels of antiinflammatory AGE receptor AGER1 and increased levels of proinflammatory receptor RAGE. AGER1, AGE and ROS may be influenced by dietary changes, becoming potentially effective targets to prevent or manage AKI (Anderson et al., 2011) (Table 1).

AKI Pathophysiology in the Elderly The causes of AKI in the elderly include the typical causes observed in other populations. However, these patients are often exposed to several renal insults, resulting in a multifactorial origin of AKI, with an increased incidence of prerenal, nephrotoxic and obstructive causes (Table 2) (Rosner, 2013). Indeed, although most studies are unable to discriminate between acute tubular necrosis Table 2

Causes of acute kidney injury in the elderly

•

Prerenal

•

Renal/Intrinsic

•

Postrenal

 Real/effective hypovolemia (dehydration due to vomiting, diarrhea, diuretic use; heart failure, liver disease)  Cardiorenal syndrome  Drug mediated hemodynamic changes (NSAIDs, ACEIs, ARBs)  Surgery/vascular procedures  Drug-induced acute tubular necrosis  Contrast-induced nephropathy  Acute interstitial nephritis  Nephrotoxic substances (hemoglobin, myoglobin, light chains of myeloma)  Prostatic disease  Pelvic malignancies

NSAID: Nonsteroideal antiimnflammatory drugs, ACE: angiotensin converting enzyme inhibitor, ARB: angiotensin II receptor blocker.

Acute Kidney Injury in the Aged

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(ATN) and prerenal AKI effectively enough, reports estimate that 40% of AKI are caused by ATN, 30% by prerenal causes, and almost a quarter is caused by obstruction (Stallone et al., 2012; Coca, 2010; Cheung et al., 2008).

Prerenal Prerenal AKI is the result of decreased renal perfusion which leads to a reduction in glomerular filtration rate (GFR), most commonly due to real or effective hypovolemia (e.g.: heart failure [HF], liver disease, nephrotic syndrome). Although it is commonly thought to be a benign condition, prerenal AKI is associated with a high mortality risk and it may progress to ATN (Rosner, 2013; Del Giudice and Aucella, 2012). Cardiac disease is highly prevalent in the elderly, and HF is among the most frequent causes of effective hypovolemia resulting in AKI. Indeed, several reports revealed that between 20% and 40% of patients admitted to a hospital for acute HF has comorbid renal failure (Del Giudice and Aucella, 2012). This scenario is currently termed “cardiorenal syndrome,” a disorder whereby acute or chronic worsening of one organ’s function may prompt acute or chronic dysfunction of the other (Chronopoulos et al., 2010a). Elderly individuals are especially prone to dehydration, one of the leading causes of volume depletion, not only due to impairment in the ability of the aged kidney to reabsorb water and sodium, but also because of the extensive use of diuretics, impaired thirst sensation or inability to increase fluid intake (postration, delirium, etc.) (Rosner, 2013; Del Giudice and Aucella, 2012; Lautrette et al., 2012; Commereuc et al., 2014). In this setting of volume depletion, the elderly kidney may be unable to successfully adapt its glomerular pressure gradient. Vasodilation of the afferent arteriole may be defective due to arteriosclerotic disease, as well as vasoconstriction of the efferent arteriole, which could be affected by drug-mediated blockade of normal autoregulatory responses such as activation of renin–angiotensin–aldosterone system (i.e., angiotensin converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs]) (Del Giudice and Aucella, 2012; Lautrette et al., 2012). Nonsteroidal antiinflammatory drugs (NSAIDs) are also frequently prescribed in this population, and affect the ability of the afferent arteriole to dilate through a reduction of prostaglandins (Hain and Paixao, 2015). Major surgery, especially cardiac surgery, is another frequent cause of prerenal AKI in this population. The risk of developing AKI in this scenario is increased with advanced age, as well as in presence of other predisposing factors such as comorbidities or emergency surgery. Many intraoperative and perioperative factors contribute to a reduction in kidney perfusion, such as decreased cardiac output, hypotension induced by anesthetics, infection, bleeding, and insensible fluid loss. Intraabdominal hypertension may occur unexpectedly during the perioperative period and could affect kidney function dramatically (Chronopoulos et al., 2010b; Chronopoulos et al., 2010c). Prerenal AKI may also be a consequence of acute vascular obstruction due to emboli, dissection or compression or the renal arteries, most frequently occurring during vascular surgery or angiographic procedures (Del Giudice and Aucella, 2012; Abdel-Kader and Palevsky, 2009). The development of anuria in this context may reflect bilateral embolization, or unilateral embolization in the presence of a solitary kidney (Lautrette et al., 2012). While cholesterol emboli resulting in AKI are most frequent in patients over 70 years of age, other causes such as emboligenic heart disease are less specific of the elderly population. These patients can also suffer from thrombotic microangiopathies (TMA), where AKI may be associated with haemolysis, purpura and thrombocytopenia. In these cases, it is wise to investigate possible causes of secondary TMA, such as drugs or neoplasms (Commereuc et al., 2014).

Renal/Intrinsic Intrinsic AKI is distinguished from prerenal AKI by the presence of persistent structural damage of the kidneys after removal of the precipitating factors (Del Giudice and Aucella, 2012; Abdel-Kader and Palevsky, 2009). Elderly individuals may suffer from all parenchymal nephropathies, which can be categorized according to the histologic compartment of the kidney that is mostly affected, including injury to tubular epithelium ATN, interstitium (acute interstitial nephritis [AIN]), glomeruli (acute or rapidly progressive glomerulonephritis), and the vessels (Del Giudice and Aucella, 2012; Lautrette et al., 2012; Abdel-Kader and Palevsky, 2009). In several reports, ATN is the most common cause of AKI in the elderly (Stallone et al., 2012; Coca, 2010; Rosner, 2013; Cheung et al., 2008). It is most commonly attributed to the use of nephrotoxic agents including drugs and contrast material, as well as prolonged ischemia, especially due to sepsis, severe and prolonged volume depletion, and major surgery (Hain and Paixao, 2015; Rosner, 2013; Cheung et al., 2008). It may be challenging to discriminate between nephrotoxic and ischemic ATN, as these conditions may coexist and have a multifactorial origin (Hain and Paixao, 2015). Elderly individuals may be more susceptible to infections given the presence of alterations in cell and humoral mediated immunity associated with aging. Other factors that contribute to this predisposition include malnutrition, hospitalization, physiological changes in lungs, bladder, skin and glucose homeostasis, and coexistence of multiple comorbidities. This has huge implications as sepsis is an important cause of AKI (Hain and Paixao, 2015; Commereuc et al., 2014; Chronopoulos et al., 2010a), Septic ATN is thought to have a complex pathophysiology in which endotoxemia may activate inflammatory mediators, leading to endothelial damage and increasing the possibility of renal injury produced by hypoperfusion (Anderson et al., 2011; Del Giudice and Aucella, 2012). Indeed, serum IL-6 levels may act as a predictor of AKI development, severity and mortality among patients admitted to the intensive care unit (ICU) with infections or other forms of systemic inflammation (Anderson et al., 2011). Drug-induced ATN is more frequent among elderly patients, compared to younger individuals. This is usually the result of polypharmacy, which can also induce the expression of drug interactions, as well as other factors such as an increased susceptibility of the aged kidney to toxic agents, in part due to a reduction in renal function, and the lack of correct posology adjustments in this

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Acute Kidney Injury in the Aged

situation. The decreased ability to metabolize medications and the reduced lean body mass commonly observed in the elderly are also contributors to drug toxicity (Hain and Paixao, 2015; Del Giudice and Aucella, 2012; Lautrette et al., 2012; Commereuc et al., 2014). Several studies have investigated the pathophysiology of drug-induced nephropathy, and most have concluded that it is at least partially mediated by an excessive renal vasoconstriction (Chronopoulos et al., 2010c). Nephrotoxic drugs capable of producing ATN include antimicrobial agents, particularly aminoglycosides, amphotericin B and vancomycin, furosemide therapy, and chemotherapeutic agents such as cysplatinum. More recent evidence suggests that the use of atypical antipsychotic drugs in older adults also increases the risk of AKI (Hain and Paixao, 2015; Del Giudice and Aucella, 2012). Contrast-induced nephropathy (CIN), another common cause of iatrogenic AKI in hospitalized older adults, may be a complication of angiographic procedures (especially cardiac catheterization) or contrast-enhanced computer tomography. (Hain and Paixao, 2015; Anderson et al., 2011). CIN is defined as an absolute (> 0.5 mg/dL) or relative (> 25%) increase in serum creatinine at 48–72 h after exposure to a contrast agent, after alternative causes of AKI have been ruled out. The risk of renal dysfunction following a contrast-enhanced procedure is typically low (0,6-2,3%) in the general population (Del Giudice and Aucella, 2012). However, it is increased (up to 20%) in the presence of different factors, including previous renal impairment, female sex, cardiovascular disease, diabetes mellitus, volume depletion, cirrhosis, hypertension, and concomitant use of other nephrotoxic agents (Hain and Paixao, 2015; Anderson et al., 2011; Del Giudice and Aucella, 2012; Chronopoulos et al., 2010a). Although older age has been reported to be an independent risk factor for the development of CIN, this association has been found to be attenuated after adjustment for comorbidities (Anderson et al., 2011; Del Giudice and Aucella, 2012). Originally, gadolinium was considered an attractive alternative contrast agent for individuals with high risk of CIN. Nevertheless, it should not be used in patients with kidney dysfunction, given the possibility of developing nephrogenic systemic fibrosis (Chronopoulos et al., 2010c). Acute interstitial nephritis (AIN) should always be considered as a possible diagnosis in the elderly population, given the high number of medications that are prescribed to these patients. It is usually suspected with the finding of urine eosinophils, and the clinical presentation may include extrarenal manifestations such as skin rash. However, these are not always present, and the diagnosis must be confirmed with a biopsy specimen (Rosner, 2013; Lautrette et al., 2012; Commereuc et al., 2014). AKI resulting from acute or rapid progressive glomerulonephritis is also more frequent in older adults, compared to younger patients, and it may carry a worse prognosis (Del Giudice and Aucella, 2012). This diagnosis should be suspected when the urinalysis reveals dysmorphic red blood cells, red blood cell casts, and proteinuria. In the elderly, the most common cause of this presentation would be antineutrophil cytoplasmic antibody (ANCA)-associated diseases, most commonly p-ANCA or positive antimyeloperoxidase. When rapidly progressive glomerulonephritis is suspected, a biopsy should be performed in order to initiate specific treatment as early as possible (Rosner, 2013; Lautrette et al., 2012; Commereuc et al., 2014). Another relevant cause of kidney dysfunction in the elderly is amyloidosis, accounting for approximately 15% of the nephrotic syndromes observed in older adults (Lautrette et al., 2012). It may be a consequence of multiple myeloma, which should always be suspected in an elderly individual with AKI, urine light chains, hypercalcemia, anemia and bone pain. In addition, the hypercalcemia associated with this condition may also cause renal dysfunction by excessive vasoconstriction (Lautrette et al., 2012; Commereuc et al., 2014). ATN may also be triggered by other endogenous nephrotoxins, such as circulating myoglobin or hemoglobin, resulting from rhabdomyolysis or haemolysis, respectively (Hain and Paixao, 2015). Uric acid can also provoke AKI. Massive hyperuricemia may be the result of a tumor lysis syndrome, a condition where an acute destruction of a high mass neoplasm, spontaneously or induced by chemotherapy, results in a rapid onset of uricemia, hyperkalemia and hyperphosphatemia. It usually occurs after initiating chemotherapy for lymphomas, and may also present with solid tumors or multiple myeloma (Kasper et al., 2015).

Postrenal Postrenal AKI is especially common in older adults, given the high prevalence of prostatic disease (benign prostatic hyperplasia [BPH] or prostate adenocarcinoma) in men, and pelvic malignancies in women (Del Giudice and Aucella, 2012; Lautrette et al., 2012; Abdel-Kader and Palevsky, 2009). Additionally, the use of anticholinergic agents may induce postrenal AKI by promoting acute urinary retention (Rosner, 2013). BPH affects almost 50% of men over 50 years of age, and around 90% of men older than 90. Likewise, the incidence of cancer rises with increasing age (Lautrette et al., 2012). Intrarenal causes of obstruction or urolithiasis less frequently lead to manifest AKI, as bilateral obstruction is most commonly needed to observe a reduction in GFR. Exceptions to this are the presence of a solitary kidney, or previous renal dysfunction.

Diagnosis Serum creatinine (SCr) elevations are typically used to clinically diagnose AKI, along with changes in urine output. However, this laboratory measure is known to be an unreliable marker of renal dysfunction in most patients, which is particularly true in the elderly. Firstly, SCr only rises 24–48 h after the renal injurious event, given that the GFR must be reduced to approximately half its normal level before de SCr concentration begins to rise above its upper normal limit (Haase et al., 2011). Secondly, SCr levels depend on muscle mass, which is typically reduced in older adults, particularly in frail patients (Chronopoulos et al., 2010a; Haase et al., 2011). As a consequence, an elderly individual may have renal dysfunction with low

Acute Kidney Injury in the Aged Table 3

AKI staging

Stages

Serum creatinine (mg/dL)

Urine volume (mL/min)

1

1.5–1.9 times baseline or  0.3 increase 2.0–2.9 times baseline 3 times baseline or increase in serum creatinine 4 mg/dL or initiation of RRT or in patient 507 Deep-sea sponge Monorhaphis chuni 11,000  3000

Growth bands count on shells Stable isotopes

George et al. (1999) Nielsen et al. (2016) Butler et al. (2013) Jochum et al. (2012)

Short-lived species are not reported. These records should not be considered as definitive, as they can reflect the age at capture and not the real lifespan. Abbreviations: SD: standard-deviation, SEM: standard-error of the mean.

year. When it comes to happen, fish die and desiccation-resistant eggs survive in diapause in the mud, waiting for months for better times, i.e. for the rainy season. Because of such conditions that shaped life-history traits, N. furzeri live for less than 3 months in the laboratory (Cellerino, 2009). A more extreme example is the coral reef fish Eviota sigillata whose adults are seemingly subjected to a high extrinsic mortality and live only for 4 weeks (larval stage: 3 weeks, Depczynski and Bellwood, 2005). Thus, while explaining short lifespans is not always an issue, the challenge could be to explain record lifespans of some marine animals. As for other species, the lifespan depends on other life-history traits but, contrary to mammals, it can also depend on environmental conditions such as temperature, because most marine animals are ectotherms. Another difference with mammals is that fish can grow for many years, with a lower growth rate at older ages, but some species do not grow during their entire life (Woodhead, 1985). The fecundity of fish also increases with age (Reznick et al., 2002), which is opposite to mammals. Table 1 lists recorded or inferred record lifespans, from shortest to longest lifespans, of various long-lived marine animals. However, determining lifespans of marine species is not easy because they live underwater in the wild, and it can be needed to rely on indirect methods (see below), because capturing and re-capturing animals living underwater is difficult. It is thus not surprising that it has been stated that a given species can live for, say, 1 century, even if there are no robust data to support this conclusion. For instance, it is commonly said that green sea turtles Chelonia mydas can live for 80 years, but not a single article has been published in support of this statement: these claims are not reported in Table 1. In the absence of a direct lifespan record, reported lifespans in Table 1 should be only considered as estimates, whose precision is dependent on the method used for estimation.

Measuring Lifespans in Marine Organisms Most studies estimating the age of marine animals are done for fisheries stock management purpose. Indeed, poor age estimation (usually underestimation) may result in wrong estimation of growth and natural mortality rates, leading to risk of overexploitation of populations and their eventual collapse (Campana, 2001). Consequently, it is critical to use accurate methods to estimate the age of marine animals. Table 1 shows that various methods are used to determine age and lifespan. In the laboratory, recording birth and death date allows knowing lifespans of model species, e.g. flies or mice, which is not possible in most of the cases for marine animals not kept in the laboratory. Therefore, it is needed to implement other, indirect, methods to determine the age or lifespan of samples. The methodologies used to estimate age or lifespan of marine animals are more or less taxa or tissue-specific. For example, measurement of lead 210 and radium 226 ratio and quantification of lipofuscin are limited to teleost otoliths and crustacean brains respectively. By contrast, growth band counts and growth models are used in various taxa. Most of the aging methods are part of the discipline of sclerochronology, i.e. the study of physical and chemical variations in hard tissues in animals.

Growth Bands Count Growth bands count is one of the most commonly used aging method for marine animals. Alternation of growth bands, formed regularly from diurnal to annual time scales, can be observed on various hard tissues in various animal taxa. In some of these tissues, annual growth bands may appear as an alternation of opaque and translucent bands of different widths. Opaque bands appear as

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Age Determination and Lifespan of Marine Animal Species

dark when observed with transmitted light but as bright when observed with reflected light or naked eye. They are wide and highlight a period of fast growth (Fowler, 2009; Aldanondo et al., 2016). By contrast, translucent bands appear as bright when observed with transmitted light but as dark when observed with reflected light or naked eye. They are narrow and highlight a period of slow growth (Fowler, 2009; Aldanondo et al., 2016). Opaque and translucent bands are also frequently associated with summer and winter temperatures respectively (Fowler, 2009; Aldanondo et al., 2016; La Mesa et al., 2008; Wakefield et al., 2017), although variations of this pattern may appear in some cases (Wakefield et al., 2017; Jones, 1983; Jones and Quitmyer, 1996). As a result, direct estimation of age is possible by counting alternations of growth bands. Various tissues may be studied in order to estimate the age of marine animals with growth band counts (Fig. 1). For teleosts, age was previously estimated by counting annuli on scales but this method underestimates the age of old individuals (Beamish and McFarlane, 1983; Baudoin et al., 2016). From now on, age is usually estimated by counting growth increments in otoliths (Fig. 1A). Otoliths are present in various vertebrate taxa, but have been mainly studied in teleosts (e.g. La Mesa et al., 2008; Kadison

Fig. 1 Examples of tissues displaying growth bands and being used to estimate the age of marine animals. (A) Sectioned otolith from a 23 year-old teleost (Dentex dentex). Annual growth bands are indicated by white dots. Picture from (Baudouin et al., 2016). (B) Statolith from a gastropod (Polinices pulchellus) with larval ring (LR), settlement ring (SR), and 2 years growth rings (1st and 2nd). (C) Sagittally sectioned vertebrae from a 4 yearold shark (Spyrna lewini). (D) Sectioned shell from a bivalve (Arctica islandica) with each black bar showing 1 year of growth. (E) Sectioned eyestalk of a 4 year-old crustacean (Euphausia superba). Annual growth bands are indicated by green dots. Green and white arrows respectively indicate the epicuticle and endocuticle layers. (A, B) Picture from Richardson, C.A., Kingsley-Smith, P.R., Seed, R., Chatzinikolaou, E. (2005b). Age and growth of the naticid gastropod Polinices pulchellus (Gastropoda: Naticidae) based on length frequency analysis and statolith growth rings, Marine Biology 148, 319–326. (C) Picture from Piercy, A.N., Carlson, J.K., Sulikowski, J.A., Burgess, G.H. (2007b) Age and growth of the scalloped hammerhead shark, Sphyrna lewini, in the north-West Atlantic Ocean and Gulf of Mexico. Marine and Freshwater Research, 58, 34–40. (D) Picture from Wanamaker, A.D. Jr, Heinemeier, J., Scourse, J.D. et al. (2008). Very long-lived mollusks confirm 17th century ad tephra-based radiocarbon reservoir ages for north icelandic shelf waters. Radiocarbon 50, 399–412. (E) Picture modified from Kilada, R., Reiss, C.S., Kawaguchi, S., King, R.A., Matsuda, T. et al., (2017). Validation of band counts in eyestalks for the determination of age of Antarctic krill, Euphausia superba, PLoS One 12, e0171773 reprinted with permission.

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et al., 2010; Yershov et al., 2016). Otoliths are calcified structures in the inner ears of teleosts and play a role in equilibration. They continue to grow as teleosts age (Fowler and Doherty, 1992; Campana and Thorrold, 2001) and are not resorbed even under conditions of high stress (Campana, 1983a,b). As a result, otoliths are considered as one of the best tools to estimate age of teleosts (Campana and Thorrold, 2001). Analysis of sectioned otoliths appears to produce the highest and most accurate estimation of age by improving the readability of growth bands (Baudoin et al., 2016). Statoliths (Fig. 1B) are a structure similar to otoliths present in various invertebrate taxa, and annual or daily growth increments in these structures can be used to estimate the age of box jellyfish (Ueno et al., 1995; Gordon et al., 2004), gastropods (Barroso et al., 2005; Richardson et al., 2005; Hollyman et al., 2018) and cephalopods (Jackson et al., 1997; Bettencourt and Guerra, 2001; Liu et al., 2015). In elasmobranchs (sharks and rays), growth bands are usually counted on sectioned vertebrae (e.g. Skomal and Natanson, 2003; Piercy et al., 2007; Porcu et al., 2015, Fig. 1C). In squaliforme sharks, because annual growth bands are poorly visible on the vertebrae (Clarke et al., 2002; Braccini et al., 2007; Cotton et al., 2011), dorsal spines are used to estimate age, either by counting growth bands on the enameled surface (Braccini et al., 2007; Cotton et al., 2011) or in the sectioned spine (Clarke et al., 2002; Braccini et al., 2007). In holocephalans (chimaeras), a relative taxon of elasmobranchs, dorsal spines have no enameled surface and thus sectioned dorsal spines are used to estimate age (Calis et al., 2005). In bivalves, age is estimated by counting annual growth increments in internal shells (Fig. 1D), which are less affected by environmental disturbances than external shells (Jones, 1983). Other hard tissues displaying growth rings and being used or having the potential to be used for age estimation include jaws in errand polychaete (Britayev and Belov, 1994; Plyuscheva et al., 2004), cephalopod beaks (Liu et al., 2015; Perales-Raya et al., 2010), fin spines in billfish (Istiophoridae and Xiphiidae: Kopf et al., 2010; Shimose et al., 2015 and teeth from odontocete whales: Stewart et al., 2006). However, using growth bands has several limitations and validation is still needed (Campana, 2001). In old individuals, the increasing narrowness of growth bands at the edge of the studied structure (La Mesa et al., 2008; Francis et al., 2007; Brooks et al., 2011; Henry and Cerrato, 2007) reduces their visibility, leading to underestimation of age (Bettencourt and Guerra, 2001; Francis et al., 2007; Harry, 2018). The increasing narrowness of growth bands is the result of a reduction of somatic growth rates with age. Overestimation of age may also occur when counting growth bands (Greely et al., 1999; Andrews, 2016; Kastelle et al., 2017) as non-annual growth bands may appear (Brooks et al., 2011; Kastelle et al., 2017; Uriarte et al., 2016). It may be due to environmental factors that may alter the pattern of growth bands such as salinity (Narvaez et al., 2016) and food availability (Henry and Cerrato, 2007; Narvaez et al., 2016). For example, slow growth translucent bands were previously known to be formed only during winter in internal shells of hard clams Mercenaria mercenaria in Rhode Island (Jones et al., 1989) but reduction of phytoplankton availability in summer led to the formation of slow growth translucent bands also in summer, meaning that a pattern of four bands instead of two became yearly for this species in this region. Furthermore, the compression of growth bands in older individuals reduces the visibility of the fall opaque band at the edge of the shell (Henry and Cerrato, 2007). The pattern of growth bands may also not be yearly in hard tissues of some taxa (Greely et al., 1999; Narvaez et al., 2016; Fisher et al., 1997; Russel and Meredith, 2000) making them invalid for age estimation. Molting has also hampered direct estimation of crustacean age. As a result, the possibilities to directly estimate age of crustaceans using growth bands has begun to be investigated only recently in gastric mill and eyestalks (Fig. 1E) with contrasting results (Kilada et al., 2012; Sheridan et al., 2016; Kilada and Driscoll, 2017; Kilada et al., 2017).

Analyzing Chemistry of Hard Tissues Calcified structures also incorporate environmental elements during their formations but are usually metabolically inert once formed. As a result, compounds present in growth bands are preserved over time and variations of chemical composition occur from the core to the edge of the chemical structures (Jones and Quitmyer, 1996). These variations may be a tool for estimating age of marine animals but are mainly used to validate age estimation obtained by band counting (Campana, 2001) as these methods are more expensive than growth band counting. Stable isotope ratios of oxygen (18O:16O, denoted d18O) in calcified structures are negatively linked to seawater temperature (Epstein et al., 1951; Epstein et al., 1953). Consequently, cyclical variations of d18O occur in calcified structures along seasons, with maximum d18O during winter and minimum d18O during summer. Thus, the number of d18O cycles from the core to the edge of calcified structures may indicate the age of the organism. This method has been used either for age determination (Gurney et al., 2005; Naylor et al., 2007) or for validation of other methods (Hollyman et al., 2018; Kastelle et al., 2017). Another well-known methodology is bomb radiocarbon. Atmospheric nuclear testings in the late 1950s led to an sharp increase of 14C levels in the atmosphere and in the marine dissolved organic carbon. Indeed, the levels of 14C in the environment are also integrated in the successive growth layers of calcified tissues of growing individuals (Francis et al., 2007; Leaf et al., 2008; Hamaday et al., 2014; Andrews et al., 2016), and in particular, in the core of the calcified tissues, i.e. the birth mark. The integration of environmental 14C levels in organisms resulted in the appearance of a temporal profile of 14C levels in environment and species that reflects the pre and post-bomb testing 14C levels in the environment (Andrews et al., 2016; Kalish, 1993; Baker and Wilson, 2001; Kerr et al., 2004) (Fig. 2). As a result, 14C levels in the core of calcified tissues reflect 14C levels in the environment at the birth of individuals and thus can be used to estimate the age of animals (Andrews et al., 2005; Roark et al., 2005) or, more frequently, to validate (Stewart et al., 2006; Baker and Wilson, 2001; Kerr et al., 2004; Campana et al., 2002; Neilson and Campana, 2008) or adjust (Francis et al., 2007; Hamaday et al., 2014) the year of birth determined with sclerochronology by comparing 14C levels in studied organisms with a reference chronology of known-age animals (Fig. 2). The main drawbacks for this technique are

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Fig. 2 Temporal evolution of 14C levels (614C) recorded in coral layers from Kure Atoll (Northwestern Hawaiian Islands, Andrews et al., 2016), in otolith cores from Lutjanus campechanus from the northern Gulf of Mexico (Baker and Wilson, 2001), Chrysophrys auratus from New Zealand (Kalish, 1993) and Sebastes ruberrimus from southeast Alaska (Kerr et al., 2004) and in the atmosphere of the northern hemisphere (zone 2, Hua et al., 2013).

that it is dependent on a time-specific event and that there are regional variations of 14C levels and trends (Mahadevan, 2001; Scource et al., 2012). The radiometric method consists in comparing the abundance of a radioactive isotope with its daughter product (Smith et al., 1991). For aging marine animals, the use of this method is limited to teleost otoliths as an assumption to this methodology is that the carbonate acts as a closed system. The most commonly used pair of radioactive isotopes are radium 226 (226Ra) and lead 210 (210Pb). Radium is a naturally occurring radioactive element. Its isotopes are highly soluble in water in comparison of their parent and daughter radio-isotopes and efficiently absorbed by tissues as a proxy of calcium. As a result, radium is integrated in calcified tissues. In particular, teleost otoliths integrate 226Ra and discriminate against its daughter radio-isotope 210Pb. Consequently, the subsequent decay of 226Ra into 210Pb, which is itself retained by the otoliths, occurs at predictable rates according to the halflife of the two isotopes. As a result, the ratio of 210Pb over 226Ra (210Pb/226Ra) increases consistently and thus can be used as an independent chronometer to estimate the otolith’s, and thus the teleost’s, age. It is possible to determine 210Pb/226Ra in both the whole otolith or the core of the otolith. However, analyzing 210Pb/226Ra in the whole otolith requires to take into account the growth of the otolith (Fenton et al., 1991). Indeed, as the otolith grows, it continuously integrates radium that subsequently decays, leading to variation of 210Pb/226Ra from the core to the edge of the otolith. By contrast, 210Pb/226Ra in the core provides more accurate ages (Smith et al., 1991) and improvement of technology made it possible to work on small amounts of samples. 210 Pb/226Ra has been used either to assess the age of teleosts of age up to 100 years or as a validation tool for growth zones count (e.g. Fenton et al., 1991; Brooks et al., 2011; Andrews et al., 2016; Andrews et al., 2011; Andrews et al., 2009). Another pair of isotopes that can used to estimate teleost age is thorium 228 (228Th) and radium 228 (228Ra). However, as the age limit with this dating method is 10 years (Smith et al., 1991), this method is more suited to estimate the age of short-lived teleosts. However, it has only been used once (Campana et al., 1993) since its first documentary reference (Smith et al., 1991).

Other Methods Outside of the Sclerochronology Discipline Lipofuscin are fluorescent aggregates made of oxidized proteins and lipids that are no more degraded by cell metabolism and thus continuously accumulate within lysosomal residual bodies. Consequently, in areas of the brain where neurons persist throughout life, lipofuscin is accumulated with age in various taxa, notably crustaceans (Sheehy, 1990a). The correlation between lipofuscin content and age of crustaceans (Sheehy et al., 1999; Sheehy, 1990b) led lipofuscin quantification to be a common tool to estimate the age of crustaceans (Kilada and Driscoll, 2017). Lipofuscin quantification can be done by using successive histological sections of the brain where lipofuscin is quantified as an area fraction (e.g. Bluhm and Brey, 2001; Bluhm et al., 2001) or percent volume fraction (e.g. Sheehy et al., 1999; Sheehy, 1990b). Lipofuscin content can also be determined using spectrophotometry and is expressed as a concentration relative to protein content (e.g. mg mg 1 protein, e.g. Ju et al., 1999; Bosley and Dumbaul, 2011). Age determination can thus be done by using the relationship between lipofuscin content and age in individuals of known age (e.g. Sheehy et al., 1999; Sheehy, 1990b), or by separating age groups derived from lipofuscin content frequency histograms (e.g. Bluhm and Brey, 2001; Bluhm et al., 2001; Bosley and Dumbaul, 2011). Limited knowledge on growth rates of an organism may allow a preliminary estimation of lifespan. However, these lifespans are highly likely to be inaccurate or imprecise. For example, the antarctic sea star Odontaster validus was estimated to live between 50 and 100 years but these ages were estimated assuming that the growth rate of O. validus with age is linear (Pearse, 1969). However,

Age Determination and Lifespan of Marine Animal Species

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animals grow until a maximum size and then continue to live. Actually, growth of animals usually follows the von Bertalanffy’s (1934) growth model, where growth rates decrease with age as length is approaching an asymptote. Knowledge on variations of growth rates during life and several given parameters (e.g. size at birth) allow to generate growth models. These growth models then help to estimate the age of animals according to their size, and longevity is estimated according to the age estimated for the largest organism (e.g. Ebert and Southon, 2003; Bergquist et al., 2000; Nielsen et al., 2016).

Attempting to Explain Long Lifespans of Some Species Some long-lived marine animals can live strikingly longer than terrestrial ones. While the maximal recorded lifespan of humans is 122 years, clams can live at least for 5 centuries and sharks for c. 400 years and, at a first sight, such lifespans are astounding. Yet, some mechanisms explaining lifespan of terrestrial species may be applied to marine animals too.

Longevity and Life-History Strategies Longevity is an integral part of life history strategies. Species reproducing in a single season, as mice do (Phelan and Austad, 1989), are not expected to live long simply because a long life is not necessary to make the species thrive. These species are well able to quickly take advantage of plentiful food to reproduce heavily: they are called opportunistic species (Demetrius, 2005). This lifehistory strategy is also present in the marine environment. Opportunistic species include animals such as small pelagic teleosts (i.e. anchovies and sardines), with a small size, a fast maturation, a rather short lifespan (from 1.5 to 15 years, Greely et al., 1999; King and McFarlane, 2003), and strong abundance fluctuations over time. One can thus understand why the stock of these species (e.g. the numerous anchovies) can recover if overfished (Adams, 1980). However, some of these opportunistic species still have a lifespan (e.g. 13 years in Pacific sardines and 15 years in herrings) that may be considered as long in, say, dogs, and a challenge is to explain why “short-lived” fish can live so long. Another example of opportunistic species are planktonic cladocerans which have population maxima during periods of favorable conditions but are practically absent from the water column for the rest of the year. Indeed, their life cycle is characterized by fast maturation and a period of asexual reproduction followed by a period of sexual reproduction, resulting in the seasonal abundance fluctuations for this group (Atienza et al., 2008; Miyashita et al., 2011). By contrast, species unable to quickly reproduce and thrive even if resources are plentiful are called equilibrium species (Demetrius, 2005), such as for instance humans that can only have one offspring every 2 years at a maximum and need parental care for c. 15 years. This pattern is not only observed in terrestrial species but also in marine ones. Marine species with low fecundity reproduce repeatedly during life, and the offspring need time to reach maturity. This is the case for whales or sharks. For instance, short-finned pilot whales have their first calf at 8–10 years of age, after a c. 16 months gestation, sucking lasting for c. 5 years and up to 15 years for the last calf (Bernard and Reilly, 1999). Such a life-history strategy requires living long for whales being able to survive and the species to thrive. However, a main difference between the so-called fish and mammals is that, even if marine biologists make use of the term “parental investment” in fish (Winemiller, 1989), this investment is rudimentary when compared to parental care in mammals. In the best of the cases, parents will simply protect larvae from predators, like the male lingcod Ophiodion elongatus does (O’Connell, 1993). As a result, while elasmobranchs are still considered as equilibrium species because of low fecundity, large eggs and important parental investment (e.g. gestation), long-living teleosts may instead be considered as “periodic strategists” (King and McFarlane, 2003). Periodic strategists are “slow-growing, long-lived demersal species (with) a lower degree of variability in abundance” and the authors stressed that lifespans greater than 20 years ensure “a relatively long reproductive cycle, which minimizes the risk that periods of unfavorable environmental conditions will result in the loss of a stock.” However, teleosts, like most other marine taxa, actually display a great fecundity by releasing large numbers of eggs in the water column. It is a little bit surprising that longlived animals can display a great fecundity, by contrast to terrestrial mammals, but one should not forget that one million of eggs of an oviparous marine organism does not mean one million of new adults, because of a high predatory pressure on eggs and juveniles for instance. Fish often grow throughout life and their fecundity increases with age (Reznick et al., 2002), but the increased number of eggs produced by older fish could result in only a few more adult fish than at younger ages. Yet, laying as many eggs as possible may be the only available life-history strategy when eggs are simply dispersed in water, and thus offered to predators. Therefore, the increased fecundity with age could explain why many fish live long: without a long lifespan, these fish could not reproduce and these species would be extinct.

Temperature and Metabolism of Ectotherm Species Fish and other marine animals, except mammals, are ectotherms and, as for any ectotherm species, their lifespan is expected to be longer at lower temperatures (Munch and Salinas, 2009). However, experimentally testing this hypothesis can only be done with very short-lived species for obvious reasons. For instance, mean lifespans of the freshwater fish Cynolebias belotti are 14 months at 25  C and 19 months at 20  C: transfer at 8 months of age from 20  C to 15  C increases lifespan to 23 months, while the reverse change has nearly no effect (15 months; Liu and Walford, 1975). Because temperature is lower in deep sea than near the surface, it has been hypothesized that deeper-dwelling fish live long, but as deep sea also means higher pressure, lower light, oxygen, and food levels than near the surface (references in Cailliet et al., 2001),

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it is rather difficult to tease apart these factors. In any case, the evidence showing that deep-sea fish live longer is fragile: in a review on deep-dwelling fish, Cailliet et al. (2001) concluded that metabolic rate was lower with increasing depth, and that because of a lower oxygen pressure, oxidative stress could be lower, all of this possibly explaining long lives but, as stressed by the authors “our findings are at best correlative.” Another review on bivalves showed that depth only explains 4% or the variance of lifespan (Fig. S4 in Moss et al., 2016, and see also Montero-Serra et al., 2018), bivalves living longer at higher depths, but there is a caveat in the fact that most of depths were in the 0–100 m range. Nevertheless, it remains that a low temperature could explain partly why fish and other ectotherm marine species can live so long. For instance, sampled Salmo trutta trouts are older at higher latitudes in Norway where water temperature decreases (Jonsson et al., 1991). Bivalves of various species have been shown to live longer at higher latitudes, and thus in increasingly cold waters, even if this is not always observed (Fig. S2 in Moss et al., 2016). This results not only from temperature decrease per se, because predation is more important in the tropics and metabolism could be lower at higher latitudes because of a reduced food supply during winter (Moss et al., 2016). If food supply is lower at high latitudes, starvation could occur. It has been argued that species unable to emigrate in the event of starvation have to wait at the same place for better times and thus that food restriction can make them living longer (e.g. nematodes, mice), while larger and less predated species (e.g. elephants, humans) do not need to live longer because they can emigrate to discover new food sources (Le Bourg, 2016). Because bivalves cannot emigrate, one could make the hypothesis that food restriction would increase their lifespan: such a hypothesis could be tested with short-lived bivalves. By contrast, whales or sharks could try to discover new food sources and thus food restriction could have no effect on lifespan: anyway, it is simply impossible to test this hypothesis by recording lifespan of food-restricted whales or sharks. Therefore, it seems possible to explain why ectotherm marine species can live long. Their metabolism is highly dependent on their environment, not only regarding temperature, but also food supply, and it is not surprising that a long lifespan, for instance in some bivalve species, has been selected. Because bivalves can hardly move away, populations could become extinct and possibly the whole species, too, if they were unable to sustain a low food supply: like spiders on their web, Arctica islandica clams have to wait for food coming to them and, as spiders (Austad, 1989), living longer can be a strategy to wait for better times. Combined with a low temperature under the surface, and thus a longer life with lower temperature as in other ectotherms, this could make they can live long. However, this would not be observed if life would be ended at an early age because of a severe predatory pressure.

A Low Predatory Pressure.Except From Fishery Overfishing is an issue, particularly for slow-growing long-lived species. Fisheries predate preferably large subjects, while marine predators usually prefer prey smaller than their own size, because gape limitation prohibits ingesting too large individuals (see e.g. Schmitt and Holbrook, 1984). Indeed, as large subjects need an extended time to grow, catching them means catching the most prolific ones, which can make soon a species becoming endangered, at risk not to recover even after years or decades (Musick, 1999; Barnett et al., 2017), and these consequences are similar to those of hunting adult African elephants, even if does not result in extinction (Le Pape et al., 2017). Predating large subjects could select for animals investing their resources in reproduction at an earlier age at the expense of their size (Dieckmann et al., 2009). Therefore, the main predator of marine species is the fisherman and not the marine predators. It has been estimated that “among nonhuman predators across all oceans, 50 % of exploitation rates were less than 1 % of annual adult biomass. In contrast, fisheries exploited more than 10 % of adult biomass in 62 % of cases. Overall, the median fishing rate (0.14) was 14.1 times the take (0.01) by marine predators” (Darimont et al., 2015). Therefore, in the absence of fishing, it can be assumed that the predatory pressure is low and sustainable. Oceans are immense, and for many species they are a three-dimensional world allowing more escape than for mice in sight of a cat, for instance. This may explain why even the highly predated sardines during the sardine run in South Africa (van der Lingen et al., 2010) can sustain such an annual toll in a few days, and this every year from ancient times. For slow-growing species, a long lifespan is mandatory; thus, if protected from predators, because they can escape or hide in the ground like clams do, individuals of these species can indeed live long. The clam A. islandica is buried in sands and is hardly visible, waiting for carbon particles and, as stressed by Morton (Morton, 2011), “the lifestyle of A. islandica is characterized by slow, deliberate, near undetectable, movements possibly to avoid detection.” Therefore, if the predatory pressure is low, there is no selective pressure for a reduced lifespan combined with a higher fecundity at younger ages (see Le Bourg, 2014) and longer lifespan can evolve, as in opossums living on an island free from predators for millenaries (Austad, 1993). This could be particularly the case for the clam A. islandica that can live for 5 centuries (Butler et al., 2013). However, it may happen that a mere accident has dire consequences and kill most animals. For instance, A. islandica clams were subjected to a mass extinction in Iceland after a storm. Innumerable clams were “swept from their natural sandy habitat at depth of more than 9 m, up onto the hard bottom in shallower water (7–9 m)” and thus, “lying exposed, unable to escape, they were easy prey for fish as wolffish. and invertebrate predators” (Thórarindsóttir et al., 2009). One year after the storm, only empty shells and no living clam were seen on the ground.

Marine Ectotherms and Mammals Therefore, taking into account a lower metabolism at lower temperatures in ectotherms, a low predation rate, a fecundity often increasing with age, and iteroparity, it seems possible to (partly?) explain why marine species can live so long. However, it remains that marine ectotherms can live much longer than marine mammals. Table 1 shows that Greenland shark Somniosus microcephalus

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Fig. 3 Relationship between body mass and maximal lifespan in mammal species (log scales). Drawn from the database AnAge (http://genomics. senescence.info/species/, (Tacutu et al., 2013). Each point is for a species and marine mammals are shown with black squares.

can live for 4 centuries while the whales Eubalaena glacialis live only for several decades and Balaena mysticetus up to 200 years. Thus, in the best case, mammals live for only half the lifespan of large Greenland sharks: it could be linked to the fact that sharks are ectotherms and not endotherms like whales. The 211-year lifespan of the bowhead whale B. mysticetus is however not exceptional, given that this whale is the largest living mammal and that larger mammals usually live longer (Stearns, 1983). Indeed, bowhead whales live only twice as long as humans, a species with a small body size when compared to the up to 100 tonnes whales. However, it is a caveat that the 122-years lifespan of the record woman Jeanne Calment has been observed among several billions of people, while sharply less bowhead whales can be observed, with a lower chance to observe exceptional individuals. The other massive blue and fin whales (Balaenoptera musculus and Balaenoptera physalus, indicated respectively just below the bowhead whales point on Fig. 3) do not display an extraordinary lifespan. Therefore, the long lifespan of marine mammals is far from being exceptional when compared to other mammals, even if they are long-lived, and does not depart from the general trend linking the log of body mass and the log of maximal lifespan in mammals (Fig. 3): explaining the lifespan of marine mammals is not an issue but explaining why only rather large marine mammals exist is surely an issue. The marine otter Lontra felina, which weighs c. 4 kg and whose lifespan is unknown (and thus not shown on Fig. 3), is probably the smallest marine mammal (Valqui, 2012). By contrast, lifespans of marine ectotherms can be impressive and are not so easy to explain: more studies are necessary to ascertain and explain the variation of lifespan among marine species.

Acknowledgments Many thanks are due to Emmanuelle Cam, University of Brest, France and to Michel Marengo, University of Liège, Belgium, for their helpful comments on a previous version of this article.

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Perales-Raya, C., Bartolomé, A., García-Santamaría, M.T., Pascual-Alayón, P., Almansa, E., 2010. Age estimation obtained from analysis of octopus (Octopus vulgaris Cuvier,1797) beaks: Improvements and comparisons. Fisheries Research 106, 171–176. Phelan, J.P., Austad, S.N., 1989. Natural selection, dietary restriction, and extended longevity. Growth Development and Aging 53, 4–5. Piercy, A.N., Carlson, J.K., Sulikowski, J.A., Burgess, G.H., 2007. Age and growth of the scalloped hammerhead shark, Sphyrna lewini, in the north-West Atlantic Ocean and Gulf of Mexico. Marine and Freshwater Research 58, 34–40. Plyuscheva, M., Martin, D., Britayev, T., 2004. Population ecology of two simpatric polychaetes, Lepidonotus squamatus and Harmothoe imbricata (Polychaeta, Polynoidae), in the White Sea. Invertebrate Zoology 1, 65–73. Porcu, C., Bellodi, A., Cannas, R., et al., 2015. Life-history traits of the commercial blonde ray, Raja brachyura, from the Central-Western Mediterranean Sea. 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Very long-lived mollusks confirm 17th century ad tephra-based radiocarbon reservoir ages for north icelandic shelf waters. Radiocarbon 50, 399–412. Winemiller, K.O., 1989. Patterns of variation in life history among south American fishes in seasonal environments. Oecologia 81, 225–241. Woodhead, A.D., 1985. Feral fishes. In: Lints, F.A. (Ed.), Non-mammalian models for research on aging. Karger, Basel, pp. 22–50. Yershov, P.N., Marshal, C., Ereskovsky, A.V., Vishnyakov, A.E., 2016. New data on the longevity of coastal cod Gadus morhua Linnaeus, 1758 in the White Sea. Journal of Applied Ichthyology 32, 350–352.

Further Reading Green, B.S., Mapstone, B.D., Carlos, G., Begg, G., 2009. Tropical fish otoliths: Information for assessment, management and ecology. Springer, Dordrecht. Panfili, J., de Pontual, H., Troadec, H., Wright, P.J., 2002. Manual of fish sclerochronology. Ifremer-lRD coedition. https://archimer.ifremer.fr/doc/00017/12801/. Stearns, S.C., 1992. The evolution of life histories. Oxford University Press.

Relevant Websites www.fishbase.orgdFishbase: A global database of fish species.

Aging and Entropy Alvaro Macieira-Coelho, INSERM, Versailles, France © 2020 Elsevier Inc. All rights reserved.

Introduction The Molecular Reorganization Through the Organism’s Life Span The Reorganization of Tissues, Organs, and Functions Changes in Energy Transduction During Aging The Thermodynamics of Aging References Further Reading

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Introduction Most attempts made to find a cause for aging have implied the concept of damage. Whether they considered aging as the result of wear and tear, the accumulation of deleterious metabolites, the accumulation of errors in proteins, the accumulation of stress, they implied always the idea of inflicted harm. Some gerontologists still believe that aging is the result of self-harm, nothing else. Moreover, some theories of aging have limited the cause of the phenomenon to an organ or function when everything in the organism works globally through interactions. The cross-linking or the free radical theories focalized on a molecular event in a universe of metabolic reactions. Some suggestions had a cultural background such as the protein error hypothesis, which originated from the belief common to some cultures that humans are finite because of the accumulation of faults. The endocrine theory sees aging as a programmed event. The immune theory envisioned aging as a progressive decline of the immune response, however, it is a remodeling of the immune system that takes place (Bonafé et al., 2001). This feature is fundamental to explaining aging as is described below; it is the permanent reorganization progressing at all hierarchical levels of structure, that leads to senescence. Evolutionary theories interpreted the phenomenon through the differential expression of specific genes acted upon by natural selection. A phenomenon as complex as aging cannot be attributed to a few genes; genes are not single, selfish entities, there expression depends on multiple interactions between intracellular and extracellular factors. The rate of living theory suggests that the duration of life varies in inverse proportion to the rate of energy expenditure; it comes closer to reality but lacked the concretization of what is exhausted. It claimed that senescence would be the result of the exhaustion of a finite total amount of “vitality”dan undefined entity. The first step for survival in the biosphere is the capacity to meet energy requirements, thus it depends on the availability of free energy. This implies that the life of the organism has to follow thermodynamic rules and cannot escape the second law; the free energy becomes less available because of its dispersal. There is no need to find a cause of agingdaging happens by default (Macieira-Coelho, 2016a).

The Molecular Reorganization Through the Organism’s Life Span The human organism is constituted by hierarchical levels of structures: atomsdmoleculesdcellsdtissuedorgansdmental activity, through which information flows with new properties emerging with the increasing complexity at each level. From DNA to the cell membrane and to the extracellular matrix, a structural continuum extends to the tissue, and from the tissue to the organ and to the whole organism. The functioning of the organism depends basically upon the storage and the flow of information through this continuum, two parameters which evolve permanently through the organism life span. The organism is remodeled from the molecular, to the cellular, tissue, and organ levels from the beginning to the end. This remodeling causes an impaired adaptive response to the environment due to a different availability of effectors (e.g. hormones). The fusion of the gametes triggers cell division that drives the human organism with a continuous reorganization through the developmental stages to reach maturity, reproduce, and senesce. Once a cell reaches its final function, either it goes on dividing in the new state or becomes post-mitotic, in both cases it cannot reach a steady state. Division of somatic cells is the way to evolve toward their role in the organism but there is a price to pay since daughter cells are different from the mother cell. During DNA synthesis and separation of two new cells there are reorganizations in the genome, which are unpredictable (Macieira-Coelho, 1990); moreover, DNA synthesis and cell division are asymmetric (Macieira-Coelho et al., 1982; Macieira-Coelho, 1995, 2007), and mutations accumulate from infancy on and through the whole human life span (Yokoyama et al., 2019). These multiple events lead to cumulative cellular modifications.

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DNA in the cell nucleus forms an elaborate hierarchical organization through the folding of the double helix with bound proteins. The first folding constitutes the 11 nm “beads on a string” fiber with the nucleosomes, which in turn folds into the 30 nm fiber. The latter folds into a 120 nm chromonema, then into the 300–700 nm chromatid, and finally the 1400 nm mitotic chromosome. The functioning of this elaborate packing depends on the biology of conformation (Ivanov et al., 1973), hence, is thermodynamically unstable. Gene expression depends on conformational changes that expose or cover DNA sequences, this way controlling the access of molecular regulators of transcription. The flexibility of these structures depends upon several biochemical events that regulate the binding of proteins to DNA. One of these events is the covalent binding of branched chains of ADP-ribose to nuclear proteins (ADP-ribosylation). It weakens the binding (mainly of histone H1) through an increase in the protein negative charge and probably also by distorting the chromatin structure through the presence of the long chain (Kanungo, 1995). Acetylation and methylation are other biochemical reactions regulating protein-DNA binding; the former decreasing the net positive charge would dissociate the binding, whereas methylation would render the binding stronger through an increase of the positive charge. Kanungo (1995) could ascertain the disturbance of these reactions during senescence suggesting a decreased conformational flexibility. A fourth biochemical reaction controlling protein-DNA binding is phosphorylation. Phosphorylation and dephosphorylation are fundamental tools to activate energy barriers through modifications of molecular conformation. Changes at the different DNA structural levels have been described during aging of mitotic cells. There is a decline in the hybridization signal for certain genes in some genome regions and new bands become apparent showing a reorganization at this level (Icard-Liepkalns et al., 1986). Reorganizations have been observed at the level of the 11 nm and 30 nm fibers (Dell’Orco et al., 1986; Macieira-Coelho, 1991) and also at the level of chromosomes (Saksela and Moorhead, 1963) accompanied by an evolution of cell morphology (Macieira-Coelho, 2016b). The DNA of post-mitotic cells also changes, inter alia through somatic gene recombination as has been described in normal neuronal genomes (Lee et al., 2018). Other structural changes occur in DNA, which hampers the flexibility of conformation of the molecule. The temperature needed to separate the two strands increase with aging of the brain (Hahn, 1963; Kurtz and Sinex, 1967), it was interpreted in terms of increased binding of proteins to DNA, it could also be due to the decreased phosphorylation of histones and modifications of acetylation and methylation (Kanungo, 1995). A decline of non-histone chromosomal proteins has also been reported (Kurtz and Sinex, 1967) contributing to the loss of conformational flexibility of the chromatin structure.

The Reorganization of Tissues, Organs, and Functions The modifications at the molecular level lead to a reorganization of the tissues, organs and functions due to a new equilibrium between cell compartments, which induces a continuous evolution. The restructuring that occurs in bone is the result inter alia, of the continuous shift that takes place in the balance between the activity of osteoblasts and osteoclasts leading to a functionally deficient architecture. This shift between cell compartments extends to all organs; with advancing age for instance, a progressive decrease in the density of striated muscle cells can be observed in the urinary bladder’s sphincter with the associated replacement by fat cells and connective tissue (Strasser et al., 1999). The structural changes in the sphincter can explain the high incidence of urinary incontinence in the elderly. During normal aging the number of parietal gastric cells increases and the number of mucous cells is reduced (Farinati et al., 1993). Since the mucus protects from acid secretion the decline of the latter cells can explain an increased susceptibility of the gastric mucosa to damage in the elderly. In the skin the loss of elasticity and increased wrinkling are the result of the rearrangements in the relative proportions of the molecular and cellular constituents. In the brain the astrocytes control synapse number (Ullian et al., 2001), with the decline of glial cell proliferation (Fedoroff et al., 1990) fewer synapsis form in the absence of glial cells and the few synapses that do form are functionally immature. The restructuring involving the glial cell compartment will profoundly influence neuron signal transmission. The increase in human body weight during the second half of the life span may be due in part to modifications in neuronal activity (Dani, 1997). Humoral response to effectors becomes altered due to the changes in cell metabolic activity. The induction, for instance, of glucokinase, tyrosine aminotransferase and microsomal NADPH: cytochrome c reductase in rat liver following treatment with glucose, ACTH, and phenobarbital respectively, are characterized by an age-dependent adaptive latent period whose duration increases progressively from 2 to 24 months of age (Adelman, 1972). In humans blood glucose tolerance levels change with age because of the slower response to insulin secretion. The normalcy of blood cholesterol levels evolves with age so that higher values are acceptable in humans after the age of 55. The structural reorganization of the Central Nervous System and of the whole human body have repercussions on the structure of the psyche which goes through a continuous remodeling through the life span of the organism. In early childhood the growth of consciousness progressively overtakes instinct in human behavior. Changes occur through adulthood becoming more pronounced during the approach to the middle of life coinciding with the involution of the sexual drive. Later the traits that distinguished the two sexes become more blurred and the time structure is altered by senescence. Selective changes in the different types of memory and altered performance takes place. The treatment of information and the time structure evolve with a compression of the time frame. In the very old there is a tendency for detachment from the external environment with a contraction of the psychological space and introversion (Jung, 1976).

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Changes in Energy Transduction During Aging Molecular interactions consume energy for the induction of the right conformations to perform biochemical reactions. Molecular conformation is assumed by gradients of the electrical potential created by the transfer of electrons, protons and ions and by phosphorylation, which activate energy barriers. There is a probability that not all molecules have the adequate functional shape, there is a distribution of conformations diverging from the most adequate one. The biology of conformation wears down during aging (Macieira-Coelho, 2016b), which is one of the reasons why functions become increasingly less optimal. There is a decreased mitochondrial oxidative phosphorylation that impairs cellular metabolism (Lesnefskyad and Hoppelbebc, 2006). During cellular senescence ATP content decreases following exposure to metabolic poisons, showing a defect at the point of origin of inorganic phosphate (Muggleton-Harris and Defuria, 1985). The pathways of the phosphorylation cascade initiated at the cell periphery are impaired. Qualitative modifications of the phosphorylation of some proteins and a relative decrease of others were observed with the presence of new isozymic forms of protein kinases and new phosphoproteins (Kahn et al., 1982). The components of the signaling transduction system at the cell periphery are differently affected. In the kidney the GTP binding ratio to G-proteins is increased for some proteins and decreased for others (Parekh et al., 1999). Hence, it seems that different steps of the centripetal pathway of information transfer become modified during senescence. Disturbances of the centrifugal information pathway also take place since protein synthesis declines with elongation, this being the most sensitive step to aging (Parrado et al., 1999). A decrease in the translational capacity of ribosomes has been observed in rodent tissues such as muscle, brain, liver, lens, testis, and parotid glands (Rattan, 1995). Defects in the centrifugal pathway are also due to the markedly decreased amount of mRNA transported from nuclei because of age-dependent charges in polyadenylation, splicing, release of mRNA from the nuclear matrix, translocation through the nuclear pore complex, and association of the transported mRNA with the cytoskeleton (Müller et al., 1995). Different corners of the web where energy transduction takes place are affected by aging. Soluble protein kinase C (PKC) is maintained in an inactive conformation by interaction of the regulatory with the catalytic unit. An increase in free Ca2 þ and in membrane diacylglycerol, changes the conformation of the enzyme favoring the interaction of the regulatory subunit with the membrane. The ability of PKC to translocate and thus to change conformation, as indicated by an increase in the particular activity coupled to a decrease in soluble activity, is lost in aged rats in both cortex and hippocampus; there are also selective modifications in PKC isoforms (Battaini et al., 1995). The energy pool depends on glucose metabolism since one molecule of the sugar synthesizes 38 molecules of ATP (Meier-Ruge et al., 1994). In physically and mentally healthy senescent subjects, a 23% reduction was found in the cerebral metabolic rate of glucose metabolism without any change in cerebral oxygen utilization, but with a fall in ATP formation (Hoyer, 1995). The adrenergic system of energy transduction is also affected, brain cortex adrenoreceptor density decreases progressively with advancing age (Piantanelli et al., 1985). At the level of the hippocampus a decreased cyclic AMP-dependent phosphorylation was observed (Magnoni et al., 1992). In old brains the protein kinase and the adenosine triphosphatase activities associated with microtubules are decreased affecting synapse plasticity (Schröder et al., 1983).

The Thermodynamics of Aging A complex organism that would not age would either have to pursue development indefinitely to nowhere or reach a steady state, a developmental plateau, without any further modifications, a hypothesis incompatible with the biology of the organism. Living means continuous adaptation through change away from equilibrium. The second law states that all systems change in such a way as to decrease their capacity for subsequent change because of the dispersion of energy, an increased disorder, i.e., the increase of entropy. Structure is coupled with function and the flow of information depends upon the structural integrity; the remodeling occurring through the organism life span modifies the function, storage and flow of information through the hierarchical structures. Lorenz (1977) recognized energy transfer and the storage of information as two cornerstones coupled in a multiplying interaction to assert the power of life. Leo Szilard (Szilard, 1959) demonstrated that information is equivalent to negative entropy, i.e., less disorder and more free energy available. Aging is inherent to living beings because life is dependent on the utilization and transduction of energy and has to follow thermodynamic rules, i.e., the second law. When two bodies at different temperature establish contact, heat passes from the hotter to the colder body and does not returndthe thermodynamic arrow of time is unidirectional. A system driven by the utilization of energy cannot escape the second law, entropy increases inexorably. It has been claimed that the plateau observed in mortality curves suggests that there is no natural limit on life span (Barbi et al., 2018). On the contrary, the mortality plateau is the expression of the dispersal of free energy available pushed to the limitdthe increase in entropy that establishes an irreversible barrier on life span.

References Adelman, R.C., 1972. Age-dependent control of enzyme adptation. In: Strehler, B. (Ed.), Advances in Gerontological research, vol 4. Academic Press, New York, pp. 1–23. Barbi, E., Lagona, F., Marsili, M., Vaupel, J.M., Wachter, K.W., 2018. The plateau of human mortality: Demography of longevity pioneers. Science 29, 1459–1461.

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Battaini, F., Elkabes, S., Bergamaschi, S., Ladisa, V., Lucchi, L., et al., 1995. Protein kinase C activity, translocation and calcium-dependent isoenzymes in the aging rat brain. Neurobiology of Aging 16, 137–146. Bonafé, M., Valensin, S., Gianni, W., Marigliano, V., Franceshi, C., 2001. The unexpected contribution of immunosenescence to the levelling off of cancer incidence and mortality in the oldest old. Critical Review of Oncology and Hematology 39, 227–233. Dani, S.U., 1997. The metabolic basis of encephalization prolongs life span, and the evolution of longevity. In: Dani, S.U., Hori, A., Walter, G.F. (Eds.), Principles of neural aging. Elsevier, Amsterdam, pp. 205–216. Dell’Orco, R.T., Whittle, W.L., Macieira-Coelho, A., 1986. Changes in the higher order organization of DNA during aging of human fibroblast-like cells. Mechanisms of Ageing and Development 35, 199–208. Farinati, F., Formentini, S., Della Libera, G., Valiante, F., Fanton, M.C., et al., 1993. Changes in parietal and mucous cell mass in the gastric mucosa of normal subjects with age. Gerontology 39, 146–151. Fedoroff, S., Ahmed, I., Wang, E., 1990. The relationship of expression of statin, the nuclear protein of non-proliferating cells, to the differentiation and cell cycle of astroglia in cultures and in situ. Journal of Neuroscience Research 26, 1–15. Hahn, H.P., 1963. Age-dependent thermal denaturation and viscosity of crude and purified DNA prepared from bovine thymus. Gerontologia 8, 123–131. Hoyer, S., 1995. Brain metabolism during aging. In: Macieira-Coelho, A. (Ed.), Molecular basis of aging. CRC Press Inc, Boca Raton, Florida. Icard-Liepkalns, C., Dolly, J., Macieira-Coelho, A., 1986. Gene reorganization during serial proliferation of normal human fibroblasts. Biochemical and Biophysical Research Communications 141, 112–123. Ivanov, V.I., Minchenkova, L.E., Schyolkina, A.K., Poletayev, A.I., 1973. Different conformation of double-stranded nucleic acid in solution as revealed by circular dichroism. Biopolymers 12, 89–110. Jung, C.G., 1976. The portable Jung. Penguin Books, Middlesex, England. Kahn, A., Meienhofer, M.C., Guillouzo, A., Cottreau, D., Baffet, G., et al., 1982. Modifications of phosphoproteins and protein kinases occurring with in vitro aging of cultured human cells. Gerontology 28, 360–370. Kanungo, M., 1995. Changes in gene expression during aging of mammals. In: Macieira-Coelho, A. (Ed.), Molecular basis of aging. CRC Press Inc, Boca Raton, Florida, pp. 183–218. Kurtz, D.I., Sinex, F.M., 1967. Age-related differences in the association of brain DNA and nuclear proteins. Biochemica Biophysica Acta 145, 840–842. Lee, M.-H., Siddoway, B., Kaeser, G.E., Segota, I., Rivera, R., et al., 2018. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature 563, 639–645. Lesnefskyad, E.J., Hoppelbebc, C.L., 2006. Oxidative phosphorylation and aging. Aging Research Reviews (5), 402–433. Lorenz, K., 1977. Behind the mirror. Harcourt, Brace, Jovanovich, New York. Macieira-Coelho, A., 1990. Reorganization in the different hierarchical structures of DNA during cell senescence. In: Finch, C.E., Johnson, T.E. (Eds.), Molecular biology of aging, UCLA Symposia on molecular and cellular biology, vol. 123. Wiley-Liss, New York, pp. 351–364. Macieira-Coelho, A., 1991. Chromatin reorganization during senescence of proliferating cells. Mutation Research 256, 81–104. Macieira-Coelho, A., 1995. Chaos in DNA partition during the last mitoses of the proliferative life-span of human fibroblasts. FEBS Letters 358, 126–128. Macieira-Coelho, A., 2007. Asymmetric distribution of DNA between daughter cells with final symmetry breaking during aging of human fibroblasts. In: Macieira-Coelho, A. (Ed.), Progress in Molecular and Subcellular Biology, vol. 45. Springer, Berlin, Heidelberg, pp. 227–242. Macieira-Coelho, A., 2016a. Aging happens by default. Journal of Gerontoloy and Geriartric Research 5, 6. Macieira-Coelho, A., 2016b. Slowing down of the cell cycle during fibroblast proliferation. In: Rattan, S.I.S., Hayflick, L. (Eds.), Cellular aging and replicative senescence. Springer International Publishing, Switzerland, pp. 29–47. Macieira-Coelho, A., Bengtsson, A., Van der Ploeg, M., 1982. Distribution of DNA between sister cells during serial subcultivaton of human fibroblasts. Histochemistry 75, 11–21. Magnoni, M.S., Govoni, S., Battaini, F., Trabucchi, M., 1992. Changes in neuronal function downstream from the receptor in the aging brain: Protein kinases and phosphoproteins. Review of Neurosciences (3), 249–270. Meier-Ruge, W., Bertoni-Freddari, C., Iwangoff, P., 1994. Changes in brain glucose metabolism as a key to the pathogenesis of Alzheimer’s disease. Gerontology 40, 246–252. Muggleton-Harris, A.L., Defuria, R., 1985. Age-dependent metabolic changes in cultured human fibroblasts. In Vitro Cellular & Developmental Biology 21, 271–276. Müller, E.G.W., Agutter, P.S., Schröder, H.C., Macieira-Coelho, A., 1995. Transport of mRNA into the cytoplasm. In: Molecular basis of aging. CRC Press Inc, Boca Raton, Florida, pp. 353–388. Parekh, V.V., Maier, K.G., Roman, R.J., Joshua, I.G., Falcone, J.C., et al., 1999. Altered expression and activity of G-proteins, mitogen activated protein kinases, and tyrosine kinases in aging kidney cortex. Journal of Investigative Medicine 47, 462–467. Parrado, J., Bougria, M., Ayala, A., Castaño, A., Machado, A., 1999. Effects of aging on the various steps of protein synthesis: Fragmentation of elongation factor 2. Free Radical Biology & Medecine 26, 362–370. Piantanelli, L., Gentile, S., Fattoretti, P., Viticchi, C., 1985. Thymic regulation of brain cortex beta-adrenoreceptors during development and aging. Archives of Gerontology and Geriatrichs 4, 179–185. Rattan, S.I.S., 1995. Translation and posttranslational modifications during aging. In: Macieira-Coelho, A. (Ed.), Molecular basis of aging. CRC Press Inc, Boca Raton, Florida, pp. 389–420. Saksela, E., Moorhead, P.S., 1963. Aneuploidy in the degenerative phase of serial cultivation of human cell studies. Proceedings of the National Academy of Sciences USA 50, 390–395. Schröder, H.C., Bernd, A., Zahn, R., Müller, W.E.G., 1983. Age-dependent alterations of microtubule-associated enzyme activities from bovine brain (protein kinase, adenosine triphosphatase). Mechanisms of Ageing and Development 22, 35–50. Strasser, H., Tiefenthaler, M., Steinlechner, M., Bartsch, G., Konwalinka, G., 1999. Urinary incontinence in the elderly and age-dependent apoptosis of rhabdosphincter cells. The Lancet 354, 918–919. Szilard, L., 1959. On the nature of the aging process. Proceedings of the National Academy of Sciences USA 45, 35–45. Ullian, E.M., Sapperstein, S.K., Christopherson, K.S., Barres, B.A., 2001. Control of synapse number by glia. Science 291, 657–660. Yokoyama, A., Kakiuchi, N., Yoshizato, T., 2019. Age-related remodeling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317.

Further Reading Hayflick, L., 2007. Entropy explains aging, genetic determinism explains longevity, and undefined terminology explains misunderstanding both. PLoS Genetics 3, e220. Atkins, P., 2010. The laws of thermodynamics: A very short introduction. Oxford University Press, Oxford.

Aging and Skeletal Muscle Gordon S Lynch, Centre for Muscle Research, Department of Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia © 2020 Elsevier Inc. All rights reserved.

Age-Related Muscle Wasting and Weakness Defining Sarcopenia Pathophysiology of Sarcopenia Neuromuscular Deficits With Aging Hormonal Changes With Aging Exercise and Sarcopenia Nutrition and Sarcopenia Systems Physiology Approach to Understanding and Treating Sarcopenia Pharmacotherapies for Sarcopenia Conclusion Acknowledgments References

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Age-Related Muscle Wasting and Weakness Some of the most serious consequences of aging are its effects on skeletal muscle particularly the progressive loss of mass and function which impacts on quality of life and ultimately on survival. We need skeletal muscles to breathe, to eat, and to interact with the environment. Building and maintaining healthy muscle is required for generating body heat, metabolism and movement throughout life. Sadly, as we age, muscles atrophy, lose their strength and fail to repair properly. The term “sarcopenia” describes this slow but progressive loss of muscle mass with advancing age and is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement and a decline in strength. Sarcopenia affects all elderly and does not discriminate based on ethnicity, gender, or wealth. Frail older adults who have lost significant muscle mass and strength often require assistance to complete basic tasks of independent living, and their loss of strength and mobility places them at increased risk of serious injury from sudden falls and fractures, placing increasing demands on the world’s healthcare systems. The significance of the problem of sarcopenia is clear when one considers that the proportion of adults aged over 60 years is expected to increase to 27% by 2050 and that 5–13% of older adults have low muscle mass (as high as 50% in those aged 80 years and older). In normal aging there is a 1% loss of muscle mass after 30 years of age, which tends to accelerate after 70 years of age (Morley et al., 2014; Baugreet et al., 2017). Understanding the biological mechanisms responsible for age-related changes in skeletal muscle is critical for the development of safe and effective interventions that can preserve or restore muscle mass and function and quality of life.

Defining Sarcopenia Clinically defining sarcopenia has proved challenging. In 2010 the European Working Group on Sarcopenia in Older People (EWGSOP) defined sarcopenia based on both low muscle mass and function (Cruz-Jentoft et al., 2010). The Foundation for the National Institutes of Health (FNIH) Sarcopenia Project provided recommendations for sarcopenia based on maximal grip strength (< 26 kg in men; < 16 kg in women) and appendicular lean mass adjusted for body mass index (< 0.789 in men; < 0.512 in women), with the view that sarcopenia be considered in all older patients showing a decline in physical function, strength, or overall health. Sarcopenia was described as the age-associated loss of skeletal muscle mass and function, with the causes being multifactorial, including: disuse, diminishing endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies (Evans, 2010). Sarcopenia was specifically considered in patients who were bedridden, unable to rise from a chair independently, or who had a measured gait speed < 1.0 m/s. Body composition assessment using dual-energy X-ray absorptiometry was used to define sarcopenia as having lean muscle mass of the arms and legs that was two standard deviations (SD) less than that of young adult and a gait (walking) speed of < 1 m/s (Evans, 2010). Aging compromises skeletal muscle structure, metabolism and function, although generally there is a greater loss of muscle strength than mass, and weakness appears more closely associated with the risk of disability and mortality (Evans, 2015). It has been suggested that a more comprehensive definition of sarcopenia should also include measures of insulin resistance and basal metabolic rate and these measurements together with accurate assessments of muscle mass and strength would provide an index of the actual contribution of skeletal muscle to the age-associated risk of morbidity and mortality (Evans, 2015).

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In January 2019, the EWGSOP provided an updated definition of sarcopenia as a progressive skeletal muscle disorder associated with increased likelihood of adverse outcomes, including falls, fractures, physical disability and mortality (Cruz-Jentoft and Sayer, 2019). Sarcopenia was probable when low muscle strength was detected, and a diagnosis confirmed by the presence of low muscle quantity or quality. Low physical performance can identify the severity of sarcopenia, with the condition considered severe when low muscle strength, low muscle quantity/quality and low physical performance are all detected (Cruz-Jentoft et al., 2019). Debate continues regarding the nuances of various definitions as they relate to specific populations, but the fundamental basis of sarcopenia remains centred on a progressive loss of muscle mass and quality that impacts on function. Some definitions may move away from requiring an assessment of muscle mass and specific cut-points because of discrepancies in and between populations, thus focussing attention on functional impairments. Despite continuing debate, sarcopenia is now recognized in many countries as a muscle disease with an ICD-10-CM Diagnosis Code for billing care related to this condition (Cao and Morley, 2016).

Pathophysiology of Sarcopenia The pathophysiology of sarcopenia is mechanistically different from the acute muscle atrophies associated with disuse, cachexia, denervation and other conditions. The potential mechanisms underlying sarcopenia have been described in detail elsewhere (see Larsson et al., 2019; Lynch, 2011; Ryall et al., 2008). The age-related loss of muscle mass and strength is attributed to the progressive atrophy and loss of individual muscle fibers associated with the loss of motor units, and a concomitant reduction in muscle “quality” due to the infiltration of fat and other non-contractile material. These changes involve a complex interaction of factors affecting neuromuscular transmission, muscle architecture, fiber composition, and excitation-contraction coupling, leading to impairments in force producing capacity and speed of shortening, and a “metabolic dysregulation,” with deleterious effects on insulin sensitivity, oxidative defenses, and mitochondrial function (Sakuma et al., 2017). Skeletal muscles generate reactive oxygen species (ROS) at rest and during exercise which can cause oxidative damage, particularly to proteins that accumulate during aging (Jackson and McArdle, 2016; Vasilaki et al., 2017). Increased generation of ROS and reactive nitrogen species (RNS) and altered redox control contribute to the initiation and progression of muscle atrophy with sarcopenia (Sakellariou et al., 2017). Many other factors influence skeletal muscle homeostasis and the balance between muscle protein synthesis and protein degradation that determines the rate and magnitude of muscle atrophy and weakness with advancing age. These include changes in nutritional status, anabolic hormones, genetics, the preservation or loss of motor units, chronic low-grade inflammation or episodes of inflammation associated with injury, oxidative stress, existing or future diseases and conditions, and physical activity (Fig. 1). These and other factors contribute to the regulation of muscle mass and can work synergistically to either counteract and hence slow the rate of progression of sarcopenia, or alternatively, exacerbate and hasten the decline in muscle mass and function.

Neuromuscular Deficits With Aging As sarcopenia is often described as a “neuromuscular syndrome” it is important to assess possible age-related changes in neuromuscular function, including possible changes to the neuromuscular junction (NMJ) affecting neurotransmission, motor unit remodeling, and altered muscle function from single muscle fibers through to the recruitment of muscles to complete functional tasks. The NMJ undergoes remodeling during embryogenesis, which is essential for successful development, but it also undergoes detrimental changes during aging that can impair neuromuscular transmission (Ham and Rüegg, 2018). The NMJ could contribute to sarcopenia through impaired transmission efficiency and/or impaired stability leading to loss of contact between the pre-synapse and post-synapse (Taetzsch and Valdez, 2018; Ham and Rüegg, 2018) and there is molecular and proteomic evidence for sarcopenia-related functional denervation and neuromuscular junction remodeling (Ibebunjo et al., 2013). These changes include a decrease in the number of synaptic vesicles, nerve terminal area, acetylcholine receptors, and the architecture of the nerve-muscle interface (Gilmore et al., 2017). Interestingly, fast-twitch skeletal muscles appear to experience a greater level of NMJ remodeling than slow-twitch muscles (Rosenheimer and Smith, 1985; Prakash and Sieck, 1998), consistent with the age-related decline in muscle function in mammals being more apparent in fast- than in slow-twitch muscles (Brooks and Faulkner, 1994; González et al., 2000; Lynch et al., 2001; Graber et al., 2015). Muscle contraction is initiated and sustained through the appropriate recruitment of motor units. A motor unit is defined as a motor neuron and all the muscle fibers under its control. Motor unit remodeling, whereby muscle fibers are progressively denervated (losing the contact between nerves and muscle fibers) and either lost completely or subsequently reinnervated by the sprouting of remaining neurons, is a contributing factor to the age-related loss of muscle force and power, and studies on animals and humans have demonstrated a preferential loss of fast motor units with advancing age (Faulkner et al., 2007; Naro et al., 2019). The extent of motor unit losses and quality of the motor unit remodeling process differs greatly among individuals and may be influenced by long-term physical activity (Gilmore et al., 2017) and by the neurotrophic effects of circulating growth factors (e.g., insulin-like growth factor-I, IGF-I) that can promote motor neuron/motor unit survival (Messi and Delbono, 2003). It has been proposed that with very old age, motor unit death outpaces remodeling, leading to muscle fiber atrophy and altered muscle quality, that accelerates the loss of muscle function (Gilmore et al., 2017). In some cases, however, the motor unit losses might be

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Fig. 1 Some of the many factors that can influence skeletal muscle homeostasis and the balance between muscle protein synthesis and protein degradation that determines the rate and magnitude of muscle atrophy and weakness with advancing age. These include changes in nutritional status, anabolic hormones, genetics, innervation (especially affecting the preservation or loss of motor units), chronic low-grade inflammation or episodes of inflammation associated with injury, oxidative stress, existing or future diseases and conditions, and the level (and type) of physical activity. These factors and others help regulate muscle mass and can work synergistically to either counteract and hence slow the rate of progression of sarcopenia, or alternatively, exacerbate and hasten the decline in muscle mass and function.

relatively small, in the order of  10–15% even in advanced age (Edstrom et al., 2007). The magnitude of remodeling or loss of motor units is likely linked to the degree or stage of sarcopenia, but in many cases these deleterious changes to the neuromuscular system are progressive and impact severely on motor performance. Aging can cause a decline in the size and number of muscle fibers through selective motor unit remodeling involving either a denervation and subsequent loss of muscle fibers, or a denervation of fast muscle fibers with their subsequent reinnervation by a slow nerve, leading to a slower phenotype overall. Consistent with fast muscles being more susceptible to age-related changes in muscle structure-function than slow muscles, at the cellular level, atrophy of muscle fibers based on girth or cross-sectional area (CSA) is greater in fast, type II muscle fibers, especially the fastest contracting fibers (type IIB or type IIX), compared with slow, type I muscle fibers (Widrick et al., 1996; Larsson et al., 1997; Claflin et al., 2011).

Hormonal Changes With Aging The importance of the circulating milieu in the development of age-related changes in skeletal muscle became evident from studies that showed impairments in the regenerative potential of cross-transplanted muscle grafts (in rats) was determined by the age of the host rather than of the donor (Carlson and Faulkner, 1989) an effect later confirmed in parabiotic models in young and old mice with a shared circulation (Conboy et al., 2005). Muscles from old mice receiving the blood supply of a young mouse had an enhanced regenerative potential without recruitment of young cells from the shared circulation (Conboy et al., 2005). Several hormonal systems decline gradually in their activity with aging, especially circulating anabolic hormones such as testosterone, dehydroepiandrosterone (DHEA), growth hormone (GH) and insulin-like growth factor-I (IGF-I), accompanied by higher levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and C reactive protein (CRP). Circulating levels of catecholamines and paracrine/autocrine systems (including local IGF-I production) have also been implicated in sarcopenia (Lynch et al., 2007). Hormonal interventions for age-related muscle wasting and weakness like testosterone replacement or GH administration have produced only modest improvements in muscle mass and strength, especially in the absence of complementary exercise regimes. The loss of muscle mass can also be exacerbated by other medical conditions including some cancers, kidney disease, diabetes, and peripheral artery disease (Buford et al., 2010).

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Exercise and Sarcopenia Different types of exercise are beneficial for sarcopenia. While age-related changes in skeletal muscle are inevitable, exercise can potentially slow the rate of decline by promoting muscle strength, endurance, and joint range of motion; factors that can reduce the incidence of falls and fractures and promote functional independence and quality of life. Progressive resistance training (lifting weights) for muscle strength, aerobic exercise for maintaining cardiorespiratory fitness, and flexibility and balance exercises for maintaining range of motion, stability and reaction time, are all recommended as part of an overall exercise program for older adults that can promote independent living. However, it should be noted that exercise alone cannot prevent sarcopenia, as evident from the most active older ‘Masters’ athletes who despite training and competing regularly throughout adulthood and beyond, still exhibit age-related changes in muscle mass and strength that compromises performance in different sports (Piasecki et al., 2016; Lazarus and Harridge, 2018). Regardless, exercise combined with good nutrition (especially adequate protein intake), can attenuate progression of sarcopenia (Aagaard et al., 2010; Piasecki et al., 2019).

Nutrition and Sarcopenia Sarcopenia has been linked with a chronic disturbance in the regulation of skeletal muscle protein turnover leading to an imbalance between protein synthesis and protein breakdown (Koopman and van Loon, 2009; Koopman et al., 2009). Since the rate of muscle loss with aging is < 2% per year, it has been argued that basal fasting protein synthesis and/or rates of protein breakdown are not substantially impaired with advancing age but the protein synthetic response to anabolic stimuli such as protein ingestion and physical activity is impaired (Wall et al., 2015). This “anabolic resistance” leading to skeletal muscle atrophy with aging, is attributed to older adults being physically inactive and having conditions associated with chronic low-grade inflammation (Moore, 2014; Ham et al., 2014; Murton, 2015; Fougere et al., 2017; Morton et al., 2018). Inflammation impairs the anabolic response to amino acids such as leucine and so simply providing more substrate may not be sufficient to overcome anabolic resistance (Ham et al., 2016). Other nutrients or treatments that can sensitize skeletal muscle to leucine have therapeutic potential for sarcopenia and other muscle wasting conditions (Koopman et al., 2017). Older adults are more likely to experience extended periods of inactivity through lifestyle changes or illness and can rapidly progress from being otherwise healthy to frail and losing their functional independence (Lynch and Koopman, 2018). Other factors contributing to nutritional deficiencies in older adults, include changes in cognitive function, taste and chemosensory acuity, chewing and swallowing, and the need to take medications which may have their own contraindications (Baugreet et al., 2017).

Systems Physiology Approach to Understanding and Treating Sarcopenia While understanding age-related changes to the structure and function of skeletal muscles is essential for devising interventions that can preserve mass and function and tackle overall weakness and frailty, there is growing appreciation for a more systems physiological understanding of sarcopenia, one that considers age-related alterations in the communication and signaling between multiple organ systems and tissues, not just skeletal muscles. This includes potential alterations in tissue cross-talk between nerves, muscles and bones (Bonewald, 2019; Gorski and Price, 2016; Guo et al., 2017), and recognizing that factors released from different organs can circulate and communicate with other target tissues, including the liver, kidney, pancreas, fat, muscles, bones, and the brain (Delezie and Handschin, 2018; Zhang et al., 2018). The mechanical relationship between muscle and bone is particularly sensitive to age-related changes in muscle mass and function (Novotny et al., 2015). Skeletal muscles secrete proteins (myokines), metabolites, microRNAs (miRNAs), and exosomes, many of which are regulated by exercise (Kaji, 2016; Barlow and Solomon, 2018). Myokines, especially, can act as endocrine and paracrine hormones, signaling to many other tissues (Trovato et al., 2019). Age-related changes in bone mass and architecture may result in increased falls and fractures, and changes in tendons and ligaments linking muscles to bones, can lead to an increased susceptibility to failure at the myotendinous junction (Frontera, 2017; Nielsen et al., 2018). There is also a greater appreciation for how different conditions/body systems influence each other and contribute to comorbidities and accelerated functional decline with aging. Osteoporosis/osteopaenia, sarcopenia and obesity, have similar risk factors like genetics, endocrine function, and mechanical factors, and bones and muscles interact with each other anatomically, chemically and metabolically; that together are implicated in the development of “osteosarcopenia” (Hirschfeld et al., 2017). Similarly, the co-existence of osteopenia/osteoporosis, sarcopenia, and increased adiposity (obesity) in older adults has led to some researchers advocating for “osteosarcopenic obesity” as a distinct entity (Bauer et al., 2019). Whether the concurrent existence of sarcopenia, osteoporosis and obesity leads to an increased risk of adverse musculoskeletal outcomes and mortality above and beyond the risks associated with the sum of the component parts was examined by an expert panel of musculoskeletal researchers who concluded there was insufficient evidence (as of 2019) to support “osteosarcopenic obesity” as a discrete clinical entity (Bauer et al., 2019). Understanding the interplay between signals from these different tissues (e.g., bone, muscle, nerve, fat, tendon, kidney, pancreas, liver, and brain) and their influence on the mechanisms responsible for age-related changes in skeletal muscle, is an exciting area of research that will help identify novel targets and treatments for sarcopenia and related conditions. This

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will also help our understanding of how physical activity confers benefits upon multiple organ systems and why an exercise prescription for “healthy aging” can potentially slow the rate of sarcopenia development.

Pharmacotherapies for Sarcopenia While it is generally accepted that a loss of muscle mass and function with aging is inevitable and individuals may be at increased risk for accelerated sarcopenia due to genetic, lifestyle and environmental factors, pharmacological therapies specifically for sarcopenia have not been widely pursued (Hardee and Lynch, 2019). Therapies that promote net protein accretion to preserve muscle mass are likely to be complementary to an exercise prescription designed to restore, retain or improve muscle function, but safe and effective drug strategies for sarcopenia have yet to be developed. Pharmacotherapies for other muscle wasting disorders such as muscular dystrophy or cancer cachexia may also prevent, attenuate or reverse age-related losses of muscle mass and function (Lynch, 2008; Hardee and Lynch, 2019). As sarcopenia is often considered a “neuromuscular syndrome,” targeting neural- and/or musclespecific mechanisms that can preserve neurotransmission and motor units, especially those of the fastest contracting muscle fibers, is important. Readers interested in the development of pharmacological approaches for sarcopenia (1997–2019) are directed to extensive reviews evaluating specific drug targets and compounds, including ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), survival motor neuron (SMN) agonists, neuregulin, growth hormone, IGF-I, myostatin, selective androgen receptor modulators (SARMs), and beta-adrenoceptor agonists (b-agonists) (see Lynch, 2002, 2004, 2008; Hardee and Lynch, 2019). Potential pharmacotherapies designed specifically for sarcopenia including those that have been evaluated in phase 2 (or higher) clinical trials, have been reviewed in detail (Hardee and Lynch, 2019). Some of the most promising candidates include growth promoting agents such as myostatin inhibitors, testosterone and derivatives, b-agonists, and SARMs, which have potential to promote lean mass and improve muscular strength. In some cases, these powerful anabolic drugs can have deleterious off-target effects on other tissues (potentially the heart) and so separating beneficial from harmful effects must be overcome if they are to have widespread clinical application for treating sarcopenia. Combining these pharmacotherapies with exercise/physical activity is possible but requires further evaluation to determine efficacy and safety. Inflammation is really a double-edged sword in sarcopenia, since an inflammatory response is essential for activation pathways responsible for effective muscle repair and growth, but excessive (and sustained) inflammation is linked with pathways of muscle atrophy. Therefore, inhibiting inflammatory cytokines as a therapeutic intervention for sarcopenia is problematic given that intermittent inhibition/activation of inflammatory pathways would likely be needed to maintain muscle mass and function during aging. There is also growing interest in repurposing drugs for tackling sarcopenia, including angiotensin-(1–7) receptor agonists and antihyperglycemic agents for type 2 diabetes, which have positive effects on muscle anabolic and metabolic processes. These therapies have potential for improving muscle mass and function and delaying hallmarks of aging across multiple tissues and processes (Hardee and Lynch, 2019).

Conclusion Age-related muscle wasting and weakness leading to frailty and loss of independence is a major public health problem facing the world’s growing number (and proportion) of older adults. Despite advances in understanding the pathophysiology of sarcopenia and it recently being recognized as a disease, there is a lack of effective therapies that can slow the effects of aging on muscle function and restore muscle size and strength. Sarcopenia remains a considerable challenge for biomedicine; one that demands rigorous fundamental research to identify novel therapeutic strategies for safe and effective clinical translation.

Acknowledgments GS Lynch is grateful for research grant support from the Australian Research Council (DP190101937, DP150100206), the National Health & Medical Research Council (GNT1144772, GNT1124474, GNT1120714, GNT1065456), the Duchenne Parent ProjectdNetherlands (18.015), and Cancer Council Victoria (APP1120752).

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Aging Bone, Osteoporosis and Fragility Fracture J Zanker, SL Brennan-Olsen, and G Duque, Department of Medicine-Western Health, The University of Melbourne, St Albans, VIC, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St Albans, VIC, Australia © 2020 Elsevier Inc. All rights reserved.

Introduction Epidemiology Pathophysiology Assessment Presentation of Osteoporosis Secondary Causes of Osteoporosis History and Physical Examination Bone Mineral Density (BMD) Vertebral Imaging Bone Turnover Markers Fracture Risk Calculation Management Non-Pharmacological Dietary Calcium Vitamin D Physical Activity Pharmacological Therapy Duration and Sequence Models of Care Future Directions Conclusion References Further Reading Relevant Websites

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Introduction Osteoporosis is a skeletal disease characterized by reduced bone mass and microarchitectural deterioration of bone that results in an increased susceptibility to fractures. As the global population ages, the number of older adults living with osteoporosis will increase. Osteoporotic fractures are highly prevalent in older persons and are associated with higher morbidity and mortality, reduced quality of life, disability and institutionalization. Osteoporosis is potentially preventable and treatable; however, osteoporosis and fracture risk are not routinely assessed in older persons with most people at high risk being underdiagnosed and undertreated. To close the gap between diagnosis and treatment, and to improve knowledge on the best management for individuals with this condition, here we address the epidemiological, pathophysiological and management aspects of osteoporosis in older persons.

Epidemiology Osteopenia and osteoporosis are well-described as conditions characterized by reduced density and quality of bone, which leads to brittle and weak bones, and a subsequent increase in fracture risk, particularly of the hip, spine and wrist (Osteoporosis Australia, 2013; International Osteoporosis Foundation, 2015; Watts et al., 2010). Using the World Health Organization guidelines, osteopenia is “defined” as a bone mineral density (BMD) d1 standard deviation (SD) below the young healthy adult reference population, and osteoporosis is defined either by the presence of a minimal trauma fracture (most commonly of the hip, spine, wrist, ribs, humerus or femur), or according to measures of BMD ascertained from dual-energy x-ray absorptiometry (DXA), whereby a Tscore at the hip and/or lumbar spine is identified as being at or below 2.5 SD below the young healthy adult reference population (World Health Organization, 1994). Commonly referred to as a “silent disease,” osteopenia/osteoporosis is asymptomatic until a fracture occurs (Watts et al., 2013). Data suggests that one in three women and one in five men aged 50 years or older will experience an osteoporotic fracture (International Osteoporosis Foundation, 2007), with one fracture estimated to occur every 3 s (Watts et al., 2013). Following a hip fracture, 10–20% of people will require long-term nursing care, and one if five people will die in the first 12 months post-hip fracture (Katsoulis et al., 2017; Haentjens et al., 2010). Worldwide, osteoporotic fractures account for

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0.83% of the global burden of non-communicable diseases (NCDs) (Johnell and Kanis, 2006); whilst Disability Adjusted Life Years (DALYs) attributable to low BMD increased from > 3 million in 1990 to > 5 million in 2010 (Sanchez-Riera et al., 2014).

Pathophysiology Osteopenia and osteoporosis are associated with aging. There is a normal age-related bone loss of about 0.5%/year after the third decade of life. In a proportion of older persons ( 25% of people older than 60), this bone loss is accelerated and more significant thus affecting bone mass and architecture, and predisposing them to fracture. This accelerated bone loss is associated with multiple risk factors which closely associate with well-known pathophysiological mechanisms (Zanker and Duque, 2019). Appropriate bone turnover is the consequence of the synchronic resorption of low-quality bone by the osteoclasts followed by new bone formation by the osteoblasts (Fig. 1). Bone resorption is exerted by the osteoclasts via activation of several factors that release calcium and phosphate from the hydroxyapatite and break down the bone matrix. Among those factors, cathepsin K is a protease that catabolizes elastin, collagen, and gelatin with the capacity to break down bone and cartilage. High osteoclast number or activity will increase bone resorption thus breaking the balance between resorption and formation and inducing osteopenia/osteoporosis (Kim and Koh, 2019). Bone formation is conducted by the osteoblasts, which are cells of mesenchymal origin with strong capacity to produce unmineralized matrix while also facilitating its mineralization. After completing their bone forming activity at one specific bone multicellular unit, the osteoblasts could become lining cells, which keep their bone forming capacity, could differentiate into osteocytes and become embedded within the matrix, or die by apoptosis. The predominance of one of these potential cell paths will determine healthy or unhealthy bone turnover (Sanchez-Riera et al., 2014; Zanker and Duque, 2019). The osteocytes are the most abundant cells in the bone matrix, which reside in small pockets within the mineralized bone matrix called lacunae. After embedding within the matrix, osteoblasts change their phenotype and become “neuron-like” cells that send their dendritic processes (ranging from 40 to 100 per cell) through canaliculi to develop highly interconnected networks, which

Fig. 1 Bone remodeling. Bone remodeling cycle. Bone remodeling is initiated by microcracks or changes in mechanical loading and consists of four consecutive steps: activation, resorption, reversal, and formation. Activation of osteoclasts is controlled through the RANK/RANKL/OPG pathway. Following bone deposition, osteoblasts can differentiate to osteocytes (osteocytogenesis), turn to bone-lining cells, or enter apoptosis. Adapted with permission from Owen R and Reilly GC. In vitro models of bone remodelling and associated disorders. Frontiers in Bioengineering and Biotechnology (2018);6:134.

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are used for exchange of nutrients and waste through gap junctions. Until recently, the osteocytes were considered as passive players in the bone turnover process, however, recent advances in the understanding of osteocyte biology have demonstrated that osteocytes are major regulators of turnover via the secretion of pro-osteoclastogenic factors, such as receptor activator of nuclear factor kappa-B ligand (RANKL), and important regulators of osteoblastogenesis such as sclerostin (inhibitor) or Dickkopf WNT Signaling Pathway Inhibitor 1 (stimulator) (Dallas et al., 2013). Osteocytes are important mechanosensors. As such, the osteocytes respond to mechanical forces (such as exercise) by decreasing sclerostin secretion and increasing Dkk1, which induces bone formation. With aging, the number of osteocytes decline due to high prevalence of apoptosis. In addition, due to other factors such as sedentarism, decreasing levels of anabolic growth factors, or menopause, the osteocytes produce higher amounts of sclerostin, thus having a negative impact on bone formation. In addition, partially due to these age-related changes, osteocytes also secrete higher levels of RANKL, which increases bone resorption (Dallas et al., 2013). As the body ages, fat infiltrates bone. This process was formerly thought to be an age-related phenomenon and its pathophysiological implications were under-recognized. Lipotoxicity is the process by which body fat secretes inflammatory cytokines that have a negative impact on the growth and function of surrounding and distant tissues (Singh et al., 2018). The inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) and free fatty acids (mostly palmitic acid) have been associated with lipotoxicity (Singh et al., 2018). Patients with osteoporosis have high circulating blood levels of IL-6 and TNF-a (Zhang et al., 2015), a process which underlies putative inflammatory mechanisms of osteoporosis. However, the ways in which the effects of these fatty acids and inflammatory cytokines can be mitigated is poorly understood.

Assessment Presentation of Osteoporosis The clinically significant result of osteoporosis is fracture. Osteoporosis is asymptomatic until the point of fracture and many adults are not diagnosed with osteoporosis until after a fracture, however osteoporosis may precede the fracture for years or decades (Cosman et al., 2014). Therefore, low bone mass or osteoporosis should be suspected all men and post-menopausal women over the age of 50 years (Cosman et al., 2014). A vast majority of older adults who sustain a fracture experience loss of function and acute pain. Given the strong association of osteoporosis with aging, many who experience a fracture may have comorbid conditions such as dementia or sensory impairment. Such patients may have difficulty reporting symptoms and therefore fractures should be suspected where there are non-specific behavioral changes in those who may be unable to report pain due to cognitive or sensory impairments.

Secondary Causes of Osteoporosis Several specific causes of reduced bone mass are recognized as either affecting bone directly (through changes in bone cells or matrix composition) or indirectly (by increasing endogenous or ectopic hormone production) (Duque and Troen, 2016). These diseases or drugs are known as secondary causes of osteoporosis and the common causes are listed in Table 1. Some of these factors may be irreversible, however others are reversible or treatable and therefore should be included in the management of the patient with osteoporosis. Secondary causes of osteoporosis are more likely in men than women, the most common causes of which are hypogonadism and malabsorptive syndromes (Duque and Troen, 2016).

Table 1

Secondary causes of osteoporosis in adults.

Diseases

Conditions

Medications

Cancer Cholestatic liver disease Chronic hyperthyroidism Chronic kidney disease COPD Cushing’s syndrome Hypogonadism Malabsorptive disease Multiple myeloma Paget’s disease Rheumatoid arthritis Stroke Type II diabetes mellitus

Alcohol excess Cachexia or low body weight Hypercalciuria Smoking Vitamin D deficiency

Anti-epileptics Aromatase inhibitors Chemotherapeutics Excess thyroxine Glucocorticoid therapy GnRH agonists Heparin

COPD, chronic obstructive pulmonary disease; GnRH, gonadotrophin releasing hormone.

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History and Physical Examination The history and physical examination are an integral component of assessing a patient for osteoporosis. The information gathered by the history and physical examination should be combined with targeted investigations to assist in calculating fracture risk and therefore guide management decisions. A key component of the assessment includes a thorough falls history given fracture is the clinical endpoint of osteoporosis and falls are one of the greatest risk factors for fracture. A history of a previous fracture carries the most significant risk for future fracture and similarly, a prior history of falls carries the most significant risk for future falls (Deandrea et al., 2010). The history and physical should focus on the reversible or modifiable risk factors for falls and fractures. A focused and multifactorial assessment is advised to address these risk factors systematically. Table 2 outlines important potentially modifiable and nonmodifiable falls risk factors in older adults.

Table 2

Risk factors for falls in older adults.

Potentially modifiable

Non-modifiable

Cardiac Arrhythmias Congestive cardiac failure Hypertension and hypotension Environmental Carpets, rugs, crowding (people, objects), tripping hazards within the home Pets Functional Use of a gait aid or assistive device Impairment in activities of daily living Medications Particularly centrally-acting medications such as psychotropics, anti-depressants and benzodiazepines Metabolic Diabetes Mellitus Low body mass index (BMI) Vitamin d deficiency Musculoskeletal Balance impairment Foot problems Gait impairment Limited activity Musculoskeletal pain Neurological Delirium Dizziness or vertigo Movement disorder (Parkinson’s disease) Peripheral neuropathy Psychological Depression Fear of falling Sensory impairment Visual impairment Auditory impairment Multifocal lens Other Acute illness Anemia Cancer Inappropriate footwear Nocturia Urinary or fecal incontinence Obstructive sleep apnea Postural hypotension

Age Arthritis Dementia Female sex History of stroke History of falling History of fractures Recent discharge from hospital

Adapted from Moncada LVV, Mire LG. Preventing Falls in Older Persons. American Family Physician. 2017;96(4):240–7.

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Bone Mineral Density (BMD) BMD assessment is the most important investigation for making the diagnosis of osteoporosis. BMD is defined as the amount of bone per unit volume, or the amount of bone per unit area (Roux and Briot, 2017). BMD assessment can be used for both diagnosis of osteoporosis or osteopenia, but also can assist in predicting future fracture risk and guide treatment decisions in those who are untreated, or are undergoing treatment, for osteoporosis. BMD can be measured using a variety of diagnostic tools. The most commonly used method is DXA (Roux and Briot, 2017). Other diagnostic tools include peripheral DXA (pDXA), quantitative ultrasound (QUS), quantitative computed tomography (QCT), and radiographic absorptiometry. These diagnostic tools have a high specificity but low sensitivity in fracture prediction (Oei et al., 2016). That is, a majority of people who experience a minimal or low trauma fracture have normal or low bone mass with BMD not in the osteoporotic range. This phenomenon arises due to a majority of the population being in the normal or low bone mass range. Therefore, these diagnostic techniques should form part of the fracture risk assessment and not used in isolation. The BMD assessment and respective diagnostic criteria are listed in Table 3. The recommended method by the World Health Organization is BMD assessment of the hip or spine using DXA. In general, the indications for BMD assessment include; -

Women  65 years, and men aged  70 years; Younger postmenopausal women and women in menopausal transition; Men aged 50–69 years with risk factors for fracture; Adults who have a fracture at, or after the age of 50 years; and Adults with a condition (e.g., rheumatoid arthritis) or taking medications (e.g., glucocorticoids > 5 mg per day for 3 months) associated with low bone mass or bone loss (Cosman et al., 2014).

Vertebral Imaging The presence of a minimal trauma vertebral fracture of > 20% loss of vertebral height is consistent with a diagnosis of osteoporosis, with or without BMD assessment. Therefore, BMD assessment is not required to commence osteoporosis treatment in those with a vertebral or other minimal trauma fracture. Proactive vertebral imaging is advised in high risk populationsdsuch as those with previous history of falls or multiple risk factors for osteoporosisdparticularly given that incident vertebral fractures may be asymptomatic in up to a third of older adults (Cosman et al., 2014). The National Osteoporosis Foundation (NOF) advise the use of lateral thoracic and lumbar spine X-ray to diagnosis vertebral fractures and monitor progression. In addition, vigilant reporting of routing chest X-rays should be undertaken, even in the absence of symptoms suggestive of fracture, as vertebral fractures are under-reported when the indication for the X-ray is not a fall or back pain. This represents a missed opportunity for increased diagnosis, treatment and prevention of osteoporotic fractures.

Bone Turnover Markers Bone turnover markers (BTMs) are metabolites that appear in the serum that reflect the metabolic activity of bone. BTMs are comprised of resorption and formation markers. Resorption markers include serum C- and urinary N-terminal telopeptides of type 1 collagen (CTX and NTX). Formation markers include serum bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and aminoterminal propeptide of type I collagen (PINP). There is increasing evidence that BTMs may be useful in fracture risk determination, however, the role of BTMs in prediction of fracture healing or adherence to medications remains uncertain (Yoon and Yu, 2018). International reference standards are yet to be developed and the routine inclusion of BTMs in clinical management has not yet been recommended in international guidelines.

Table 3

Definition of osteoporosis and osteopenia based on BMD (Kanis and On Behalf of the WHO Scientific Group, 2008).

Classification

BMD at the femoral neck

T-Score

Normal

50 nmol/L at the end of winter/early spring, with optimal levels > 75 nmol/L, which has been reported to have a beneficial effect on bone and health: a minimal dose equivalent to 1000 IU per day (25 mg/day) is necessary to achieve that target (Duque et al., 2017).

Physical Activity Age-specific requirements for physical activity (in terms of types, duration, intensity, regularity) have been proposed to maximize bone health, which may also have a beneficial effect on muscle mass and function (Ebeling et al., 2013); however, there are some commonalities across the life-course in terms of types. The impact of selected exercise modalities on bone health range from highly osteogenic exercises (basketball/netball, impact aerobics, tennis, jumping), moderately osteogenic (running/jogging, hill walking, resistance training, stair climbing), low osteogenic (leisure walking, lawn bowls and yoga/Pilates), to non-osteogenic (swimming, cycling) (Ebeling et al., 2013). Whilst leisure walking is not recommended as an adequate strategy for bone health, this activity nonetheless provides overall health and fitness benefits for all ages across the life course.

Pharmacological The goal of pharmacological therapy for osteoporosis is to reduce fracture risk. Given the large burden of osteoporosis globally and the aging population, there has been significant focus on research and development of preventative treatments for osteoporosis in recent decades. The mechanisms by which approved pharmacological agents either increase bone mass, or reduce loss of bone mass, is highly varied. Across the globe, the indications, availability and regulatory approval of pharmacological agents is variable. The NOF recommend that pharmacological therapy should be initiated in adults, in addition to the non-pharmacological measures outlined above, meeting any of the following criteria (Cosman et al., 2014): - Minimal trauma vertebral or hip fracture; - Hip or lumbar spine T-score  2.5 on DXA; or - Low bone mass and a FRAXÒ 10-year fracture risk (adapted to the US) of the hip  3% or of any major osteoporosis-related fracture  20%. Table 5 outlines the approved pharmacological agents used in the treatment of osteoporosis. No single treatment is advised in preference to another. This is due in part to the paucity of head-to-head trials comparing anti-fracture efficacy of pharmacological agents. Individual risk assessment using the FRAXÒ or other validated fracture risk calculation tools, in addition to patient circumstance and preferences, should be used to determine the most appropriate treatment modality. National and regional guidelines, funding and medication availability may also influence treatment options. Therefore, the choice of agent should always be patient- and contextspecific. Age, low socioeconomic status and/or degree of functional dependence could be barriers to initiation of pharmacological therapy for osteoporosis. Vitamin D and calcium, whilst important components of osteoporosis treatment, are insufficient on their own to treat osteoporosis. Treatment of osteoporosis in the “oldest old” may have more rapid efficacy than in younger patients (Vandenbroucke et al., 2017). Those living in nursing homes or long-term care facilities are at higher risk of osteoporosis and osteoporotic fracture than community-dwelling older adults (Aguilar et al., 2015). However, there is under-recognition and undertreatment of older adults living in these settings. Where BMD assessment is not possible due to logistic and patient-related factors, fracture risk assessment (FRAXÒ) should be undertaken to determine fracture risk and suitability for pharmacological therapy. Table 5 also outlines some important treatment considerations and potential adverse effects of the various pharmacological agents. Those adverse events which have attracted the greatest attention and affected treatment acceptance include the increased risk of atypical femoral fractures (AFFs) and medication related osteonecrosis of the jaw (ONJ) with the use of bisphosphonates and denosumab. The definition of AFFs by the American Society of Bone and Mineral Research (Shane et al., 2014) includes a fracture of the femoral shaft:

Table 5

Pharmacological agents for the treatment of osteoporosis. Drug name

Mechanism/s of action

Patients studied

Efficacy

Key side effects/precautions

Bisphosphonate

Alendronate

Inhibition of osteoclast activity

Men and post-menopausal women with osteoporosis

Contraindicated eGFR 5 years use)

Anabolic activity resulting in new bone formation

Men and women with osteoporosis

Reduced hip and vertebral fractures by approx. 50% over 3 years (Black et al., 1996) Reduced vertebral fractures by approx. 50% over 3 years (Chesnut 3rd et al., 2004) Reduce vertebral fractures by 41 to 49% and nonvertebral fractures by 36% over 3 years (Harris et al., 1999; Reginster et al., 2000). Approved for use in patients on glucocorticoid therapy (Cohen et al., 1999) Reduced vertebral fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25% over 3 years (Black et al., 2007) Reduced risk of vertebral fractures by 65% and nonvertebral fractures by 53% after 18 months (Neer et al., 2001)

Ibandronate Risedronate

Zoledronic acid Synthetic parathyroid hormone

Teriparatide

Parathyroid hormone-related protein (PTHrP) analog

Abaloparatide

Post-menopausal women with osteoporosis

Reduced risk of vertebral fractures by approx. 57% (Miller et al., 2016). Superior to teriparatide and zoledronate via network metaanalysis (Tsai et al., 2017)

Avoid in those at increased risk of osteosarcoma; Paget’s disease, previous radiation therapy, hypercalcemia, skeletal metastases) Commondlegs cramps, nausea and dizziness Increased risk of osteosarcoma shown in rats

(Continued)

Aging Bone, Osteoporosis and Fragility Fracture

Class

55

56

Pharmacological agents for the treatment of osteoporosis.dcont'd

Class

Drug name

Mechanism/s of action

Patients studied

Efficacy

Key side effects/precautions

BiologicdRANK-Ligand inhibitor Denosumab

Inhibits coupling of osteoclasts and reduces bone resorption

Men with low bone mass and postmenopausal women

Hormone Replacement Therapy (HRT)

Various

Maintenance estrogen levels Prevents bone resorption

Post-menopausal women or women with hysterectomy

Reduced vertebral fractures by 68%, hip fractures by 40% and nonvertebral fractures by 20% over 3 years (Cummings et al., 2009) WHI studyd5 years HRT reduced vertebral fractures by 34% and other fractures by 23% (Rossouw et al., 2002)

Selective Estrogen Receptor Modulators (SERMs)

Raloxifene

Estrogen agonist in bone preventing resorption

Post-menopausal women

Rapid bone loss after cessation UncommondHypocalcemia, cellulitis, skin rash RaredONJ, atypical femoral fracture Increased risk of myocardial infarction, breast cancer, pulmonary emboli, deep vein thrombosis No increase in cardiovascular disease if starting within 10 years of menopause UncommondLeg cramps, deep vein thrombosis

Bazedoxifene

Reduced risk vertebral fractures by approx. 30% in patients with prior vertebral fracture, and by 55% in those without a prior vertebral fracture over 3 years (Ettinger et al., 1999) Reduced incidence of vertebral fracture by approx. 30% at 3 years (Peng et al., 2017)

eGFR, Estimated glomerular filtration rate, ONJ, osteonecrosis of the jaw; WHI, Women’s Health Initiative. Adapted from Zanker, J. and Duque, G. (2019), Osteoporosis in older persons: Old and new players. Journal of the American Geriatrics Society 67: 831–840. https://doi.org/10.1111/jgs.15716.

Uncommondmuscle spasms, gastrointestinal complaints, dizziness, neck pain Uncommonddeep vein thrombosis

Aging Bone, Osteoporosis and Fragility Fracture

Table 5

Aging Bone, Osteoporosis and Fragility Fracture -

57

Associated with minimal trauma at most; That starts at lateral cortex and is mostly transverse, although it may become oblique; No or minimal comminution; Complete AFF produce a medial spike, incomplete affect lateral cortex only; Lateral cortex has localized reaction result in “beaking” or “flaring.”

In the mid-2000s, the advent of the association of bisphosphates with AFFs and subsequent media-reporting saw a 50% decline in bisphosphonate prescribing in the United states between 2008 and 2012 (Wysowski and Greene, 2013). Despite this, the risk of AFFs remains very low and the number needed to treat to prevent a hip fracture is much less than the number needed to harm to cause at AFF. The risk of AFFs is greatest after 5 years of treatment, with symptoms of pain in the thigh or groin an indication that an individual may be at risk of an AFF. Bilateral femoral X-rays should be performed if the individual is deemed at risk. Treatment includes surgical fixation with an intramedullary nail or comparable surgical technique, which can be applied to the affected or at-risk femur. Ongoing medical management of osteoporosis is still required which, in addition to calcium and vitamin D, may include the commencement of anabolic agents following the cessation of the anti-resorptive (Zanker and Duque, 2019). The prevalence of ONJ is very low, estimated to occur in up to 0.04% of patients who have used anti-resorptive therapies. ONJ is defined as: 1. Current or past use of anti-resorptive agents; 2. Exposure of the jaw bone or intraoral fistula persisting for more than 8 weeks; and 3. No history of head and neck radiotherapy. The incidence of ONJ increases with duration of treatment beyond 4 years (Patel et al., 2012). The risk is 50–100 times higher among persons with cancer, and key precipitating factors involve invasive dental work (i.e., tooth extractions) while undergoing anti-resorptive therapies or concomitant oral disease (Patel et al., 2012). Other systematic risk factors include the use of corticosteroids, advanced age, diabetes and suppressed immune system. Only in patients at high risk of this complication is it advised that an oral examination be undertaken, and any dental work required be undertaken before anti-resorptive therapy initiation.

Therapy Duration and Sequence The effect of bisphosphonates on osteoclast inhibition may persist for years after treatment cessation. In those treated for 5 years with bisphosphonate, the antifracture efficacy may persist for up to 10 years (Boskey et al., 2018). The antifracture efficacy and effect on BMD of denosumab may rapidly diminish after cessation. Therefore, comprehensive assessment should be undertaken periodically, but particularly after initial treatment of 3–5 years. The comprehensive assessment includes a thorough history including falls, medication adherence and side-effect history, physical examination and BMD assessment using DXA. Vertebral X-rays should also be performed if there has been loss of height of  2 cm between interval assessment or  4 cm since peak height, or ongoing glucocorticoid therapy. The comprehensive assessment should also include assessment of fracture risk using the FRAXÒ or another validated calculator. It may be reasonable to discontinue bisphosphonate therapy after 5 years of treatment in those who are at moderate risk of fracture. For non-bisphosphonate therapies such as denosumab, treatment decisions may include consideration of bisphosphonate or anabolic therapies based on risk calculation and individual preferences.

Models of Care Despite advances in osteoporosis knowledge, screening, diagnosis and treatment, under-treatment is a significant problem globally. Fewer than 10% of women with an osteoporotic fracture receive the appropriate investigation, therapy and follow up (Harvey et al., 2017). In response to this so-called “osteoporosis treatment gap,” specific models of care have been developed to improve the diagnosis, treatment and monitoring in order to prevent initial and subsequent fractures (Ganda et al., 2013). One of these care models is the Fracture Liaison Service (FLS). FLSs are multidisciplinary teams which are led by the FLS coordinator. The purpose of the FLS is to address the osteoporosis treatment gap and serve as conduit of communication between clinicians involved in the care of the individual at risk of osteoporotic fractures. FLSs reduce fracture rate and increase secondary prevention measures (Akesson et al., 2013). The implementation of FLSs is recommended by the International Osteoporosis Federation (IOF) and NOF.

Future Directions A monoclonal antibody targeting sclerostin, Romosozumab, demonstrated significantly lower rate of fracture in osteoporosis women in Phase III trials (Liu et al., 2018). Clinical trials testing the effect of Cathepsin K inhibitors were ceased due to unexpected cardiovascular side effects (Khosla and Hofbauer, 2017). Furthermore, questions remain regarding the duration of anti-resorptive therapy and the sequence of therapy. In addition, the preferred duration and sequence of anabolic therapy remains uncertain. Further research is required to determine the most effective and cost-effective therapy, in addition to the most appropriate treatment for osteoporosis in special population groups.

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Conclusion Despite the high prevalence of osteoporosis and fragility fractures in older persons, only a significant minority of patients at high risk are being assessed or treated. Clinicians should be aware of the catastrophic consequences of neglecting fracture risk assessment and osteoporosis treatment in high-risk patients. Therefore a proactive approach is recommended, including the use of risk identification tools, the regular use of BMD testing, and the design of a comprehensive falls and fracture prevention plan in every patient identified as having a high risk of fractures.

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Oei, L., Koromani, F., Rivadeneira, F., Zillikens, M.C., Oei, E.H., 2016. Quantitative imaging methods in osteoporosis. Quantitative Imaging in Medicine and Surgery 6 (6), 680–698. Osteoporosis Australia. Diagnosing Osteoporosis 2013, Accessed: April 2019. Patel, S., Choyee, S., Uyanne, J., Nguyen, A.L., Lee, P., Sedghizadeh, P.P., Kumar, S.K., Lytle, J., Shi, S., Le, A.D., 2012. Non-exposed bisphosphonate-related osteonecrosis of the jaw: A critical assessment of current definition, staging, and treatment guidelines. Oral Diseases 18 (7), 625–632. Peacock, M., 2010. Calcium metabolism in health and disease. Clinical Journal of the American Society of Nephrology 5, S23–S30. Suppl. 1. Peng, L., Luo, Q., Lu, H., 2017. Efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis: A systematic review and meta-analysis. Medicine (Baltimore) 96 (49), e8659. Reginster, J., Minne, H.W., Sorensen, O.H., et al., 2000. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral efficacy with risedronate therapy (VERT) study group. Osteoporosis International 11 (1), 83–91. Rossouw, J.E., Anderson, G.L., Prentice, R.L., et al., 2002. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the women’s health initiative randomized controlled trial. JAMA 288 (3), 321–333. Roux, C., Briot, K., 2017. Current role for bone absorptiometry. Joint, Bone, Spine 84 (1), 35–37. Sanchez-Riera, L., Carnahan, E., Vos, T., et al., 2014. The global burden attributable to low bone mineral density. Annals of the Rheumatic Diseases 73 (9), 1635–1645. Shane, E., Burr, D., Abrahamsen, B., et al., 2014. Atypical subtrochanteric and diaphyseal femoral fractures: Second report of a task force of the American Society for Bone and Mineral Research. Journal of Bone and Mineral Research 29 (1), 1–23. Singh, L., Tyagi, S., Myers, D., Duque, G., 2018. Good, bad, or ugly: The biological roles of bone marrow fat. Current Osteoporosis Reports 16 (2), 130–137. Tang, B., Eslick, G., Nowson, C., Smith, C., Bensoussan, A., 2007. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: A meta-analysis. Lancet 370 (9588), 657–666. Tsai, J.N., Nishiyama, K.K., Lin, D., et al., 2017. Effects of denosumab and teriparatide transitions on bone microarchitecture and estimated strength: The data-switch hr-pqct study. Journal of Bone and Mineral Research 32 (10), 2001–2009. Vandenbroucke, A., Luyten, F.P., Flamaing, J., Gielen, E., 2017. Pharmacological treatment of osteoporosis in the oldest old. Clinical Interventions in Aging 12, 1065–1077. Watts, N.B., Bilezikian, J.P., Camacho, P.M., et al., 2010. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocrine Practice 16 (Suppl. 3), 1–37. Watts, J., Abimanyi-Ochom, J., Sanders, K.M., 2013. Osteoporosis costing all Australians: A new burden of disease analysisd2012 to 2022. Osteoporosis Australia, Glebe, NSW. World Health Organization, 1994. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organization, Geneva, Switzerland. Wysowski, D.K., Greene, P., 2013. Trends in osteoporosis treatment with oral and intravenous bisphosphonates in the United States, 2002–2012. Bone 57 (2), 423–428. Yoon, B.H., Yu, W., 2018. Clinical utility of biochemical marker of bone turnover: Fracture risk prediction and bone healing. Journal of Bone Metabolism 25 (2), 73–78. Zanker, J., Duque, G., 2019. Osteoporosis in older persons: Old and new players. Journal of the American Geriatrics Society 67 (4), 831–840. https://doi.org/10.1111/jgs.15716. Zhang, J., Fu, Q., Ren, Z., Wang, Y., Wang, C., Shen, T., Wang, G., Wu, L., 2015. Changes of serum cytokines-related Th1/Th2/Th17 concentration in patients with postmenopausal osteoporosis. Gynecological Endocrinology 31 (3), 183–190.

Further Reading Black, D.M., Rosen, C.J., 2016. Clinical practice. Postmenopausal osteoporosis. The New England Journal of Medicine 374 (3), 254–262. Cosman, F., de Beur, S.J., LeBoff, M.S., Lewiecki, E.M., Tanner, B., Randall, S., et al., 2014. Clinician’s guide to prevention and treatment of Osteoporosis. Osteoporosis International 25 (10), 2359–2381. Khosla, S., Hofbauer, L.C., 2017. Osteoporosis treatment: Recent developments and ongoing challenges. The Lancet Diabetes and Endocrinology 5 (11), 898–907. Moncada, L.V.V., Mire, L.G., 2017. Preventing falls in older persons. American Family Physician 96 (4), 240–247. Zanker, J., andDuque, G., 2017. Rapid geriatric assessment of hip fracture. Clinics in Geriatric Medicine 33 (3), 369–382. Zanker, J., Duque, G., 2019. Osteoporosis in older persons: Old and new players. Journal of the American Geriatrics Society 67, 831–840. https://doi.org/10.1111/jgs.15716.

Relevant Websites www.iofbonehealth.orgdInternational Osteoporosis foundation. https://www.sheffield.ac.uk/FRAX/dFRAX®. https://www.garvan.org.au/promotions/bone-fracture-risk/calculator/dGarvan Institute Fracture Risk Calculator. https://qfracture.org/dQFracture®.

Aging in Drosophila melanogaster Sentiljana Gumeni and Ioannis P Trougakos, National and Kapodistrian University of Athens, Athens, Greece © 2020 Elsevier Inc. All rights reserved.

Introduction Drosophila melanogaster The Nutrients Sensing Signaling Pathway Insulin/IGF-1 Like Signaling Target of Rapamycin (mTOR) Signaling Diet and Nutrition Proteostasis The Ubiquitin–Proteasome Pathway Autophagy Mitostasis Concluding Remarks Acknowledgments References

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Introduction The average life expectancy is increasing, with the number of older people (> 60 aged) being estimated to reach
22% of the entire population by 2050; this number will be higher than adolescents and youth at ages of 10–24 years old. Globally, the number of persons aged 80 years old or over is projected to increase more than threefold between 2017 and 2050 (United Nations, 2017). However, healthy life (healthspan; the disease-free period of life) expectancy has not increased as much as lifespan (the length of time for which a person or an animal lives), since aging is associated with several diseases, including cancer, cardiovascular disease, metabolic disorders and dementia (López-Otín et al., 2013; Crimmins, 2015). Scientists have struggled for long to understand the biological causes of aging and there is a greater focus on healthspan and in particular on treating or preventing ageassociated diseases. It is so far understood that aging is a complex process of accumulation of stochastic molecular damage over time that varies between individuals due to the interplay of genetic and environmental factors (Weinert and Timiras, 1985; Flatt and Partridge, 2018). Studies have shown that there are several hallmarks that characterize aging and correlate with progressive functional decline of organisms; these relate to genomic instability, loss of proteostasis, telomere shortening, mitochondrial dysfunction, epigenetic alterations, cellular senescence, altered nutrient sensing, accumulation of senescent cells and altered intercellular communication (López-Otín et al., 2013). In biogerontological research the understanding of the genetic and environmental mechanisms that impact on healthspan and/or lifespan, along with their downstream effects to common aging phenotypes is fundamental. To this end, research on model organisms have significantly contributed to our current knowledge of the age-related molecular processes and have also allowed the identification of potential targets that could increase healthspan and/or longevity (Tatar et al., 2001; Edrey et al., 2011; Longo et al., 2012; Piper and Partridge, 2018). Among these model organisms, the fruit fly Drosophila melanogaster has, after its enormous contribution in understanding developmental processes, “reappear” in the scene as a key research tool in gerontology. Herein, we give a brief summary of the mechanisms and pathways that relate to aging in Drosophila and of the use of this model organism as a key in vivo experimental platform in our effort to understand complex multifactorial biological process such as aging.

Drosophila melanogaster The fruit fly was proposed as a model for genetic studies by the American entomologist Charles W. Woodworth in 1900 (Sturtevant, 1959). In more than 100 years of fly research, Drosophila continues to be the vanguard model of biology for the analysis of molecular mechanisms underlying development, behavior and diseases. Fruit fly was among the first complex organisms whose genome was sequenced (Adams et al., 2000). Its genetic information (
180 Mb) is organized in four chromosomes, of which three carry almost the majority of the
13,600 genes (Adams et al., 2000; Hales et al., 2015). Notably, approximately 75% of disease-related genes in humans have a functional homolog in fly (Lloyd and Taylor, 2010). There are several salient features that make Drosophila an effective experimental model for aging research. The fly has a very rapid life cycle and an ease of generating large populations as a single fertile mating pair can produce hundreds of offspring within 10–12 days; flies have also a relatively short lifespan (
3 months). Rearing and housing have a relatively low cost, as compared to other model organisms. Drosophila has four different developmental stages, namely embryo, larva, pupa and adult.

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Fig. 1 Drosophila melanogaster as a model organism. The use of the fruit fly as a model organism in aging research is advantageous as, apart from a rapid life cycle, the Drosophila genome is completely sequenced and annotated with most genes being significantly conserved with mammals; also,
75% of disease-related genes in humans have functional orthologs in the fly model. The adult fly has tissues/organs that perform the equivalent functions of most mammalian tissues/organs including a well-developed neuron system and a pumping heart that through hemolymph circulates regulatory molecules (e.g. insulin-like peptides) in the tissues. Consequently, flies display complex physiological processes and behavior patterns. Given the advanced “high-tech” forward and reverse genetics/molecular “tools” and despite the many obvious differences between flies and mammals, the degree of conserved physiology and biology indicate that research in flies can be an extremely valuable tool in understanding the cellmolecular mechanisms that drive aging and age-related diseases.

Since each stage shows its own specific experimental advantages, the fly may be considered as a model of multiple organisms. The adult fly consist mainly of post-mitotic cells, making Drosophila an excellent model for the study of aging and the changes that take place in cells over time. Flies have tissues which are equivalent to the mammalian nervous system, heart, liver, kidney, adipose tissue and reproductive tract (Pandey and Nichols, 2011). Also, Drosophila has conserved some basic physiological processes including glucose utilization or receptor signaling pathways (Fig. 1). In addition, given the genetic tractability and the many tools available for fly forward and reverse genetics, studies can be performed more rapidly (as compared to mammalian animal models) including those that refer to the development of human diseases models (Ashburner et al., 2011). These tools include RNAi, CRISPR/Cas9, transposon-mediated mutagenesis or excision of open reading frames (ORF), as well as chemically induced mutations e.g. via ethyl methanesulfonate (Chow and Reiter, 2017; Bellen and Yamamoto, 2015; Venken and Bellen, 2014). Another key tool provided by the fly is the sophisticated yeast GAL4 DNA-binding protein and Upstream Activator Sequence (UAS), or GAL4/UAS, which allows temporal, tissue-specific and even dose-dependent manipulation of gene expression (Brand and Perrimon, 1993). Development of new and more precise GAL4 lines make suppressor/enhancer screening and investigation of disease models in flies more accurate than ever before. All these techniques have made Drosophila a model system to address questions about tissue-specific age-related functional decline and the systemic impact that this processes can have during aging. Drosophila longevity can be affected by a number of interventions (i.e. ambient temperature, stress, physical activity, dietary interventions and reproductive status) and aging processes in flies lead to changes and deteriorations in tissue structure and function. As in all other metazoans, aging in Drosophila correlates with increased mortality rates and it is also marked by decreased spontaneous movement and climbing speed, impaired memory, heart function and reproductive capacity (Piper and Partridge, 2018; Pearl and Parker, 1921). The work of Pearl and colleges defined the basic dietary requirements, as well as other conditions of Drosophila culture and survival that we continue to employ today (Pearl and Parker, 1921); also, their pioneering studies were among the first

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on Drosophila aging. Further studies revealed the many advantages of the Drosophila model for aging research experimentation and how precise intervention (nutritional or genetic) could extend longevity. Moreover, research on the insulin signaling effects in longevity in the fly model provided the initial evidence for the evolutionary conservation of aging processes (Tatar et al., 2001; Piper and Partridge, 2018; Clancy et al., 2001; Ziehm et al., 2017). In the following sections we will describe the main pathways that affect the rate in aging appearance in Drosophila.

The Nutrients Sensing Signaling Pathway Organisms have developed numerous sensors and signaling pathways to monitor nutrients availability and their “real-time” nutritional status. Among these, the Insulin/Insulin-like growth factor signaling (IIS) and the target of rapamycin (TOR) regulatory pathways have a key role in metabolic stability and aging processes.

Insulin/IGF-1 Like Signaling IIS is evolutionary highly conserved among species and regulates several physiological functions, including development and growth, metabolic homeostasis and aging (Taguchi and White, 2008). Insulin levels have been generally associated with glucose homeostasis, a function which is partially conserved in the fly. Drosophila genome encodes eight insulin-like peptide (dIlps 1–8) and a single insulin/IGF-like tyrosine kinase receptor (InR) (Slack et al., 2011). The different dIlps are produced in distinct cell types and tissues at different developmental stages, and display pleiotropic functions (Nässel and Vanden Broeck, 2016). The fly insulinproducing cells (IPCs) are functional homologs of the human b pancreatic cells and are located in the median neurosecretory cluster of the brain; these cells produce and secrete the three (dIlp2, dIlp3, and dIlp5) of the eight dIlps (Nässel and Vanden Broeck, 2016). As in mammals, once secreted into the circulatory system dIlps activate the InR which interacts with the insulin receptor substratelike homolog, encoded by chico, to activate the serine/threonine-specific protein kinase Akt. Activation of Akt suppresses the forkhead box, subgroup O (foxo) transcription factor following phosphorylation (Kannan and Fridell, 2013). During reduced insulin signaling conditions, unphosphorylated foxo translocate to the nucleus where it enables the transcription of genes involved (among others) in organism longevity (e.g. stress-response genes, chaperones and lipases) (Kannan and Fridell, 2013). This pathway reassembles the functions of mammalian insulin and insulin like growth factor 1 (IGF-1). Notably, the IIS-Akt axis by suppressing shaggy (the fly ortholog of mammalian glycogen synthase kinase-3; Gsk-3) activates cap‘-n’-collar isoform-C [cncC; the nuclear factor erythroid 2-related factor (Nrf2) ortholog in Drosophila] (Tsakiri et al., 2017a, 2019a), which then triggers the induction of antioxidant, proteostatic and mitostatic genes (Sykiotis and Bohmann, 2010; Tsakiri et al., 2013a, 2019a) (see also below). The coordinated action of the foxo and cncC/Nrf2 regulatory pathways ensure metabolic and proteostatic stability under conditions of starvation or normal feeding (Fig. 2). The first observation of IIS pathway functional implication on longevity was made after the generation of Drosophila chico mutants, which showed an extension of adult lifespan and revealed that the role of IIS in aging is an evolutionary conserved process (Clancy et al., 2001). Additionally, increasing the activity of foxo in the fat body (the fly equivalent of mammalian white adipose tissue and liver) and in the gut increases lifespan (Giannakou et al., 2004; Hwangbo et al., 2004). Interestingly, a recent study suggests that foxo activates also other transcription factors that may extend lifespan (Alic et al., 2014). Although foxo beneficial effects depend on the cell type, quality and strength of the stress, its activity can also shift the cellular response from survival toward apoptosis (van Heemst, 2010). Nonetheless, the exact mechanistic details by which the increased foxo activity leads to increased longevity remain to be elucidated. Several other studies report the role of the neurosecretory cells and of dIlps in flies’ longevity. The removal of neurosecretory cells from Drosophila brain increases lifespan and resistance to oxidative stress and starvation (Broughton et al., 2005). Among all the dIlPs, dIlp2, which is the most abundantly expressed dIlp and possesses the highest homology to mammalian insulin (
35% identity in protein sequence), has triggered significant interest on the field (Brogiolo et al., 2001). Reduced expression of dIlp2, but not of other dIlps, was shown to increase flies’ longevity in several cases (Grönke et al., 2010). The expressions levels of dIlp2, but not of dIlp3 or dIlp5, in the brain has been reported to decrease upon over-expression of foxo in pericerebral fat body and to be associated with a decrease in insulin signaling in the fat body and lifespan extension (Hwangbo et al., 2004). dIlp6, which is mainly produced in the fat body and whose expression is regulated by foxo (Okamoto et al., 2012), modulates the expression of dIlp2. Overexpression of dIlp6 in the fat body represses dIlp2 in the brain, extends lifespan and increases longevity-associated metabolic phenotypes; these findings indicate that dIlp2 and dIlp6 have antagonist effects on longevity (Bai et al., 2012). Moreover, downregulation of Tequila (a multiple-domain serine protease; also recognized as a neurotrypsin ortholog) in fly neurons, drastically increases longevity through reduced circulation of dIlp2 (Huang et al., 2015). Although these studies underlie a close association between decreased dIlp2 expression and longevity, targeted knock down (KD) of dIlp2 in IPCs did not result in life span extension, indicating a more complex role of dIlp2 in longevity regulation (Broughton et al., 2008). More specifically the authors’ claimed a compensatory mechanism, since it was found that dIlp3 and dIlp5 expression was increased after targeted KD of dIlp2 in IPCs (Broughton et al., 2008). On the other hand, dIlp2 null mutants were found to be long-lived confirming a major role of dIlp2 in longevity control. Overall, mutants that reduce IIS show elevated total body triglycerides and carbohydrates, reduced growth, limited reproduction and extended lifespan (Clancy et al., 2001; Brogiolo et al., 2001). The main tissue involved in lifespan extension due to reduced insulin signaling is

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Fig. 2 The role of the conserved Insulin signaling pathway on longevity. The insulin receptor mediates its effects via the PI3K-AKT signaling which (among others) culminates in the negative regulation of Foxo. Reduced insulin signaling results in Foxo activation which then triggers the expression of several target genes that contribute to longevity including mitostatic genes and the autophagy-lysosome pathway. On the other hand, increased IIS activates Nrf2 which apart from antioxidant responses, it also modulates mitochondrial genes and the ubiquitin-proteasome pathway. The cycling of these responses ensures metabolic and proteostatic stability.

the fat body (Giannakou et al., 2004; Hwangbo et al., 2004), which senses the availability of nutrients and remotely regulates the secretion of dIlps (Rajan and Perrimon, 2012).

Target of Rapamycin (mTOR) Signaling mTOR signaling pathway is involved in the regulation of cell growth, ribosome biogenesis and metabolism that in turn impact on longevity. mTOR is generally considered as a cellular amino acid sensing molecule and a controller of the balance between anabolism and catabolism (Saxton and Sabatini, 2017). The first evidence that mTOR pathway affects longevity was obtained in C. elegans (Vellai et al., 2003) and it was then found that the effects of this pathway are evolutionary conserved. Specifically, genetic studies have revealed that reduced mTOR signaling also promotes longevity in Drosophila (Kapahi et al., 2004). It was shown that activation of the TSC2 (an mTOR suppressor) or administration of the mTOR inhibitor rapamycin could extend flies’ longevity (Kapahi et al., 2004; Bjedov et al., 2010). While there are now clear evidence that mTOR pathway is linked to aging, the mechanism through which this occurs is still unclear. Several lines of evidence also suggest that a reduction in mRNA translation rates and/or increased autophagic rates after mTOR inhibition ensure proteostasis and reduce stress accumulation (Taylor and Dillin, 2011). The cap-dependent translational inhibitor 4E-BP, which is phosphorylated by mTOR, regulates mRNA translation and growth in both flies and mammals (Harris and Lawrence, 2003; Shamji et al., 2003). 4E-BP once hypophosphorylated after mTOR inhibition, binds to the protein synthesis initiation factor eIF4E and blocks the activity of the eIF4F complex. Overexpression of activated 4E-BP in flies is sufficient to extend lifespan on a high nutrition diet, thus, verifying the importance of posttranslational regulation of 4E-BP by the mTOR pathway (Zid et al., 2009). On the other hand it was shown that the activity of 4E-BP in Drosophila becomes critical for survival under dietary restrictions (Tettweiler et al., 2005). In support, the down regulation of the translational activator S6 kinase, another mTOR target, extends flies’ lifespan (Kapahi et al., 2004). Considering the hurdle of mTOR signaling, its impact on aging is likely due to several mTORregulated processes and it remains challenging to understand the temporal- and tissue-specific effects of this pathway. These findings have been successfully translated in humans, as rapamycin is currently used in several therapeutic interventions (Faivre et al., 2006; Bové et al., 2011). Notably, it has been found that mTOR inhibitors can also impact on cognitive components, at least in animal models (Xu et al., 2017; Halloran et al., 2012); these findings have thus revealed another potential use of mTOR inhibitors.

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Diet and Nutrition It is a common notion that a healthy diet along with moderate exercise is beneficial for increasing healthspan. Restricting food intake without malnutrition is reported to exert an antiaging effect in several animal models, including primates (Mattison et al., 2016). A special role in applying dietary restriction (DR) as the most successful strategy to extend lifespan had the discovery of the IIS pathway (Klass, 1977; Kenyon et al., 1993). Likewise, almost 50 years ago it was reported for the first time in Drosophila that diluted food medium extends flies longevity (David et al., 1971). Further research unveiled that by reducing all the dietary components or by reducing the amount of yeast (the only protein source in fly culture medium) longevity could be extended by almost 50% (Tatar, 2007; Mair et al., 2004). However, diluted growth medium did not provide lower uptake in calories, since, as shown by ingestion techniques, the adult flies consumed more food (Carvalho et al., 2005). Moreover, Drosophila fed with low casein or low intermediate level of methionine are long lived (Min and Tatar, 2006; Troen et al., 2007). It was also found that feeding female adults with increased essential amino acids, but not carbohydrates, lipids or vitamins, decreases Drosophila longevity (Grandison et al., 2009). Dietary protein intake is an important regulator of the IGF-1 mTOR network (Efeyan et al., 2012). In humans the serum IGF-1 levels cannot be reduced even by severe calorie restriction, unless this is associated with a reduced protein uptake (Fontana and Partridge, 2015), suggesting that dietary protein or specific amino acid intake may be as or even more important than calorie intake. In addition, essential and nonessential amino acids seem to have different roles on longevity, with the former having a negative impact on lifespan extension (Grandison et al., 2009). Moreover, in response to DR Drosophila is also able to rapidly adjust the patterns of gene expression (Whitaker et al., 2014). It is now clear that diets rich in calories shorten lifespan not because of the caloric excess but rather due to dietary imbalance. In flies, the olfactory and gustatory systems can also influence lifespan. Flies carrying mutations in the olfactory system have alter metabolism, increased resistance to stress and extended lifespan (Libert et al., 2007). It was also shown that Drosophila lifespan is affected by its ability to taste, since some taste inputs reduce longevity whereas others increase it (Ostojic et al., 2014). In addition, it was suggested that different gustatory cues can modulate the activities of various signaling pathways (including dIlps production and secretion) to promote physiological changes affecting lifespan (Ostojic et al., 2014). Overall, Drosophila longevity is affected by a reduced, in relation to carbohydrates, proportion of nutrient amino acids but not from the absolute quantity of either nutrient or total calories. While the exact molecular mechanisms behind the DR effect on longevity remain to be clarified the effects appear to be exerted via both IIS-dependent and -independent mechanisms. The long lived chico mutants did not respond to optimal DR suggesting that life extension is mediated by the IIS pathway (Clancy et al., 2002), while foxo mutant flies are still sensitive to DR indicating an IIS-independent mechanism (Min et al., 2008). Supporting evidences come from dIlp2, 3, 5 deletion mutant flies (Grönke et al., 2010) or following IPCs ablation studies (Broughton et al., 2010), which highlight the role of dIlps and of the fat body, as sensors of DR. It should be mentioned however, that as the standard (control) diet conditions used for Drosophila culturing in the aforementioned studies are variable, future studies should aim to standardize the culture (control or DR) conditions in order to avoid discrepant findings.

Proteostasis Proteins are the most versatile macromolecules in living systems (Hartl et al., 2011). Consequently, proteostasis is defined as the maintenance of cellular proteome stability (i.e. polypeptide structure and function) and involves a number of processes [also referred to as the proteostasis network (PN)] that encompass: protein synthesis, folding, transport and secretion, and their final degradation. Among others, the PN includes the translational machinery, the numerous molecular chaperones, as well as the ubiquitin–proteasome (UPP) and the autophagy–lysosome (ALP) pathways (Gumeni and Trougakos, 2016). One of the hallmarks of aging is the decline of the proteostatic mechanisms functionality (López-Otín et al., 2013). Loss of proteostasis eventually results in increased protein oxidation, protein misfolding and/or protein aggregation that can lead to age-related diseases (Taylor and Dillin, 2011). PN is highly dynamic and the levels of chaperones and proteasomal subunits can be increased globally or in a compartmentspecific way to provide proteostasis (Powers et al., 2009). The PN modules are functionally coordinated by different signaling cascades, which sense and respond to imbalances in proteome stability and increased amounts of proteotoxic stress (Labbadia and Morimoto, 2015). The activation of these sensors triggers the activation of UPP, of ALP or of the unfolded protein response (UPR); UPR is triggered following accumulation of unfolded/misfolded proteins within the endoplasmic reticulum (ER) (UPRER), due to nuclear proteome imbalance or following accumulation of unfolded/misfolded proteins in mitochondria (UPRmt) (Labbadia and Morimoto, 2015). Almost 60 years ago in the fruit fly Drosophila busckii it was observed that upon heat treatment massive regions in polytene chromosomes appeared to expand relative to others (Ritossa, 1962). These expanded regions were found to encode for proteins, known as heat shock proteins (Hsp), that mediate the so-called heat shock response being required for protection against heat stress (Velazquez and Lindquist, 1984). The heat-shock transcription factors (Hsf), and specifically Hsf1, are the master transcriptional regulators of heat stress-response genes, including chaperones, ubiquitin and translational regulators (Li et al., 2017). During conditions of proteome instability (e.g. heat stress), Hsf1 is released from its repressive complex with Hsp70 and Hsp90, homotrimerizes and translocates to the nucleus to induce expression of the genes encoding molecular chaperones (Akerfelt et al., 2010; Baler et al., 1993). In particular, Hsf1 ensures general proteome quality control and proteostasis by acting against protein damage, misfolding, unfolding and/or protein aggregation (Higuchi-Sanabria et al., 2018). In addition, Hsf1 has been shown to be important for

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Drosophila oogenesis and larval development, and this function is executed through target genes that are unrelated to Hsps (Akerfelt et al., 2010; Fujimoto et al., 2004; Jedlicka et al., 1997); also, Hsf1 has been associated to aging and longevity (Hercus et al., 2003). Hsps expression is found to be up regulated in aged flies, even during unstressed conditions. In addition, Hsps expression during acute stress is higher in aged flies, as compared to young flies, suggesting that aged individuals have a greater content in misfolded or abnormal proteins (Fleming et al., 1988). Notably, work in mice indicates an age-related decline in responsiveness of Hsf1 during stress conditions (Frenkel-Denkberg et al., 1999), suggesting that the activity of this transcription factor declines during aging. Mutation of Hsp70 or Hsp22, reduce fly longevity (Kang et al., 2002; Zhao, 2005), while overexpression of Hsp68 increases lifespan (Morrow et al., 2004). However, Hsps expression in Drosophila was not always associated to lifespan extension (Minois et al., 2001; Bhole et al., 2004), suggesting that Hsps may be acting through more than one pathway. Interestingly, additional studies indicate that Hsps have an important role on the aging processes of the Drosophila nervous system (Morrow et al., 2004). Upon proteotoxic stress in the ER cells initiate an elaborated stress response, namely the UPRER, that includes actions at three different levels: (a) translational repression and general reduction of protein synthesis; (b) increased expression of chaperones and foldases to promote protein folding; and (c) activation of the ER-associated degradation (ERAD) of aberrant proteins by the proteasome (Walter and Ron, 2011). UPRER is induced by the sensor inositol requiring element-1 (IRE1), the PKR-like ER kinase (PERK) and the activating transcription factor 6 (ATF6). Upon ER stress, BiP/GRP78, a Hsp70 family member, disassociates from these three sensors, triggering the UPR and enabling BiP/GRP78 to undertake chaperone activities in response to the accumulation of misfolded and/or unfolded polypeptides (Labbadia and Morimoto, 2015). Several elements of the UPR response decline in activity during aging (Naidoo, 2009). In support, another study showed that the IRE1/XBP1 is essential for lifespan extension under dietary restriction in Drosophila, since it mediates the metabolic adaption of flies’ midgut (Luis et al., 2016).

The Ubiquitin–Proteasome Pathway Supervised protein degradation allows rapid and irreversible turn-off of protein function. This is a critical process since there is a plethora of proteins (e.g., transcription factors and protein machines of replication complexes or of the cell division cycle) that need to be eliminated by the cell at the right moment in order to ensure cellular homeodynamics and survival. These polypeptides are degraded by the 26S proteasome, through ubiquitin-dependent signaling (Gumeni et al., 2017). The UPP provides protein synthesis quality control in both the ER (via the ERAD) and in the cytosol, and it also degrades normal short-lived ubiquitinated proteins and nonrepairable misfolded or unfolded proteins (Tsakiri and Trougakos, 2015). The 26S eukaryotic proteasome is a highly conserved complex of
2.5 MDa that comprises a 20S core particle (CP) bound to 19S regulatory particles (RP). The 20S CP consists of four stacked heptameric rings (two a type surrounding two of b type) that form a barrel-like structure; the caspase-, trypsin- and chymotrypsin-like peptidase activities are located at the b1, b2, and b5 proteasomal subunits, respectively (Jung and Grune, 2012). The 19S RP is involved in substrate recognition, deubiquitination, unfolding and translocation into the 20S CP. Ubiquitinated polypeptides are degraded by the 26S proteasome, while nonnative (e.g. oxidized) polypeptides are likely degraded by the 20S proteasome via chaperone-mediated targeting (Tsakiri and Trougakos, 2015). Cells contains high numbers (
1 million/ cell) of proteasomes that respond to degradation demands, and despite the high rates of protein destruction, it is estimated that the proteasomes are underloaded during normal conditions and that proteins accumulate in the cells only after more than half (
60%) of total cellular proteasomal activity is shut down (Gumeni et al., 2017). The multiple components of the UPP are known to be negatively affected by aging (Tsakiri et al., 2013b). Aged flies have increased levels of ubiquitinated and carbonylated proteins and reduced proteasome activity (Tsakiri et al., 2013b; Vilchez et al., 2014), suggesting that aging is associated with proteome instability and insufficient activity of the PN network. In addition, we have found that proteasome functionality in D. melanogaster is sex-, tissue- and age-dependent (Tsakiri et al., 2013b). Furthermore, by developing a model of pharmacological proteasome inhibition in adult flies, we reported that prolonged impairment of proteasome function promotes several “old-age” phenotypes and markedly reduces flies’ lifespan (Tsakiri et al., 2013b). Likewise, genetic impairing of UPP shortens lifespan and increases age-associated pathology in flies (Liu and Pfleger, 2013; Tsakiri et al., 2019b). A similar age-related decline in the activity of both the 20S and 26S proteasome has been also described in other model organisms, tissues and cells (Tsakiri and Trougakos, 2015; Vilchez et al., 2014; Raynes et al., 2017). Analyses in the fly model have revealed that proteasome dysfunction causes activation of proteostatic modules, promotes mitochondria damage and enhances genomic instability (Tsakiri et al., 2019b). All these findings support a crosstalk between protein homeostasis and genomic stability; also they indicate that deregulation of these pathways contributes to age-related pathophysiological states (Gorgoulis et al., 2018). The UPP functionality is under tight control by the numerous cellular stress sensors and especially by the Nrf2 transcription factor. Nrf2 plays a central role in cell responses against oxidative and xenobiotic damage (Sykiotis and Bohmann, 2010). Normally, Nrf2 is a short-lived protein that is stabilized upon redox or proteostatic stress to increase proteasome gene expression (Tsakiri et al., 2013a; Kwak et al., 2003). Specifically, oxidative stress abrogates the Keap1-mediated proteasomal degradation of Nrf2, which in turn accumulates in the nucleus and heterodimerizes with a small musculoaponeurotic fibrosarcoma (Maf) protein on antioxidant response elements (AREs) to upregulate the expression of antioxidant genes (Sykiotis and Bohmann, 2010; Ziros et al., 2018). We recently reported that increased Nrf2 activity in flies activates not only antioxidant or proteostatic genes but also other proteostatic and mitostatic modules in a dose-dependent manner (Tsakiri et al., 2019a) in order to enhance stress tolerance. Proteasome homeostasis seems also to be regulated by the mTOR pathway signaling as it has been found that TORC1 coordinates proteasome assembly and abundance in relation to growth and cellular metabolism (Rousseau and Bertolotti, 2016).

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Elevated proteasome activity has been correlated with longevity in several model organisms and long-lived animals (Tonoki et al., 2009; Perez et al., 2009; Kruegel et al., 2011; Baraibar and Friguet, 2012; Rana et al., 2013). The role of UPP in longevity is also reinforced in IIS mutants, where UPP plays an important role in the genetic determination of mutants’ lifespan (Ghazi et al., 2007; Matilainen et al., 2013). A novel insight of this relationship was recently provided in worms and flies by the E3 ubiquitin ligase CHIP, a critical regulator of proteostasis involved in proteolysis of the insulin receptor (Tawo et al., 2017). Moreover, the expression of proteasomal subunits seems to be altered in Drosophila IIS mutant gut, while inhibition of proteasome activity abolished the IIS-mediated longevity (Tain et al., 2017). Additionally, overexpression of Rpn11 and Rpn6 proteasome subunits in D. melanogaster suppresses the age-dependent reduction of proteasome activity and extends lifespan (Tonoki et al., 2009; Tain et al., 2017). Interestingly, upregulation of the UPP modulator cncC/Nrf2 has contrary effects on Drosophila longevity based on its expression levels. We have found that sustained mild cncC/Nrf2 upregulation extends lifespan, while high cncC/Nrf2 expression levels reduce longevity and result in Diabetes Type 1-like phenotypes (DT1) (Tsakiri et al., 2019a). Mechanistically, sustained Nrf2 activation in flies, apart from activating proteostatic modules suppressed the IIS pathway, leading to metabolic stress, increased levels of circulating sugars, extensive lipolysis and phenotypes reminiscent of DT1.

Autophagy Autophagy is an evolutionary conserved lysosomal degradation pathway of intracellular macromolecules and organelles, known as autophagic cargo, where the cell mediates a catabolic self-digestion of its components. The first evidence of autophagy was obtained in yeast after nutrient deprivation (He and Klionsky, 2009). Autophagy is active at basal levels to maintain cellular homeodynamics and can be further activated by cellular stresses factors like starvation, hypoxia or drug treatments to generate amino acids and metabolic intermediates and sustain ATP production and cell survival (Anding and Baehrecke, 2015). Three main types of autophagy have been described, namely (a) microautophagy that involves the sequestration of the cargo directly through invagination of lysosomal membranes; (b) chaperone-mediated autophagy (CMA) where the delivery of the cargo is mediated by chaperones and receptors on the lysosomal membrane; and (c) macroautophagy (autophagy), where the cargo is engulfed by double membrane vesicles, named autophagosomes, prior to their fusion with lysosomes to form autophagolysosomes (Kroemer, 2015). Although autophagy degradation was initially considered as a nonspecific process now it is clear that the degradation is selective and specific for organelles and proteins. Autophagosome formation is mediated by the class III phosphatidylinositol-3 kinase (PI-3 K) and Beclin-1, which is then elongated by autophagy-related genes (Atgs). Atgs recruit microtubule light chain-3 (LC3) and conjugate phosphatidylethanolamine followed by a proteolytic cleavage of LC3 to form LC3-II. Finally, the autophagosome fuses with lysosomes to form autophagolysosome and its content is being degraded (Anding and Baehrecke, 2015). The clearance of organelles may differ among tissues but they all involve an initiation signal and the inducement of downstream events that will trigger the autophagy-related components to sequester and degrade the cargo. Autophagy is perturbed in several age-related disorders (e.g., neurodegenerative diseases, cancer and diabetes) suggesting that its activity declines with aging and that its role is important in preserving cellular and organismal health (Nixon, 2013; Huang and Klionsky, 2007; Dikic and Elazar, 2018). Accordingly, in Drosophila the expression of several autophagic genes, e.g. Atg2, Atg8a (the homolog of LC3 receptor), Atg1 (ULK1 in mammals), Atg5, and Atg6 (BECN1 in mammals) is reduced with aging in different fly tissues (Demontis and Perrimon, 2010; Bai et al., 2013). Analysis of the first autophagy null mutant (Atg7) showed that Drosophila flies have a decreased lifespan, developmental delay and are very sensitive to starvation and oxidative stress (Juhász et al., 2007). Similar phenotypes were also observed in other autophagy mutants (Kim et al., 2016; Varga et al., 2016). However, in all these mutants, flies are viable probably suggesting that in spite of the deletion of some autophagy related genes, remaining residual levels of autophagy are still operating. On the other hand, overexpressing Atg8a or Atg1 in Drosophila extends flies lifespan (Bai et al., 2013; Simonsen et al., 2008; Ulgherait et al., 2014). Yet, it is still unclear whether the mechanism that leads to lifespan extension is due to the single gene or to a total increase of the autophagy process. Several lines of evidences associate the selective autophagy and the tissue specificity of the process with age relative diseases. One of the most described types of selective autophagy is the mitophagy (Lemasters, 2005), which is activated when an unrepairable organelle damage occurs. Disruption of mitophagy has been found to correlate with neurodegenerative diseases (Parkinson’s disease, amyotrophic lateral sclerosis and Alzheimer’s disease), heart disease, retinopathy, fatty liver disease and pulmonary hypertension (Hansen et al., 2018). In this pathway, the Pink1/Parkin-mediated removal, is one the most studied pathways of mitophagy (Gumeni and Trougakos, 2016). Accordingly, studies in Drosophila showed that loss of Pink1 or parkin reduce fly locomotor activity and longevity, and lead to neurodegeneration phenotypes (Clark et al., 2006; Greene et al., 2003). Another type of selective autophagy which is thought to be disrupted during aging is the removal of protein aggregates. Accumulation of protein aggregates (tau, a-synuclein, huntingtin) in neuronal cells is considered to contribute to the neuronal toxicity and lead to neurodegeneration. Studies in Drosophila have shown that inhibition of autophagy can accelerate neurodegeneration while its induction can ameliorate the phenotypes of these disorders (Menzies et al., 2017). Consistently, inducement of autophagy in muscles has been linked to longevity in Drosophila. Specifically, overexpression of Atg8a in fly muscles increases lifespan, while overexpression of foxo is thought to maintain muscle proteostasis in part by promoting autophagy (Demontis and Perrimon, 2010). Furthermore, certain autophagy-related genes have been reported to mediate the effects of IIS signaling. As previously mentioned inhibition of mTOR is thought to lead to increased longevity in part by increasing autophagy. Under reduced nutrition, mTOR inhibits the activation of AMP-activated kinase (AMPK), a key activator of autophagy (Kim et al., 2011). Thus, the relative expression of mTOR and AMPK in different cell types and tissues will establish the levels of autophagy induction. mTOR is also considered

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a regulator of autophagy in part by phosphorylating and inhibiting the nuclear translocation of the transcription factor EB (TFEB) that is responsible for the expression of lysosomal and autophagy related genes (Martina et al., 2012; Roczniak-Ferguson et al., 2012). Overall these findings indicate that autophagy has an important role in health and homeodynamics at both the cellular and organismal level, further highlighting the critical role of the degradation pathways in modulating aging.

Mitostasis Mitochondrial DNA (mtDNA) volume, integrity and functionality decrease with aging due to accumulation of mutations and oxidative damage induced by accumulating reactive oxygen species (ROS). The decline of mitochondria function, i.e. the reduced mitochondrial respiratory capacity and changes in mitochondria subcomplexes along with decreased mitochondria numbers have been described in humans and several organism models, including Drosophila (Sun et al., 2016). Consequently, all aged tissues contain dysfunctional mitochondria, with certain specialized cells being particularly vulnerable to this loss. While these changes are well established it still remains unclear to what extent such alterations are due to the aging process or to other associated factors (e.g., loss of muscular mass). Mitochondria are the primary source of ROS production and their immediate target within the cell (Harman, 1956). The primary mitochondrial form of ROS is the reactive superoxide radical, but only hydrogen peroxide can cross the mitochondrial membranes (Murphy, 2009). Thus, disruption of the oxidative phosphorylation process could be expected to result in an increase in ROS production and oxidative damage (Murphy, 2009). Under normal physiological conditions, ROS production is tightly regulated by the ROS scavenging system, i.e. the antioxidant enzymes that neutralize ROS by directly accepting electrons from ROS. When ROS production overwhelms ROS scavenging, several cellular components, including proteins, lipids and nucleotides, endure changes that underlie the oxidative stress conditions (Bigarella et al., 2014). In response to increased oxidative load cells activate the antioxidant response pathways, which culminate in the upregulation of several enzymes and/or other molecules that provide effective defense from oxidative damage. According to one of the current theories that aim to explain aging, lifespan is determined by the rate of free radical-mediated damage at cellular and tissue levels (Murphy, 2009). It is thus assumed that increased cellular antioxidant defenses and lowering of ROS should slow the age-related phenotypes and eventually increase longevity. However, several studies have shown a different output when ROS production and/or antioxidant responses are engaged. Data from animal models showed that even in conditions of severe disruption of the respiratory chain it is difficult to detect a very high oxidative damage (Suomalainen and Battersby, 2018). In addition, Drosophila studies showed that indeed flies have increased H2O2 species as a result of aging but this output may not be the cause of aging (Cochemé et al., 2011). Moreover, increased antioxidant defense, although it evidently increased stress resistance in flies, it did not affect longevity (Orr and Sohal, 1994; Mockett et al., 2003; Orr et al., 2003). ROS production was also thought to cause mtDNA damage. However studies in Drosophila and humans have not identified a mutation pattern consistent with ROSmediated mutagenesis, suggesting that oxidative stress is not the major factor affecting mtDNA mutations (Kennedy et al., 2013; Itsara et al., 2014). Overall, studies in the fly model indicate that the age-related increases of ROS levels and oxidative damage may not be the driving force of the progeroid phenotypes and of age-related alterations; thus, further studies are needed to definitively clarify this issue. Another speculation is that mtDNA mutations contribute to aging (Linnane et al., 1989). Indeed, mtDNA mutations have been described in human nervous system, skeletal muscle and hepatocyte (Corral-Debrinski et al., 1992; Yen et al., 1991; Fayet et al., 2002). Yet, mtDNA exist in thousands of copies per cell and the presence of a mutation does not necessary imply dysfunction; it is thus believed that the number of mutations should exceed a threshold value to manifest a significant phenotype (Rossignol et al., 2003). On the other hand, accumulation of misfolded proteins from mtDNA mutations trigger the UPRmt stress response pathway. The UPRmt was first described in mammalian cells, where upon mitochondria perturbation the expression of mitochondrial chaperones was increased (Zhao et al., 2002). During mitochondrial proteotoxic stress, the organelle triggers a nuclear transcriptional response, which is now known to activate a plethora of genes involved not only in protein folding but also in ROS defenses, metabolism and in the modulation of innate immune responses (Nargund et al., 2015; Schulz and Haynes, 2015). Modulation of UPRmt was first associated to longevity in the worm, where it was found that activation of the mitochondrial response is necessary for lifespan extension (Durieux et al., 2011). In Drosophila these findings were taken one step further since a systemic effect of mitochondrial dysfunction was observed (Owusu-Ansah et al., 2013). Specifically, it was showed that increased longevity after disruption of mitochondrial Complex I was also due to the activation of UPRmt in the muscle (Owusu-Ansah et al., 2013); indeed, activation of antioxidant responses in this Drosophila model abolished lifespan extension (Owusu-Ansah et al., 2013). A parallel observation in this model was the induction of the Drosophila ortholog of insulin-like growth factor-binding protein 7, which systemically antagonizes insulin signaling and facilitates mitophagy (Owusu-Ansah et al., 2013), suggesting that mitochondrial dysfunction in one tissue can signal stress to distal tissues through secreted factors altering their function. Furthermore, transcriptome analysis of Pink1-mutant flies revealed that mitochondrial dysfunction results in the transcriptional upregulation of a subset of genes that mediate metabolic reprogramming to increase nucleotide pools and promote mitochondrial biogenesis (Tufi et al., 2014). Drosophila has also been an important model to study mitochondrial dysfunction and to understand the removal of damaged mitochondria via the Pink1/Parkin pathway-mediated mitophagy. Mitochondrial dysfunction has been associated with the pathogenesis of Parkinson’s disease (PD) (Langston et al., 1983), and among the PD-associated genes, Parkin and Pink1 are the most

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linked to mitochondria. Interestingly, even though more similar to the human, Pink1 or Parkin knockout mice do not show any obvious phenotype, while their deletion in Drosophila leads to striking phenotypes, including apoptotic flight muscle degeneration, male sterility and reduced lifespan (Clark et al., 2006; Greene et al., 2003; Park et al., 2006; Yang et al., 2006). Pink1 or parkin or lossof-function in flies display swollen mitochondria, disrupted cristae and muscle degeneration (Greene et al., 2003). Moreover, studies in flies have revealed that parkin can compensate for Pink1 loss-of-function, but not vice versa, suggesting a common genetic pathway with parkin acting downstream of Pink1 (Clark et al., 2006; Park et al., 2006; Yang et al., 2006). In addition, loss of parkin in flies reduced lifespan (Greene et al., 2003), while parkin overexpression extends Drosophila longevity without impairing fertility or food consumption (Rana et al., 2013). Other studies have showed that parkin may also reduce the proteotoxic stress during aging, as it was noted that Parkin mediates the elimination of the misfolded, mutated or oxidized proteins of the respiratory chain (Vincow et al., 2013); but it is still unclear how the removal of specific proteins occurs. Taken together, it is now clear that the role of mitochondria in cellular homeodynamics extends beyond energy production, and their imbalanced function affects most (if not all) cellular pathways. A significant number of studies link mitochondrial dysfunction to the aging process. Most of these findings show a correlative relation and only few a direct link; however, all findings support the notion that improving mitochondrial function or mitochondrial quality control can be considered as an effective strategy to delay the onset of aging and/or age-related diseases.

Concluding Remarks Aging in higher metazoans is a very complex multifactorial process; yet, a great progress has been made toward its understanding by the use of model organisms. Among others, Drosophila melanogaster has played a crucial role in identifying the main pathways involved in aging and has provided new insights regarding genetic interventions that can improve healthspan and longevity (Fig. 3). Nonetheless, and in spite of the large amount of information obtained, the translation of findings to humans is still difficult to be applied. It will be important to fully address the mechanistic insights of the role of nutrients sensing signaling pathways and of dietary restriction in extending healthspan and/or lifespan. It is now evident that the proteome quality control pathways (i.e. the proteostatic pathways) largely affect longevity. Each organelle has its own quality control system in order to maintain normal basal functionality or respond to stress conditions. These cellular pathways not only communicate with each other but they also establish communication pathways with other tissues and generate systemic effects. Understanding the crosstalk between the quality control pathways or the mediators of their intercompartmental or interorgan communication is crucial in our effort to dissect the molecular processes of aging. Furthermore, aging research has opened new opportunities for drug discovery and perhaps for delaying the age related phenotypes, i.e. increasing healthspan. Drosophila with its genetic tractability and conserved age-related pathways, offers great possibilities for genetic validation and modeling of human diseases. In addition, it provides an excellent platform for pharmacological or natural products treatments, enabling the selection of bioactive hits. Drosophila has been used for both primary screens and secondary validation of biologically active compounds for therapeutic purposes (Pandey and Nichols, 2011; Tsakiri et al., 2017a, b). We suggest that the foreseen discoveries in the Drosophila experimental model can provide valuable preclinical insights and elucidate potential therapeutic avenues against aging and age-related diseases.

Fig. 3 The hallmarks of aging. Aging hallmarks are cellular processes that contribute or define aging in different organisms across evolution. These act in combination or even independently with exogenous and endogenous cumulative insults. Specific interventions can ameliorate or even slow down the rate of the appearance of age-associated phenotypes.

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Acknowledgments The authors apologize to those authors whose work was not cited due to space limitations. IPT acknowledges funding from the EU project TASCMAR (EU-H2020/634674) and the Hellenic GSRT project BIOIMAGING-GR (MIS 5002755).

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Aging in Rodents Herminia Gonza´lez-Navarro, INCLIVA Health Research Institute, Valencia, Spain; CIBER Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain; and Department of Didactics of Experimental and Social Sciences, University of Valencia, Valencia, Spain Soner Dogan, Department of Medical Biology, Faculty of Medicine, Yeditepe Universty, Istanbul, Turkey Bilge G Tuna, Department of Biophysics, Faculty of Medicine, Yeditepe Universty, Istanbul, Turkey Paul K Potter, Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom Gea Koks, Prion Ltd., Tartu, Estonia Sulev Koks, Prion Ltd., Tartu, Estonia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA, Australia; and The Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia © 2020 Elsevier Inc. All rights reserved.

Introduction Choice of Strain/Model Study Design Assessment of Aging Aging in Rodents Through the Study of Mouse Models Mice With Progeroid Syndromes as Models to Study Aging Hutchinson-Gilford Progeria Syndrome Mouse Models Impaired DNA Repairing Mechanisms in Premature Aging Mouse Models Mouse Models of Werner Syndrome (WS) Mouse Models of Impaired NER Mechanism WFS Mouse Models Klotho Mice as a Model of Aging Roles of Calorie Restriction in Aging in Rodents The Effects of Calorie Restriction in Lifespan The Effects of Calorie Restriction on Age-Related Memory Loss and Learning Ability The Effects of Calorie Restriction on Age-Related Neuronal Diseases The Effects of Calorie Restriction on Age-Related Cardiovascular Diseases The Effects of Calorie Restriction on Inflammation The Effects of Calorie Restriction in Cancer Development The Effects of Calorie Restriction on Osteoporosis and Bone Mass Possible Molecular Mechanisms in the Effects of Calorie Restriction in Aging and Age-Related Health Problems Transposable Elements and Aging References Further Reading

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Introduction Undertaking an aging study in a mammalian system is a major commitment of time, money and resources even with a short lifespan model, such as mice. These are generally a “one-shot” experiment with little chance of repeating results. As such detailed planning is essential, with as many factors as possible that may influence outcome taken into consideration to ensure valid, reproducible results are achieved. There is no one-size-fits-all plan as the use of aging mice will be as varied as the underlying biological questions. They may involve investigating the progression of a chronic or age-related model of disease, investigation of central aging pathways, or an intervention study to improve health span. As such, we have focussed on aspects of study design that may influence outcome rather than a specific experimental design.

Choice of Strain/Model The first step in planning should be in the choice of model or strain to be employed in the study. For the study of a specific disease the choice of models may be limited but even then consideration should be made of the suitability of the model: does it reflect all the aspects of disease you wish to study? Have aging studies been carried out before using this model? Is it an induced model and does it produce the same results in aged animals as in young littermates? These may seem like obvious questions but the translation of results has faltered in some cases due to the limited ability of some mouse “models” to recapitulate human disease (Franco and Cedazo-Minguez, 2014). The discussion of whether to use inbred outbred/mixed background strains has resurfaced. The argument

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for inbred strains has always been one of reproducibility and standardisation, as well as many other factors, but the limited genetic variation may affect translation of results into the outbred human population. However a recent analysis of the literature has indicated that results from inbred strains are no less variable than outbred mice; of 26 parameters analysed only 6 exhibited reduced variability in inbred strains, and indeed 3 parameters were more variable when compared to outbred strains (Tuttle et al., 2018). There is significant interstrain variability in lifespan (Yuan et al., 2009), but the data on lifespan variation in outbred mice is limited and comes primarily from the data generated by the Intervention Testing Programme, which employs a four way random cross of inbred strains (Chrisp et al., 1996; Nadon et al., 2008). The choice of strain will obviously be limited when studying strains with specific characteristics or particular genetic modifications, and such modifications are more difficult to introduce onto a truly outbred population.

Study Design It is clear there are differences between males and females in a range of diseases and therefore, whilst there are considerable financial and logistical implications, it is essential to study both sexes. There is a clear reporting bias, but not always in favour of using male mice (Florez-Vargas et al., 2016), and single sex studies may limit the translation or significance of findings. There are known sex specific responses in aging pathways, as well as age-related disease (Garratt et al., 2017). Sex differences have been demonstrated in the activity of the mTOR pathway with aging, as well as differences between tissues (Baar et al., 2016a), with obvious implications in the outcome of aging studies. Fundamental planning should include whether cross-sectional or longitudinal studies are required, the impact of assessments on mice (especially in longitudinal studies), and the completion of power calculations to determine sample size. In this case it is wise to over-estimate given the increasing variation of results observed with aging. This has ethical implications, as well as financial, in that more mice may be used than needed but the ethical consequences of having too few mice to complete a study would be more severe. As with any mouse experiment, stringent breeding protocols must be employed to ensure the similar genetic background of animals. However, as has become apparent recently the effect of breeding stock’s age and health status can have significant influence on the aging of offspring and thus the more tightly controlled the breeding of cohorts the better. The age of the breeding stock can have long term effects on metabolic (Dearden et al., 2018) and behavioural phenotypes (Xie et al., 2018), or indeed survival (Tarin et al., 2005) in the offspring which could have implications in aging studies. Sex also influences the response to rapamycin, an intervention known to influence lifespan (Zhang et al., 2014; Fischer et al., 2015). More recently maternal age has been demonstrated to influence the response of offspring to caloric restriction (CR) in a lower order model, with lifespan extension greatest in offspring from older mothers (Bock et al., 2019). Given the effect of CR across a wide range of organisms it will be intriguing to see if this translates to mammalian species and if this goes some way to explaining the variation in lifespan observed within mouse strains in many studies (Yuan et al., 2009). Informed decisions also need to be made about the timing of interventions as they may not influence aging pathways alone (Neff et al., 2013).

Assessment of Aging Whilst, in an ideal world, there would be a small number of parameters or biomarkers indicative of the biological age of an individual that correlate with human aging, these are unfortunately few and far to be perfect. (Cardoso et al., 2018; Sebastiani et al., 2017). The key parameters in assessing aging are lifespan and health span, with the latter providing a richer data set and a more qualitative assessment of the effects of aging but with the additional complication of more labour intensive assessments. Lifespan studies have been very informative, with major advances in our understanding achieved through this simple measure (Fontana et al., 2010a). Further data can be obtained from post mortem analysis but this provides limited information on the health of an individual mouse over time. However, there are ethical implications in allowing a mouse to become moribund in many countries, and a more detailed analysis of the process of aging may be required. Thus, healthspan is becoming the favoured measure, not the least because the clinical problem we are facing is not people living longer per se but the amount of time they spend in ill-health, but also because health span and lifespan may not be directly linked (Partridge et al., 2018; Bellantuono, 2018). To assess overall health span it is necessary to carry out a range of tests reflecting the main physiological functions affecting health in aging (Niccoli and Partridge, 2012). Whilst this is time consuming and expensive a rich data set can be achieved revealing the intricacies of the effects of aging and/or interventions (Neff et al., 2013) but can also be achieved with a range of simple tests giving an indication of the progression of aging within individual mice (Xu et al., 2018). However some phenotypic assessments are difficult to carry out and are affected by the previous experience of the mice thereby limiting them to cross-sectional studies (Wooley et al., 2009; Vorhees and Williams, 2014). Multimorbidity is a key feature of aging that needs to be assessed to translate results into the clinic. Unfortunately, the pattern of multimorbidity between individuals can vary by the range of disease, order of disease occurrence and severity (Rockwood et al., 2017; Figueira et al., 2016). A more accessible measure of overall aging that is coming to the fore in aging studies, and indeed is comparable between studies in mice and patients is the concept of a Frailty Index (FI) (Fried et al., 2001; Rockwood et al., 2005). There are a variety of Frailty Indices but some have been successfully applied to mice and reflect the aging process (Parks et al., 2012; Liu et al., 2014). Adverse outcomes can be predicted in individuals with a high FI (Rockwood et al., 2017; Guaraldi et al., 2017) and interventions known to affect aging can improve FI (Kane et al., 2016; Palliyaguru et al., 2019), thus validating such assessments in aging studies. These FIs are relatively easy to establish and are comparable between patients and mice (Liu et al., 2014; Whitehead et al., 2014).

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Associated with the acquisition of frailty with age is the loss of resilience (Hadley et al., 2017; Miller et al., 2017). Thus another possibility is to challenge with a stressor to assess resilience as a measure of aging. For an overall assessment of aging it is essential that the stressor(s) reflect a loss of general resilience, rather than age-related changes in a specific organ (Baar et al., 2016b). Such challenges may involve temperature, sepsis, exercise, or hypoxia and whilst some protocols are available their use is not well established, especially with regard to aging studies (Kirkland et al., 2016; Schosserer et al., 2019). In summary there is an increasing array of tools available to investigate the aging process in mice, whether natural aging or investigating the efficacy of interventions in models of aging or strains of mice. There continue to be advances, but as with most areas of biology, standardised protocols are required to enable the comparison of data between studies. In addition to assessing outcomes of aging experiments, assessments of aging may be useful in determining the time of interventions. For example should an intervention be given to all mice at a specific age, where there may be individual differences in the biological age? Or should mice be treated when they attain a certain FI score? Protocols for aging studies will have to be continually reassessed and refined as more results become available, and modern technology is now allowing us to assess aging at a cellular as well as organismal level (https:// www.biorxiv.org/content/10.1101/662254v1).

Aging in Rodents Through the Study of Mouse Models Altered aging syndromes have been highly valuable to study human natural aging process. Many of these syndromes share phenotypic characteristics which suggest potential common mechanisms of physiological aging (Hofer et al., 2005; Koks et al., 2016). Most importantly, the use of spontaneous and of genetically-modified mouse models have given a great opportunity to understand the pathogenic molecular mechanisms predisposing to normal physiological aging. Although there are important differences between normal and premature aging, the characterisation of mouse models displaying both accelerated and delayed aging which have given mechanistic insight about the normal process of physiological aging (Vanhooren and Libert, 2013). In addition, recent studies in mouse models with tissue-specific mutations or deficiencies have allowed a more precise identification of the molecular mechanisms of organ-specific physiological aging. Here, we summarise the main underlying molecular mechanisms in the best characterised mouse models displaying accelerated aging.

Mice With Progeroid Syndromes as Models to Study Aging Progeroid human syndromes are extremely rare genetic disorders characterised by a premature aging and death of patients. These patients display many pathogenic features shared by normal physiological aging, but these also display other alterations not observed in elderly individuals. In general, these syndromes are rare diseases and display two main genetic alterations that finally affect cellular division and DNA repair mechanisms. In mouse models the most studied are the laminopathies, such as the Hutchinson-Gilford progeria syndrome (HGPS), and syndromes with mutations in the DNA repairing mechanism Werner syndrome (WS), and trichothiodystrophy (TTD), Xeroderma Pigmentosum (XP) and Cockayne syndrome (CS) (Liao and Kennedy, 2014). In addition, we also discuss non-progeroid syndromes with premature aging such as the Wolfram syndrome (WFS) and Klotho-deficient mice.

Hutchinson-Gilford Progeria Syndrome Mouse Models Patients suffering from HGPS display growth retardation, lipodystrophy, scleroderma, general bone abnormalities which induce impaired mobility provoked by osteodysplasia with osteolysis, alopecia and midface hypoplasia. The individuals usually die in the second decade of life due to cardiovascular complications caused by premature atherosclerosis such as myocardial infarction or stroke. HGPS is a laminopathy produced by a de novo genetic mutation in the Lamina A gene (Lmna) (De Sandre-Giovannoli et al., 2003) which encodes A-type lamin (lamin A/C) proteins that form the nuclear envelope. Most of the mutations in the Lmna gene results in a deletion in the C-terminal protein domain eliminating a farnesylated proteolytic cleavage site for the zinc metalloproteinase Zmpste24. The unprocessed farnesylated protein, which is called progerin, accumulates and affects the nuclear envelop architecture, morphology and function. The altered nuclear envelop produces genomic instability inducing aberrant proliferation and telomere shortening. There are several HGPS mouse models which are based on modifications of the Lmna gene or its processing enzyme Zmpste24 (Zhang et al., 2013). The knock-in LmnaHG mice (Yang et al., 2005) expresses only the farnesylated form of lamin A, progerin that resulted in nuclear pebbling. The phenotype of these mice included subcutaneous fat and hair loss, osteoporosis and premature death but they did not develop cardiovascular complications. Interestingly treatment with a farnesylation inhibitor prevented progerin accumulation nuclear pebbling. Another mouse model of laminopathy are LmnaG609G mice which encompasses a silent mutation in 1827C > T; Gly609Gly that produces a defective splicing and abnormal progerin accumulation nuclei changes (Osorio et al., 2011). Likewise, LmnaG609G mice exhibit growth retardation, impaired weight gain, curvature in the spine, vascular calcification (Villa-Bellosta et al., 2013) and death at about 4 months (Osorio et al., 2011). Interestingly, progerin accumulation by expression of LmnaG609G restricted to vascular smooth muscle cells (VSMCs) resulted in enhanced plaque vulnerability and atherosclerosis and provoked premature death (Hamczyk et al., 2018) by increasing endoplasmic reticulum stress in

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(Hamczyk et al., 2019). A similar phenotype to that in HGPS patients has been also obtained in two different mice deficient in Zmpste24 gene (Zmpste24
/
mice), the pre-lamin processing enzyme. They both exhibited accumulation of the farnesylated prelamin A protein (Pendas et al., 2002). Interestingly, Zmpste24
/
mice are viable while Zmpste24 gene deficiency in humans causes perinatal death suggesting additional functions of this enzyme. Slightly differences were observed between the two mouse models. Bergo and co-workers described growth retardation, alopecia, muscle weakness and bone fractures in their Zmpste24
/
mouse model (Bergo et al., 2002) while the Pendas and others described dilated cardiomyopathy, muscular dystrophy, lipodistrophy and premature death (Pendas et al., 2002). Consistent with this later phenotype, specific expression of lamina mutant in cardiomyocytes provoked the characteristic dilated cardiomyopathy observed in human laminopathies (Chen et al., 2019). Moreover, the observed mechanisms included fibrosis, apoptosis, cardiac dysfunction and premature death by a mechanisms mediated by the E2F/DNA damage response/p53 pathway (Chen et al., 2019).

Impaired DNA Repairing Mechanisms in Premature Aging Mouse Models Accelerated aging is characterised by genomic instability. In fact, in the absence of risk factors for some age-associated diseases such as cardiovascular disease development is attributed to genomic instability induced defective DNA repairing mechanism. This knowledge has been achieved from human and mouse models of progeroid syndromes characterised by DNA damage usually caused by impaired DNA repairing mechanisms such as the nucleotide excision repair (NER) mechanisms or defective helicases/ exonuclease (Wu and Roks, 2014). The study of mouse models of syndromes with mutation in these systems has given information about the physiological aging associated with DNA damage. The best studied are the Werner Syndrome (WS) and three syndromes associated with UV-induced damage, Xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS). All four are extremely rare genetic and inherited diseases with a wide variety of clinical manifestations in humans.

Mouse Models of Werner Syndrome (WS) WS is a progeroid syndrome known also as “progeria of the adult” because, at difference of other progeroid syndromes, the onset of disease is in the third decade of life and with an average of death around 50 years of age (Cox and Faragher, 2007). In humans, clinical characteristics include bilateral cataracts, short stature, graying and thinning of scalp hair, skin disorders, risk of developing cancer, melanomas or sarcomas, senile dementia, diabetes, immunodeficiency, and frequently death by cardiovascular disease induced by extensive atherosclerosis. WS is an inherited genetic mutation in the RECQ3/WRN protein, an ATP-dependent helicase WRN helicase/exonuclease involved in DNA metabolism and in telomere homeostasis. The mutations which range from nonsense mutations to deletions/insertions and substitutions lead to genome instability, impaired DNA damage repair and aberrant proliferation (Huang et al., 2006). Three different WS mouse models were initially developed consisting of a total null Wrn mice, a deletion of helicase domain resulting in a truncated protein and a transgenic mice expressing inactive helicase activity (Kudlow et al., 2007). Mice deficient for the WRN helicase activity had elevated levels of reactive oxygen species (ROS), oxidative DNA damage and increased incidence of cancer (Lebel and Leder, 1998; Massip et al., 2006). Total WNR helicase deficiency, Wrn
/
mice, however do not display premature aging (Lombard et al., 2000) but combined with deficiency in the Telomerase RNA component mice develop progeroid symptoms closely related to human WS (Chang et al., 2004). Thus, Wrn
/
Terc
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mice developed greying and loss of hair, osteoporosis, type 2 diabetes mellitus, cataracts and cancer due to chromosomal instability. Importantly, severity in later generations was correlated with telomeric DNA loss. Similarly, Wnr
/
p53
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double deficient mice show an increased mortality rate relative to Wrnþ/
p53
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animals which is due to genome instability and by that Wrn-deficiency speeds up the cancer phenotype (Lombard et al., 2000). Consistent with these studies WRN helicase is essential for microsatellite unstable cancer cells and its depletion promotes p53-induced apoptosis (Chan et al., 2019). These studies suggest that telomere attrition is a key factor in the manifestation of WRN deficiencies, and highly probably as well as a key factor contributing to genome instability and defective DNA damage repair associated with physiological aging.

Mouse Models of Impaired NER Mechanism Trichothiodystrophy (TTD), Xeroderma Pigmentosum (XP) and Cockayne syndrome (CS) are extremely rare syndromes with accelerated aging due to increased levels of DNA-damage. These are the result of impaired function of NER mechanisms produced by mutations in the different protein subunits of the complex. Thus, NER complex is involved in DNA repair caused by UV light, environmental mutagens and chemotherapeutic drugs. These syndromes and mouse models resembling to these, have pointed out to DNA damage as a main factor in the aging process. TTD patients, with inherited defects in the either XPB or XPD subunits of the transcription factor II H (TFIIH), are photosensitive but do not develop skin cancer, exhibit hair dysplasia and neurological symptoms, showing most of them mental retardation and ataxia (Bergmann and Egly, 2001). XP syndromes are classified depending on the subunits mutated in the NER mechanism, giving rise to classical XP (XPA to XPG) and XP variant (XPV) and provoke high photosensitivity and predisposition to skin cancer. In CS syndrome, cells show a specific defect in transcription-coupled DNA repair (genes CSB and CSA), a subpathway of NER for UV-induced DNA damage (Bukowska and Karwowski, 2018). TTD (XPD mutants) mice display skin abnormalities and enhanced UV- and chemical-induced tumorigenesis but not as pronounced as in Xpa
/
mice (Bergmann and Egly, 2001). TTD mice display premature aging which premature aging, including osteoporosis, osteosclerosis, early greying, cachexia, infertility, and reduced life-span. TTD mice carrying an additional mutation in XPA greatly accelerated the aging

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phenotype and enhanced sensitivity to oxidative DNA damage (de Boer et al., 2002). Likewise, Xpc
/
mice display decreased survival, enhanced lung cancer and oxygen-induced stress sensitivity while Xpa
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have normal survival but develop liver cancer. (Melis et al., 2008). On the other hand, mice deficient for CS subunits, CsA
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and CsB
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mice, are predisposed to hearing loss and hair loss induced by drugs such as cisplatin, suggesting cell damage in the mammalian organ of Corti, the mammalian auditory sensory epithelium, and emphasize the importance of transcription-coupled DNA repair in the protection against ototoxicity induced by drugs (Rainey et al., 2016). CS mouse model carrying a human mutation CsBm/m also display motor dysfunction, loss of cells in the retina and sensorineural hearing loss (Karikkineth et al., 2017). Crossing the Csbm/m or Csa
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mice with mice deficient in XP subunits, Xpc
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or Xpa
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mice also produces neurodegeneration and early death (Karikkineth et al., 2017).

WFS Mouse Models Wolfram syndrome (WFS) is a very rare neurodegenerative genetic disorder characterized by diabetes insipidus, type I diabetes mellitus, optic atrophy and deafness (DIDMOAD) with decreased lifespan and an average life expectancy of 30 (Collier et al., 1996). WFS also provokes neurological manifestations, such as brain stem atrophy, altered balance and coordination (ataxia), probably related to dysfunction/death of neurons induced by defective neurotransmitters and neurotrophic factors secretion (Koks et al., 2009). WFS1 gene encodes for a ER transmembrane protein Wolframin, having a role in calcium homeostasis and unfolded protein response and this function could be related to cell survival and degeneration. Wfs1-deficient mice develop premature death and display growth retardation, diminished body weight and fertility, degeneration in several tissues and shorter lifespan (Koks et al., 2009; Noormets et al., 2009). Some Wfs1 mutant mice develop diabetic phenotype. It has been described a rise in non-fasted blood glucose levels and overt diabetes at 36 weeks of age (Ishihara et al., 2004), reduced number of pancreatic islets due to increased (Noormets et al., 2009) and impaired stimulus-secretion from b-cells, suggesting a role in the proper folding and processing of the precursor of the insulin, pro-insulin. Consistent with a role in insulin secretion, b-cell specific deletion of exon 8 in the WFS1 gene (Riggs et al., 2005) induced diabetes due to low blood insulin levels, impaired glucose tolerance and reduced body weight. Wfs1-deficiency in these mice promoted apoptosis and unfolded protein response (Riggs et al., 2005). A third available mouse model for WFS studies was engineered to mimic WFS, by fusing N-terminal part of WFS1 gene to LacZ reporter (Koks et al., 2009). These Wfs1-deficient mice displayed a severe phenotype with a 30% reduction in size at 8 weeks of age compared with wild type littermates (Koks et al., 2009), although mice had normal growth hormone pathway and increased IGF-1 levels (Koks et al., 2009). The phenotype also consisted of a gradual degeneration of pancreatic islets and diabetes (Noormets et al., 2009). Finally, the psychiatric symptoms have also been observed in WFS1 deficient mice with alteration in physiology of emotions and behavioural adaptation (Luuk et al., 2009). Therefore, Wfs1deficient mice display degenerative processes associated with aging such as predisposition to diabetes and tissue degeneration.

Klotho Mice as a Model of Aging The human klotho gene encodes a multifunctional transmembrane protein that regulates phosphate metabolism, calcium, and vitamin D (Xu and Sun, 2015; Kuro-o, 2009). Also there is an extracellular domain that can be clipped and secreted exerting distinct functions in different cell-types and tissues and potentially functioning as an endocrine factor (Kuro-o, 2009). Thus, the secreted Klotho has the capacity to modify glycans on the cell surface, regulating the activity of multiple ion channels and growth factors including insulin, IGF-1, and Wnt. It has been shown to protect against oxidative stress and to regulate phosphatase and calcium absorption (Xu and Sun, 2015). Klotho-deficient mice display age-associated characteristics such as premature atherosclerosis, infertility, osteoporosis and skin alterations but most importantly shorter lifespan (Kuro-o et al., 1997). These mice have been claimed as a human premature aging model because they recapitulate many age-associated alterations and fulfil many of the pathophysiological criteria for human aging. Interestingly, human polymorphism variants affecting activity of Klotho correlate well with the onset and severity of human agerelated phenotypes (Arking et al., 2002). Consistent with all these, mice overexpressing Klotho display extension of the lifespan (Xu and Sun, 2015). In another study, klotho-deficient mice showed accelerated high fat diet-induced arterial stiffening and hypertension by diminishing AMPK activity (Lin et al., 2016). Recent studies also attribute to Klotho a key role in brain inflammation during the brain aging process by its expression in the choroid plexus (Zhu et al., 2018). Deficiency of Klotho in this area was shown to trigger inflammation and activation of innate immune cells while in cell culture klotho inhibited macrophage activation (Zhu et al., 2018). Another characteristic of aging is a diminished kidney function and point mutations in human Klotho gene are associated with hypertension and kidney disease, suggesting that is essential to the maintenance of normal renal function (Xu and Sun, 2015). Consistent with this, mice lacking Klotho also exhibit hyperphosphatemia which can be restored by decreasing phosphate retention (John et al., 2011) suggesting a link between aging and phosphate metabolism. Klotho has been shown to highly express in kidney functioning as an obligate coreceptor for fibroblast growth factor 23 (FGF-23) which is a bone-derived hormone that suppresses phosphate reabsorption and vitamin D synthesis in the kidney. In patients with chronic kidney disease (CKD), phosphate retention has been associated with increased mortality risk. CKD subjects display high serum FGF-23 levels and decreased klotho expression in the kidney rendering these as potential biomarkers and therapeutic targets for CKD.

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Roles of Calorie Restriction in Aging in Rodents Historically, it has been shown that human being has always wanted to live longer and tried to stay younger. To achieve their goal, they have tried varieties of techniques including spiritual ones and natural and unnatural medications. No matter how human beings life style is, where we live, what our economic and social status are, aging is unavoidable natural event. Although, numerous methods and medications have been tried to prevent or delay aging process, studies have shown that one of the most effective intervention methods to delay the aging process and support healthy aging is calorie restriction (CR). Using rodent models, in general most of the studies have reported that CR shows its beneficial effects in lifespan and healthy aging by reducing the risk factors for age related diseases such as neuronal, cardiovascular, autoimmune, kidney, and respiratory diseases, bone deposition, frailty, diabetes, and all kinds of cancer (Fontana et al., 2010a; Trepanowski et al., 2011; Speakman and Mitchell, 2011; Fontana et al., 2010b; Dogan et al., 2010a). However, the exact molecular mechanism (s) of this phenomenon is/are still clearly not known.

The Effects of Calorie Restriction in Lifespan Studies have shown that lifespan or longevity has been directly modified by calorie or dietary restriction in rodent models. For example, using Fisher 344 male rats, it was reported that even application of 10% CR starting at 6 weeks of age, lifespan was increased significantly compared to AL group (Richardson et al., 2016). Interestingly, in the same study positive effects of 10% CR effects on lifespan were similar with 40% CR effects. However, there was a significant reduction in neoplasia, especially in leukemia incidence in 40% CR applied group of rats while no significant effects was observed in 10% CR group of rats (Richardson et al., 2016). Similar results were also found in another recent study which reported 20% increase in lifespan of wild type mice which were applied to 30% CR (Patel et al., 2016). But, the same amount of CR significantly reduced lifespan of mouse model which was deficient for circadian clocking transcription factor called BMAL1 (brain and muscle ARNT [aryl hydrocarbon receptor nuclear translocator]-like protein 1). In addition, factors like IGF-I and Insulin which were generally modulated by CR in most models were not affected by 30% CR in BMAL1 deficient mouse model which aging is accelerated (Patel et al., 2016). These results made authors of the research claim that CR shows its effects in aging and biological clock by modulating BMAL1 activation. Moreover, application of 40–60% CR in either male or female mouse models resulted in 30–50% increase in longevity, and reduced the incidence rate of age-related loss of function and variety of diseases (Fontana et al., 2010a,b; Trepanowski et al., 2011; Speakman and Mitchell, 2011). Although it is commonly believed that lifespan is extended by CR there are some studies which have reported otherwise. One of the keystone research in this area was conducted by Liao et al in 2010 using 40 different strains of male and female mice (Liao et al., 2010). They showed that lifespan of some strains of mice was extended while others either was reduced or not affected by the application of CR. These results let them conclude to not every stains of animals responds the same way to application of CR (Liao et al., 2010). Likewise, there are other studies also reported no effects of CR in extending lifespan of mice including wild-caught mice (Harper et al., 2006; Forster et al., 2003). Beside the different backgrounds in animal strains, another possible explanation for the controversial results for the effects of CR in lifespan could be the amount of, type of and duration of CR which was applied to the experimental animals. In this context, some studies have reported direct correlation of extending lifespan with the amount of CR up to certain points which is about 60% CR (Weindruch et al., 1986). In their study, using C3B10RF1 mice strain application of 25%, 55%, and 65% CR extended lifespan of female mice by according to the CR levels ranging from 25% to 65% (Weindruch et al., 1986). These results were supported by another study conducted with rats as well (Duffy et al., 2001). Furthermore, the effects of the types of calorie consumption on lifespan was studied. In a recent study, it was reported that intermittent fasting applied by 3 months of fasting and 4 months of ad-libitum feeding style starting at 10 months of age until death increased lifespan in obese mice despite the animals regain the weight that was lost during fasting period both in male and female mice (Smith Jr. et al., 2018). Beneficial effects of intermittent calorie restriction in age-related health problems have also been supported by other studies (Dogan et al., 2010b, 2011, 2017; Tuna et al., 2017). Numerous studies have reported that diet composition is also another important factor for aging in rodents. For example, consuming the total daily calorie in a high energy density diet as a single meal had similar effect with 30% CR on longevity of male mice (Mitchell et al., 2019). Starting at 4 month of age feeding male mice either in a single meal or application of 30% CR extended mean life span by 11% and 28% respectively and also improved health conditions compared to ad libitum group (Mitchell et al., 2019). In addition, high-fat diet was reported to reduce longevity in C57BL/6 mouse model (Surwit et al., 1995). On the other hand, recent study has reported that compared to the control group ketogenic diet which was applied starting at 12 months of mouse age extended longevity by 13.6% in C57BL/6 mouse model (Roberts et al., 2017). In their study, ketogenic diet was shown to be beneficial for healthy aging since mice fed with ketogenic diet preserved their memory in old age and also did better in object recognition test, the hanging wire and grip strength tests compared to age matched control mice (Roberts et al., 2017). Also, mice fed with ketogenic diet were more active in the rearing test and faster in the Locotronic speed tests (Roberts et al., 2017). But, this research topic is also contentious because another study reported no significant effect of ketogenic diet on longevity in the same strain of mouse model (Douris et al., 2015). All these results show that right amount of CR application in rodents has beneficial effects on lifespan although this is depends on animal models.

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The Effects of Calorie Restriction on Age-Related Memory Loss and Learning Ability Beneficial effects of calorie restriction has have also been shown in age related memory loss or learning impairments. Recent studies have showed that male mice which were applied 30% CR for 10 months had lower average escape latency and shorter swimming distance in water maze test compared to both control and high energy consumed groups (Ma et al., 2016, 2018). These beneficial effects of CR were associated with apoptosis signaling proteins since Bax, caspase 3 and PARP protein expression levels in brain tissues of mice in calorie restricted group were lower than the either control or high energy fed dietary groups (Ma et al., 2016). In addition, mice in CR group had higher AMPK and GLUT4 proteins and mRNA expression levels compared to the high energy consumed group of mice (Ma et al., 2018). Moreover, in another study less number of damaged neuronal cells, decreased GFAP, mTOR and S6K protein levels were detected in hippocampus region of mice in CR group compared to group of mice consumed high energy (Dong et al., 2016). Furthermore, the effects of types of diet composition on memory and learning ability have also been shown in rodents. Using adult mice, application of ketogenic diet starting at 12 months of mouse age was shown to be beneficial for memory and learning ability since animals fed with in ketogenic diet preserved their memory in old age and also did better in object recognition test compared to age matched control group (Roberts et al., 2017).

The Effects of Calorie Restriction on Age-Related Neuronal Diseases Another important area where CR effects have been shown is age-related neuronal diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases and stroke (Van Cauwenberghe et al., 2016; Bondolfi et al., 2004a; Patel et al., 2005a). Using different mouse models recent studies have reported beneficial effects of CR including intermittent calorie restriction and small meal size on neurogenesis, survival of neuronal cells, and restoring neuronal function following injury (Bondolfi et al., 2004b; Patel et al., 2005b; Park et al., 2013; Wu et al., 2008; Halagappa et al., 2007; Hornsby et al., 2016; Mattson et al., 2003). In another study, Park et al. (2013) has reported that CR increases the number of dividing neuronal stem cells and progenitor cells in the dentate gyrus of female NestinGFP mouse line. Then, they suggested CR may increase the number of divisions that neural stem and progenitor cells undergo in the aging brain of females (Park et al., 2013). Moreover, Halagappa et al. (2007) have reported protective effect of different types of calorie restriction (CR and intermittent fasting, IF) for neurons against the negative effects of Ab and tau pathologies on synaptic function. They concluded that CR and IF dietary regimens can ameliorate age-related deficits in cognitive function (Halagappa et al., 2007). All these studies have shown beneficial effects of CR on aging and age related neuronal diseases using different mouse models.

The Effects of Calorie Restriction on Age-Related Cardiovascular Diseases Cardiovascular diseases (CVD) are the main cause of death in general and prevalence of CVD including hypertension, atherosclerosis, aortic aneurysm (AA) and coronary vascular disease with myocardial infarction (MI) significantly increase with aging. Age related CVDs are complex pathophysiological processes initiated and progressed by multiple contributors such as changes in blood pressure, artery structure, remodeling, stiffness, intima to media thickness ratio, endothelial dysfunction, and collagen content of heart or arteries (VanBavel and Tuna, 2014; Tuna et al., 2013a,b). Many studies performed in rodents reported that CR has beneficial effects on these contributors and eventually was suggested to delay onset of the CVDs and increase healthspan and lifespan (Wang et al., 2018a; Dolinsky et al., 2010; Sheng et al., 2017). For example, B6D2F1 mice subjected to life-long (up to 31 month) 40% CR were reported to reduce blood pressure, vascular remodeling and stiffness and improved endothelial function compared to AL group (Donato et al., 2013). In addition, spontaneously hypertensive rats subjected to 5 weeks of 40% CR and Zucker obese (fa/fa) male rats subjected to 2 weeks of 20% CR were also reported to have lower systolic blood pressure, reduced vascular remodeling and stiffness, improved endothelial function compared to AL group (Dolinsky et al., 2010; Garcia-Prieto et al., 2015, 2019). These functional improvements due to CR feeding both life-long or short term application at old age in rodents were suggested as mechanistically related to enhanced adiponectin, adenosine monophosphate-activated protein kinase (AMPK), endothelial nitric oxide synthase (eNOS) and oxidative stress levels (Dolinsky et al., 2010; Donato et al., 2013; Garcia-Prieto et al., 2015, 2019). In addition, CR is suggested to reduce proinflammatory processes associated with aging in aorta (Wang et al., 2018a). Wang et al. showed that rats which were fed 40% CR for 24 months had lower platelet-derived growth factor density and matrix metalloproteinase type II (MMP2) activity in aortic tissue in addition to reduced intima to media thickness, reduced elastin and increased collagen content compared to AL group (Wang et al., 2018a). Intriguingly, Sheng et all showed 40% CR application for 12 weeks reversed cardiac remodeling, inflammation and mitochondrial damage in middle aged and old animals (12 and 19 months old respectively) while accelerated in young ones (3 months old) (Sheng et al., 2017). In another study, the protective effect of CR for AA formation suggested to be related to SIRT1 levels in angiotensin II-induced AA formation in male ApoE
/
mouse model (Liu et al., 2016). They showed that application of 25% CR for 12 weeks elevated SIRT1 levels which was shown to be modulated by histone modifications in the promoter region of MMP2 gene (Liu et al., 2016).

The Effects of Calorie Restriction on Inflammation In general, most studies have reported increase in inflammation and its related health problems with aging both in mouse and rat models. Studies have shown that calorie restriction, especially intermittent calorie restriction, has been reported to have beneficial

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effects on inflammation and related health problems in rodents. For example, calorie restriction, especially intermittent calorie restriction applied for 64 weeks had beneficial effects against inflammatory cytokines in C57BL/6 mouse model (Dogan et al., 2017). Specifically, compared to AL group, significant reduction in levels of serum IL-6, TNF-a, and leptin by CR were reported in mice in a cross sectional study (Dogan et al., 2017). In addition, changes in levels of adipokines including adiponectin and leptin with aging were reported to be modified by the application of two different types of CR in aging MMTV-TGF-a breast cancer mouse model (Dogan et al., 2010b). In this context, levels of the adiponectin to leptin ratio which was shown to be more important than the levels of adiponectin and leptin individually, decreased with aging. However, the degree in reduction level of the ratio was less in intermittent calorie restricted group than that of in AL group in mice (Dogan et al., 2010b). In another time restricted study (3 h of feeding in a day) conducted with 11 weeks old male C57Bl6 mice, increase in levels of inflammatory cytokines such as IL-6, TNF-a, NFkB, IL-1, and also increase in level of CRP which is a possible marker for coronary heart disease was reported. Similarly, only 8 weeks of CR in the amount of 20% and 40% has been reported to inhibit the mRNA expression of IL-1b and IL-18 (Wang et al., 2018b). Moreover, using different mouse models it was reported that CR decreases expression levels of inflammation related genes in the hippocampus, which is known to be responsible for novel object recognition and contextual fear conditioning memory (Bondolfi et al., 2004b; Patel et al., 2005b; Park et al., 2013; Wu et al., 2008; Hornsby et al., 2016; Mattson et al., 2003).

The Effects of Calorie Restriction in Cancer Development Even though everybody wants to live longer life there is no question that aging itself is a risk factor for cancer development. It is even generally accepted that if everyone lived over 100 years most people would have developed cancer. One of the areas where beneficial effects of CR has been reported is in cancer development. Using variety of mouse and rat models including chemically induced and spontaneous cancer models, studies including our group have reported significant amount of reduction in cancer development by CR. For example, it was reported that tumour incidence rate was significantly lower in calorie restricted group compared to the AL group in different spontaneous or chemically induced cancer rodent models (Dogan et al., 2010b, 2011; Rogozina et al., 2009; Bonorden et al., 2009). On the other hand, there are also studies which reported no effects or negative effects of CR in cancer development in rodent studies (Mehta et al., 1993; Tagliaferro et al., 1996). Whether CR is beneficial or harmful could be depended on four major factors; (1) duration of CR application, (2) levels of CR, (3) the way calorie restriction was applied (intermittent calorie restriction or not) and (4) genetic background of rodent models. It is also worth to mentioning that there is a fine tune to see the beneficial effects of CR. It is like a sword with two edges; while the moderate level of CR has numerous beneficial effects for the healthy aging and age related diseases, the severe level of CR application may have serious consequences including cancer development.

The Effects of Calorie Restriction on Osteoporosis and Bone Mass CR is suggested to prevent age-associated bone loss and osteoporosis although, adverse effects were reported on bone mineral density and bone mineral content (Tatsumi et al., 2008; Talbott et al., 2001; Shen et al., 2013; Devlin et al., 2010). In this context studies reported contradictory results related to bone mass. For example, studies reported short term (up to 6 months) application of CR started at early age or old age, starting at 3 or 68 weeks of mice age respectively, resulted reduced bone mass and suppressed mineral density and bone formation both in cortical and trabecular bone tissue in either mice or rats (Tatsumi et al., 2008; Devlin et al., 2010; Ahn et al., 2014; Behrendt et al., 2016). However, beneficial effects of CR was reported when CR was applied for lifelong since these animals had significant increased lifespan and more bone mass compared to AL fed ones (Tatsumi et al., 2008). Similarly, Benhrendt et al. reported that application of lifelong 40% CR improved bone mineral density in lumbar vertebrae specifically in trabecular bone tissue (Behrendt et al., 2016). The molecular mechanism of effects of CR on bone structure and density were shown to be related to SIRT1 and leptin signaling pathways (Tatsumi et al., 2008; Zainabadi et al., 2017; Devlin et al., 2016). A 50% CR fed leptin receptor-deficient mice at early age had similar bone mass and bone formation with AL fed mice which suggests beneficial effects of leptin during growth on bone structure (Tatsumi et al., 2008). However, in another study bone mass density of leptin treated 50% CR fed mice were similar compared to CR group without any improvements on bone structure (Devlin et al., 2016). These results suggested that lifelong CR is beneficial for age-associated bone loss with high bone density while sort term CR have adverse effects independent of intervention age (Tatsumi et al., 2008; Behrendt et al., 2016).

Possible Molecular Mechanisms in the Effects of Calorie Restriction in Aging and Age-Related Health Problems Although beneficial effects of calorie restriction in healthy aging or age-related health problems have been shown in numerous studies, the exact molecular mechanism(s) of this phenomenon is/are yet to be clarified. In this context, studies have reported that CR performs its healthy aging effects through variety of molecular mechanisms such as IGF-I, sirtuins, oxidative stress, mTOR, inflammatory related molecules and miRNAs. For example, numerous studies have reported changes in different miRNAs level during normal aging (Weilner et al., 2013; Szafranski et al., 2015; Yamakuchi et al., 2008; Abraham et al., 2017; Dhahbi, 2014; Williams et al., 2007) as well as age-related conditions such as cell growth and differentiation, apoptosis, senescence, CVD, inflammation, neurological disorders, and cancer in variety of species including mouse models (Stark et al., 2005; Cui et al., 2007; Salta and De Strooper, 2012; Rome, 2015; Lages et al., 2011; Li et al., 2011; Olivieri et al., 2012). For example, Dhahbi et al. (2013) have studied the effects of CR on age related miRNA both in young and old mice (Dhahbi et al., 2013). They detected changes in the

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levels of 48 circulatory miRNAs associated with aging and their levels were reversed by CR in old mice. These 48 miRNAs have been previously associated with age-related conditions such as cancer, cardiovascular, inflammatory and neurodegenerative disorders (Dhahbi et al., 2013). Studies have also reported that there are other factors involved in the anti-aging effects of CR such as SIRT1, mTOR, AMPK, and BMAL1. For example, it was reported that 30% CR significantly increased lifespan of wild type mice but, the same amount of CR did not have any effects on lifespan in mouse model which was deficient for circadian clock transcription factor called BMAL1 (brain and muscle ARNT [aryl hydrocarbon receptor nuclear translocator]-like protein 1). In addition, factors like IGF-I and Insulin which were generally modulated by CR in most models were not affected by 30% CR in BMAL1 deficient mouse model which aging is accelerated (Patel et al., 2016). This made authors of the research claim that CR shows its effects in aging and biological clock by modulating BMAL1 activation (Patel et al., 2016). SIRT1 signaling is another necessary pathway for the beneficial effects of CR. In this context, increased lifespan, several behavioural and physiological changes induced by CR were not observed in SIRT1 KO mice (Boily et al., 2008; Chen et al., 2005). Moreover, involvement of mTOR signaling pathway in CR induced lifespan and health aging in rodent models was also reported in various studies (Roberts et al., 2017; Houtkooper et al., 2010). In summary, although the beneficial effects of calorie restriction on healthy aging has been widely accepted by the scientific communities, the type of CR, amount and duration of its application are still controversial. This could only be clarified by systematic and well planned animal studies especially with rodent studies. In addition, reduction in total food amount has similar beneficial effects with reduction in individual ingredients of diet such as protein or carbohydrate amount in aging and age related diseases. Moreover, identifying molecules including miRNAs and epigenetic mechanisms may be important in determining an effective strategy to deal with aging and age-related health problems including neuronal, inflammatory and CVD and cancer. Enhanced understanding of the important roles of these molecules in the control of age-related health problems through CR may lead to clinical advances in healthy aging and/or therapy of age-associated diseases. Therefore, modifying the levels of specific targets both in general circulation and at the targeted tissues level by using methods like CR and dietary factors which have no known side effects will have significant contribution in healthy aging and/or age related diseases. Rodent studies are important in this process because long term CR studies with non-primate or human subjects are more challenging.

Transposable Elements and Aging In the following part, we will cover the role of transposable elements (TEs) in aging and provide some evidence from the studies with rodents. Human genome contains at least 45% of TEs that are derived from the ancient viral integration to our genome (Kõks and Kõks, 2018). TEs have retained the ability to be expressed and become retrotransposed leading to the structural variations in the genome and genome instability. These sequences have been considered as “junk” DNA for long time, despite their ability to generate genetic diversity both within a population and within and individual. According to our current understandings, TEs have significant role in gene regulation, response to environmental factors and aging (De Cecco et al., 2013a; Savage et al., 2019). The role in pathogenesis of more than 100 diseases has been identified. Convincing evidence suggest the involvement of HERVs (subclass of TEs) in multiple sclerosis, schizophrenia, ALS and bipolar disorder (Kõks and Kõks, 2018; Savage et al., 2019). In addition to the pathogenesis of diseases, accumulating research has identified the role of TEs in aging (De Cecco et al., 2013a,b). As aging is the primary risk factor for many of the diseases, the molecular mechanisms of TEs in the aging would interfere with the age-dependent pathologies. The activation of TEs is related to the retrotransposition that causes generation of somatic mutations and copy number variants. It has been described that retrotransposition is multi-stage process where retrotransposition is the latest event preceded by the molecular events trying to stabilise the genome (De Cecco et al., 2013a). Multistage activation means that there is a time-gap between different stages and the activation of the steps is dependent on the preceding steps. The active transposition is normally inhibited in quiescent cells and this is considered to be a defensive mechanisms to inhibit retrotransposition in the nondividing cells (Yuan et al., 2011; Shi et al., 2007). It is a general understanding, that during the senescence these protective mechanisms are relaxed, and transposition will be allowed at later times. The chromatin changes and expression of transposable elements was evident in cells being in senescence 6–8 weeks after cessation of proliferation (De Cecco et al., 2013a). At the same time, the culture that had just reached proliferative barrier showed minimal TE expression. Increased copy numbers as a result of retrotransposon events, will appear only at 3–4 months after the entry into senescence (De Cecco et al., 2013a). While the activation of TEs during aging is viewed as a degenerative change, rather than a cause of cellular aging, additional details and better understanding about the role of TEs in the aging is necessary. The idea that transposons cause aging is not new and was initially proposed in 1990 (Murray, 1990). The hypothesis was attractive as it could explain many of the properties of senescent cells. Most importantly, it helps to explain the increased number of duplications and the potential inactivation of an essential gene leading to the senescence of cell (Murray, 1990). Indeed, upregulation of SINE/Alu transcription upon ex vivo aging induces cytotoxicity and formation of persistent DNA damage loci and defective repair in pericentric chromatin (Wang et al., 2011). Depletion of the Alu transcription reversed the senescent phenotype and restored the self-renewing properties. TEs are usually silenced by methylation and during aging this methylation can be changed by the environmental factors. In a cohort study the association between methylation of TEs and lung function was analysed (Lange et al., 2012). Bivariate and multivariate modelling identified clear correlations between the methylation of TE sites and the lung function decline caused by normal aging (Lange et al., 2012). The findings from mouse models are even more suggestive. In liver, the transcription of L1 LINEs is increased in the mice aged 24 and 36 months, compared to the 5 month old mice (De Cecco et al., 2013b). L1 RNA was

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unchanged at 24 months and showed a statistically significant increase at 36 months. L1 LINEs are the largest family of potentially active TEs and are capable of independent retrotransposition. Therefore, higher expression of L1 LINEs clearly suggest the increased transposition activity. Satellite elements is another group of repetitive sequences that are localized mostly in the centromeric, pericentromeric and telomeric regions of the genome compromising a significant fraction of the heterochromatin (Pezer et al., 2012). Satellite elements are repressed, but they are responsive to the stress and differentiation signals. Satellites become massively derepressed during aging and the studies have shown transcriptional activation of satellites in the mouse liver with the largest changes between 24 and 36 months (De Cecco et al., 2013b). Major pericentromeric satellite element, MSAT showed a strong 5-fold increase at 24 month and a further 11-fold increase at 36 months in the liver of mice (De Cecco et al., 2013b). In the muscle, MSAT showed 90-fold increase at 36 months (De Cecco et al., 2013b). Similarly to LINEs and satellites, the expression of SINE elements was also upregulated in the mouse liver and muscle during the aging (De Cecco et al., 2013b). Several manipulations reducing TE expression have been shown to reduce the aging effects. Caloric restriction is a known intervention to increase lifespan in a wide range of organisms from invertebrates to mice. Dietary restriction was able to delay the agerelated increase in TE transposition in fruit flies and in mice (De Cecco et al., 2013b; Wood et al., 2016). In mice, the upregulated expression of MSAT, L1, MusD, B1 and B2 elements was attenuated with caloric restriction (De Cecco et al., 2013b). Similarly, caloric restriction prevented the TE activation in fruit flies (Wood et al., 2016). Dietary restriction was shown to counteract the age-related increase in TE expression that was common in high calorie diet group (Wood et al., 2016). Importantly, pharmacological suppression of reverse transcriptase activity with lamivudine reduced the activity of TEs. This effect was accompanied with the extended life span of flies (Wood et al., 2016). Similarly, a high-fat diet induced significantly pronounced TE expression in the livers of middle-aged mice and it is postulated that calorie restriction could inhibit this increase and normalise the TE activation (Lai et al., 2019). ERVL and ERV1 were negatively correlated with the life-span of mice with correlation coefficients
0.83 and
0.58 respectively (Green et al., 2017). Mouse chromodomain helicase DNA binding protein 1 (Chd1) was identified as one of the targets for the life-span related interventions. Knockdown of the Chd1 mimicked the effect of high-fat diet and aging induced activation of TEs (Lai et al., 2019). ERVL-MaLR and ERVL largely displayed elevated expression compared with other TEs during aging or high-fat diet and elevated expression was also evident after the knockdown of the Chd1 (Green et al., 2017). This derepression was in significant correlation with the enrichment of Chd1 binding sites indicating its role in regulation of TE expression. Chd1 may act as an repressors of TE transcription in correlation of aging and high-fat diet exposure (Green et al., 2017). Therefore, TEs are not just important for aging but also for the longevity and environmental manipulations can alter this the activity of TEs. In addition to the specific transcription factors, Piwi-piRNA pathway has ability to repress TE activity and promotes posttranscriptional processing of TEs (Sousa-Victor et al., 2017). Piwi-piRNA pathway is a common strategy to silence the transposition and it is considered to be regulator of aging as Piwi overexpression prevents age-dependent decline (Sousa-Victor et al., 2017; Lenart et al., 2018). It is evident that uncontrolled TE activity is a threat to genome integrity and is required for proper regulation of the gene expression on genomics scale. Silencing of TEs is especially important in the germline, as the mistakes in this lineage will immediately pass to the next generation and have a huge effect on the organismal health and survival. Somatic cells are more tolerable and disposable in this sense. Accordingly, the Piwi-piRNA pathway is mainly active in the germline, although recent evidence suggests that it can also be active in the brain and maybe some other tissues and are related to the age-depended pathologies. Recent data suggest that tauopathies induce Piwi-piRNA depletion that promotes the neuronal cell death (Sun et al., 2018). In consideration of the age-dependent brain pathologies, tau-induced pathologies are associated with the increase in the mobilisation of TEs (Sun et al., 2018; Guo et al., 2018). Neurofibrillary tangle burden was associated with the differential expression of several retrotransposons like LINE1 and HERVs (Guo et al., 2018). Among other elements, HERV-Fc1 and HERV-K were also upregulated in the brains affected by tauopathies (Sun et al., 2018). Elevated HERV-K has been associated with the amyotrophic lateral sclerosis and with several other human diseases (Kõks and Kõks, 2018). All this evidence suggests, that several subclasses of TEs are involved in the age-dependent disorders. The complex involvement of TEs in the aging and diseases is somehow comparable with the effects of mutations in some wellknown protein coding genes. One example is WFS1 gene. The function of the WFS1 gene is still unknown, but there is evidence for its involvement in the aging and degeneration (Koks et al., 2009). We have developed a mouse model with WFS1 deficiency and have shown that a non-functional Wfs1 gene causes growth retardation and shortens life expectancy (Koks et al., 2009; Ehrlich et al., 2016). Moreover, these mice display activation of degenerative biological processes, resulting in a reduced number of pancreatic islets, body weight and fertility (Noormets et al., 2009). Wfs1-deficient mice have permanently activated ER stress, which leads to neurodegeneration and development of variable neuropsychiatric diseases (Koido et al., 2005; Must et al., 2009; Lindholm et al., 2017). The WFS1 gene is highly variable with more than 170 different mutations described so far (Rigoli et al., 2018). The genomic locus of this gene contains at least two evolutionary younger TE elements indicating potential regulation of the WFS1 activity that could explain the association with longevity and aging. However, direct interaction between TEs and WFS1 gene has not been analysed yet. In summary, TEs are epigenetically repressed during normal development and staying silenced is required for normal health and physiology. During aging the TEs become gradually activated and increase the instability of our genome leading to the enhanced aging and development of age-related diseases. The analysis of mouse models is invaluable tool to understand the mechanisms regulating TEs and their silencing during the aging or age-related diseases. TEs are also responsive for the changes caused by the environmental factors, like food intake. It would be fundamentally important to describe the environmental factors that can alter the TE silencing and the mechanisms how it is done. Given the role of TEs in carcinogenesis and neurodegenerative diseases, understanding of these mechanisms could potentially help us to treat these diseases.

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Further Reading Ackert-Bicknell, C.L., et al., 2015. Aging Research Using Mouse Models. Current Protocols in Mouse Biology 5 (2), 95–133. Blease, A., et al., 2018. Generation and Identification of mutations resulting in chronic and age-related phenotypes in mice. Current Protocols in Mouse Biology 8 (2), e42. Burtner, C.R., Kennedy, B.K., 2010. Progeria syndromes and ageing: What is the connection? Nature Reviews. Molecular Cell Biology 11 (8), 567–578. Crimmins, E.M., 2015. Lifespan and healthspan: Past, present, and promise. Gerontologist 55 (6), 901–911. Carmona, J.J., Michan, S., 2016. Biology of healthy aging and longevity. Revista de Investigación Clínica 68 (1), 7–16. Koks, S., et al., 2016. Mouse models of ageing and their relevance to disease. Mechanisms of Ageing and Development 160, 41–53. Kudlow, B.A., Kennedy, B.K., Monnat Jr., R.J., 2007. Werner and Hutchinson-Gilford progeria syndromes: Mechanistic basis of human progeroid diseases. Nature Reviews. Molecular Cell Biology 8 (5), 394–404. Kirkland, J.L., Stout, M.B., Sierra, F., 2016. Resilience in aging mice. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 71 (11), 1407–1414. Liao, C.Y., et al., 2010. Genetic variation in the murine lifespan response to dietary restriction: From life extension to life shortening. Aging Cell 9 (1), 92–95. Lenart, P., Novak, J., Bienertova-Vasku, J., 2018. PIWI-piRNA pathway: Setting the pace of aging by reducing DNA damage. Mechanisms of Ageing and Development 173, 29–38. Menting, M.D., et al., 2019. Maternal obesity in pregnancy impacts offspring cardiometabolic health: Systematic review and meta-analysis of animal studies. Obesity Reviews 20 (5), 675–685. Pendas, A.M., et al., 2002. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nature Genetics 31 (1), 94–99. Richardson, A., et al., 2016. Measures of healthspan as indices of aging in mice-A recommendation. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 71 (4), 427–430. Xu, Y., Sun, Z., 2015. Molecular basis of Klotho: From gene to function in aging. Endocrine Reviews 36 (2), 174–193. Xu, M., et al., 2018. Senolytics improve physical function and increase lifespan in old age. Nature Medicine 24 (8), 1246–1256.

Aging in the Nematode Caenorhabditis elegans Ioanna Daskalaki, Foundation for Research and Technology-Hellas, Heraklion, Greece; and Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Greece Maria Markaki, Foundation for Research and Technology-Hellas, Heraklion, Greece Nektarios Tavernarakis, Foundation for Research and Technology-Hellas, Heraklion, Greece; and Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Greece © 2020 Elsevier Inc. All rights reserved.

Introduction Genetic Regulation of Lifespan Insulin/IGF-1 Signaling AMPK TOR Signaling Mitochondria-Mediated Lifespan Control The Jnk-1 Pathway The Reproductive System Nongenetic Regulation of Aging Epigenetic Alterations and Aging Chromatin modifications Environmental stimuli, epigenome remodeling, and more Stress response pathways in lifespan control Pharmacological Interventions Modulating Aging Concluding Remarks Acknowledgments References

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Introduction Aging is a complex, multifaceted process that takes place over time and is experienced by the vast majority of living organisms. Aging can be defined as the progressive accumulation of damage to molecules, cells and tissues, ultimately leading to physical and functional deterioration of the entire organism. As such, aging is associated with increased susceptibility to disease onset, including neurodegeneration, muscle atrophy, cancer and type II diabetes (Tosato et al., 2007; Lopez-Otin et al., 2013). Over the past decades, much effort has been invested in understanding the regulatory mechanisms and the key factors involved in the aging process. Evidence up to now obtained from studies performed in model organisms such as yeast, worms, flies and mice indicates that aging is affected not only by genetic alterations but also by epigenetic mechanisms and environmental factors. Research in the aging field focuses on the elucidation of the basic cellular and molecular mechanisms underlying the progressive decline in cellular function that accompanies aging. The ultimate goal of such studies is to develop efficient intervention strategies to slow the aging process, thereby prolonging healthspan (maintaining a healthy state) (Madeo et al., 2015). The most robust output of aging studies is the measurement of lifespan. Lifespan is the maximum time period an organism is alive. Several theories have been developed over time, trying to explain the fundamental biological phenomenon of aging. For instance, the “somatic mutation,” “cellular waste accumulation,” “rate of living,” “free radical,” and the “wear and tear” are among the most important theories of aging that have evolved within the last four decades of research (Vina et al., 2007). The fact that none of these theories can fully explain aging supports the notion that a multilevel and holistic view of the complex processes of aging and senescence is needed (Jin, 2010). Over the past 20 years, much progress has been made in the field of aging. Research using model organisms revealed that aging is subject to regulation, like many other biological processes (Kenyon, 2010). This was first shown in the nematode C. elegans where genetic manipulations or changes in the way of living could reverse age-related phenotypes even when some of these were performed in already old animals (Smith et al., 2008). C. elegans has been widely used in aging studies during the last 100 years (Tissenbaum, 2015). The nematode offers unique advantages, highly relevant to the scientific questions to be tackled, which are not available in any other model system and this is proved by the fact that key findings in the field are derived from studies carried out in the worm. Specifically: It is short lived. C. elegans lives approximately 2 weeks, in contrast to other models which live several months or years. Additionally, it has a short life cycle and reproduces very easily in large numbers, creating genetic clones of itself due to self-fertilization. This is really important as it enables researchers to perform multitudinous experiments that improve data accuracy, thus increasing the impact of their studies (Gershon and Gershon, 2002). Also, elimination of the genetic variation among single individuals in a population allows robust interpretation of the results obtained by targeted manipulations. Another advantage is its transparent body at all stages, trait that enables optical monitoring and in vivo analysis of fundamental biological processes inside single cells and tissues during aging (Corsi et al., 2015). Also, C. elegans has approximately the same number of genes when

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compared to humans, most of which are evolutionarily conserved (Aboobaker and Blaxter, 2000). So, investigators can study and understand molecular mechanisms that are conserved in higher eukaryotes, including humans, using a very simple eukaryote instead. Importantly, its nervous system is fully charted, with the position and the connectivity of its 302 neurons precisely described. This unique trait among multicellular eukaryotic organisms allows a comprehensive study of age-related neurodegeneration events (Chew et al., 2013). Moreover, transgenic animals or viable mutants can be generated quite easily and efficiently, allowing the genetic dissection of signaling pathways and molecular mechanisms mediating aging (Wilkinson et al., 2012). It is worth noting that C. elegans is becoming an attractive platform for developing drug discovery and drug target identification methodologies. In this article, we will discuss the main advances in our understanding of the genetic and nongenetic modulators of the aging process. We will refer to the effector mechanisms and key factors that are activated downstream of signaling pathways focusing on studies pioneered in C. elegans. We will also discuss the contributions of epigenetics and environmental factors to aging phenotypes in the worm.

Genetic Regulation of Lifespan Insulin/IGF-1 Signaling One of the first lifespan-influencing pathways identified in C. elegans is the endocrine insulin/IGF-1 pathway. The first gene mutation in this pathway shown to significantly increase lifespan was in age-1, which encodes the nematode orthologue of the mammalian phosphoinositide-3 kinase (PI3K) p110 subunit (Friedman and Johnson, 1988). A few years later, the C. elegans orthologue of the mammalian insulin and IGF-1-like receptors was identified. This is encoded by the daf-2 gene (Kenyon et al., 1993; Dorman et al., 1995). Interestingly, it was shown that mutations in the insulin receptor gene that impair its function confer significant lifespan extension in a cell nonautonomous manner in various species, including worms, flies and mice (Apfeld and Kenyon, 1998; Selman et al., 2008; Partridge et al., 2011). The insulin/IGF-1 receptor is recognized by several insulin-like peptides (ILPs) which either act as agonists or antagonists of the receptor. Despite the fact that more than 40 different insulin-like peptides have been identified up to now, none of them is similar to human insulin. When an agonist peptide binds to and activates the receptor DAF-2, then AGE-1 is phosphorylated and activated. Subsequently, AGE-1 phosphorylates and activates the Akt/protein kinase B family of serine/threonine protein kinases, AKT-1 and AKT-2 in C. elegans and the serum- and glucocorticoid-inducible kinase 1(SGK-1). AKT-1, AKT-2 and SGK-1 phosphorylate the DAF-16/FOXO (controlled, germline tumour affecting-1) transcription factor (Lin et al., 2001). Phosphorylation of DAF-16 leads to its sequestration in the cytoplasm, with consequent inhibition of its transcription factor activity. Mutations in daf-2, which lead to lifespan extension, dauer larvae formation, and increased stress resistance, require the nuclear translocation of DAF-16 and activation of its downstream target genes (Honda and Honda, 1999; Barsyte et al., 2001; Scott et al., 2002; Lithgow et al., 1995). Microarray analysis of DAF-16 target genes and potential mediators of the daf-2 mutant lifespan extension revealed an increase in the expression of genes involved in environmental stress responses and of antimicrobial genes mediating immune responses. Surprisingly, downregulation of each of these genes does not reverse the long lifespan of daf-2 mutants. This finding supports the idea that not a single target/pathway, but instead, a global response mediates the daf-2 longevity phenotype (Murphy et al., 2003). Tissue-specific expression analysis revealed that daf-16 expression in muscles is not needed for lifespan extension, while its neuronal expression only moderately enhances the longevity of daf-16(
);daf-2(
) mutants. On the other hand, intestinal expression of daf-16 increases substantially the lifespan of these animals. Interestingly, however, the activity of DAF-16 in additional tissues, besides the intestine, is required to fully restore the lifespan of daf-16(
);daf-2(
) animals (Libina et al., 2003). Complementary studies proved that DAF-16 functions cell non-autonomously to promote longevity. Despite the fact that its activation in a single tissue (mainly the intestine) produces insulin-like molecules or hormones that can signal to the rest of the tissues, DAF-16 activity in these “downstream” tissues is also required for activation of, at least part of, its targets genes in these locations. Surprisingly, the signaling for lifespan extension differed from that for dauer formation. In the latter case, neuronal daf-16 expression was needed (Libina et al., 2003). Concomitantly, it was found that neuronal daf-2 expression harbors the signaling for longevity (Wolkow et al., 2000). Moreover, DAF-2 loss postdevelopmentally is sufficient to confer lifespan extension and stress resistance as shown by parallel experiments in which daf-2 RNAi treatment was initiated at the young adult stage and at hatching. Indeed, DAF-2 depletion in young adults results in the same lifespan extension as DAF-2 deficiency from the time of hatching. The same effect was observed when adult animals were treated with paraquat. Enhanced resistance to oxidative stress is a trait of daf-2 mutants and it was shown that animals subjected to daf-2 RNAi from adulthood were as resistant to oxidative stress as the ones treated from larval stages (Dillin et al., 2002a). Analysis of the pathways that influence lifespan extension downstream of the insulin/IGF-1 pathway showed that genes related to vesicle sorting, endocytotic trafficking to the lysosomes, autophagy, heat shock response (hsf-1 upregulation) and proteostasis, energy metabolism homeostasis (aak-2), fat and lipid homeostasis, and transcription- and translation-related genes were among the most important regulators. Reducing their activity caused progeria-related phenotypes in daf-2 mutant animals (Samuelson et al., 2007; Hsu et al., 2003; Li et al., 2013). The transcription factor SKN-1 (SKiNhead-1) is also required for the daf-2 lifespan extension. SKN-1 and HSF-1 (Heat shock transcription factor-1) act synergistically to DAF-16 and activate distinct target genes (Tullet et al., 2008; Seo et al., 2013). More recently, SMK-1, a regulatory molecule that determines DAF-16 transcriptional specificity, and PQM-1, a zinc finger transcription factor, have assigned a role in longevity mediated by reduced DAF-2 activity. Interestingly, the nuclear localization of PQM-1 and DAF-16 appears to be mutually exclusive (Wolff et al., 2006; Tepper et al., 2013) (Fig. 1).

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ILPs

Nutrients, growth factors Cell membrane

JKK-1

AMP/ATP

P AGE-1 CGEF-1

PAR-4 mTOR

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RSKS-1

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CTRC-1 Nucleus

CRH-1

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SKN-1 PHA-4

HSF-1

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SMK-1

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Fig. 1 Genetic regulation of lifespan. The insulin/IGF- (IGF-1), the target of rapamycin (TOR), and the AMPK signaling pathways act both in parallel and synergistically to affect lifespan. Phosphorylation events and pathway crosstalk fine-tune transcription factor activation in the nucleus and determine longevity. More details and description of additional signal transduction cascades that influence lifespan in C. elegans can be found in the text.

AMPK AMPK (AMP-activated kinase) is a multimeric complex that consists of one catalytic (a subunit) and two regulatory (b and g) subunits (Apfeld et al., 2004). Two homologues of the catalytic a subunit of AMPK were identified in C. elegans, AAK-1 and AAK-2 (Apfeld et al., 2004; Lee et al., 2008; Curtis et al., 2006). Despite their high sequence similarity, only AAK-2 plays a role in lifespan regulation (Apfeld et al., 2004). It acts as an energy sensor inside cells and is induced when energy levels drop. AAK2 activation is mainly mediated by PAR-4 in C. elegans, the mammalian LKB1 (liver-kinase-B1) orthologue which phosphorylates AAK-2 at Thr243 (Lee et al., 2008; Narbonne and Roy, 2006). Activated AMPK phosphorylates multiple substrates to stimulate catabolic processes, ultimately restoring homeostasis (Moreno-Arriola et al., 2016). Indeed, transcriptomic analysis of aak-2 mutant animals revealed that ribosomal and histone genes, translation-related and sperm genes, as well as oxidative phosphorylationrelated genes were significantly downregulated as compared to their control counterparts (Shin et al., 2011). This is partially mediated through allosteric mechanisms, when the AMP/ATP ratio is significantly increased (Hardie, 2011). An elevation in the AMP/ ATP ratio is monitored, for example when animals are exposed to stress, starvation, mitochondrial dysfunction, exercise, or upon dysfunction of the insulin/DAF-2 receptor (Apfeld et al., 2004; Lee et al., 2008; Curtis et al., 2006; Shin et al., 2011; Fukuyama et al., 2012; Chang et al., 2017). Regulation of the energy metabolism status of the cell through AMPK/AAK-2 is an important lifespan regulatory mechanism. This is supported by findings showing that aak-2 mutation or downregulation either from hatching or in adulthood causes premature aging phenotypes and significantly decreases lifespan in C. elegans (Apfeld et al., 2004; Curtis et al., 2006). In contrast, lifespan is increased when aak-2 is overexpressed or mutated to be constitutively active (Mair et al., 2011; Greer et al., 2007). Furthermore, AAK-2 has been shown to mediate part of the daf-2 longevity acting in parallel with DAF-16 (Apfeld et al., 2004). AAK-2 phosphorylates DAF-16 and enhances its transcription activity. Also, loss of AAK-2 function decreases the longevity of daf-2 mutant animals (Greer et al., 2007). Reciprocally, DAF-16 is also needed for aak-2-induced lifespan extension as it upregulates two of the AMPK core subunits, AAKG-4 and AAKB-1, even though only AAKG-4 is linked with lifespan. As a result, AAK-2 and DAF-16

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form a positive feedback loop which enhances the effect of DAF-16-dependent lifespan extension (Tullet et al., 2014). Apart from DAF-16, SKN-1 is also activated by AAK-2 (Onken and Driscoll, 2010). Interestingly, it was shown that the AAK-2 agonist, metformin induces SKN-1 nuclear translocation and enhances its transcriptional activity (Onken and Driscoll, 2010). Moreover, AAK-2 activity triggers autophagy. This is achieved directly through phosphorylation of UNC-51 by AAK-2 and indirectly through activation of DAF-16 (Possik et al., 2014; Egan et al., 2011). Autophagy activation has also been linked to lifespan extension in various genetic backgrounds, such as daf-2 and rsks-1 mutants. Importantly, autophagy induction and enhanced stress resistance reportedly mediate aak-2 lifespan extension. The longevity phenotype induced by aak-2 overexpression or when AAK-2 is constitutively active has also been linked with CTRC-1 (cAMP response element binding protein-regulated transcriptional coactivator-1) inhibition. More specifically, it was shown that AAK-2 kinase directly phosphorylates CRTC-1, triggering its nuclear exclusion and inactivation. Neuronal inhibition of CTRC-1 is a prerequisite for AAK-2 dependent lifespan extension, as mutation of CRTC-1 at the AAK-2 recognition phosphorylation sites renders it unresponsive to AAK-2 phosphorylation and constitutively nuclear, blocking the lifespan extension phenotype triggered by aak-2 overexpression (Mair et al., 2011; Burkewitz et al., 2015). More specifically, it was shown that neuronal CRTC-1 acts cell nonautonomously through the octopamine signaling to regulate lifespan by modulating metabolism and mostly mitochondrial metabolism in distal tissues. Also, NHR-49 activation in neurons is sufficient for AMPK-mediated longevity as it possesses antagonistic to CRTC-1 functions (Burkewitz et al., 2015). Complementary studies showed that NHR-49 and MDT-15 mediate the metabolic changes related to fat metabolism, fatty acid oxidation, and lipid synthesis downstream of AAK-2 activation (Moreno-Arriola et al., 2016). Nuclear exclusion of CTRC-1 leads to impaired activity of the CRH-1 transcription factor, which is the cyclic AMP response element binding (CREB) transcription factor family CREB homologue in C. elegans (Mair et al., 2011). This mechanism functions downstream of AAK-2, when the kinase is activated, to prolong lifespan (Fig. 1).

TOR Signaling Increased availability of nutrients, growth factors, and amino acids has been linked to shortened lifespan in various model organisms. By contrast, lifespan is significantly increased upon nutrient or growth factor deprivation (Kapahi et al., 2017). The regulation of lifespan under these conditions has been consistently linked to TOR (target of rapamycin) signaling. TOR, which is a highly conserved serine/threonine kinase, is inhibited when nutrients and growth factors are limited as well as when cellular energy levels drop (Sengupta et al., 2010). Increased amounts of nutrients and growth factors lead to activation of Akt, which phosphorylates its targets and activates TOR (Laplante and Sabatini, 2012; Sancak et al., 2007; Manning et al., 2002; Inoki et al., 2002). Moreover, under conditions where cellular energy levels decrease, AMPK is activated and phosphorylates either Tsc2 (which does not have a C. elegans homologue) or Raptor and subsequently represses TORC1 activity (Inoki et al., 2003; Gwinn et al., 2008). In C. elegans, the let-363 gene encodes the mammalian homologue of TOR (Long et al., 2002). As known from mammals, and is also the case in C. elegans, TOR forms two distinct complexes with discrete functions, TORC1 and TORC2. TORC1 formation requires TOR/LET-363 association with its co-activator DAF-15 (the nematode homologue of Raptor), the Rag GTPases RAGA-1 and RAGC-1, and RHEB-1 (the nematode homologue of mammalian Rheb) (Hara et al., 2002; Lapierre and Hansen, 2012). Another, recently identified factor that regulates TORC1 activity in C. elegans is CGEF-1, the homologue of Dbl in mammals. Recent evidence indicates that CGEF-1 interacts with RHEB-1 and activates TORC1 (Li et al., 2018). TORC1 activation inhibits DAF-16 and SKN-1 activity, while DAF-16 can reciprocally inhibit DAF-15, forming a negative feedback loop (Robida-Stubbs et al., 2012; Jia et al., 2004). Placing additional complexity to this system, SKN-1 increases the expression of TORC1 genes (Robida-Stubbs et al., 2012; Zhao and Wang, 2016). Moreover, TORC2 formation requires the TOR/LET-363 interaction with its coactivator RICT-1, the homologue of the mammalian Rictor (Lapierre and Hansen, 2012). TORC2 formation and activation inhibits SKN-1 transcriptional activity (Robida-Stubbs et al., 2012; Ruf et al., 2013). On the other hand, it is not fully understood yet whether only one out of two complexes or both TORC1 and TORC2 contribute to PHA-4/FOXOA inhibition. Nevertheless, evidence up to now suggests that LET-363 suppresses PHA-4 through RSKS-1, the homologue of the mammalian S6 kinase (S6K) (Sheaffer et al., 2008). Interestingly, it has been shown that TOR hyperactivity is linked to shortened lifespan while downregulation or inhibition of the TOR pathway leads to lifespan extension (Lamming and Sabatini, 2011; Vellai et al., 2003). Pharmacologic inhibition of TOR activity by rapamycin also leads to lifespan extension in several model organisms. Again in this case, TORC1 is more vulnerable to rapamycin while TORC2 is quite unaffected (Ballou and Lin, 2008). Furthermore, genetic inhibition of rsks-1, raga-1 and daf15/Raptor, among other components downstream of the TORC1/TORC2 complexes, also increases lifespan (Robida-Stubbs et al., 2012; Jia et al., 2004; Pan et al., 2007). This beneficial effect on lifespan is mediated by the initiation of a transcription program that includes activation of HLH-30/TFEB, SKN-1, DAF-16 and HIF-1a target genes (Robida-Stubbs et al., 2012; Lapierre et al., 2013; Land, 2007). The effect on lifespan is also governed by transcription-independent mechanisms which involve the phosphorylation of the translation regulators, RSKS-1/S6K and the translation initiation factor 4E binding protein 1 (4E-BP1) as well as ribosome biogenesis regulators (Showkat et al., 2014). Additionally, HSF-1 transcriptional activity is also needed for lifespan extension by let-363 and rsks-1 suppression, as HSF-1 depletion even from adulthood suppresses the extended lifespan of rsks-1 mutants (Seo et al., 2013). Deeper analysis showed that the HSF-1 target gene hsp-16 is partially needed for rsks-1 longevity (Seo et al., 2013). The driving mechanisms of lifespan extension resulting from TOR downregulation rely on vital processes: translation inhibition, lipid metabolism, and autophagy induction (by PHA-4) (Long et al., 2002; Johnson et al., 2013). Both translation inhibition and autophagy induction have been directly associated with lifespan extension in various model organisms (Pan et al., 2007; Syntichaki et al., 2007; Nakamura and Yoshimori, 2018; Hansen et al., 2007). Inhibition of let-363 has also been linked to elevated

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lipolysis and LIPL-4 levels (Seah et al., 2016). Additionally, let-363 deletion leads to fat accumulation as shown for monounsaturated fatty acids (MUFAs), a phenotype that has also been linked to long lifespan, while both daf-15 and rict-1 mutants contain increased number of lipid droplets (Shi et al., 2013; Han et al., 2017). These are adaptive responses to TORC1 inhibition which are activated to regulate organism metabolism by switching from anabolic, energy consuming processes to more catabolic ones (Fig. 1).

Mitochondria-Mediated Lifespan Control Mitochondria are semiautonomous organelles containing their own genome, which encodes only about 1%–2% of their protein content. The rest of their components are encoded by the nuclear genome and after being translated in the cytoplasm, they are imported and targeted to the various suborganellar compartments. Mitochondria serve important functions that influence many aspects of cellular and organismal physiology, ultimately impinging on organismal healthspan and lifespan. Specifically, they primarily regulate energy production in the form of ATP through oxidative phosphorylation of the electron transport chain (ETC). They have essential roles in the maintenance of heme and iron/Sulphur cluster homeostasis, the regulation of lipid metabolism, calcium and copper homeostasis, amino acid production, apoptosis, and cell cycle (Guda et al., 2007; Lill et al., 2012; Alaynick, 2008; Duchen, 2000; Horn and Barrientos, 2008; Wang and Youle, 2009; Antico Arciuch et al., 2012). The reason why mitochondria have attracted so much interest is because their dysfunction is linked to several pathological conditions such as diabetes, premature aging, neurodegeneration, cancer, and cardiomyopathy as shown in several model organisms (Ventura and Rea, 2007; Rivera-Torres et al., 2013; Zong et al., 2016; El-Hattab and Scaglia, 2016; Newsholme et al., 2012). To date, mild perturbation of mitochondrial function by either pharmacological treatments or genetic inhibition of electron transport chain components (ETC) has been linked to lifespan extension and increased stress resistance (Rea et al., 2007; Ristow and Schmeisser, 2014). This phenomenon is called mitohormesis. Interestingly, mutation or downregulation of ETC components (Mit mutants) associated with increased oxidative damage to mitochondrial proteins severely affects lifespan in C. elegans and other organisms. For example, mutation or genetic inhibition of either mev-1 or gas-1 shortens the worm lifespan (Baruah et al., 2014; Kayser et al., 2004). By contrast, downregulation of atp-3, clk-1, cco-1, nuo-1, nuo-6, isp-1, frh-1 significantly increases lifespan independently of the daf-2/daf-16 axis (Ventura and Rea, 2007; Rea et al., 2007; Cristina et al., 2009; Chin et al., 2014; Lee et al., 2010; Curran and Ruvkun, 2007). Surprisingly, some genetic inhibitions may not have the same effect with mutation in the same gene (Yang and Hekimi, 2010a). Nevertheless, the effect of downregulation of mitochondrial components on lifespan is evident only when the intervention occurs during development, unlike to what happens in the long-lived insulin mutants described previously (Dillin et al., 2002b). Lifespan extension, in response to a mitochondrial perturbation, is most probably mediated through altered production of oxidative phosphorylation metabolites such as ATP and ROS (Van Raamsdonk et al., 2010). For example, mutations that decrease respiration and ATP levels, thus metabolism, increase lifespan, as suggested in the “rate of living theory of aging” first introduced by R. Pearl in 1928. In other cases, ETC mutations cause elevated ROS levels and through mitohormesis enhance longevity (Lee et al., 2010). Initially, it was believed that ROS levels are a determinant of lifespan. According to this theory, increased ROS production due to oxidative phosphorylation causes mtDNA damage that contributes to cellular damage which over a lifetime triggers aging (Cui et al., 2012). This is the so-called free radical or oxidative damage theory of aging (Harman, 1956). Later, it was shown that, in contrast to what was initially believed, O2
levels are totally uncoupled from aging and mild ROS production is even beneficial as both mutation in the sod-2 gene, which encodes a superoxide dismutase isoform, and mild paraquat treatment increase lifespan in C. elegans according to the “mitohormesis theory” (Lee et al., 2010; Van Raamsdonk et al., 2010; Doonan et al., 2008). This occurs because ROS act as signaling molecules inside cells and can either activate and stabilize HIF-1 or activate the intrinsic apoptotic pathway, among other responses (Lee et al., 2010; Yee et al., 2014). Mitochondrial mutations trigger the activation of several pathways or transcription factors to counteract stress and confer the lifespan extension phenotype observed. A number of pathways are activated in response to mitochondrial perturbation, such as the selective mitochondrial autophagy (mitophagy), mitochondrial unfolded protein response (mtUPR), activation of the intrinsic apoptosis pathway, elevation of antioxidant genes and the detoxification response, mitochondrial biogenesis, fatty acid oxidation, metabolic reprogramming, and activation of the aak-2 pathway (Burkewitz et al., 2015; Ventura and Rea, 2007; Yee et al., 2014; Jovaisaite et al., 2014; Sun et al., 2016; Weir et al., 2017; Butler et al., 2010, 2013; Palikaras et al., 2015; Yang and Hekimi, 2010b). Several transcription and transcription-related factors are also activated such as ATFS-1, HIF-1, FSTR-1/2, CHE-23, SKN1, the TAF-4/TFIID complex, and cep-1, among others (Baruah et al., 2014; Cristina et al., 2009; Lee et al., 2010; Khan et al., 2013; Walter et al., 2011; Durieux et al., 2011). Nevertheless, discrete transcriptional programs and downstream mechanisms are activated in a mutation-specific manner as shown, for example in clk-1, isp-1, and cyc-1 mutants (Cristina et al., 2009). Additionally, it was shown that in isp-1 and mev-1 mutants, cep-1 oppositely affects longevity by activating different subsets of genes (Baruah et al., 2014). mtUPR is a stress response pathway that is induced when misfolded/unfolded proteins accumulate in the mitochondrial matrix. It consists of a transcription program that relies on ATFS-1 and DVE-1 transcription factors and the transcription coactivator UBL-5 to produce mainly chaperons which are transported to the organelle to alleviate stress (Haynes et al., 2013). mtUPR is also activated by ROS-induced mtDNA lesions and when components of the translation machinery of mitochondria are perturbed (Ventura and Rea, 2007; Moehle et al., 2018). To note, the lifespan extension of long-lived mitochondrial translation mutants such as mrps-5 depends on the activation of mtUPR (Jovaisaite et al., 2014; Houtkooper et al., 2013). Furthermore, it has been shown that mtUPR induction even in a single tissue can signal and initiate the response to additional tissues through yet not well-understood mechanisms (Durieux et al., 2011). Nevertheless, artificial activation of mtUPR cannot extend lifespan

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or be used as a longevity marker by itself (Bennett et al., 2014). Another age-related phenotype is the accumulation of mtDNA mutations during aging but their impact on the aging process is still debated (Hirose et al., 2016). Interestingly, besides the organelle’s function, mitochondrial morphology, density and subcellular organization and localization are features that have been correlated with aging and age-related pathologies (Weir et al., 2017; Morsci et al., 2016; Yasuda et al., 2006; Chaudhari and Kipreos, 2017). On the other hand, despite being associated with the aging process, alterations in these characteristics are not sufficient to trigger cellular senescence by themselves (Regmi et al., 2014). Last, a recent study showed that dysfunctional mitochondria accumulate during aging in C. elegans. In young or long-lived animals, a healthy mitochondrial pool is retained through the balanced actions of mitochondrial biogenesis and mitophagy. In old animals, however, such quality control mechanisms decline. Moreover, mitophagy is partially required for the extended lifespan of specific long-lived C. elegans mutants (Palikaras et al., 2015).

The Jnk-1 Pathway JNK-1 is a serine/threonine protein kinase, member of the broader family of the mitogen-activated protein kinases (MAPK). In C. elegans, jnk-1 that encodes the homologue of the mammalian c-Jun N-terminal kinase (JNK) is expressed only in neurons. An additional component of the JNK pathway, which is also present in C. elegans, is JKK-1, a MAPKK family kinase which functions upstream of JNK-1 and activates it (Sakaguchi et al., 2004; Oh et al., 2005; Kawasaki et al., 1999). Besides its role in regulating stress responses, development, and inflammation, a role for JNK-1 in lifespan regulation has recently been established (Sakaguchi et al., 2004; Oh et al., 2005; Gerke et al., 2014). Indeed, overexpression of jnk-1 increases lifespan, in contrast to its genetic inhibition. The longevity effect of jnk-1 is also dependent on the presence and functionality of the upstream activating kinase JKK-1. JNK-1 regulates lifespan by directly interacting with and phosphorylating DAF-16 on its N-terminus (Oh et al., 2005; Gerke et al., 2014; Zhao et al., 2017). This phosphorylation event on DAF-16 seems to trigger its nuclear localization and transcriptional activation of target genes in a daf-2-independent manner. This is evident by the finding that jnk-1 overexpression has an additive effect on daf-2 longevity despite the fact that jnk-1 is needed for daf-2 lifespan extension (Oh et al., 2005). Apart from DAF-16, JNK-1 also triggers the expression of jun-1 and fos-1 transcription factors which also regulate fasting-induced lifespan extension in C. elegans (Gerke et al., 2014; Uno et al., 2013). Last, the MAPK kinases p38/PMK-1 and ERK/MPK-1 also affect longevity in C. elegans (Okuyama et al., 2010; Park et al., 2018) (Fig. 1).

The Reproductive System C. elegans gonad is a complex organ consisting of two distinct compartments: the somatic gonad and the stem cell niche, or the germline. Consistent with findings in several model organisms, where reduced reproduction positively affects lifespan, germline ablation, or genetic mutation in gld-1 (encoding a protein containing a K homology RNA binding domain) increases the worm lifespan more than 50% (Yamawaki et al., 2008). Intriguingly, this positive effect on lifespan is lost when the somatic gonad is concomitantly ablated, uncoupling sterility per se from lifespan extension (Yamawaki et al., 2008). Subsequent studies indicated that germline loss triggers steroid signaling initiated by the somatic gonad which is targeted to distal tissues (Antebi, 2013). Core mediators of this steroid signaling are the nuclear hormone receptor DAF-12 and its ligands, the dafachronic acids (DAs) (Hsin and Kenyon, 1999; Dumas et al., 2010). DA production is mainly regulated by enzymes such as DAF-9 (cytochrome P450), DAF-36 (Rieske oxygenase), and DSH-16 (3-hydroxysteroid dehydrogenase). Mutation in these enzymes abrogates the lifespan extension of germline-less animals (Jia et al., 2002; Wollam et al., 2011, 2012). While DA supplementation alone is not enough to extend the lifespan of wild-type worms, it does restore lifespan extension of animals lacking both the somatic gonad and the germline (Yamawaki et al., 2010; Gerisch et al., 2001). Downstream of the DA/DAF-12 axis, DAF-16 is activated specifically in the intestine in a daf-2 independent manner, while it is not clear yet whether DAF-12 mediates its effect through a single/specific tissue or not (Uno and Nishida, 2016). This was confirmed when lifespan extension of germline-less animals was abrogated by daf-16 mutation. DAF-12 activation by DA triggers an increase in the levels of mir-241 and mir-84, which negatively regulate AKT-1 and LIN-14 expression and finally trigger DAF-16 activity (McCormick et al., 2012). DAF-16 intestinal nuclearization and longevity of animals lacking the germline is regulated also by the Ankyrin repeat-containing protein KRI-1, which is also expressed in the intestine. KRI-1 is orthologous to the human KRIT1/CCM1 and its effects are daf-2 independent (Berman and Kenyon, 2006). Additionally, DAF16 nuclearization and lifespan extension of germline-less animals is enhanced by mir-71 (Boulias and Horvitz, 2012). In addition, HSF-1, SMK-1/SMEK-1, DAF-18/PTEN, and the transcription elongation factor TCER-1/TCERG1 are also shown to be important for promoting longevity in germline less animals (Wolff et al., 2006; Yamawaki et al., 2008; Chen et al., 2013; Wang et al., 2008; Ghazi et al., 2009). Furthermore, other factors needed for the enhanced longevity of germline deficient animals have been identified. For example, the nuclear receptors NHR-80 and NHR-49 which are fat metabolism regulators and the transcription factor PHA-4 (Goudeau et al., 2011; Ratnappan et al., 2014). NHR-80-dependent fat-6 elevation is important for lifespan extension and is also dependent on DAF16 (Goudeau et al., 2011; Ackerman and Gems, 2012). As far as PHA-4 is concerned, it mediates its effect by inducing autophagy in the intestine of germline-less animals. Lipolysis is also implicated because the triglyceride lipase LIPL-4 is induced in a DAF-16dependent manner upon germline loss (Lapierre et al., 2011). This induction is necessary for the lifespan extension observed. Moreover, the lipase LIPS-17 and the fatty acid reductase FARD-1 also play a role, while it was shown that germline-less animals have increased fat content (Uno and Nishida, 2016; McCormick et al., 2012; Hansen et al., 2013).

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Nongenetic Regulation of Aging Epigenetic Alterations and Aging As previously mentioned, the aging process is influenced by both genetic and nongenetic factors such as various environmental stimuli, including caloric restriction and stress. Importantly, emerging evidence supports a role for epigenetics in lifespan regulation in diverse species, including C. elegans. The term epigenetics strictly refers to long lasting and potentially heritable changes in phenotype or gene expression that are not due to changes in the underlying DNA sequences (Goldberg et al., 2007). In this regard, much excitement was generated by reports describing chromatin alterations that occur during aging. Additionally, several intriguing studies suggest that interfering with chromatin modifying enzymes influences longevity in diverse organisms ranging from yeast to mammals (Benayoun et al., 2015). These findings are not surprising given that chromatin modifications can eventually cause transcriptional changes that affect genomic stability, with consequences for healthspan and lifespan. Below, we summarize the most important mechanisms that link epigenetic modifications to lifespan regulation in C. elegans, starting with the role of chromatin modifiers (Table 1).

Chromatin modifications Posttranslational modifications of histone proteins are accomplished by enzymes that add or remove modifications in vulnerable histone residues, causing alterations in chromatin features during aging. DNA methylation in C. elegans. The nematode lacks DNA methylation on the fifth position of cytosines in CpG dinucleotide sites (5-mC), a modification that is frequent in mammals. This led to the conclusion that DNA methylation is absent in worms. However, a recent study revealed the presence of adenine N6-methylation (6mA) in the nematode DNA. Notably, 6mA levels increase transgenerationally in spr-5 mutant animals that are deficient for the histone H3 lysine 4 dimethyl (H3K4me2) demethylase SPR-5 (Katz et al., 2009), which is a homologue of the mammalian LSD1/KDM1A (Shi et al., 2004). Further analysis identified a DNA demethylase, NMDA-1, and a potential DNA methyltransferase, DAMT-1, which regulate the levels of 6mA and the functional interplay between DNA 6mA and histone H3K4 methylation (Greer et al., 2015). Histone methylation and modulation of aging. This form of modification in core histone proteins is associated with either active or repressed genome regions and is considered as a dynamic mark in health and disease (Benayoun et al., 2015). Histone methylation is regulated by histone methyltransferases and histone demethylases, some of which have already been implicated in the regulation of lifespan in model organisms (Benayoun et al., 2015). Indeed, accumulating findings support the notion that widespread alterations in heterochromatin organization occur during aging and may be causatively linked to the aging process. In this regard, and consistent with previous work suggesting that loss of repressive chromatin is detrimental to longevity, knockdown of the H3K27me3 demethylase UTX-1 extends lifespan in C. elegans and increases the levels of H3K27me3, implying their beneficial impact on longevity. Furthermore, UTX-1 genetically interacts with the Insulin/IGF-1 signaling pathway to regulate longevity independently of the germline (Jin et al., 2011; Maures et al., 2011). In contrast, overexpression of the H3K27me3 demethylase KDM6B/ JMJD-3 prolongs lifespan, suggesting that accumulation of H3K27me3 at specific genes such as stress response genes negatively affects longevity. The fact that the removal of germline stem cells preserves jmjd-3.1 expression, prevents the accumulation of H3K27me3 at stress gene loci and maintains the heat stress response (HSR) suggests that differential investment strategies between the soma and the germline compete with each other to promote organismal stress resistance at the onset of reproduction (Labbadia and Morimoto, 2015).

Table 1

Epigenetic regulators influencing lifespan in C. elegans.

Modulator

Function

UTX-1 JMJD-3 MES-2 ASH-2 SET-2 WDR-5 RBR-2

Chromatin Chromatin Chromatin Chromatin Chromatin Chromatin Chromatin

RBR-2 MET-1 SIR-2.1 SIR-2.4 OGT-1 OGA-1

Chromatin modifier, H3K27me3 demethylase Chromatin modifier, H3K36me3 methyltransferase Chromatin modifier, histone deacetylase Chromatin modifier, histone deacetylase O-linked N-acetylglucosamine (O-GlcNAc) transferase O-linked N-acetylglucosamine (O-GlcNAc)-selective Nacetyl-beta-D-glucosaminidase (O-GlcNAcase) Chromatin remodeler

ATPH-2

modifier, H3K27me3 demethylase modifier, H3K27me3 demethylase modifier, Polycomb group protein modifier, methyltransferase modifier, methyltransferase modifier, methyltransferase modifier, H3K27me3 demethylase

Genetic manipulation

Lifespan effect

Downregulation Overexpression Downregulation Downregulation Downregulation Downregulation Downregulation

Extension Extension Extension Extension Extension Extension Shortening, extension (condition-dependent) Extension Shortening Extension Extension Shortening No effect in wild-type animals, extension in daf-2 mutants Extension

Overexpression Downregulation/mutation Overexpression Overexpression Downregulation Mutation Downregulation

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However, downregulation of MES-2, which is a Polycomb group protein with an essential role for germline development and patterning, increases the lifespan of sterile worms. Interestingly, flies heterozygous for mutations in the Enhancer of zeste (E(z)) (the Drosophila melanogaster homologue of mes-2) are long-lived, suggesting that the role of MES-2 in longevity is evolutionarily conserved (Ni et al., 2012). Altogether, these data indicate that different H3K27me3 modifiers regulate longevity in a complex manner. Moreover, downregulation of proteins that form the COMPASS (complex protein associated with SET1) chromatin complex, which catalyzes trimethylation of lysine 4 on histone 3 (H3K4me), increases lifespan in C. elegans. Specifically, it has been shown that knockdown or mutation in the ash-2, set-2, and wdr-5 genes prolongs lifespan. On the other hand, knockdown of rbr-2, which encodes the demethylase H3K4me3, shortens lifespan, whereas the overexpression of RBR-2 in the germline results in lifespan extension, most likely by ameliorating the effects of stress imposed by reproduction (Greer et al., 2010). However, it was also shown that RNAi-mediated knockdown or mutation of rbr-2 promotes longevity under certain experimental conditions (Greer et al., 2010; Alvares et al., 2014). Further analysis showed that RBR-2 together with the SPR-5 H3K4me demethylase contributes to the effect of Insulin/IGF-1 signaling on longevity. Specifically, RBR-2 and SPR-5 increased adult lifespan of stress-resistant daf-2 mutants and enhances germ cell immortality at high temperature (Alvares et al., 2014). A recent study revealed a novel link between H3K4me3 modifiers and fat metabolism in regulation of lifespan in C. elegans. Indeed, depletion of H3K4me3 methyltransferase, which prolongs lifespan, leads to accumulation of MUFAs. The underlying mechanism relies, at least partially, on the downregulation of germline targets including rsks-1 and on the upregulation of delta-9 fatty acid desaturases in the intestine (Han et al., 2017). Another histone H3K36me3 methyltransferase, MET-1, was also shown to have a role in regulation of lifespan in C. elegans. Indeed, RNAi-mediated knockdown or mutation in the met-1 gene shortens lifespan (Greer et al., 2010). This finding combined with the fact that H3K36me3 levels decrease with age suggests that equilibrium in H3K36me3 levels may have a crucial impact on the regulation of lifespan. Collectively, these data highlight the importance of specific histone methyltransferases or demethylases for aging research. Further supporting the impact of histone methylation on the aging process, a recent study revealed that the histone lysine demethylases JMJD-1.2/PHF8 and JMJD-3.1/JMJD3 act as important regulators of lifespan in response to mild mitochondrial dysfunction both in C. elegans and mice. Indeed, these demethylases are required for electron transport chain-mediated longevity and the induction of (mtUPR) (Merkwirth et al., 2016). Histone acetylation and impact on longevity. The extent of histone acetylation is regulated by histone acetyltransferases and deacetylases, several of which have been associated with aging modulation in diverse species, including C. elegans. For example, sirtuins, which are NADþ-dependent protein deacetylases, were reported to extend lifespan in yeast, worms, flies, and mice, though their role as longevity regulators is somehow controversial (Kenyon, 2010; Burnett et al., 2011). Nevertheless, the mechanism through which sirtuins function to influence lifespan remains poorly characterized. At least in yeast, SIR2 (silent information regulator 2) was originally assigned a role as a chromatin silencing component that represses gene transcription at selected loci (Michan and Sinclair, 2007). Later, it was shown that genetic or pharmacological activation of SIR-2.1 and sirtuin 1 (SIRT1), which are the homologues of SIR2 in the nematode and mammals, respectively, enhances survival, at least partially, through autophagy (Morselli et al., 2010). In addition, SIR-2.4 (the nematode homologue of mammalian SRT6 and SRT7) is reportedly required for stress resistance and lifespan extension. SIR-2.4 regulates the nuclear localization of the DAF-16/FOXO transcription factor by antagonizing the acetyltransferase CBP-1, thereby attenuating DAF-16 acetylation and eventually promoting its activation under stress conditions (Chiang et al., 2012). Notably, sirtuins are located in distinct cellular compartments, that is, in the nucleus where they function to deacetylate histones, altering gene expression epigenetically, in the cytoplasm or in mitochondria where they regulate the activity of metabolic enzymes (Chang and Guarente, 2014). Together, these findings indicate that sirtuins exert their longevity effects not only through changes in the chromatin state but also by affecting the acetylation status of nonhistone substrates. Other histone modifications and their role in modulation of aging. Besides histone methylation and acetylation, the addition of O-Nacetyl-glycosamine (O-GlcNAc) to H2A, H2B, and H4 and to promoters of genes linked to insulin-like signaling, metabolism, aging, stress, and pathogen-response pathways may epigenetically modulate gene expression in C. elegans, as resulted from whole-genome chromatin immunoprecipitation (ChIP)-on-chip tiling arrays, and transcriptional profiling (Love et al., 2010). In line with these findings, mutation in OGT-1, which is the enzyme that adds O-GlcNAc, shortens the lifespan of both wild-type and daf-2 mutant animals. By contrast, mutation in OGA-1, the enzyme that removes O-GlcNAc, promotes longevity only in daf-2 mutants (Love et al., 2010; Rahman et al., 2010). To summarize, the mechanisms by which histone modifications regulate gene expression remain elusive. They may promote or inhibit the recruitment of transcriptional machinery or they may act to silence transcription through the formation of heterochromatin (i.e., H3K9me3, H4K20me2) and to regulate genome stability (i.e., H3K56ac, H3K14ac) (Lauberth et al., 2013). Whatever the mechanism is, it is important that these modifications change during aging (Benayoun et al., 2015). Nucleosome remodeling and aging modulation. Nucleosome remodelers can change nucleosome positioning, chromatin state, and overall nuclear organization. Therefore, it is not surprising that their activity can influence aging. For example, the chromatin remodeler SWI/SNF was linked to DAF-16-mediated stress resistance and longevity in the nematode (Riedel et al., 2013). Moreover, inactivation of ATPH-2, a key component of the putative nematode homologue of yeast imitation switch complex (ISWI), which is an ATP-dependent chromatin remodeling complex, extends the worm lifespan mimicking the beneficial effects of calorie restriction in activating stress response genes during aging (Dang et al., 2014).

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Environmental stimuli, epigenome remodeling, and more Emerging findings suggest that various environmental stimuli such as food intake, nutrient, and energy sensing and physical exercise, among others, affect aging. Below, we will briefly discuss how dietary restriction and crucial energy sensors and metabolism regulators that influence longevity are linked with age-related epigenetic changes. Dietary restriction. Reduced food intake without malnutrition is the only intervention that extends lifespan in all species tested so far. The beneficial effects of dietary restriction on healthspan and lifespan are mediated by multiple mechanisms. For example, the insulin/IGF-1 and TOR pathways have a predominant role, among the nutrient sensing pathways involved in the response to dietary restriction. On the other hand, sirtuins and AMPK have crucial roles in mediating the adaptation to decreased ratios of NADH/NAD and ATP/ADP, respectively, under dietary restricted conditions. As such, they are important players in dietary restriction-induced longevity. Another key player of the response to dietary restriction is chromatin. Indeed, dietary restriction induces changes in the expression of genes implicated in metabolism, stress responses, DNA damage repair and regulation of chromatin structure, among others. In brief, these gene expression changes not only contribute to the metabolic adaptation of the cell but also help to protect genome integrity and chromatin structure (Vaquero and Reinberg, 2009). Adding another layer of complexity, dietary restriction extends C. elegans lifespan through SIR-2.1-dependent induction of autophagy (Morselli et al., 2010). Moreover, the PHA-4/FOXA transcription factor was shown to regulate adult lifespan extension by dietary restriction in C. elegans, and autophagy is induced specifically by PHA-4 activation under limited food conditions (Hansen et al., 2008). Interestingly, a recent study showed that autophagy specifically in the intestine is crucial for lifespan extension in dietary-restricted eat-2 mutants. Furthermore, intestinal-specific inhibition of autophagy reduces the intestinal integrity of eat-2 mutants and decreases their motility during aging (Gelino et al., 2016). The nutrient and energy sensor AMPK is also involved in lifespan extension in response to dietary restriction. In this case, AMPK exerts its beneficial effects on lifespan in part by phosphorylating DAF-16/FoxO and activating DAF-16/FoxO-dependent transcription, suggesting that the AMPK-FoxO axis is involved in the antiaging effects of dietary restriction (Greer et al., 2007).

Stress response pathways in lifespan control It is becoming apparent that lifespan is closely related to stress resistance (Morley and Morimoto, 2004). Evidence shows that longlived mutants in C. elegans and other model organisms are more resistant to environmental stress, while the efficiency of most stress response pathways deteriorates with aging. This increases the probability of homeostatic collapse and disease onset, eventually leading to senescence and death. On the other hand, when the stress response pathways remain functional as the animal ages, age-prone dysfunction is alleviated and the organism bypasses the risk of disease-onset or death. According to this theory, long lifespan is itself a marker of increased stress resistance which also predicts that stress-response mechanisms are activated inside cells (Johnson et al., 2001). An excellent example is the insulin/IGF-1 mutants which are both long-lived and extremely resistant against several stressors as compared to their control counterparts (Lithgow and Walker, 2002). Effector mechanisms and factors activated in response to stress such as heat shock, oxidative stress, hypoxia, and/or DNA damage have also important roles in the regulation of the aging process (Haigis and Yankner, 2010; Kourtis and Tavernarakis, 2011). Also, hormetic responses, initiated upon mild exposure to the aforementioned stressors, increase lifespan in C. elegans, while very severe stress has the opposite effects (Cypser and Johnson, 2002; Epel and Lithgow, 2014; Gems and Partridge, 2008; Kumsta et al., 2017). For example, animals subjected to mild heat stress become long-lived. In parallel, long-lived mutants exhibit increased thermotolerance, effect that tightly couples heat stress resistance to lifespan (Lithgow et al., 1995). Upon heat stress, HSF-1 (the nematode homologue of mammalian HSF1-4) is activated (Morton and Lamitina, 2013). Upon its activation, HSF-1 trimerizes and forms distinct nuclear foci (Morton and Lamitina, 2013). Its activation triggers transcription of target genes, most of which encode chaperones which function in proteostasis restoration (Pirkkala et al., 2001). This finding combined with the fact that hsf-1 expression and activity increase lifespan in C. elegans provides evidence that the HSF-1 pathway regulates lifespan by diminishing protein aggregation during aging (Morley and Morimoto, 2004). Indeed, wild-type animals accumulate toxic protein aggregates in contrast to the long-lived daf-2 mutants in which activity and expression of HSF-1 is highly induced. On the other hand, hsf-1 downregulation decreases the lifespan of wild-type animals and long-lived insulin mutants (Hsu et al., 2003; Morley and Morimoto, 2004). Recently, autophagy was identified as the effector mechanism downstream of HSF-1. In fact, either hormetic heat stress or hsf-1 overexpression can induce autophagy, which in turn mediates the beneficial effects on proteostasis, lifespan, and stress resistance in C. elegans (Kumsta et al., 2017). HSF-1 activation in response to heat stress is posttranslationally regulated by the deacetylase SIR-2.1/SIRT1 (Brunquell et al., 2016). Inhibition of sir-2.1 abrogates the expression of some of the HSF-1 target genes while its overexpression or allosteric induction by resveratrol enhances the heat stress response and increases lifespan (Viswanathan et al., 2005; Wood et al., 2004) (Fig. 2). Another example is the oxidative stress response. It was first shown in C. elegans that long-lived mutants of the insulin/IGF-1 pathway retain a robust oxidative stress response at old ages as compared to their control counterparts (Honda and Honda, 1999). This was supported by the finding that aged age-1 mutants display higher levels of catalase and SOD as well as enhanced activity of the enzymes compared to synchronous wild-type animals (Vanfleteren, 1993). Later on, it was revealed that the oxidative stress response is mediated by the activation of DAF-16 and SKN-1 as well as HIF-1 transcription factors (Park et al., 2009; Senchuk et al., 2018; Zhang et al., 2009). Interestingly, activation of SKN-1 target genes in response to oxidative stress is also required for normal lifespan (Park et al., 2009). Moreover, skn-1 and daf-16 are induced in several long-lived mutants while their downregulation severely shortens the lifespan both in these mutants and wild-type animals (Senchuk et al., 2018; Ewald et al., 2015). Also, as already mentioned, mild ROS elevation induces mitohormesis and triggers lifespan extension in C. elegans. This was also confirmed by paraquat treatment, which increases lifespan when administered at low doses (Yang and Hekimi, 2010a). Importantly though,

Aging in the Nematode Caenorhabditis elegans

Heat stress

Oxidative stress

Hypoxia

Lifespan extension

(A)

HSF-1

97

HIF-1

Low

Mild stress

High

DAF-16

SKN-1 HIF-1 DAF-16

(B)

Urolithin A

Rapamycin

Resveratrol

ROS Mitochondrial damage

SIR-2.1 Autophagy Spermidine

Histone acetylases Lifespan extension

Irradiation-induced oxidative stress

Fig. 2 Environmental and pharmacological factors that modulate lifespan. (A) Animals exposed to mild heat, oxidative, and hypoxic stress exhibit lifespan extension, which is mediated by the activation of distinct transcriptional programs (black arrows are representative of heat stress-related responses, red arrows of oxidative stress, and blue arrows of hypoxic stress); (B) treatment with rapamycin, resveratrol, urolithin A, and spermidine confer lifespan extension by inducing autophagy-related mechanisms.

oxidative stress is not linearly associated with lifespan extension. For example, mev-1 mutants which are very oxidative stress challenged are short lived (Yang et al., 2007). Interestingly, treatment with antioxidants can alleviate their short lifespan, while it does not affect wild-type animals (Yang et al., 2007; Phulara et al., 2015). Moreover, antioxidant treatment could even decrease the lifespan of long-lived mutants (Yang and Hekimi, 2010a). These results indicate that only a specific window in ROS production triggers lifespan extension while overproduction of ROS can have the opposite effects on longevity (Fig. 2). Last but not least, the hypoxia stress-related pathway has been recently implicated in the regulation of longevity. Hypoxia is a condition where cells and entire organisms are challenged with low oxygen levels. In response to hypoxia, the HIF-1 transcription factor is activated (Shen et al., 2005). Response to hypoxic stress is very well-conserved and involves the activation of HIF-1-target genes in C. elegans and other model organisms. Active HIF-1 exists in a heterodimeric complex which nuclearizes and through its target genes rewires metabolism toward anaerobic glycolysis (Jiang et al., 2001). Interestingly, it was recently shown that oxygen deprivation increases lifespan in C. elegans in a HIF-1- and DAF-16-dependent manner (Leiser et al., 2013). Exposure of animals to hypoxia during the late stages of larval development or even at the first day of adulthood is sufficient to positively influence lifespan by activating several downstream mechanisms (Leiser et al., 2013; Daskalaki et al., 2018). Supporting evidence indicates that genetic HIF-1 stabilization by VHL mutation can extend lifespan even under normal oxygen conditions (Leiser et al., 2013; Mehta et al., 2009). Also, hif-1 overexpression is proportionally correlated with lifespan extension and increased heat and oxidative stress resistance. Further studies indicated that HIF-1 acts in parallel to DAF-16 and SKN-1 to increase lifespan (Zhang et al., 2009) (Fig. 2).

Pharmacological Interventions Modulating Aging Pharmacological agents used to extend lifespan in model organisms act mainly as inducers of general autophagy. Also, agents that promote healthy aging by activating the selective mitochondrial autophagy known as mitophagy have been reported. Interestingly, many of the natural/pharmacological inducers of autophagy act by mimicking the effects of calorie restriction. Although beyond the scope of this article, pharmacological modulators of autophagy, such as rapamycin, resveratrol, and spermidine, have been shown to extend the worm lifespan. Their beneficial effects on longevity are mediated by diverse mechanisms that often converge on autophagy (Fig. 2).

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More specifically, rapamycin, which is the best characterized inducer of autophagy, extends lifespan independently of SIR-2.1 (Morselli et al., 2010). By contrast, resveratrol, a well-studied plant polyphenol found in grape berry skin, red wine, knotweed, peanuts, and other plants reportedly promotes longevity in C. elegans through SIR-2.1-mediated activation of autophagy (Morselli et al., 2010). Moreover, resveratrol protects worms against irradiation-induced oxidative stress, by lowering ROS levels and preventing mitochondrial damage (Ye et al., 2010). Spermidine is a naturally occurring ubiquitous polyamine produced by putrescine and is the precursor of spermine. Several studies showed that the cellular content of polyamines decreases with age and this is often causatively associated with disease onset (Minois et al., 2011). Spermidine supplementation extends lifespan in several organisms, including yeast, worms and flies (Eisenberg et al., 2009). This beneficial effect on longevity is observed in both wild-type and sir-2.1 mutant animals (although sir-2.1 lesions attenuate autophagy induction by spermidine), suggesting that, in contrast to resveratrol, lifespan extension by spermidine is independent of sir-2.1 (Eisenberg et al., 2009). In yeast, spermidine functions as an inhibitor of histone acetylases. Modulation of the acetylation state of histones affects the transcription of several genes, some of which are involved in the autophagic degradation machinery (Eisenberg et al., 2009). Together these findings indicate that spermidine and resveratrol enhance longevity by activating autophagy through distinct pathways that converge on acetylproteome (Morselli et al., 2010, 2011). Ellagitannins, which belong to bioactive polyphenols, are found in fruits and nuts and have antioxidant, anti-inflammatory, and tumor suppressive properties (Losso et al., 2004). Pomegranate juice is the most prominent source of ellagitannins in nature (Johanningsmeier and Harris, 2011). Upon their consumption, ellagitannins are metabolized from gut microbiota into urolithins, which are subsequently absorbed and distributed to the entire human body through blood stream (Espin et al., 2013). Most of their effects have been tested in artificial conditions in vitro (Kang et al., 2016; Piwowarski et al., 2015; Seeram et al., 2007; Lansky et al., 2005). However, it was recently shown that urolithins can influence whole homeostasis during aging. Indeed, supplementation of urolithin A, which is the most prevalent ellagitannins-derived metabolite in humans, promotes mitophagy in nematodes and mammals (Ryu et al., 2016).

Concluding Remarks Research using model organisms such as the lowly nematode C. elegans has culminated in the identification of several signaling pathways that control aging in a well-conserved fashion. In addition to genetic factors, a growing body of evidence indicates that epigenetic mechanisms and environmental factors can modulate healthspan and lifespan. These advances support the idea that similar mechanisms, albeit with variations, may operate in humans to regulate aging. However, more work is necessary to consolidate this notion. We anticipate that continued studies in C. elegans, where aging modulators can be easily manipulated, will further advance our understanding of aging and will facilitate the development of novel approaches aiming to maintain human health and quality of life in the elderly.

Acknowledgments We apologize to those colleagues whose work could not be referenced owing to space limitations. Work in the authors’ laboratory is funded by grants from the European Research Council (ERC-GA695190dMANNA and ERC-GA737599dNeuronAgeScreen).

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Aging in Zebrafish Dimitris Beis and Adamantia Agalou, Biomedical Research Foundation Academy of Athens, Athens, Greece © 2020 Elsevier Inc. All rights reserved.

Introduction Forward and Reverse Genetic Engineering in Zebrafish Fluorescent Reporter Lines Modeling Telomere Attrition Modeling Age-Associated Diseases Osteoporosis Cutis Laxa Fanconi Anemia Alzheimer’s Disease Laminopathies Cognitive Disorders Retinal Disorders Study of Age Associated Parameters Immune and Endocrine System Decline Dietary Control Circadian Clock Mitochondrial Dysfunction Revisiting Cellular Aging in Zebrafish: BiomarkersdStaining Methods Heart Aging Aging and Cancer in Zebrafish Concluding Remarks References Further Reading Relevant Websites

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Abbreviations AD Alzheimer’s disease ARCL Autosomal recessive Cutis Laxa disease DDR DNA damage repair DR Dietary restriction ENU N-Ethyl-N-nitrosourea EZRC European Zebrafish Resource Center FA Fanconi anemia GFP Green fluorescent protein GWAS Genome-wide association studies IGF Insulin growth factor MO Morpholino OP Osteoporosis SA-b-gal Senescence-associated b-galactosidase TALENs Transcription activator-like-effector nucleases TERC Telomerase RNA component TERF Telomere repeat binding factor TERT Reverse transcriptase telomerase TILLING Targeting induced local lesions in genomes TUNEL Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling ZFNs Zinc-finger nucleases ZIRC Zebrafish International Resource Center ZMP Zebrafish mutation project

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Introduction Several model organisms have been used in research over the years to investigate the complicated mechanisms of aging. From microscopically small invertebrates to evolutionary advanced nonhuman primates, they have all contribute to our understanding of the profoundly intricating process of aging. Given that each animal model has certain advantages and limitations, an integrative approach that uses diverse species is necessary in order to uncover the critical elements of the developmental origins of aging. The zebrafish (Danio rerio) has recently emerged as an outstanding model organism to explore the age-related changes in biology and behavior. In the past 20 years, this small, freshwater, tropical fish, originating from Indiadthat is very popular for home aquaria because of its easy maintenanced, has been widely used for studying mechanisms of vertebrate development. Zebrafish has several advantages for the study of developmental processes, including the rapid extrauterine development, the transparency of the embryos (allowing direct visualization and noninvasive imaging), the prolific reproductive capacity, and the relatively modest husbandry costs. Moreover, the high genetic similarity to humans, the genetic and biological resources for the zebrafish that continue to expand, and the development of optimized protocols of genome editing, have made zebrafish a favorable model for studying human disorders. In this context, zebrafish also has the potential to be of great value in gerontology research. The process of senescence in zebrafish has been for long considered as negligible (due to their indeterminate growth and the robust regenerative capacity). There is now ample evidence suggesting that zebrafish, like most vertebrates, generally undergoes gradual senescence: the growth rate diminishes with age, they develop senescent morphology, they are prone to age-related diseases, and they are subject to age-related morbidity and mortality. All nine widely recognized hallmarks that represent common denominators of aging in the different organisms have been shown to evolve in zebrafish. Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, that are all considered to contribute to determination of the aging phenotype (López-otín et al., 2013) can be recognized in zebrafish aging process (Van houcke et al., 2015). The significant advantages in zebrafish gerontology and the contribution of zebrafish into the understanding of the complex and pleiotropic phenomenon aging will be discussed in this review.

Forward and Reverse Genetic Engineering in Zebrafish During the last decades there has been an explosion in the number of tools and techniques available to manipulate the zebrafish genome. Traditionally, zebrafish mutant lines have been generated by forward genetic screens, using initially gamma irradiation and later, the chemical mutagen N-ethyl-N-nitrosourea (ENU) to introduce random point mutations that result in loss-of-function, gain-of-function, and conditional (e.g., temperature sensitive) mutations. Even though the identification of randomly mutated genes might be laborious, the recent advantages in genome technologies and next-generation sequencing have improved and simplified the procedures of recognizing the phenotype-related loci. Insertional mutagenesis was also applied in zebrafish and introduced as an alternative approach to chemicals, using either retroviral vectors or transposons that randomly integrate into the genome to disrupt gene functions (Sivasubbu et al., 2007). Even though less efficient than ENU chemical mutagenesis, the insertional mutagenesis has the advantage of the rapid identification of the mutated gene. Such short or large-scale screens have been extensively used to identify many zebrafish mutants with particular developmental defects. Kishi et al. (2008) performed the first large scale screens, for identification of zebrafish mutants with age-related phenotypes. They used both an established retrovirus insertional collection and an ENU chemically mutagenized collection to evaluate the SA-b-gal early biomarker of aging. From these forward screens, several genes were identified that have been linked to cellular senescence and the organismal aging process, including the telomeric repeat binding factor 2 (terf2) that had been already correlated to senescence in human cells and the spinster homologue 1 (spns1), associated previously with reduced lifespan in Drosophila (Kishi et al., 2008). ENU-based mutagenesis has also been used in TILLING reverse genetics approaches in which random mutagenesis is followed by targeted sequencing to screen for mutations in selected genes. TILLING (targeting induced local lesions in genomes) has been used in large scale screens designed to hunt for mutations in many genes simultaneously and by this approach a big collection of target-selected knockouts in zebrafish was created (Wienholds et al., 2003). The telomerase mutant isolated in such a screen is the most well-studied zebrafish mutation concerning aging and senescence (Anchelin et al., 2011). Nowadays, The Zebrafish Mutation Project (ZMP), that aims to create a knockout allele in every protein-coding gene of zebrafish, generated a considerable collection of mutant lines available to the research community through the major zebrafish stock centers (ZIRC and EZRC). In the age of the Genome-wide association studies (GWAS) and the exome/genome sequencing, the in vivo functional testing of the individual genes putative linked to human disease is essential in order to confirm the importance and characterize each diseaserelated candidate loci. In this respect, the employment of high-throughput reverse genetic approaches seems necessary. Zebrafish has contributed a lot to this direction since several strategies enable researchers to generate mutants in specific loci with relative ease. Morpholinos-antisense oligonucleotides that inhibit translation or affect splicing can be used to inhibit gene function transiently. Morpholinos are extremely stable, and when injected into one to two cell stage zebrafish embryos can remain active for the first few days of development. They provide an easy, rapid and efficient loss-of-function manipulation without multigenerational genetic screens and for many years they had been the tool of choice for the creation of “knockdown” phenotypes. However,

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several studies have highlighted the limitations of this approach and suggested guidelines for their use (Stainier et al., 2017). Morpholinos offer a method to assess phenotypes of genes of interest during early development, which limits their utility in processes occurring in later developmental stages. Phenotypic rescue of zygotic mutants by maternally provided mRNA or protein could also be a drawback of this method. Additionally, the injection of large amounts of synthetic molecules might cause off-target effects because of an upregulation of the p53 apoptotic pathway and activation of innate immune responses (Stainier et al., 2017). Moreover, concerns have been raised since morphants frequently show more severe phenotypes than stable mutants generated for the same gene, probably due to the transcriptional compensation that often occurs in stable mutated organisms (El-Brolosy et al., 2019). However, MOs when properly controlled remain a valuable, rapid, low-cost approach to study genes implicated in agerelated disorders such as the cataract associated Cysteine-rich motor neuron 1 (Crim1) (Brastrom et al., 2019) or the Lowdensity lipoprotein receptor-related protein 4 (Lrp4) linked to osteoporosis (Tian et al., 2019). In order to generate stable mutants, alternative methods have been developed. Zinc-finger nucleases (ZFNs) and transcription activator-like-effector nucleases (TALENs) (Kawahara et al., 2016) are both successfully used to target genes in zebrafish. They are both chimeric fusions of a DNA binding protein (a Zinc-finger transcription factor or the TALE proteins of the plant pathogen Xanthomonas respectively) and the bacterial endonuclease Fok1 DNA cleavage domain. This complex introduces double-strand breaks in specific genomic targets sequences, which are imprecisely repaired by nonhomologous end joining introducing in this way, specific genetic lesions. The CRISPR/cas9 system is based on a defense system that evolved in bacteria to target and degrade foreign viral DNA (Kawahara et al., 2016). It utilizes indels resulting from incorrect repairing of a double-strand break at a specific target site. CRISPR/cas9 system offers an efficient method to create stable mutant lines. A limitation of this method is that it could also induce additional, off-target mutations and that mutations caused by such genetic engineering, often result in altered mRNA processing or trigger genomic compensation effects (El-Brolosy et al., 2019) eventually failing to introduce strong phenotypes. Alternative approaches, such as targeting of the promoter region, have been suggested in order to overcome some of these problems (El-Brolosy et al., 2019).

Fluorescent Reporter Lines Using tissue-specific promoters, responsive elements from signaling pathways, or transcription factor binding sites that drive expression of fluorescent proteins, a diverse collection of stable zebrafish reporter lines was generated. In these lines, the fluorescent protein of choice is expressed in developing cells, tissues or organs, allowing spatial or even temporal analysis of the specific genes, and pathways in various developmental processes. The establishment of these reporter lines has facilitated analyses that focus on dynamic processes that are hard to visualize otherwise. Given the complexity of the aging process and its multifunctional nature, there are several choices of reporter lines depending on the question that needs to be answered. For example, when studying agerelated metabolic bone diseases like osteoporosis, one could use transgenic lines for the musculoskeletal system (reviewed in (Bergen et al., 2019)), while for neurodegenerative disorders, such as Alzheimer’s disease, neurospecific reporter lines (e.g., spinal cord or neural crest) could be used (Saleem and Kannan, 2018).

Modeling Telomere Attrition Telomeres are repetitive nucleotide sequences and a complex of associated proteins, which cap and protect the ends of eukaryotic chromosomes (Carneiro et al., 2016). Telomeres are crucial for genome stability since they protect the end of the chromosome from deterioration and end-to-end fusion of neighboring chromosomes. With every round of replication in dividing cells, telomere attrition occurs, resulting in the shortening of telomeres. When telomeres become critically short, they recognized as DNA double-strand breaks and trigger mechanisms of DNA damage responses, cell cycle arrest, and senescence. The maintenance of the telomeric DNA depends on a complex composed by the reverse transcriptase telomerase (TERT) and the telomerase RNA component (TERC). In human, however, telomerase expression decreases dramatically after embryonic development and detectable levels are only present in germ cells and specific stem cells while is missing in the majority of differentiated somatic cells. The critical role of telomeres in aging is supported by studies showing that mutations in genes crucial for telomere maintenance, trigger degenerative disorders that phenocopy the events occurring during natural aging and cause premature aging symptoms. Zebrafish has emerged as an important model to study the role of telomeres and telomerase in aging and disease. Compared to mouse, the primary model for studying pathophysiology of human disease, zebrafish is advantageous in studying the deleterious impacts of telomere shortening. Zebrafish has short average telomere length similar to human (5–15 kb) in relation to mouse telomeres that range from 20 to 150 kb in length. Additionally, the functional domains of zebrafish telomerase are highly similar to their human counterparts and the telomerase promoter is regulated by the same transcription factors, Myc and NF-kB (Anchelin et al., 2011). Even though telomerase expression is detected in most zebrafish tissues, it declines, as in humans, with age while the expression and activity depends on the specific tissue (stabilizes in low levels in fin, gut and muscle but is retained high in gonads) (Anchelin et al., 2011; Carneiro et al., 2016). Telomerase-deficient zebrafish (terthu3430/hu3430 or tert
/
) have shorter telomeres than wild type zebrafish and display premature aging phenotypes. They develop several degenerative phenotypes (infertility, gastrointestinal atrophy, inflammation, sarcopenia, retinal atrophy),

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exhibit an accelerated onset of age-related diseases (cachexia, gas bladder infection, and cancer) and have reduced lifespan (Carneiro et al., 2016). Just like in human, that individuals carrying mutations in telomerase genes display, immediate (first generation) tissue-dysfunction phenotypes, tert
/
zebrafish exhibit, even from the first generation, severe age-related disease phenotypes while in the second generation more than 50% of tert
/
mutants die within the first week of life (Anchelin et al., 2011). In contrast, telomerase-deficient mice are viable through several generations of incrossing possible due to their long telomeric ends. Interestingly tertþ/
zebrafish have also reduced longevity compared with wild type, indicating that telomerase haploinsufficiency, like in humans, leads to telomere shortening and decreased lifespan, regardless of the presence of telomerase. All these make the zebrafish telomerase mutant an excellent model of premature aging. Zebrafish mutants for the telomere repeat binding factor Terfa (Terf2 for mammals), exhibit premature retinal neurodegeneration and senescence in the brain and spinal cord and they are embryonically lethal. Terfa heterozygotes have premature retinal degeneration and reduced lifespan compared to the wild type (Kishi et al., 2008).

Modeling Age-Associated Diseases Osteoporosis Osteoporosis (OP) is a degenerative bone disease that affects the elderly. It is characterized by a reduction in bone mass and mineral density, resulting in brittle bones that are more prone to fracture. The use of zebrafish as a powerful model in OP research has been recently reviewed (Bergen et al., 2019). The simple assessment and imaging of zebrafish skeleton, the existence of many transgenic lines available to mark musculoskeletal tissues, and the increasing number of zebrafish genetic mutants in skeletally relevant genes, are some of the apparent advantages of zebrafish on studying OP disease. For example, mutant zebrafish for atp6v1h (Zhang et al., 2017) and itga10 (Huo et al., 2018) and Igmn (Jafari et al., 2017) have been used recently to model human OP, in order to provide an insight for the role of these genes on the disease progression or to test the effect of specific pharmacological agents on OP phenotypes. Alternatively, a novel zebrafish osteoporosis model was also established using high iron stress and was used to test the efficacy of known osteoporosis drugs (Zhang et al., 2018). Transgenic fish that label osteoblasts or other relevant cell types are consistently reported (more recently, the bone transgenic fish Tg(ola.Sp7:nlsGFP) (Huang et al., 2018)). These are explicitly generated to evaluate the bone mass and density in order to be used in anti-osteoporosis chemical screens (Huang et al., 2018). Additional assays such as the Caudal Fin Regeneration and the Fracture Repair assays have been extensively used for studying the wound healing responses and the identification of therapeutics that can improve fracture healing. In parallel, the elasmoid scales assays offer an opportunity to study bone cell behavior in a mature context. Pharmacological Manipulation of Bone Tissue and Chemical Genetic Screens using either zebrafish embryos or elasmoid scales are also discussed for the evaluation of novel compounds for treating OP patients.

Cutis Laxa Very recently a zebrafish model for the Autosomal Recessive Cutis Laxa (ARCL) disease, caused by homozygosity and heterozygosity in the pyrroline-5-carboxylate reductase 1 (PYCR1) gene in humans with progeroid appearance has been reported (Liang et al., 2019). Patients with ARCL disease, display lax and wrinkled skin, joint laxity, osteopenia, ophthalmologic disorders, and abnormalities in the central nervous system. Even though in a previous study, transient morpholino loss-of-function of the pycr1 gene induced massive apoptosis in both zebrafish and Xenopus embryos (Reversade et al., 2009), recently, a stable knock out zebrafish for the pyrc1 gene was generated using TALEN methodology. Detailed biochemical and behavior analyses carried out in order to characterize this mutant. Ablation of the pycr1 gene induced dwarfism, retinal disorganization, senescence from the embryonic stages, accelerated aging, and reduction of fecundity. Biochemical assays showed that pycr1 knock-out fish have a significant reduction in antioxidative capacity and possible mitochondrial dysfunction. Additionally, several behavior alterations demonstrated, including stronger anxiety-like behaviors, dysregulated circadian rhythm, and sleep dysregulation (Liang et al., 2019). This pycr1 knock out zebrafish model, with the obvious accelerating aging phenotypes, provides an in vivo platform for examining the PYCR1 functions in the aging process and ARCL.

Fanconi Anemia Among the monogenic accelerated aging disorders, Fanconi anemia (FA) is the one most studied in zebrafish. FA is a rare, autosomal, recessive hereditary disorder that is characterized by severe anemia, progressive bone marrow failure, genome instability and congenital malformations that range in severity and can involve any of the organ systems and has been associated with more than 20 genes, all participating in DNA damage repair. Patients with FA have an elevated risk for leukemia, as well as other solid tumors. A few loss-of-function models for genes involved in FA have been described: zebrafish mutants of fancd2, the brca2/fancd1 and the rad51 (Cheung and Taniguchi, 2017) have been characterized in detail, link their phenotype to ones observed among FA patients and associate their function with p53-mediated apoptotic pathways. Recently mutations in 19 genes related to FA were generated and characterized in zebrafish using CRISPR/Cas9-mediated mutagenesis, providing an integral resource for understanding the pathophysiology associated with the FA disease (Ramanagoudr-Bhojappa et al., 2018).

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Alzheimer’s Disease Many studies have focused on the use of zebrafish as a model system for neurodegenerative diseases, including Alzheimer’s disease. Even though clearly distinguished from age-associated memory impairment, which is considered as part of the normal aging process, AD as a progressive disease emerges typically in the elderly. Because of the Neuroanatomical similarity between human and zebrafish and the conserved behavioral mechanisms, several zebrafish models have been established to mimic AD. Recently, the use of zebrafish as a model for AD had been reviewed together with its potential for neurospecific drug discovery (Saleem and Kannan, 2018).

Laminopathies Laminopathies, such as Hutchinson-Gilford progeria syndrome have also been studied in zebrafish. Using over-expression studies and MO knock-down approaches the role of the implicated gene prelamin A was elucidated. A detailed analysis of this zebrafish disease model for premature aging was conducted including biochemical and morphological characterization (Koshimizu et al., 2011).

Cognitive Disorders Since zebrafish exhibit age-related declines in cognitive functions, it has also the potential to develop as a powerful model organism for studying behavioral and biological changes during aging and their neurobiological consequences. Over the years, a long list of behavioral assays has been established in order to access the rich repertoire of behavioral phenotypes that have been identified for cognitive and perceptual functioning. Typically, old zebrafish have less performance on tasks relevant to learning and memory (Yu et al., 2006). This is attributed to subtle changes in cellular and synaptic functions. During aging, there is reduced neurogenesis (Edelmann et al., 2013) and a decline in genes related to cellular and synaptic structure and growth in the brain (Arslan-Ergul and Adams, 2014). Interestingly, all these alterations, just like in mammals, depend on the gender of the animal (Arslan-Ergul and Adams, 2014). Moreover, enhanced oxidative stress may contribute to behavioral and cognitive impairments in the aging zebrafish (Ruhl et al., 2015). Characterizing aging-related changes in zebrafish behavior has significant impact on the understanding of cognition and perception and the underlying cellular and molecular mechanisms. To this respect, the acetylcholinesterase (a protein that terminates synaptic transmission) zebrafish mutant was shown to exhibit better performance in learning and entrainment (Yu et al., 2006). By elucidating the biological mechanisms of aging-related cognitive decline, the ultimate goal is to determine possible interventions to restore cellular and synaptic function and ameliorate the cognitive decline of aging.

Retinal Disorders Among the abnormalities associated with the onset of aging are degenerative retina phenotypes. In zebrafish, several works have been done to determine the cellular base of the observed age-dependent retinal defects (Kishi et al., 2008; Wang et al., 2019). Structural abnormalities, mitochondrial dysfunction, and alterations in signaling pathways (Akt/mTOR, Ampk/Sirt1/ Pgc1a) are linked to age-related oculopathy (Wang et al., 2019). Cataracts that broadly refer to any opacity of the lens, can be congenital but mostly age-related conditions. Zebrafish develop age-related cataracts and such optical dysfunctions have been used for the characterization of progeroid phenotypes in gerontology research in fish (Kishi et al., 2008; Liang et al., 2019) Recently, the cataract associated Cysteine-rich motor neuron 1 (Crim1) was down-regulated in zebrafish using MO injection. Morphants, probably due to the low-dose injection of crim1 MO, produce a mild cataract phenotype that does not disrupt significantly visual function (Brastrom et al., 2019). There are currently several assays that analyze optical function in zebrafish: the loss of visual function can be evaluated by VIZN (Visual Interrogation of Zebrafish maNipulations), the visual impairment by the optokinetic response (OKR) and the optomotor response (OMR), have been also used for studying how retina degeneration progresses with age.

Study of Age Associated Parameters Immune and Endocrine System Decline The zebrafish immune system declines over time, just like it is proposed by the hallmarks of aging in other organisms. The ratio of myeloid to lymphoid cells gradually increases with age indicating the activation of the innate immune system and the occurrence of chronic inflammation in the aging fish (Carneiro et al., 2016). Moreover, an increase in the number of innate immune cells, microglia, and macrophages, in the aged zebrafish retina has also been reported (Van houcke et al., 2015). On myelin damage of the optic nerve in aged zebrafish, there is also a decreased number of inflammatory cells and reduced remyelination of the optic nerve, comparing to younger animals (Münzel et al., 2014), pointing toward a possible connection between reduced inflammatory response and decline in tissue repair capacity.

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The decline of the endocrine system has been suggested as a key factor in the hormonal regulation of aging. Especially the somatotrophic axis, comprising growth hormone (GH) and its secondary mediator, insulin-like growth factor 1 (IGF-1) has been implicated on several aging mechanisms. In agreement to this, IGF-1 signaling is repressed in brains of aged fish (Arslan-Ergul and Adams, 2014). Overexpression of the GH in zebrafish is associated with increased production of ROS, reduction of the expression of genes from the antioxidant defense system and induction of aging phenotypes and reduced lifespan (da Rosa et al., 2010). More recently, an age-related expression decline of the in IFG1-receptor in zebrafish brain was identified. Expressing of the ligand IGF2b, induced divisions in young brains but resulted in incomplete divisions in aged animals (Obermann et al., 2019). An ortholog of mammalian Klotho gene that is consider an aging suppressor has been identified in zebrafish with relatively similar structure and expression pattern (Sugano and Lardelli, 2011). Klotho has been reported to inhibit insulin/insulin- like signaling pathways that are considered important and conserved strategy for extending life span. Inhibition of this insulin pathway results in upregulation of several genes including the catalase and manganese-superoxide dismutase (SOD2) an essential component for the protection of the cell against oxidative stress.

Dietary Control In all investigated eukaryotic species, dietary restriction (DR) increases life span. This is consistent with the relevance of deregulated nutrient-sensing as a hallmark of aging. Accordingly, lifespan experiments in zebrafish are dependent on caloric uptake (Gerhard and Cheng, 2002). Early reports in zebrafish indicated that caloric restriction prevents specific causes of mortality (such as infection) (Park et al., 2013). However, it has become well accepted that DR has more impacts that might affect healthy aging and longevity. Dietary control has an impact on energy metabolism, somatic growth, fat accumulation, and reproduction (Leibold and Hammerschmidt, 2015). DR affects neurogenesis by altering cell cycle and senescence dynamics (Arslan-Ergul et al., 2016). Furthermore, there are indications that DR impairs lifespan by shortening telomere lengths (Arslan-Ergul et al., 2016).

Circadian Clock Age-related changes to the circadian clock can also be studied in zebrafish, with numerous advantages over mice. There are important physiological differences between diurnal and nocturnal species. Although the neuronal, endocrine and molecular cogwheels of the circadian clock show night and day in a similar way in nocturnal mice and diurnal humans, these conditions of the clock mechanism carry different downstream signals (Kishi et al., 2008). The “morning-ticking” of the clock during daytime corresponds to the peak of locomotor and cognitive activity in humans, while associated with resting time in mice. Similarly, melatonin production during the night is associated with sleep in humans, but active movement and social interactions, in mice. Such differences are significant because the molecular components of the circadian clock are not only important for this mechanism of internal synchronization. They have a pivotal role in intracellular processes (Kishi et al., 2008; Zhdanova et al., 2008) acting as transcription factors for several genes or as direct modulators of epigenetic processes, including chromatin remodeling. Changes of the circadian clock are increasing during the aging process while circadian disruption contributes to morbidity and the development of diseases including metabolic disorders, cardiovascular disease, and cancer. Mutations in clock genes were found to lead to premature aging and age-related changes of the circadian clock include disruption of the endocrine hormone rhythm and changes to the clock-controlled genes. Current theories that suggest that changes in heterochromatin may be responsible for agerelated changes in gene expression profile have been confirmed and partially explained in zebrafish by the function of specific of diurnal noncoding RNAs and the changes in facultative heterochromatin (Park and Belden, 2018). The levels of melatonin progressively decline in zebrafish muscle and brain (Zhdanova et al., 2008). This reduction correlated with observed abnormalities in circadian rhythm, sleep deregulation, and lower activity levels. Age-related cognitive impairment in zebrafish can be partially rescued by systemic administration of melatonin (Zhdanova et al., 2008).

Mitochondrial Dysfunction The mitochondrial free radical theory of aging proposes that accumulation of reactive oxygen species (ROS) that are produced as natural by-products of metabolism leads to mitochondrial deterioration and in turns, cumulative DNA, protein, and lipid damage and thereby global cellular dysregulation and aging. Both the reduced number and functional impairment of mitochondria has been contributed to the mitochondrial deficiencies appearing during aging (López-otín et al., 2013). Nevertheless, zebrafish is also prone to protein and lipid oxidation during aging. Increased protein oxidation levels have been reported in the brain (Ruhl et al., 2015), skeletal muscles (Kishi et al., 2008) while lipid peroxidation was elevated in mitochondria isolated from zebrafish (Almaida-Pagán et al., 2014). Additionally, mitochondria appear morphologically abnormal in aging skeletal muscles (Gerhard and Cheng, 2002) and an age-related damage to mitochondrial oxidative status and mitochondrial membrane phospholipid compositions has been demonstrated (Almaida-Pagán et al., 2014). Finally, sphingomyelindthat is associated with mitochondrial-mediated apoptosis is upregulated in old zebrafish (Lightle et al., 2000). These data confirm the conserved physiology of human and zebrafish concerning mitochondrial function and oxidative stress response and support the use of zebrafish for studies of mitochondrial dysfunction during the aging process.

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Revisiting Cellular Aging in Zebrafish: BiomarkersdStaining Methods For the assessing aging phenotypes and the characterization of aging-related mutants, biomarkers, staining methods, and biochemical analyses have been adapted to using in zebrafish. Senescence-associated b-galactosidase (SA-b-gal) staining is among the first biomarkers used in embryos and adult fish as an indicator of aging and was used in screenings aiming to identify age-related genes (Kishi et al., 2008). SA-b-gal is used as cellular senescence marker in vitro and in vivo for many organisms and probably represents a general adaptive response to cellular senescence. Lipofuscin, also known as “age pigment,” is a “by-product” of the impaired lysosomal function over time and is accumulated in aging cells. It is considered a characteristic trait of aging and the accumulation rate in some tissues correlates with longevity. During natural aging, several physiological and molecular events occur that can distinguish physiological from pathological maturation. One of these features is the dramatic increase in intestinal permeability. Many organisms, including zebrafish, experience this dysfunction and can be assessed by the “smurf” phenotype that can be observed in vivo using a noninvasive assay (Dambroise et al., 2016). The phenotype increases with chronological age and all the individuals will undergo this change before dying from natural causes. DNA damage and dysfunctional DNA damage repair (DDR) underlies many features of aging and age-related diseases. Known apoptotic assays such as TUNEL and acridine orange can be used in the embryo or adult zebrafish tissues. The existing tools for identification and characterization of DDR responses in zebrafish have been reviewed recently (Cayuela et al., 2019). Lately, the carbonic anhydrase 2 (CA2), the myosin regulatory light chain 2 (MYL2), and the selenium-binding protein 1 (SBP1), whose transcription levels are remodeled in an age-dependent fashion have been proposed as putative aging biomarkers (Feng et al., 2018).

Heart Aging Aging is the dominant risk factor for the development of cardiovascular diseases (CVD), the leading cause of death in most developed countries. Age-related changes occur from the molecular to whole organ level and result in progressive deteriorations in cardiac structure and function. These changes include several anatomical and electrophysiological alterations accompanied with altered mitochondrial metabolism (Chiao and Rabinovitch, 2015). Although the phenotypes of cardiac aging have been well characterized in mammals and human, the molecular mechanisms underlying these phenotypes remain largely unexplored. Altered nutrient and growth signaling, mitochondrial oxidative damage and mitochondrial dysfunction, adverse extracellular matrix (ECM) remodeling, impaired calcium homeostasis and chronic activation in neurohormonal signaling are some of the mechanisms involved in the pathogenesis of the aging heart (Chiao and Rabinovitch, 2015). The zebrafish has proven to be a powerful experimental model for the study of cardiac electrophysiology and disease. Despite, two-chambered, the operation of the zebrafish heart is fundamentally similar to the four-chambered mammalian. In aged zebrafish, several structural and functional changes have been reported (Sun et al., 2015), under physiological and stress conditions (Gilbert et al., 2014). Additionally, the functional modifications that distinguish between age or disease-related cardiovascular alterations have also been evaluated. An array of indicators of myocardial fitness were evaluated: morphology, pumping ability, electrophysiological response to stress, and biochemical markers of poor myocardial function were recruited to investigate the potential mechanisms and the effects of age-related cardiac modifications (Sun et al., 2015). An intriguing characteristic of the zebrafish heart is that, unlike mammals, maintains the ability to efficiently repair damaged myocardium throughout life. This regenerative capacity exists in mammals during the early embryonic stages and coincides with the period of active cardiomyocyte proliferation (Vivien et al., 2016). However, this cardiac repair potential is rapidly lost in the later developmental stages being negligible in adults. The exact mechanism underlying the regenerative mechanisms of the zebrafish heart regeneration remains mostly unknown. However, It has been established that telomerase is essential for zebrafish heart regeneration since telomerase knockout (tert
/
) zebrafish are unable to regenerate their cardiomyocytes after cryoinjury and fibrotic scar persists instead of being replaced by regenerated tissue at the point of injury (Bednarek et al., 2015). In aged zebrafish, this regenerative capacity is reduced possibly due to the age-induced telomerase inactivation. The zebrafish represents a potentially powerful model for aging-related CVDs since various cardiac pathologies have been already modeled in the zebrafish, including heart failure and cardiac ischemia. Understanding of the underlying mechanisms governing the intrinsic aging of the heart together with the pathophysiology of these cardiac diseases will help to develop novel strategies and interventions to delay or reverse cardiac aging.

Aging and Cancer in Zebrafish Cancer can be considered an age-related disease because the incidence of most cancers increases with age. At first sight, aging and cancer seem opposite processes: aging is characterized by loss of cellular robustness while cancer is the consequence of the aberrant gain of cellular fitness. However, at a deeper level, some of the same biologic mechanisms that regulate aging also may be involved in the pathogenesis of cancer. Accumulation of cellular damage is the general cause of aging. This damage might randomly provide aberrant advantages to individual cells, which will eventually produce cancer (López-otín et al., 2013). In

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another view, the degenerative mechanism of aging and the hyperplastic pathologies of cancer are linked by the senescence mechanism (Campisi, 2013). Many of the tools and resources that have been developed for studying cellular senescence and DNA damage responses have been discussed earlier with respect to the aging process. Similarly, the same techniques can be utilized in short or long scale to study cancer-related mechanisms. Additional advantages from the use of zebrafish in cancer research and drug development have been reviewed recently (Cayuela et al., 2019).

Concluding Remarks Despite the initial belief that zebrafish is not the optimal model for studying aging processesdbecause of the supposed negligible senescence, its indeterminate growth, and the continued regenerative capacityd, it has now gained enormous popularity on gerontological research. That is because zebrafish, like most mammals, undergoes gradual senescence, with many similarities to human senescence. Moreover, the extensive characterization of the well-conserved molecular function and cellular physiology together with the enormous toolbox for genome editing have made this little fish an outstanding animal model for understanding the complicated mechanisms of aging. Zebrafish has contributed to the identification of genes that regulate aging and modeled several agedepending or age-inducing human diseases. The integration of embryonic assays that are amenable to high-throughput chemical screens guarantees the identification of several lead molecules to further validate. The future challenge of zebrafish gerontologic research is designing interventions for extending healthy lifespan and developing effective treatments for aging-related pathologies (Fig. 1).

(B)

Reporter lines

(A)

(C) Modeling aging diseases

Antiaging screening

Aging biomarkers

(D)

Behavior studies

(E)

Fig. 1 A schematic overview of the areas zebrafish is used in gerontological research. (A) Chemical libraries can be utilized to screen for in vivo activity in zebrafish embryos employing phenotypic and (B) transgenic line assays in 96 well plates. Alternatively, zebrafish scales can be used to screen for putative active compounds relative to metabolic bone diseases like osteoporosis. (C) Genomic editing, loss-of-function studies can be performed to test the effect of specific disease- relevant genes. Forward (chemical or insertional mutagenesis) and reverse (Tiling, morpholino, CRISPR) genetic methods can be applied to model several aging associated diseases or progeroid syndromes. (D) A large set of biomarkers of aging is already applied in zebrafish aging studies. Development of new assessment tools and evaluation of new putative age-related biomarkers is an open field that will contribute to the progress of aging research. (E) Zebrafish is also used as genetic model in behavioral gerontology. A wide range of behavior studies exploiting adult fish or larvae are used to investigate aging- behavior changes on the sleep process, the circadian clock or the cognitive functions. A wide variety of stable transgenic reporter lines have been generated to facilitate live imaging in zebrafish. Depending on the field of interest and the aging parameter that is evaluated, the suitable transgenic line can be selected from the available collection. Transgenic zebrafish lines that label cells or activating signaling pathways and mark musculoskeletal, neuronal and optical tissues, mitochondrial or immune cells have already been successfully used in gerontological research.

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Long-term hyperphagia and caloric restriction caused by low- or high-density husbandry have differential effects on zebrafish postembryonic development, somatic growth, fat accumulation and reproduction. PLoS One 10 (3), 1–31. Liang, S.-T., Audira, G., Juniardi, S., et al., 2019. Zebrafish carrying pycr1 gene deficiency display aging and multiple behavioral abnormalities. Cell 8 (5), 453. Available from: https://www.mdpi.com/2073-4409/8/5/453. Lightle, S.A., Oakley, J.I., Nikolova-Karakashian, M.N., 2000. Activation of sphingolipid turnover and chronic generation of ceramide and sphingosine in liver during aging. Mechanisms of Ageing and Development 120 (1–3), 111–125. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11087909. López-otín, C., Blasco, M.A., Partridge, L., Serrano, M., Kroemer, G., 2013. The hallmarks of aging. Cell 153 (6), 1194–1217. Münzel, E.J., Becker, C.G., Becker, T., Williams, A., 2014. Zebrafish regenerate full thickness optic nerve myelin after demyelination, but this fails with increasing age. Acta Neuropathologica Communications 2, 77. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25022486. Obermann, J., Wagner, F., Kociaj, A., et al., 2019. The surface proteome of adult neural stem cells in zebrafish unveils long-range cell-cell connections and age-related changes in responsiveness to IGF. Stem Cell Reports 12 (2), 258–273. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30639211. Park, J., Belden, W.J., 2018. Long non-coding RNAs have age-dependent diurnal expression that coincides with age-related changes in genome-wide facultative heterochromatin. BMC Genomics 19 (1), 777. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30373515. Park, J.-H., Glass, Z., Sayed, K., et al., 2013. Calorie restriction alleviates the age-related decrease in neural progenitor cell division in the aging brain. European Journal of Neuroscience 37 (12), 1987–1993. https://doi.org/10.1111/ejn.12249. Ramanagoudr-Bhojappa, R., Carrington, B., Ramaswami, M., et al., 2018. Multiplexed CRISPR/Cas9-mediated knockout of 19 Fanconi anemia pathway genes in zebrafish revealed their roles in growth, sexual development and fertility. PLoS Genetics 14 (12), 1–27. Reversade, B., Escande-Beillard, N., Dimopoulou, A., et al., 2009. Mutations in PYCR1 cause cutis laxa with progeroid features. Nature Genetics 41 (9), 1016–1021. Ruhl, T., Jonas, A., Seidel, N.I., et al., 2015. Oxidation and cognitive impairment in the aging zebrafish. Gerontology 62 (1), 47–57. Saleem, S., Kannan, R.R., 2018. Zebrafish: An emerging real-time model system to study Alzheimer’s disease and neurospecific drug discovery. Cell Death Discovery 4 (1), 45. Sivasubbu, S., Balciunas, D., Amsterdam, A., Ekker, S.C., 2007. Insertional mutagenesis strategies in zebrafish. Genome Biology 8 (1), S9. Available from. http://www.ncbi.nlm.nih. gov/pubmed/18047701. Stainier, D.Y.R., Raz, E., Lawson, N.D., et al., 2017. Guidelines for morpholino use in zebrafish. Barsh GS, editor PLoS Genetics 13 (10), e1007000. Available from: http://www. ncbi.nlm.nih.gov/pubmed/29049395. Sugano, Y., Lardelli, M., 2011. Identification and expression analysis of the zebrafish orthologue of Klotho. Development Genes and Evolution 221 (3), 179–186. https://doi.org/ 10.1007/s00427-011-0367-3.

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Sun, Y., Fang, Y., Xu, X., Lu, G., Chen, Z., 2015. Evidence of an association between age-related functional modifications and pathophysiological changes in zebrafish heart. Gerontology 61 (5), 435–447. Tian, J., Shao, J., Liu, C., et al., 2019. Deficiency of lrp4 in zebrafish and human LRP4 mutation induce aberrant activation of jagged-notch signaling in fin and limb development. Cellular and Molecular Life Sciences 76 (1), 163–178. Available from. http://link.springer.com/10.1007/s00018-018-2928-3. Van houcke, J., De Groef, L., Dekeyster, E., Moons, L., 2015. The zebrafish as a gerontology model in nervous system aging, disease, and repair. Ageing Research Reviews 24, 358–368. https://doi.org/10.1016/j.arr.2015.10.004. Vivien, C.J., Hudson, J.E., Porrello, E.R., 2016. Evolution, comparative biology and ontogeny of vertebrate heart regeneration. NPJ Regenerative Medicine 1 (1), 16012. Available from: http://www.nature.com/articles/npjregenmed201612. Wang, N., Luo, Z., Jin, M., et al., 2019. Exploration of age-related mitochondrial dysfunction and the anti-aging effects of resveratrol in zebrafish retina. Aging 11, 1–21. Wienholds, E., van Eeden, F., Kosters, M., et al., 2003. Efficient target-selected mutagenesis in zebrafish. Genome Research 13 (12), 2700. Available from. http://www.ncbi.nlm. nih.gov/pubmed/14613981. Yu, L., Tucci, V., Kishi, S., Zhdanova, I.V., 2006. Cognitive aging in zebrafish. PLoS One 1, e14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17183640. Zhang, Y., Huang, H., Zhao, G., et al., 2017. ATP6V1H deficiency impairs bone development through activation of MMP9 and MMP13. PLoS Genetics 13 (2), e1006481. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28158191. Zhang, W., Xu, J., Qiu, J., et al., 2018. Novel and rapid osteoporosis model established in zebrafish using high iron stress. Biochemical Biophysical Research Community 496 (2), 654–660. Zhdanova, I.V., Yu, L., Lopez-Patino, M., et al., 2008. Aging of the circadian system in zebrafish and the effects of melatonin on sleep and cognitive performance. Brain Research Bulletin 75 (2–4), 433–441. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0361923007003796.

Further Reading Keller, J.M., Keller, E.T., 2018. The use of mature zebrafish (Danio rerio) as a model for human aging and disease. In: Ram, J., Conn, M. (Eds.), Conn’s handbook of models for human aging. Elsevier, pp. 351–359. https://doi.org/10.1016/B978-0-12-811353-0.00026-9. Van Houcke, J., Bollaerts, I., De Groef, L., Moons, L., 2018. Modeling aging and age-associated pathology in zebrafish. In: Ram, J., Conn, M. (Eds.), Conn’s handbook of models for human aging, 2nd edn. Elsevier Inc https://doi.org/10.1016/b978-0-12-811353-0.00025-7. Adams, M.M., Michelle, M., Kafaligonul, H., 2018. ZebrafishdA model organism for studying the neurobiological mechanisms underlying cognitive brain aging and use of potential interventions. Frontiers in Cell and Development Biology 6, 1–5. https://doi.org/10.3389/fcell.2018.00135. Aix, E., Gallinat, A., Flores, I., 2018. Telomeres and telomerase in heart regeneration. Differentiation 100, 26–30. https://doi.org/10.1016/j.diff.2018.01.003. Anchelin, M., Alcaraz-Pérez, F., Martínez, C.M., Bernabé-García, M., Mulero, V., Cayuela, M.L., 2013. Premature aging in telomerase-deficient zebrafish. Disease Models & Mechanisms 6 (5), 1101. https://doi.org/10.1242/DMM.011635. Botthof, J.G., Bielczyk-Maczynska, E., Ferreira, L., Cvejic, A., 2017. Loss of the homologous recombination gene Rad51 leads to Fanconi anemia-like symptoms in zebrafish. Proceedings of the National Academy of Sciences of the United States of America 114 (22), E4452–E4461. https://doi.org/10.1073/pnas.1620631114. Carneiro, M.C., Pimenta de Castro, I., Godinho Ferreira, M., 2016. Telomeres in aging and disease: Lessons from zebrafish. Disease Models & Mechanisms 9 (7), 737–748. https://doi.org/10.1242/dmm.025130. Foglia, M.J., Poss, K.D., 2016. Building and Re-building the heart by cardiomyocyte proliferation. Development (Cambridge, England) 143 (5), 729–740. https://doi.org/10.1242/ dev.132910. Genge, C.E., Lin, E., Lee, L., Stevens, M., et al., 2016. The Zebrafish heart as a model of mammalian cardiac function. Reviews of Physiology, Biochemistry and Pharmacology 171, 99–136. https://doi.org/10.1007/112_2016_5. Gut, P., Reischauer, S., Stainier, D.Y.R., Arnaout, R., 2017. Little fish, big data: Zebrafish as a model for cardiovascular and metabolic disease. Physiological Reviews 97 (3), 889– 938. https://doi.org/10.1152/physrev.00038.2016. Hearps, A.C., Martin, G.E., Angelovich, T.A., et al., 2012. Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11 (5), 867–875. https://doi.org/10.1111/j.1474-9726.2012.00851.x. Henriques, C.M., Carneiro, M.C., Tenente, I.M., et al., 2013. Telomerase is required for zebrafish lifespan. PLoS Genetics 9 (1). https://doi.org/10.1371/journal.pgen.1003214. Lesnefsky, E.J., Chen, Q., Hoppel, C.L., 2016. Mitochondrial metabolism in aging heart. Circulation Research 118 (10), 1593–1611. https://doi.org/10.1161/ CIRCRESAHA.116.307505. Newman, M., Ebrahimie, E., Lardelli, M., Murakami, S., 2014. Using the zebrafish model for Alzheimer’s disease research. Frontiers in Genetics 5, 189. https://doi.org/10.3389/ fgene.2014.00189. Stoyek, M.R., Rog-Zielinska, E.A., Quinn, T.A., 2018. Age-associated changes in electrical function of the zebrafish heart. Progress in Biophysics and Molecular Biology 138, 91–104. https://doi.org/10.1016/j.pbiomolbio.2018.07.014.

Relevant Websites https://zebrafish.orgdZebrafish International Resource Centre (ZIRC). https://www.ezrc.kit.edu/dEuropean Zebrafish Recourse Centre (EZRC). http://eufishbiomed.eudEuFishBiomed. https://www.sanger.ac.uk/resources/zebrafish/zmp/dZebrafish Mutation Project (ZMP).

Aging Lungq Fatmanur Karakose Okyaltırık, Bezmialem Vakif University Medical School Pulmonology Department, Istanbul, Turkey © 2020 Elsevier Inc. All rights reserved.

Aging Lung Structural Versus Functional Changes Molecular/Cellular Changes Pulmonary Immunity, Aging of the Immune System, Immunosenescence, and Inflammaging Aging and Respiratory Diseases Aging and COPD Aging and IPF Aging and Sleep Disorders Aging and Autoimmune Diseases Conclusion References

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Glossary ACOS Asthma chronic obstructive overlap syndrome. COPD Chronic obstructive pulmonary disease. CPFE Combined pulmonary fibrosis and emphysema. DLCO Diffusion of lung for carbon monoxide. Inflammaging Chronic low-grade systemic proinflammatory state that accompanies aging. Immunosenescense Cellular and functional decrease in immune function. IPF Idiopatic pulmonary fibrosis. FEV1 Force expiratory volume 1. FVC Force vital capacity. REM Rapid eye movement. ROS Reactive oxygen species. SBD Sleep breathing disorder. Telomere A region of highly repetitive DNA at the ends of a linear chromosome that functions as a disposable DNA buffer for sequence loss during replication. TLR signaling Toll-like receptor signaling. V/Q Ventilation/perfusion rate.

Aging Lung Although aging reveals individual differences, either genetic or dependent on external impacts, it is a period in which the tendency toward disease development progressively increases. Disintegration between systems and damage on cellular and molecular levels over time lead to a decrease in physiological reserves, increased organ damage, increased disease frequency, and even death (Fig. 1) (Organisation WH, 2015; Gulhan, 2017; Thannickal et al., 2015). The global population over 65 years in age has increased in the last decade to more than 10%, and is expected to exceed 20% by 2030 (Thannickal et al., 2015; Murray and Chotirmall, 2015). The elderly population increases as life expectancy increases. While the mortality and morbidity of cardiovascular and neurological diseases are decreasing, those associated with pulmonary diseases are increasing (Murray and Chotirmall, 2015), emphasizing the importance of understanding the mechanisms that play an active role in age-dependent development and progression of pulmonary diseases. We planned to look over and reasses the mechanism of aging from the viewpoint of lung disease in this chapter.

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Change History: December 2018. Karakose Okyaltırık, Fatmanur has updated the text throughout the article.

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Disintegration between systems Cellular damage

Molecular damage Decrease in physiologic reserve

Increased disease frequency and DEATH Fig. 1 Aging Cascade. Organisation WH. World Report on Ageing and Health. 2015; Gulhan, M. Definition and epidemiology of geriatric case; Overview of pulmonary diseases. Turkiye Klinikleri (2017). Journal of Pulmonary Medicine-Special Topics 10(3), 141–144; Thannickal, V.J., Murthy, M., Balch, W.E., Chandel, N.S., Meiners, S., Eickelberg, O., et al. (2015). Blue Journal Conference. Aging and susceptibility to lung disease. American Journal of Respiratory and Critical Care Medicine 191(3), 261–269.

Structural Versus Functional Changes Alveolar ducts and collagen fibers around the alveoli, which are the most significant components of respiration, basically prevent lung collapse during inflation and deflation. The most significant protein structures forming the extracellular matrix (ECM), which supports alveolar structure, are collagen and elastin. Age-dependent changes occur in the collagen fiber network, dilatation in the alveolar duct, homogeneous enlargement in the alveolar airspace, and decreases in gas exchange areas (Murray and Chotirmall, 2015). The major difference between the senile lung and emphysema is the lack of inflammation and alveolar wall destruction. Another significant factor in alveolar stabilization involves surfactants, which decrease surface tension. However, there is no evidence that surfactants are affected by age. Because surface tension is inversely proportional to alveolar volume, alveolar enlargement in the elderly reduces the surface tension, and the lung becomes more compliant and distensible (Skloot, 2017). In extra-pulmonary structures, vertebrae degenerative changes with a tendency toward kyphosis, increased convexity of the sternum, loss of respiratory muscle mass and function, and stiffening in the rib cage lead to decreases in the compliance of the chest wall (Lowery et al., 2013; Sharma and Goodwin, 2006). All of these changes challenge the normal physiological respiratory system. Alveolar enlargement reduces elastic recoil and subsequently causes decreases in force expiratory volume 1 (FEV1) and force vital capacity (FVC), and tends to increase the functional residual capacity (FRC) and total lung capacity (TLC), and pulmonary function naturally decreases with age. Maximum pulmonary function occurs at 20–25 years of age, and then steadily declines until death. This decrease is best reflected in the FEV1 and FVC values. FEV1 decreases by 25–30 mL/year at 35–45 years of age, and decreases by 60 mL/year at approximately 70 years of age (Sharma and Goodwin, 2006; Ascher et al., 2017; Cherniac and Cherniac, 2007). Decreases in elastic recoil pressure and chest wall compliance lead to premature closure of the terminal airways, and increase closing volumes. Increases in FRC and residual volume (RV) are associated with these changes (Skloot, 2017; Lowery et al., 2013). Matching ventilation and perfusion determine the carbondioxide and oxygen exchange ability of lungs. Increased closing volumes with premature closure of terminal airways at the FRC causes ventilation/perfusion rate (V/Q) mismatch and ventilation defects. An increased low V/Q zone, general V/Q mismatch, and increased dead space ventilation (ventilated but not perfused areas) are thought to cause low arterial oxygen pressure (PaO2) and increased alveolar-arterial oxygen pressure difference (p[Aa]O2) in the elderly (Skloot, 2017; Janssens, 2005). To maintain arterial carbon dioxide pressure (PaCO2) within the normal range and ensure alveolar ventilation, the elderly must increase the total minutes of ventilation. Meanwhile, due to V/Q mismatch, a decreased diffusing capacity of the lung for carbon monoxide (DLCO) concomitantly occurs. This may depend on the decline in the alveolar surface, decreases in the intensity of pulmonary capillaries, and decreases in pulmonary blood flow (Sharma and Goodwin, 2006; Janssens, 2005).

Molecular/Cellular Changes Biological aging is characterized by physiological disintegration, loss of function, and disease tendencies at older ages, which ultimately may result in death (Thannickal et al., 2015). This cycle is associated with slow and intermittent damage formation affected by environmental and metabolic factors. Understanding pulmonary pathophysiological changes in the aging lung, as well as genomic differentiation, may be the key to understanding aging-related lung diseases.

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Infections, dietary risk factors, and environmental toxins are known to affect DNA structure, both directly and via metabolic signals. Genomic instability, telomere shortening, and epigenetic changes can alter DNA, miRNA changes can alter noncoding RNA, and proteostasis can cause changes in protein structure. (MicroRNAs are small, conserved non-coding RNA molecules involved in the regulation of gene expression.) This cellular activity forms the basis of lung diseases by causing cellular senescence, stem cell dysfunction, mitochondrial dysfunction, immune dysregulation, and extracellular matrix dysfunction (Ascher et al., 2017). The molecular and biological mechanisms of aging lose their protective properties as they lose their integrity. Because genomic instability with posttranscriptional changes leads to defective protein products, these altered proteins are generally destroyed by autophagy, and when autophagy is not possible, they accumulate in tissues, leading to functional losses. Telomeres protect chromosomal structure and facilitate genetic stability. They are gradually shortened during each sequential cellular proliferation, with excessive shortening over time leading to defects in cellular proliferation. In a similar manner, stem cell exhaustion and a decrease in appropriate regenerative capabilities, as well as mitochondrial dysfunction, limit ATP production, resulting in abnormal cellular functions (Thannickal et al., 2015; Ascher et al., 2017; Lopez-Otin et al., 2013; Meiners et al., 2015). Stem cells have self-renewal capabilities and new differential cell formation capabilities when needed, to maintain the stem cell reserve (Navarro and Driscoll, 2017). A decrease in tissue renewal potential is one of the most significant properties of aging. For example, reduction in hematopoiesis leads to a decrease in adaptive immune cells, which increases the incidence of anemia and myeloid malignancy (Lopez-Otin et al., 2013). The respiratory system consists of airways and millions of alveoli. There are more than 40 types of cells that form the complex structure of the lung (Brandenberger and Muhlfeld, 2017). The stem cell is the most important cell type for lung injury repair, new tissue formation, regeneration, and maintaining homeostasis. Stem cells either self-renew or may show asymmetric proliferation toward different cell types (Navarro and Driscoll, 2017). Lung regeneration is multifactorial. The three major stem cell types are airway, nonairway parenchymal, and alveolar stem cells. Airway stem cells are found in the trachea and bronchi in mice, and in small airways in humans. During naphthalene damage or viral infection, a response involving the Notch pathway results in differentiation to club or ciliated cells. Ciliated cells are transformed into squamous-like cells, which are dispersed in the mucosa and are involved in protection. During the repair phase, club cells differentiate into mucin glycoprotein-secreting goblet cells (Muc5ac plays a role in allergen challenge). Parenchymal (bronchoalveolar) stem cells are located in the bronchoalveolar junction, and may transform into type 2 alveolar epithelial (AEC2) and type 1 alveolar epithelial (AEC1) cells following bleomycin induction or hypoxic damage. Additionally, alveolar stem cells are capable of clonal expansion and differentiation into AEC1 and AEC2 cells. AEC2 proliferation is partly associated with pulmonary capillary endothelial cells (PCECs). When PCECs are triggered in situations like pneumonectomy, the expression of vascular endothelial growth factor receptor 2 and fibroblast growth factor receptor (FGFR1) is upregulated, leading to bronchioalveolar stem cell (BASC), AEC2, and PCEC proliferation (Ascher et al., 2017; Navarro and Driscoll, 2017; Barkauskas et al., 2013; Ding et al., 2011; Kumar et al., 2011). With regard to the mechanisms described, the regenerative capacity in the aging lung may decrease with no prior warning, which may lead to organ dysfunction and chronic lung disease (Navarro and Driscoll, 2017).

Pulmonary Immunity, Aging of the Immune System, Immunosenescence, and Inflammaging Cellular and functional decreases in immune function are defined as “immunosenescence.” Community acquired and nosocomial infections are more common in the elderly compared to younger populations, and the course of such diseases is more severe in elderly populations. This is closely associated with the physiological aging process and with immune system functions. In elderly patients, the diagnoses of pathogens, chemotaxis, number of naive T lymphocytes, phagocytosis, cytotoxicity, and the quality and quantity of antibodies all decrease. Regeneration and repair limitations accompany cellular senescence and may cause infection, autoimmune diseases, cancer, and a weak vaccine response (Murray and Chotirmall, 2015; Brandenberger and Muhlfeld, 2017; Ongrádi and Kövesdi, 2010). Age-dependent immune system changes in the lung are consistent with cellular changes as well as with functional disorders. The main cell groups in the lung and their specific dysfunctions are listed below. (1) Bronchoepithelial cells: Decreases in the numbers of cells, decreases in mucociliary clearance, and decreases in mucus secretion cause decreased or impaired mucociliary clearance. (2) Alveolar epithelial cells: Deterioration in the lamellar structure leads to changes in surfactant composition, increased oxidative stress, decreased alveolar stem cell renewal capacity related to disease, and increased disease-related alveolar damage sensitivity. (3) Endothelial cells: Decreased cellular migration and proliferation, and impaired vascular regulation-related nitric oxide signaling pathway result in sensitivity to injury. (4) Alveolar macrophages and neutrophils: Macrophages are the primary innate immune cells in the lungs. They are the first mechanism of defense against pathogens invading the lung, and have immunologically critical significance. They have the ability to initiate and terminate the inflammatory response. Under stable conditions, macrophages maintain the antiinflammatory state by continuously controlling airways; however, they quickly respond to a strong proinflammatory state, and organize neutrophils within minutes via chemoattractant cytokine secretion.

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Macrophages initiate resolution after the pathogen is eradicated and restore a stable antiinflammatory state before another threat. The steady state of both functions is of great importance for pulmonary homeostasis. For the resolution of developed inflammation, the pathogen and debris must be removed, neutrophil chemokines must be reduced, and apoptotic cells (such as used, inefficient neutrophils) must be removed. Otherwise, prolonged inflammation persisting in the lung can lead to tissue damage. Macrophage dysfunction may lead to decreased phagocytosis, decreased toll-like receptor (TLR) signaling, changes in cytokine effects, increased reactive oxygen species (ROS) production, and increased sensitivity to infections. With several antimicrobial activities, neutrophils have the ability to remove pathogens from tissues in the early stages of infection. Age-related changes that develop in neutrophils lead to decreased chemotaxis, phagocytosis, ROS production, proinflammatory cytokine (IL-6, IL-8, myeloperoxidase, and elastase) production, and increased secretion of antiinflammatory cytokines and IL-10. (5) Changes in fibroblasts and the ECM include increased fibrogenic response, decreased elastin and laminin, and increased collagens. Related to these changes is a reduction in pulmonary elasticity, resulting in the formation of a profibrotic basis (Brandenberger and Muhlfeld, 2017; Kovacs et al., 2017; Aggarwal et al., 2014; Herold et al., 2011). Aging also causes changes in humoral immune functions. Antibody production and responses decrease, and a loss of naïve B cells and an increase in the number of memory cells reduce the ability to recognize novel antigens. The T helper cell response to immunological stimulation tends toward the involvement of Th2 cells rather than Th1 cells. This situation may lead to the development of B cell-mediated immune diseases (Murray and Chotirmall, 2015; Ongrádi and Kövesdi, 2010). Pulmonary cell types can be generally classified as epithelial (bronchiolar and alveolar), endothelial, fibroblast, or immune cells. Cell type-specific senescence may cause different types of diseases. For example, the senescence of alveolar epithelial precursor cells occurs together with idiopatic pulmonary fibrosis (IPF), and mesenchymal cell exhaustion with chronic obstructive pulmonary disease (COPD) (Brandenberger and Muhlfeld, 2017; Chilosi et al., 2013). The aging immune system is characterized by a persistent low-grade proinflammatory state, which involves increased levels of proinflammatory mediators in the blood (IL-1b, IL-6, and tumor necrosis factor-alpha) without any immunological threat. In the 2000s, the concomitant course of aging and inflammation was defined as “inflammaging,” which occurs during the aging process, and is thought to play a role in the pathogenesis of age-dependent inflammatory diseases such as atherosclerosis and Alzheimer’s disease (Murray and Chotirmall, 2015; Lowery et al., 2013; Kovacs et al., 2017; Frasca and Blomberg, 2016). The cellular origin of meditators causing inflammaging is unknown. Different theories about the initiation of inflammaging have been suggested. The classical theories are those associated with DNA damage, oxidative stress, and telomere shortening, with new theories and studies involving the gut-liver-lung axis. According to this latter theory, intestinal permeability changes in the elderly allow bacteria and bacterial products (peptidoglycans and endotoxins) to pass through the lymphatic system and the blood, resulting in low-grade systemic inflammation in the blood. Exacerbation may then occur either by infection or any other damage (Kovacs et al., 2017; Kim et al., 2016; Man et al., 2015; Claesson et al., 2011). Pathways involved in immunosenescence, which decrease oxidative stress by regulating the immune response, may be exploited to develop potential treatment options. Advanced research regarding the benefits of targeted therapies is therefore required for the management of systemic inflammation.

Aging and Respiratory Diseases Respiratory symptoms and respiratory diseases such as dyspnea, chronic bronchitis, and wheezing are common in patients over 65 years of age. This situation should be assessed in association with respiratory and concomitant nonrespiratory risk factors (Marcus et al., 2015; Vaz Fragoso and Gill, 2012). Tobacco smoking, air pollution, occupational dust, and infections are thought to be the most common respiratory risk factors (Goldcopd, 2018). Multiple drug use, deconditioning in relation to physical inactivity, concomitant diseases, and lack of awareness of symptom severity can be considered nonrespiratory risk factors. COPD, asthma chronic obstructive overlap syndrome (ACOS), IPF, combined pulmonary fibrosis and emphysema (CPFE), and lung cancer are the main diseases that are increasing in the elderly (Vaz Fragoso, 2017). The global incidence of COPD is reported to be 200/10,000 for those younger than 45 years of age; however, it is 1200/10,000 for those older than 65 years of age. This remarkable increase in elderly patients has also been reported for IPF, which occurs in 4–7 in 10,000 patients over 75 years of age (Ascher et al., 2017). In addition, aging of the lung is strongly correlated with the development and incidence of chronic lung diseases (Navarro and Driscoll, 2017).

Aging and COPD Aging and COPD show similar common pathways and mechanisms (Murray and Chotirmall, 2015; Navarro and Driscoll, 2017). COPD is characterized by inflammation of the airways and lungs, mucociliary dysfunction, alveolar destruction, and airway fibrosis. The most significant risk factors are smoking and noxious gases. Smoking increases oxidative stress, leading to DNA damage and accelerated aging. Due to aging, similar changes are observed even in the elderly who have never smoked, with increased incidence of COPD sensitivity. Innate immune system suppression increases infection vulnerability and cancer risk.

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Aging is accompanied by decreased epithelial barrier function and ciliary dysfunction (Murray and Chotirmall, 2015). COPD can therefore be considered an accelerated aging process (Mercado et al., 2015; Cortopassi et al., 2017). Due to age-dependent physiological decreases in FEV1 and FVC, using spirometers and assessing clinical symptoms are advisable in diagnosing COPD in the elderly (Lowery et al., 2013).

Aging and IPF IPF is the most frequent interstitial lung disease in the elderly. Many molecular and cellular mechanisms present during aging are also present in IPF. Telomeres ensure chromosomal stability, and they are structurally sensitive to oxidative stress and inflammation. Telomeres are naturally shortened following DNA replication. As the shortening reaches a critical level, programmed cell arrest and apoptosis occur. Telomere shortening is also a natural process in aging. In IPF patients, oxidative stress markers are increased in both the airways and the systemic circulation. Telomere shortening is detected in the lung epithelium and in the peripheral blood; however, bone marrow-derived stem cells (e.g., fibrocytes) show abnormal cellular responses in IPF patients, and cell death does not occur, but causes poor prognoses (Murray and Chotirmall, 2015; Kaszubowska, 2008).

Aging and Sleep Disorders Sleep problems are common in the elderly; however, the difficulty of clearly defining “normal” within this age range creates challenges in the resolution of sleep-related problems. In the elderly, both the duration and the quality of sleep may vary. Although the elderly need less sleep, it is thought that they are usually sleepier during the day. What is unique about sleep in the elderly is the decrease in the duration and activity of sleep. The main reason for this decrease may involve frequent waking owing to diuretic intake due to cardiac failure, or dyspnea/coughing secondary to COPD. When the frequency of chronic diseases is considered in this group of patients, defining the necessity of diagnosis and treatment of sleep problems becomes more difficult. The most common sleep-related problems in the elderly are rapid eye movement (REM) behavior disorder, insomnia, and sleep breathing disorders (Feinsilver and Hernandez, 2017; Ogan, 2017; Kitakata et al., 2018). Regarding REM sleep behavior disorders, patients are unable to move during their dreams due to the lack of muscle paralysis that happens during normal REM sleep. This disorder may also occur with degenerative diseases. Should unconscious pushing, hitting, and kicking occur, the patient may hurt himself/herself or his/her sleep partner. Treatment to prevent such cases consists of pharmacological methods as well as ensuring environmental safety. Insomnia is characterized by challenges in initiating and maintaining sleep, and by accompanying daytime symptoms. With decreases in cognitive function, physical conditioning, and quality of life, depression may accompany insomnia. The treatment consists of behavioral and pharmacological treatments, and can be organized by psychosocial interventions. However, hypnotic medications should be approached with care due to potential adverse effects (Suzuki et al., 2017; AAOS Medicine, 2014). Sleep breathing disorders (SBD) are characterized by repeated complete (apnea) or incomplete (hypopnea) airway obstructions. Most often, SBD decrease blood oxygen saturation and generally result in arousal (AAOS Medicine, 2014). The most common form is obstructive sleep apnea (OSA). The prevalence of OSA in the elderly varies between 20% and 40%, as reported in different studies. The reason for such a broad range is thought to be differences in diagnostic criteria. Even when using a conservative approach, OSA frequency in the elderly is at least two times higher than that in younger patients (McMillan and Morrell, 2016). When OSA is not treated, it may become a risk factor for stroke, hypertension, and coronary artery disease. Despite the high prevalence in the elderly, complication rates have not been sufficiently clarified. Continuous positive airway pressure is the standard treatment for OSA.

Aging and Autoimmune Diseases Autoimmunity in the elderly is higher than in younger patients; however, the prevalence of autoimmune diseases is relatively lower. T-regulatory cells increase autoimmunity, and decrease the CD4 CD8 response, thus leading to increased sensitivity to infections and cancer, respectively. However, advanced studies are required to reveal other possible influences (Murray and Chotirmall, 2015).

Conclusion Understanding of the biology of aging lung may be clue for understanding the age dependent lung disease, improve the overall quality of life and lengthen the lifespan.

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Aging Muscle and Sarcopenia Ben Kirk and Steven Phu, Department of Medicine, Melbourne Medical SchooldWestern Health, The University of Melbourne, St. Albans, VIC, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia Danielle A Debruin and Alan Hayes, Department of Medicine, Melbourne Medical SchooldWestern Health, The University of Melbourne, St. Albans, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia; and Institute of Sport and Health, Victoria University, Melbourne, VIC, Australia Gustavo Duque, Department of Medicine, Melbourne Medical SchooldWestern Health, The University of Melbourne, St. Albans, VIC, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia © 2020 Elsevier Inc. All rights reserved.

Introduction Epidemiology Definition Diagnosis Prevalence Clinical Costs Clinical Implications Sarcopenia: A Consequence of Aging Muscle Loss of Muscle Mass Loss of Muscle Strength Pathophysiology Neurological Changes Calcium Imbalance Loss of Mitochondria Muscle De-capillarization Loss of Stem Cells Intramuscular Adipose Tissue Inflammaging Hormonal Changes Impaired Protein Balance Resistance Exercise, Dietary-Protein & Muscle Signaling Treatments Pharmacological Targeting Muscle LossdMyostatin/Activin Inhibitors Selective Androgen Receptor Modulators Nonpharmacological Physical Activity: Resistance Exercise Nutrition: Dietary-Protein Summary References Further Reading

121 121 121 121 122 122 123 123 123 124 124 124 124 125 125 125 125 125 125 126 126 128 128 128 128 129 129 129 129 130 131

Abbreviations ActRIIB Activin type II receptors ADL Activities of daily living ALK Activin-receptor-like Kinases ANZSSFR Australian and New Zealand Society for Sarcopenia and Frailty Research BCAA Branched chain amino acid DXA Dual-energy X-ray absorptiometry ECC Excitation-contraction coupling EWGSOP European Working Group on Sarcopenia in Older People EWGSOP2 European Working Group on Sarcopenia in Older People 2

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FNIH Foundation for the National Institutes of Health ICD-10-CM International Disease Classification-10th Revision-Clinical Modification IGF1 Insulin-like growth factor 1 IMAT Intramuscular adipose tissue IWGS International Working Group on Sarcopenia MPB Muscle protein breakdown MPS Muscle protein synthesis mTORC1 Mechanistic target of rapamycin complex 1 MU Motor units PA Physical activity RE Resistance exercise SARMs Selective androgen receptor modulators WPI Whey protein isolate

Introduction Over the past few decades, western societies have observed a decline in mortality rates, which is attributed to advancements in healthcare and socioeconomic structures. This has led to an aging society with 13% of the global population now aged 65 and older, and over the next 25 years, the number of the oldest old ( 85 years) is projected to double in some western countries (United Nations report on World Population Prospects, 2017). These demographic changes represent one of the great achievements of the 21st century, although conversely aging is characterized by a physiological reduction in the reserve capacity of the body’s major organs, increasing the vulnerability to a range of diseases. The musculoskeletal system is no exception to this, and at the forefront of health issues associated with aging is a muscle disease known as sarcopenia. In 2016, sarcopenia was officially assigned an International Disease Classification-10th Revision-Clinical Modification (ICD10-CM) (Cruz-Jentoft et al., 2018), enabling some healthcare systems to now bill for this condition. Despite this advancement, clinicians worldwide are relatively uninformed of the epidemiology, pathophysiology, diagnostic tools, clinical implications, and available treatments for sarcopenia. As such, this article will provide an overview of the aforementioned.

Epidemiology Definition Dr. Irwin Rosenberg derived the term sarcopenia in 1989 from the Greek words “sarx” (flesh) and “penia” (loss) to describe the agerelated loss of skeletal muscle mass. By conceptualizing sarcopenia, the intention was to raise clinical and scientific awareness of an unknown phenomenon at the time. Over the ensuing decades, this definition has advanced, due to an upsurge of research into diseases of aging. Various expert working groups now define sarcopenia as the progressive and generalized loss of muscle mass, strength and/or functional capacity (Cruz-Jentoft et al., 2018). The advanced definition incorporated muscle strength and functional capacity into diagnostic algorithms as longitudinal trials demonstrated a deterioration in both aspects across the lifespan (Daly et al., 2013), and not solely muscle mass as originally described by Rosenberg. In addition, reviews (Clark and Manini, 2008) have identified muscle function to be a more powerful indicator of adverse outcomes when compared to muscle mass alone.

Diagnosis Since sarcopenia was identified as a disease, a multitude of consensus statements have followed in the hope of assisting clinical diagnosis (Landi et al., 2018). These include; the European Working Group on Sarcopenia in Older People (EWGSOP), and its revised edition (EWGSOP2), the International Working Group on Sarcopenia (IWGS), the Foundation for the National Institutes of Health (FNIH), and the continent specific Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR) Task Force, and the Asian working Group on Sarcopenia (AWGS) (Landi et al., 2018). Whilst these guidelines differ somewhat in their cut-off points and medical devices used to capture sarcopenia, all agree that low muscle mass, strength and/or functional capacity are needed for diagnoses. At present, the most cited guidelines and endorsed by a range of international scientific societies (Cruz-Jentoft and Sayer, 2019) are that of the European working group, which first recommend searching for case findings of sarcopenia, such as older persons who are hospitalized, in care homes, or rehabilitation settings (Cruz-Jentoft et al., 2018). A validated method with high-specificity but low-sensitivity, is the SARC-F tool (Cruz-Jentoft et al., 2018). This validated survey screens for five scored items: strength, assistance in walking, rising from a chair, climbing stairs, and falls, with a low score symptomatic of sarcopenia (Cruz-Jentoft et al., 2018) . Table 1 gives the possible risk factors for sarcopenia.

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Possible risk factors for sarcopenia.

Primary Age Physical inactivity/sedentarism Low protein intake Low socioeconomic status Secondary Cancer Bone and joint conditions Cardiorespiratory disorders Metabolic and endocrine disorders Neurological disorders Liver and kidney disorders

Following this, the EWGSOP2 recommends a systematic diagnostic algorithm, which defines presarcopenia as low muscle strength, while sarcopenia diagnosis is confirmed in the presence of sex specific cut-off points for low appendicular lean (muscle) mass (Cruz-Jentoft et al., 2018), and severe sarcopenia encompasses low performance in muscle mass, strength, and functional capacity. These thresholds are derived from normative data of young healthy populations (Cruz-Jentoft et al., 2018). According to the EWGSOP2, diagnoses begins by assessing grip strength or chair-stand time, which are easy to perform and provide strong prognoses of adverse health outcomes (Cruz-Jentoft et al., 2018). Estimates of muscle mass are followed with a wide-range of techniques recommended such as dual-energy X-ray absorptiometry (DXA), bioelectrical impedance analysis, computed tomography, magnetic resonance imaging and more recently ultrasound. Of these, the most commonly used is DXA, which is readily available is clinical and research settings thanks to the prevalence of bone disorders. While DXA is confounded by other lean mass components such as bone minerals and organ masses, at present, it is the most widely accepted method for estimating muscle mass. The final assessment to screen for is functional capacity, which can be evaluated by measuring 4 m gait speed, 400 m walk distance, the Short-Physical Performance Battery (which evaluates timed balance, grip strength, chair-rises and gait speed), or the Timed Up and Go test. All of these functional measures have evidence-based cut-off points and are easily administrable with no special equipment required in clinical settings (Cruz-Jentoft et al., 2018) Table 2. It should be noted that unlike osteoporosis where a universal agreement exists on diagnosing low bone mineral density (via DXA), there is a lack of consensus for sarcopenia, which has hindered clinical interpretation and translation, and likely contributed to an underdiagnosis of this disease. As a result, these guidelines have been the subject of hot debate, with some leading experts even suggesting their abolishment and instead proposing the term muscle failure to describe sarcopenia (Suetta and Maier, 2019). However, recent advancements in the field have identified a noninvasive approach to gauge muscle mass, via the dilution rate of oral d3 creatine. When paired off against DXA, this method is a better predictor of functional capacity (Evans et al., 2019) and may play a more prominent role in future diagnostic criteria.

Prevalence The prevalence of sarcopenia varies substantially, which is a consequence of differing study populations, measurements, and cut-off points used in research practices (Mayhew et al., 2018). An observational trial of 4502 older adults approximated sarcopenia at 7% and 10% in men and women respectively, when using low muscle mass (via bio-impedance analysis) as the single proxy (Janssen et al., 2002). A meta-analysis of 58,404 older adults provided slightly higher estimates in men (10%, 95% CI: 8–12%) and women (10%, 95% CI: 8–13%) when pooling studies using the EWGSOP1, IWGS, and AWGS (Shafiee et al., 2017). Another analytical analysis discovered much broader ranges between 9.9% and 40.4% when comparing different studies and definitions, although again, only used cut-off points for muscle mass (Mayhew et al., 2018). Others have estimated the prevalence ranges from 15% at 65 years increasing to 50% at 80 years (Cruz-Jentoft et al., 2018). Despite the varying prevalence rates, on a global scale, evidence suggests at least 10% of older persons suffer from this condition.

Clinical Costs On an economic scale, sarcopenia represents a huge financial burdening on healthcare systems. In the United States, costs associated with sarcopenia were estimated at $18.5 billion in the year 2000, and if hospitalized in the same country the cost attributed to sarcopenia was $40.4 billion in 2019, with an average cost of $260 per individual (Goates et al., 2019). The cost of keeping an older compared to a younger adult with sarcopenia in intensive care is also higher in the former population ($375 vs. $204), which is unsurprising given age is a risk factor for a host of chronic disease. In the United Kingdom too, annual costs attributed to muscle weakness, a phenotype of sarcopenia, was estimated at £2.5 billion (£2707 per case) in 2018 (Pinedo-Villanueva et al., 2018). Alarmingly, this financial strain is likely to grow as the World Health Organization projects that sarcopenia will affect more than 200 million people worldwide by 2050, a fourfold increase since 2014 (United Nations report on World Population Prospects, 2017).

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An example of cut-off points for common algorithms used to screen for sarcopenia.

Definition

Year

Muscle mass

Muscle strength

Function

Revised European Working Group on Sarcopenia in Older Persons (EWGSOP2)

2019

ALM/m2 (DXA) Men 11 g/dL

Bone marrow

No leukemic cells and B-lymphoid nodules

> 100
109/L or increase 50% from baseline >11 g/dL or increase 50% from baseline Presence of leukemic cells and B-lymphoid nodules

B

Decrease 49% form baseline, but increase 49% from baseline decrease 49% form baseline, but increase 49% from baseline Decrease 49% form baseline, but increase 49% from baseline No change in bone marrow morphology

PD

increase 50% from baseline Decrease 50% from baseline Decrease 50% from baseline Increase of leukemic cells

ALC, lymphocyte count; PLT, platelet count; Hgb, hemoglobin; CR, complete remission; PR, partial remission; SD, stable remission; PD, progressive disease.

these drugs’ mechanism of action, an increase in peripheral blood lymphocytes  50% from baseline, without other indices of progression, should not be considered as disease progression. In patients who are treated continuously, the response should be evaluated at least 2 months after the maximum response (Hallek et al., 2018).

References Binet, J.L., Auquier, A., Dighiero, G., et al., 1981. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48, 198–204. Burger, J.A., Tedeschi, A., Barr, P.M., et al., 2015. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. The New England Journal of Medicine 373, 2425–2437. Byrd, J.C., Brown, J.R., O’Brien, S., et al., 2014. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. The New England Journal of Medicine 371, 213–223. Byrd, J.C., Furman, R.R., Coutre, S.E., et al., 2015. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 125, 2497–2506. Byrd, J.C., Hillmen, P., O’Brien, S., et al., 2019. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood 133, 2031–2042. Chastain, E.C., Duncavage, E.J., 2015. Clinical prognostic biomarkers in chronic lymphocytic leukemia and diffuse large B-cell lymphoma. Archives of Pathology & Laboratory Medicine 139, 602–607. CLL-IPI working group, 2016. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): A meta-analysis of individual patient data. The Lancet Oncology 17, 779–790. Cortese, D., Sutton, L.A., Cahill, N., et al., 2014. On the way towards a “CLL prognostic index”: Focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort. Leukemia 28, 710–713. Döhner, H., Stilgenbauer, S., Benner, A., et al., 2000. Genomic aberrations and survival in chronic lymphocytic leukemia. The New England Journal of Medicine 343, 1910–1916. Dreger, P., Montserrat, E., European Society for Blood and Marrow Transplantation (EBMT), European Research Initiative on CLL (ERIC), 2015. Where does allogeneic stem cell transplantation fit in the treatment of chronic lymphocytic leukemia? Current Hematologic Malignancy Reports 10, 59–64. Eichhorst, B., Robak, T., Montserrat, E., et al., 2015. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 26, v78–v84. Eichhorst, B., Fink, A.M., Bahlo, J., et al., 2016. First-line chemoimmunotherapy with bendamustine and rituximab versus fudarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): An international, open-label, randomised, phase 3, non-inferiority trial. The Lancet Oncology 17, 928–942. Furman, R.R., Sharman, J.P., Coutre, S.E., et al., 2014. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. The New England Journal of Medicine 370, 997–1007. Goede, V., Firsche, K., Dyer, J.S., et al., 2018. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: Final survival analysis of the CLL11 study, EHA Library. Abstrakt 151. Goldin, L.R., Landgren, O., Marti, G.E., Caporaso, N.E., 2010. Familial aspects of chronic lymphocytic Leukemia, monoclonal B-cell lymphocytosis (MBL), and related lymphomas. European Journal of Clinical Medical Oncology 2, 119–126. Hallek, M., Cheson, B.D., Catovsky, D., et al., 2018. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 131, 2745–2760. Hanna, K.S., 2019. Updates in the management of chronic lymphocytic leukemia/small lymphocytic leukemia. Journal of Oncology Pharmacy Practice. https://doi.org/10.1177/ 1078155219853030 [Epub ahead of print]. Kater, A.P., Seymour, J.F., Hillmen, P., et al., 2019. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: Post-treatment follow-up of the MURANO phase III study. Journal of Clinical Oncology 37, 269–277. Kipps, T.J., Stevenson, F.K., Wu, C.J., et al., 2017a. Chronic lymphocytic leukaemia. Nature Reviews. Disease Primers 3, 17008. Kipps, T.J., Stevenson, F.K., Wu, C.J., et al., 2017b. Chronic lymphocytic leukaemia. Nature Reviews. Disease Primers 3, 16096. Mato, A.R., Thompson, M.C., Nabhan, C., Svoboda, J., Schuster, S.J., 2017. Chimeric antigen receptor T-cell therapy for chronic lymphocytic leukemia: A narrative review. Clinical Lymphoma, Myeloma & Leukemia 17, 852–856. Montserrat, E., Moreno, C., 2008. Chronic lymphocytic leukemia: A short overview. Annals of Oncology 19, 320–325.

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Nørgaard, C.H., Søgaard, N.B., Biccler, J.L., et al., 2018. Limited value of routine follow-up visits in chronic lymphocytic leukemia managed initially by watch and wait: A North Denmark population-based study. PLoS One 13, e0208180. Parker, T.L., Strout, M.P., 2011. Chronic lymphocytic leukemia: Prognostic factors and impact on treatment. Discovery Medicine 11, 115–123. Pepper, C., Majid, A., Lin, T.T., et al., 2012. Defining the prognosis of early stage chronic lymphocytic leukaemia patients. British Journal of Haematology 156, 499–507. Puente, X.S., Bea, S., Valdes-Mas, R., et al., 2015. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524. Rai, K.R., Chiorazzi, N., 2003. Determining the clinical course and outcome in chronic lymphocytic leukemia. The New England Journal of Medicine 348, 1797–1799. Rai, K.R., Sawitsky, A., Cronkite, E.P., et al., 1975. Clinical staging of chronic lymphocytic leukemia. Blood 46, 219–234. Robak, T., 2019. Treatment of relapsed and refractory chronic lymphocytic leukemia. In: Hallek, M., Eichhorst, B., Catovsky, D. (Eds.), Chronic lymphocytic leukemia, vol. 107. Springer Nature. Robak, T., Dmoszynska, A., Solal-Céligny, P., et al., 2010a. Rituximab plus udarabine and cyclophosphamide prolongs progression-free survival compared with udarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. Journal of Clinical Oncology 28, 1756–1765. Robak, T., Jamroziak, K., Gora-Tybor, J., et al., 2010b. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: A phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). Journal of Clinical Oncology 28, 1863–1869. Robak, T., Stilgenbauer, S., Tedeschi, A., 2017. Front-line treatment of CLL in the era of novel agents. Cancer Treatment Reviews 53, 70–78. Roberts, A.W., Davies, M.S., Pagel, J.M., et al., 2016. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. The New England Journal of Medicine 374, 311–322. Seymour, J.F., Kipps, T.J., Eichhorst, B., et al., 2018. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. The New England Journal of Medicine 378, 1107–1120. Siegel, R., Ma, J., Zou, Z., Jemal, A., 2014. Cancer statistics. CA: A Cancer Journal for Clinicians 64, 9–29. Slager, S.L., Kay, N.E., 2009. Familial CLL: What does it mean to me? Clinical Lymphoma & Myeloma 9, S194–S197. Stilgenbauer, S., Eichhorst, B., Schetelig, J.I., et al., 2018. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: Results from the full population of a phase II pivotal trial. Journal of Clinical Oncology 36, 1973–1980. Tait DS. Predicting clinical outcome in CLL: How and why. Hematology 2009; ASH Annual Meeting, 421-429 (Abstract). Voorhies, B.N., Stephens, D.M., 2017. What is optimal front-line therapy for chronic lymphocytic leukemia in 2017? Current Treatment Options in Oncology 18, 12.

Chronic Renal Disease in the Elderly and Senescent Nephropathy Mercedes Capotondo, Italian Hospital of Buenos Aires, Buenos Aires, Argentina Carlos G Musso, Italian Hospital of Buenos Aires, Buenos Aires, Argentina; and University Institute of Italian Hospital of Buenos Aires, Buenos Aires, Argentina © 2020 Elsevier Inc. All rights reserved.

Introduction Chronic Kidney Disease and Its Differential Diagnosis Difference Between Renal Aging and CKD Serum Creatinine and Urea Erythropoietin Synthesis Kidney Imaging Urinalysis Parathyroid Hormone CKD Etiologies in the Elderly Prerenal Disease Vascular Renal Disease Glomerular Diseases Tubular and Intersticial Diseases Postrenal (Obstructive Nephropathy) Nephroprevention in the Elderly Conclusion References

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Introduction Normal aging is a process which induces a series of changes in the organisms through time, characterized by the attenuation of functional performance compared to the maximal functional strength reached around the second decade of life (Musso and Jauregui, 2016a). However, few individuals present a successful aging which means that the characteristics aging changes are insignificant compared to young people (Musso and Jauregui, 2016b). In addition, frailty is a cumulative decline of multiple physiological systems that occur with aging and lead individuals to a status of diminished physiological reserve and increased vulnerability to stressors, In this case aging turns into senescence or pathologic aging (Aiello et al., 2017; Lakey et al., 2012; Woods et al., 2005). FRAIL scale is a useful tool for the diagnosis of frailty and is based on the evaluation of fatigue, resistance, ambulation, illnesses and loss of weight (Morley et al., 2012; Woo et al., 2015). Finally, a chronic disease refers to an abnormal process that deteriorates the functionality of any organ or system of organs. Since aging is a heterogeneous and asynchronous process, normal kidney aging usually presents with a reduced glomerular filtration rate (GFR), and chronic kidney disease (CKD) can be combined with frailty phenotype, four different renal clinical settings can be found in the elderly, which should be clearly differentiated: renal aging, successful renal aging, pathological renal aging (senescent nephropathy), and chronic renal disease. These clinical settings are described in detail below.

Chronic Kidney Disease and Its Differential Diagnosis Normal renal aging is documented in those individuals who only have an expected reduction in their glomerular filtration rate (GFR) (expected reduction rate: 1 mL/min since 40 years), but they have normal serum values of urea, creatinine, hematocrit, parathyroid hormone, normal urinalysis and renal ultrasound. Therefore this clinical setting does not require any renal treatment (Aiello-Battan et al., 2017). Successful renal aging, which can be documented in a minority of the aged population (around one third), consists of elderly people whose aging related renal changes are slightly (quantitatively and qualitatively) marked, leading to insignificant functional changes compared to young individuals. Successful renal aging has all the characteristics of normal renal aging except for not presenting or presenting minimally the age-related GFR reduction (less than 1 mL/min since 40 years). Just like normal renal aging, successful renal aging does not require any renal treatment (Aiello-Battan et al., 2017). Regarding CKD, it can be diagnosed when evidence of kidney damage, such as reduced GFR, presence of albuminuria, proteinuria, glomerular hematuria and/or abnormal renal imaging, are documented for at least 3 months or more. Thus, a CKD patient can have any GFR value, since chronic nephropathy diagnosis can be based on other markers of kidney damage. CKD patients should be

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408 Table 1

Chronic Renal Disease in the Elderly and Senescent Nephropathy Clinical comparison among different renal agings and chronic kidney disease (CKD)

GFR Serum urea Serum creatinine Hematocrit Parathyroid hormone Urinalysis Renal imaging Clinical functional status Renal treatment

Normal renal aging

Successful renal aging

CKD (any stage)

SN

Low (expected value for age) Normal Normal Normal Normal Normal Normal Robust/frail None

Normal Normal Normal Normal Normal Normal Normal Robust/frail None

Any value Normal/high Normal/high Normal/low Normal-high Normal/altered Normal/abnormal Robust Nephroprevention

Any value Normal/high Normal/high Normal/low Normal-high Normal/altered Normal/abnormal Frail Nephroprevention rehabilitation

GFR: Glomerular filtration rate, SN: Senescent nephropathy.

treated by their specific treatment (etiological) and nonspecific treatment (nephroprevention strategies) (Musso et al., 2018; Rennke and Denker, 1994; Walker et al., 2014). Finally, senescent nephropathy consists of the combination between a chronic disease and frailty phenotype, which can lead to a senescent variety of this condition. Senescent nephropathy has worse evolution and prognosis compared to the CKD (chronic nephropathy in robust patients). It is worth pointing out that to treat senescent nephropathy implies not only to treat patient’s CKD but also his/her frailty, which could require antifragility interventions to reduce hospitalization, functional deterioration and mortality. The treatment of frailty requires rehabilitation, low-intensity resistance and aerobic exercise, adequate caloric and protein intake, avoidance of polypharmacy. All this implies a team intervention, including nurses, occupational therapists, physiotherapists, physicians, psychologists, and social workers (Aiello et al., 2017; Aiello-Battan et al., 2017; Musso et al., 2018; Walker et al., 2014). Therefore, it is important to differentiate normal renal aging from CKD, as well as CKD from senescent nephropathy due to their different therapy and prognosis (Table 1).

Difference Between Renal Aging and CKD Renal aging and CKD are different entities, frequently confused. Treating healthy old individuals as CKD patients can be harmful because a low protein diet can induce sarcopenia and malnutrition and the use of renin-angiotensin-aldosterone system inhibitors can frequently generate adverse effects in the elderly, such as hyperkalemia, hyponatremia, and/or significant GFR reduction (Musso and Jauregui, 2016a). CKD can be confused with normal aging when both settings have the same level of GFR reduction, which usually happens with stage III-CKD. The clinical differences between normal aging and stage III-CKD are described in detail below (Table 1) (Cockcroft and Gault, 1976; Keller, 1987; Manley and O’Neill, 2001; Moghazi et al., 2005; Musso, 2004; Musso and Macías Núñez, 2006; Musso and Oreopoulos, 2011a; Musso & Oreopoulos, 2012; Musso et al., 2004; Musso et al., 2005; Musso et al., 2006; Musso et al., 2015a; Platt et al., 1988; Rennke and Denker, 1994):

Serum Creatinine and Urea Serum urea and creatinine values are generally increased in stage III-CKD patients but normal in renal aging, since despite the agedrelated GFR reduction serum urea and creatinine are normal in healthy elderly. This phenomenon has been attributed to the sarcopenia (creatinine) and high urinary urea excretion (urea) characteristically found in the elderly (Musso and Jauregui, 2016a).

Erythropoietin Synthesis Erythropoietin serum level is usually reduced in stage III-CKD patients, but not in healthy elderly people. Thus, anemia can be documented in stage III-CKD patients but not in healthy old individuals (Musso and Jauregui, 2016a; Musso and Oreopoulos, 2011a; Musso et al., 2004; Rennke and Denker, 1994).

Kidney Imaging Kidney imaging is usually normal in healthy elderly people but is usually altered in most of the stage III-CKD patients. It is worth mentioning that kidney normal size does not exclude CKD since diabetic nephropathy patients can show a preserved renal size (Cockcroft and Gault, 1976; Manley and O’Neill, 2001; Moghazi et al., 2005; Musso and Jauregui, 2016a; Musso and Macías Núñez, 2006; Platt et al., 1988).

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Urinalysis Urinalysis is normal in healthy elderly, being proteinuria < 0.3 g/day considered normal in this group. Conversely, urinalysis is usually altered in CKD patients (Musso and Jauregui, 2016a; Rennke and Denker, 1994).

Parathyroid Hormone Serum parathyroid hormone levels are normal in healthy old individuals who are well-nourished, and have adequate sunlight exposition, but stage III-CKD patient usually suffers from secondary hyperparathyroidism (Rennke and Denker, 1994; Musso and Oreopoulos, 2011a; Musso et al., 2004). Therefore, an isolated GFR reduction, which is the expected to the age, in absence of elevated creatininemia, uremia, hyperparathyroidism, anemia, altered kidney imaging and/or abnormal urinalysis, should be interpreted as normal renal aging and not as CKD.

CKD Etiologies in the Elderly Prerenal Disease CKD secondary to a prerenal mechanism (persistent renal hypoperfusion) can be found in heart failure or cirrhotic patients. Regarding the intrinsic renal diseases in the elderly, they can be classified in vascular renal disease, glomerular disease and tubular/intersticial disease.

Vascular Renal Disease Nephrosclerosis is the most common chronic renal vascular disease, which involves the blood vessels but ultimately damages the tubule-interstitium and glomeruli. Renal artery stenosis secondary to atherosclerosis can cause ischemic nephropathy, characterized by tubule-interstitial fibrosis and glomerulosclerosis (Textor, 2004).

Glomerular Diseases Renal biopsy is useful for diagnosing these diseases, and defining their prognosis and appropriate treatment. In the elderly who underwent renal biopsy, 59% had primary glomerulonephritis, and only 20% had secondary glomerulonephritis. Primary glomerulonephritis in the elderly was the most frequent biopsy-proven renal disease. Even though, the incidence of kidney biopsy complications is equally frequent in the elderly and young adults, generally when appear they are more serious in the elderly than in the young adults. Membranous nephropathy, crescentic, membrano-proliferative glomerulonephritis, minimal change disease, and acute poststreptococcal glomerulonephritis are all more frequent in the elderly than in younger patients. Only Ig A and non-IgA mesangioproliferative nephritis and focal segmental glomerulosclerosis were less frequent in elderly patients than in the younger patients (Appel, 2008; Ponticelli and Glassock, 2009; Vendemia et al., 2001). Secondary glomerulopathies such as nephroangiosclerosis secondary to essential hypertension, diabetic nephropathy and those associated with abnormal plasma-cell proteins are frequent in the elderly. Nephrotic syndrome is the cause of 50% of kidney biopsies indications and its most prevalent causes are: diabetic nephropathy, membranous, minimal change, and amyloidosis nephropathy (Cameron, 1995; Ponticelli and Glassock, 2009; Vendemia et al., 2001). Renal vasculitis are more common with age, since the incidence of microscopic polyangeitis and Wegener’s granulomatosis increases with age.

Tubular and Intersticial Diseases The main causes of tubule-inerstitial CKD are polycystic kidney disease, nephrocalcinosis, sarcoidosis, Sjögren’s syndrome, reflux nephropathy, and medullary cystic kidney disease.

Postrenal (Obstructive Nephropathy) This entity can be caused by prostatic disease, abdominal/pelvic mass or retroperitoneal fibrosis. Prostatic hyperplasia can be asymptomatic generating silent renal damage, and when the diagnosis of nephropathy is delayed, kidney damage does not revert after the surgical treatment of the prostate.

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Nephroprevention in the Elderly Nephroprevention guidelines in the robust (non frail) elderly CKD patients are similar to the guidelines used in the young adult CKD patients, but they are different (targets) in the very elderly or frail CKD patients. In Table 2 the differences between the nephroprevention strategies used in robust elderly CKD patients and very elderly/frail CKD patients are described (Levey et al., 1996; Bowling and O’Hare, 2012; De Santo and Cirillo, 2013; Forciea et al., 2000; Grupo de Trabajo de la Sociedad Europea de

Table 2

Nephroprevention strategies in adults with CKD and in Senescent Nephropathy

Dietary Salt Intake (References De Santo and Cirillo, 2013; KDIGO CKD Work Group 2013; Musso and Oreopoulos, 2011b; Musso et al., 2015b)

Dietary protein intake (References Levey et al., 1996; Houston et al., 2017; Kaysen et al., 1989a; Kaysen et al., 1989b; KDIGO CKD Work Group, 2013; Levey et al., 1999)

Robust old CKD patient

Very old/frail old CKD patient


If GFR > 60 / no dietary restriction.
If GFR < 60 þ hypertension or proteinuria / sodium intake 0.3 g/day), progressive reduction of glomerular filtration rate and increase of blood pressure (Nadolnik et al., 2018). Kidney changes are considered normal in health people and it is estimated that renal blood flow decreases by 10% starting from the 40th year of age. This kidney impairment is accelerated and worsen by DM and it is estimated that one in three patients with diabetes is in great risk of kidney disease (Nadolnik et al., 2018). Moreover, elderly diabetic patients have other risk factors as aging itself, hypertension, atherosclerosis, obesity, heart failure, smoking cigarettes, geriatric hypodipsia (Nadolnik et al., 2018). Diabetic retinopathy is present in more than half of diabetic population by different kind of visual diseases causing variable range of vision lost (Zatic et al., 2015). In particular, in diabetics, cataract represents a major cause of visual impairment with a three to four-fold increased risk under the age of 65 years, and up to a twofold excess risk above 65 years (Pizzol et al., 2019). Regardless the type of impairment, visual lost deprives of crucial cognitive function with severe negative impact on quality of life and on ability to live independently. The gastrointestinal tract is often affected in DM patients by several disorders as oral candidiasis, gastroparesis, nonalcoholic fatty liver disease, gastro-esophageal reflux, dysphagia, and chronic diarrhea (Martinez et al., 2013). Moreover, in long lasting diabetic people also small intestinal and colorectal tracts can be affected by constipation altering with painless diarrhea and fecal incontinence worsening quality of life (Krishnan et al., 2013). As natural consequence, especially elderly patients are at risk of malnutrition, physical debilitation and immunity impairment (Menon et al., 2016). In particular, the loss of muscle mass, strength and function leads to sarcopenia contributing to frailty syndrome (Vellas et al., 2018). Frailty syndrome defined by the three conditions out five: comprising weakness, slowness, low level of physical activity, exhaustion, and weight loss (Yanase et al., 2018). Frailty in elderly is a global health concern considering its association with adverse outcomes as falls, disability, hospitalization, care home admission and mortality (Yanase et al., 2018). Moreover, others risk factors commonly present in elderly as smoking, peripheral neuropathy, peripheral vascular disease, limitation of mobility in joints, and trauma contribute to the onset of diabetic foot and to a worse healing of ulcers (Nongmaithem et al., 2016). Other than physical decline, DM is associated also with a reduction in cognitive functions and mental health impairment (Groeneveld et al., 2016). In particular, diabetes and depressions seem to be associated, increasing each other the risk of occurrence and, the two diseases coincide about two times often than they would be predicted by chance alone (Holt et al., 2014). In fact, on one

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hand DM impairs health status inducing depression. On the other hand, depression negatively influences glycemic control and therapy adherence, and leads to an unregulated diet causing over or under nutrition (Asuzu et al., 2017). In addition, diabetic neuropathy, most of all if not properly treated, can further make work or accelerate depression (Ishizawa et al., 2016). Growing evidence is paying attention to the association between diabetes and cancers especially in elderly. Some authors observed a 26% increased risk of death from any cancer in Asian population (Chen et al., 2017) while Giovannucci and colleagues reported an increased risk of twofold or higher for liver, pancreas, and endometrium and a risk of 1.2 to 1.5-fold for colon or rectum, breast, and bladder cancers (Giovannucci et al., 2010). Again, urinary tract dysfunctions are worsened in diabetic patients. In fact, DM is one of the most important risk factor for urinary incontinence with consequent social isolation (Demir et al., 2017). Furthermore, a frequent condition, especially in elderly diabetic patients with long term diabetes and poor glycemic control, is cystopathy. This disease includes impairment of bladder sensation and contraction, increase in bladder capacity, and post-voiding volume (Wittig et al., 2019). Finally, in diabetics male, erectile dysfunction is more than three times higher relative to healthy ones, further affecting quality of life (Kouidrat et al., 2017).

Management The main goal of management is to prevent DM from people at risk or genetically predisposed, in order to reduce the burden of disability in elderly people (Tyrovolas et al., 2015). Primary prevention, including healthy lifestyles and behavior, as reduction in fat and sugary food, and physical activity are the key points to prevent DM, cardiovascular and other chronic diseases not only in elderly but in adulthood too. Particularly important, in preventing obesity and insulin resistance, is the physical activity that has been demonstrated to be most efficacious in preventing and treating DM when the exercise intensity is moderate to high (Ferriolli et al., 2014). Indeed, although presenting higher risks for lesions and contraindications as angina, coronary disease, arrhythmias etc.) high-intensity exercises have been shown as the most favorable for the elderly with type 2 DM (Frankel et al., 2006). Interestingly, a recent meta-analysis showed that lifestyle modification strategies implemented also under real-world conditions are promising approaches for preventing diabetes in older people (Galaviz et al., 2018). When the primary prevention fails, it is crucial to make an early diagnosis to avoid complications. In elderly, it is quite complicated due to the increase of renal threshold for glucose and the impairment of the thirst mechanisms (Chentli et al., 2015). Therefore, commonly the DM diagnosis is made through late stage complications as micro and macro vascular problems, neuropathy or urinary infections. For these reasons, it is mandatory for health workers taking care of elderly to record an accurate medical history and to perform a careful physical examination and, in case of suspicion, to test for glycemic control. When an elderly patient has been diagnosed with diabetes, the aim is to achieve an optimal glycemic control in order to improve the quality of life and life expectancy and to reduce morbidity and mortality (Atif et al., 2018). Regarding the glycemic goals, there is no a sole consensus among different societies/associations. Following the IDF elderly classification, the same Federation recommends for the category 1 a HbA1c target of 7.0%–7.5%/ 53–59 mmol/mol; for category 2 of 7.0%–8.0%/53–64 mmol/mol and, for category 3 just avoid symptomatic hyperglycemia (Dunning et al., 2014). Although exist few data specifically addressing drug therapy in elderly patients, many authors suggest metformin as initial therapy for who do not have contraindications as renal impairment or heart failure (Qaseem et al., 2017; Scheen, 2017). Insulin is also considered initial therapy, especially for patients with high glycemic and HbA1c levels (Scheen, 2017; Neumiller and Setter, 2009). Main non-insulin therapeutic options are reported in Table 1. A growing concern is represented by the hypoglycemia caused by medications that can have dramatic consequences and, thus, deserves as much attention as hyperglycemia (Bansal et al., 2015). The DM treatment and the achievement of optimal HbA1c levels is not enough and it is necessary to consider the whole patient including possible complications. When patients have few or no complication, it is easy to manage them. On the contrary, multi complicated patients and those with additional and severe diseases are difficult to treat also in highly specialized centers. Finally, an adequate management cannot be separate from educational policies and practices across whole populations and within specific settings (school, home, workplace) that contribute to good health for everyone, regardless of whether they have diabetes, such as exercising regularly, eating healthily, avoiding smoking, and controlling blood pressure and lipids. It is mandatory a multi sectorial approach, in which all sectors systematically consider the health impact of policies in trade, agriculture, transport, education and urban planning, recognizing that health is enhanced or obstructed as a result of policies in these and other areas.

Future Perspective The increasing number of elderly people diagnosed with DM raises concern on which will be one of the main problems for the healthcare of this population in the next future. In fact, besides being one of the most expansive disease, it is associated with geriatric conditions and complications (Lipscombe and Hux, 2007; Zhang et al., 2010). In 2010, the health costs related to DM were USD 376 billions and it is estimated to grow up to about 500 billions in 2030 (Zhang et al., 2010). Moreover, the estimates indicate that > 75% of this amount will be expended for people aged between 50 and 80 years (Hodge et al., 2013). Thus, to promote healthy and active aging is mandatory in order to reduce economic health costs but, it is the main objective also in order to provide a better quality of life mainly in elderly people. In fact, it is well known that the quality of life is generally lower in elderly patients and it gets

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Noninsulin therapeutic options

Class

Agents

Limitations and contraindications

Biguanides

Metformin

Second generation sulfonylureas

Glimepiride Glipizide Glyburide

Gastro-intestinal troubles Gastro intestinal effects Creatinine clearance 65% 1 repetition maximum) than low load resistance training (< 60% 1 repetition maximum) (Schoenfeld et al., 2016). Apart from the intensity of the loads, other important elements of an effective exercise prescription for muscle benefits include training frequency, training volume (i.e., sets and reps), length of rest periods between exercise sets and reps, and duration of the training program. A recent meta-analysis of resistance training for improving muscle strength in older adults (> 65 years) found the greatest effect sizes were observed for resistance training that was undertaken twice per week, with exercises performed for 2–3 sets of 7–9 repetitions at an intensity of 70–79% 1 repetition maximum with 4-s rests between repetitions and 60-s rests between sets (Borde et al., 2015). Perhaps not unexpectedly, the authors also noted that long term resistance training programs (e.g., approximating 1 year) resulted in better muscle strength outcomes than shorter programs (Borde et al., 2015). The speed at which resistance training exercises are undertaken is also important, particularly for older adults who suffer a considerable age-related decline in muscle power. For instance, while resistance training performed at low speeds tends to improve muscle performance and physical function in older adults, when performed at high speeds, greater improvements in physical function, and specifically muscle power, are achieved (Ramirez-Campillo et al., 2014). Exercise recommendations for improving muscle health are most commonly developed with reference to the prevention and management of sarcopenia (Siparsky et al., 2014; Iolascon et al., 2014; Law et al., 2016; Phu et al., 2015). The strength of the evidence to date, however, is not sufficient to produce definitive exercise intervention recommendations (Vlietstra et al., 2018). Nonetheless, it is largely accepted that approaches to improving muscle mass, strength, and endurance in those most susceptible will typically include resistance training (with gym equipment or resistive bands), aerobic exercise, balance exercises, gait training/walking, or any combination of the former. A recent meta-analysis of exercise interventions of older adults with sarcopenia found that the most effective interventions for improving muscle strength (e.g., grip strength and knee extensor strength) and functional performance measures (e.g., gait speed and timed up-and-go) were multimodal interventions (Vlietstra et al., 2018). The combination of progressive strengthening exercises (resistive bands and ankle weights), balance activities, and gait training, for instance, performed at each session for 1 h, twice per week for 3 months resulted in significant improvements in strength and functional performance in older Japanese women with sarcopenia (Kim et al., 2012). It should be noted, however, that participants were simultaneously supplemented with amino acids and thus the independent effects of the interventions are unclear. The inclusion of nutritional supplementation (e.g., vitamin D, amino acids, or micronutrients) with exercise training has the potential to offer enhanced muscle outcomes, however current evidence is considered to be insufficient to develop clear recommendations (Denison et al., 2015). Not unlike bone, the intensity requirements for exercise to be effective for muscle are relatively high, particularly for improving muscle size and strength. It is prudent to introduce and progress moderate and high intensity exercises gradually to minimize the risk of injury, particularly for those not accustomed to the activity. Likewise, gradual introduction of exercises and their complexity and a steady progression of intensity over time may be necessary to facilitate adherence to the program, given that abrupt increases in activity or intensity may lead to undesirable muscle soreness and fatigue. Adherence and enjoyment are particularly important given that longer programs are most effective (Borde et al., 2015) and detraining effects occur quickly (Kalapotharakos et al., 2010). For healthy adults undertaking resistance training for increasing muscle strength, the American College of Sports Medicine recommends progressing the intensity 2–10% of the load at a given repetition maximum level once the person can achieve 1–2 repetitions greater than the designated number (American College of Sports Medicine, 2009). There is no evidence that this rate of progression should be altered for older people, however it may be wise to progress at the lower end of the range for older people with minimal experience in resistance training. Similarly, for power training, the American College of Sports Medicine suggests a progression

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according to two strategiesdthe first being strength training and the second being the use of light loads (0–60% 1RM for lower limb exercise and 30–60% 1RM for upper limb exercise) performed quickly with lengthy 3–5 min rest periods between sets (American College of Sports Medicine, 2009). Such recommendations for exercise progression provide a good “starting point” for most people, but should be applied in an individualized fashion taking into consideration physical ability, exercise experience, and other health needs.

Preventing Falls and Fractures Perhaps the most problematic sequelae of a weak neuromusculoskeletal system are falls and fractures. In fact, approximately one in three community-dwelling older people will fall at least once every year (Lord et al., 1993). Falls are associated with high morbidity and mortality and are responsible for around 90% of all hip fractures (Goldacre et al., 2002). For this reason, a broad approach to preventing fracture should include targeted exercise to both strengthen bone and minimize falls. Exercise considerations for older people then should extend beyond tissue-specific approaches to more holistic practices that address muscle strength, bone health, and balance. Care must be taken to strike the right balance between prescribing an exercise that is sufficiently challenging to enhance stability and one that inherently increases a patient’s risk of falling. Falls prevention necessarily involves addressing a wide variety of factors including balance, strength, vision, cognition, medications and their side-effects and interactions, pain management, nutrition, and home safety. Group and home-based exercise programs and home safety interventions are among the most effective approaches to reducing the rate of falling and the risk of falls (Gillespie et al., 2012). Stronger evidence for falls prevention is found for interventions that combine different types of exercise (e.g., resistance training and balance exercise) than for single exercise mode approaches (e.g., resistance training only) (Gillespie et al., 2012). Exercise programs that include challenging balance activities at high doses (i.e., > 3 h per week) are particularly effective in preventing falls in community-living older people (Sherrington et al., 2017). Challenging balance activities might include decreasing the base of support while standing (e.g., with feet close together or standing on one foot), moving the center of gravity in different directions while standing (e.g., through reaching activities or transferring body weight from one leg to the other), dual or multitask balance activities (Trombetti et al., 2011), or for some very frail older people, a challenge to balance might be achieved by simply standing without using arm support for brief moments (Sherrington et al., 2017). Brisk walking may be an acceptable inclusion in a falls prevention exercise program, but is not recommended for frail individuals due to a potential to actually increase falls (Sherrington et al., 2017). Fortunately, efficiencies can be achieved in exercise prescription for falls prevention as tissue-targeted programs have demonstrated simultaneous efficacy for reducing risk of falls. For instance, high intensity resistance training is both a potent stimulus for muscles and bones, and improves risk factors for falls. A recent example of this effect was seen in the LIFTMOR trial for postmenopausal women with low bone mass, where women performed high intensity resistance and impact training for 8-months but no specific balance training. The intervention group not only experienced improvements in bone mass, but also enhanced performance on the timed up-and-go test, five times sit-to-stand test, and functional reach (Watson et al., 2018), all markers for risk of falling. In fact, even when undertaken only once per week, high intensity resistance training has been shown to improve lower limb muscle strength as well as neuromuscular performance and functional outcomes (e.g., chair rise test) (Taaffe et al., 1999). There is additional evidence suggesting that when resistance training is undertaken at high velocities (i.e., “power training”), the functional benefits, including balance and walking ability, for older people can be even greater (Tschopp et al., 2011). Power training may therefore be a desirable exercise strategy for those older people whose physical condition is beginning to limit their ability to perform activities of daily living. Ultimately, some form of falls prevention should be included in any exercise regime for older people, whether it be achieved through effective single-modality approaches (e.g., high intensity resistance training) or as part of a multimodal exercise approach.

Summary and Conclusion The primary objectives of maximizing musculoskeletal health with aging are to maintain physical function and prevent falls and fracture. All three elements will assist with the maintenance of independence and optimize quality of life. Fortuitously, the optimum exercise prescription for bone largely coincides with that for muscle, and provides a strong foundation for the maintenance of balance. While a general exercise prescription targeting musculoskeletal systems can be universally adopted by most ambulant aging adults, careful assessment of comorbidities is required in order to tailor exercise that is effective, practical, and achievable for the individual. In broad terms, older people should aim to minimize sedentary behaviors and maximize engagement in a wide variety of physical activities. Those who are able, should attempt to meet general physical activity guidelines and sustain physical activity participation over the long term. Ideally, older people should aim to include a combination of impact loading, resistance training, and challenging balance activities to maximize musculoskeletal tissue health and prevent falls and fractures. For those older people who are inactive, participation in any activity will be a “good start,” but to maximize musculoskeletal health with meaningful gains in muscle and bone strength and functional performance, engagement in the “right types” of activities at sufficiently high intensities is critical. Exercising at high intensity should be undertaken with appropriate guidance from a health professional, at least in the first instance, in order to maximize gains and minimize risk of harm.

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Further Reading American College of Sports Medicine, 2009. American College of Sports Medicine position stand. Progression models in resistance training for healthy adults. Medicine and Science in Sports and Exercise 41 (3), 687–708. Beck, B.R., Winters-Stone, K., 2010. Exercise in the prevention of osteoporosis-related fractures. Chapter 9. In: Adler, R. (Ed.), Osteoporosis: Pathophysiology and Clinical Management, 2nd edn. Humana Springer, Totowa, NJ, pp. 207–239. Beck, B.R., Daly, R.M., Singh, M.A., Taaffe, D.R., 2017. Exercise and Sports Science Australia (ESSA) position statement on exercise prescription for the prevention and management of osteoporosis. Journal of Science and Medicine in Sport 20 (5), 438–445. Brown, W., Moorhead, G., Marshall, A., 2005. Choose Health: Be Active: A physical activity guide for older Australians. Commonwealth of Australia and the Repatriation Commission, Canberra. http://www.health.gov.au/internet/main/publishing.nsf/content/phd-physical-choose-health. Department of Health, 2014. Australia’s Physical Activity and Sedentary Behaviour Guidelines. Commonwealth of Australia, Canberra. http://www.health.gov.au/internet/main/ publishing.nsf/content/health-pubhlth-strateg-phys-act-guidelines. Phu, S., Boersma, D., Duque, G., 2015. Exercise and sarcopenia. Journal of Clinical Densitometry 18 (4), 488–492. World Health Organization, 2010. Global recommendations on physical activity for health. WHO Press, Geneva. https://www.who.int/dietphysicalactivity/factsheet_ recommendations/en/.

Relevant Websites https://www.acsm.org/dAmerican College of Sports Medicine. http://www.health.gov.au/internet/main/publishing.nsf/content/phd-physical-choose-healthdDepartment of HealthdChoose Health: Be Active: A physical activity guide for older Australians. http://www.health.gov.au/internet/main/publishing.nsf/content/health-pubhlth-strateg-phys-act-guidelinesdDepartment of HealthdAustralia’s Physical Activity and Sedentary Behaviour Guidelines. https://www.who.int/dietphysicalactivity/factsheet_recommendations/en/dWorld Health OrganizationdGlobal recommendations on physical activity for health.

Falls in Older Persons Maysa Seabra Cendoroglo, Geriatric Division, Federal University of São Paulo, São Paulo, Brazil Neide Alessandra Perigo Nascimento, Social Service of Commerce, São Paulo, Brazil © 2020 Elsevier Inc. All rights reserved.

Epidemiology Risk Factors Assessment Prevention and Multifactorial/Multicomponent Intervention Conclusion References Further Reading

78 78 80 81 83 83 83

Epidemiology Falls can cause fear of falling, immobility, hospitalization, fragility, institutionalization and death. It is the fifth cause of mortality in the elderly; increases with age, especially after 80 years and over and at later ages and is more common in men (Table 1). Falls occur in developed and developing. There are differences between incidence and mortality among them. But in several countries, an increase in mortality has been observed since 2000, which may be because people are living longer, they are more active, there is increased polypharmacy, and reports of falls as a basic cause of death have been more frequent. Falls are coded as E880-E888 in International Classification of Disease, it is an indicator of poorer quality of life and worse quality of health services, requiring constant attention to identify, control and prevent risk factors. The absolute number of fallrelated emergency, hospital admissions and the total number of days of hospitalization for those over 80 years has increased. As the world’s population ages rapidly, this will be a major challenge.

Risk Factors There are multiple risk factors that contribute to the occurrence of falls which need to be reviewed at all times (Table 2). Most of the risk factors have an impact on balance and are related to aging. Other risk factors are modifiable in order to improve or eliminate the

Table 1

Epidemiology of falls. % Falls a

Incidence (by year) 65 and over 80 and over Community Long term care Hospitals Older persons with Dementia Mortality 80 and over Injury Minor Major Fracture Emergency Hospitalization Occurrence During the day Location Outside the home New environment Recurrence

35 56 50 56 27 60 30 56 15 20 14 4 20 56 50 40

a

Can reach these % according with different studies.

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79

Risk factors for falls. Risk factors

Older people risk factors

• • • • • • • • • • • • • • • •

Older people in Community and recurrent fallers

Nursing home residents Older hospital inpatients Older people with dementia or cognitive impairment

Centenarians

• • • • • • • • • • • • • • • • • • • • • • • • • • • • • •

Advanced age Female gender History of falls Fear of falling ADL limitations Frailty Sarcopenia Gait disorder Dinamic or static balance impairment Visual and ear problems Impaired cognition, Orthostatic Hypotension, Stroke, Parkinson disease, Arthritis, Depression, acute illness Mobility disorders Sedentarism Vit D insufficiency Use of 4þ medication; sedative hypnotics, anxiolytics, antidepressants(SSRIs, tricyclic), antipsy-chotics;antihypertensives Foot problems (bunions,toe or nail deformities, ulcers) Inappropriate shoes Familial and social isolation Home and external hazards History of fall Gait problems Walking aids use Vertigo Parkinson disease Antiepileptic drug use History of fall Walking aid use Moderate disability History of fall Acute disease History of fall Type and severity of dementia Behavioral disturbances Neuroleptics Motor impairments Functional impairments Impaired vision Low bone mineral density Male Anxiety Pain Dizziness Syncope Incontinence Number of health conditions Using assistive devices indoors

risk of falls. Systematic reviews have been shown that there are risk factors most related to older people in the community, others to people living in the nursing home or in the hospital. In oldest old, centenarians and older people with dementia or cognitive impairment it appears that there are specific risk factors that should be considered. Cognitive impairment by itself is an independent risk factor for falls. But regardless of the differences, addressing the risk factors together brings benefits.

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Assessment Falls are a major challenge for the individual and public health and, therefore, recommendations for guidelines, algorithms and acknowledgments have been accumulated to improve prevention and multifactorial and multicomponent interventions (Fig. 1). The history of falls in the last 12 months is a strong predictor of the occurrence of a new fall, so this information should be part of all assessment, at least annually. If there was a previous fall, questions about the frequency of falling, symptoms at time of fall, and injuries from fall will help to identify if it’s necessary a multifactorial fall risk assessment. The multifactorial assessment includes a history of falls and risk factors; medication review; physical examination; physical tests; functional and environmental assessment. Balance results the integration of peripheral sensory (vestibular, visual, and proprioceptive) and motor systems (skeletal, oculomotor, somatic muscles) mediated by central nervous system. Aging affects balance in different ways starting in mid-life, in one third of older people 65 and over and half of those 85 and over. To prevent or minimize the impact of those changes it’s recommended to screen risk factors for balance problems in mid-life, around 45 years old to start prevention and intervention when it’s necessary. Physical tests are useful to evaluate gait, balance, mobility levels, lower extremity joint function and lower extremities muscle strength. At age 45, some physical tests are suggested to evaluate the balance: the Get-up-and-Go test (20 s or so), and the unipodal test (at least 5 s on a single leg). In the elderly, in addition to these, other tests have been used: the Timed Up and Go Test, the Berg Balance Scale, the Performance Oriented Mobility Assessment; Running Speed (> 1.0 m/s). Physical exam must include a neurological function (cognitive evaluation, lower extremity peripheral nerves, proprioception, reflexes, tests of cortical, extrapyramidal and cerebellar function); cardiovascular status (heart rate and rhythm, postural pulse and postural blood pressure, eventually heart rate and blood pressure responses to carotid sinus stimulation); visual acuity; examination of the feet and footwear. Assessment of activity of daily living skills, including use of adaptive equipment and mobility aids, perceived functional ability and fear related to falling and environmental assessment (home and external safety).

Evaluation of Balance and Gait

History of falls

yes

yes

Multifactorial Fall Risk Assessment History Physical examination

PREVENTION

Environmental assessment

RISK CLASSIFICATION

MEDIUM RISK LOW RISK

one fall in the last year

No fall No balance and gait disturbance

Fig. 1

INTERVENTION

Physical Tests Functional assessment

Assessment for falls at least once a year.

balance and gait disturbance

HIGH RISK Two ore more than two falls in the last year balance and gait disturbance

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81

Prevention and Multifactorial/Multicomponent Intervention Fall prevention programs includes education about risk factors and strategies to minimize risk but also information and training about how to improve the skills. There is scientific evidence that supports the multifactorial or multicomponent approach to interventions to prevent falls in older persons. In community-dwelling older persons as soon as risk factors are identified, is more often to do a multifactorial intervention that target specific risk factors. In long-term care settings is more common to offer a program with a set of interventions (multicomponent intervention). For the elderly with cognitive impairment, the benefits of the recommendations are not conclusive, although some studies have shown better results for the elderly who presented higher scores in the Mental State Mini-Exam. There is strong evidence to recommend exercise, withdrawal of psychotropic medication and adaptation or modification of home environment as a single intervention and as a component of multifactorial and multicomponent intervention (Table 3). Individual and group exercise programs (Table 4) are equally effective for community-residing older people but for older persons in long-term care settings should be initiated with caution because exercise may increase the rate of falls in persons with limited mobility. It is also known that balance training contributes to reducing falls and the fear of falling but the effect of resistance exercise without balance and functional exercises, dance, or walking is not certain. In the Cochrane Database Syst Rev., Sherrington et al., included 23,407 participants living in the community in 25 countries, 77% women and with 76 years old on average. Compared with control, balance and functional exercises reduced the rate of falls by 24% (RaR 0.76, 95% CI 0.70 to 0.81) and the number of people experiencing one or more falls by 13% (RR 0.87, 95% CI 0.82 to 0.91). Multiple types of exercise (most commonly balance and functional exercises plus resistance exercises) probably reduce the rate of falls by 34% (RaR 0.66, 95% CI 0.50 to 0.88) and the number of people experiencing one or more falls by 22% (RR 0.78, 95% CI 0.64 to 0.96). Vitamin D can impair muscle strength and neuromuscular function. The evidence of supplementation with cholecalciferol plus calcium are stronger for older persons residing in long-term care when they have vitamin D deficiency. According to Bischoff-Ferrari review (2017) with clinical studies and meta-analyses on the effect of vitamin D supplementation on fall prevention the vitamin D of double benefit in bone and muscle is especially between the seniors. Further, to explain the effect

Table 3

Recommendations for individual and as a multifactorial/mulicomponent intervention.

Individual and as a component of multifactorial/ multicomponent intervention Exercise Medication Postural hypotension

Cardiovascular disorders Vitamin D

Foot Footwear Environmental assessment and adaptations

Education/training Individual intervention Vision Exercise Assistive devices Hip protectors Fall alarm devices Removal of physical restraints

Recommendation Balance, gait, strength training and coordination such as tai chi or physical therapy Discontinuation or dose reduction medication reduction, optimization of fluids, behavioral intervention, elastic stockings, abdominal binders, and medications (e.g., fludrocortisone and midodrine) Medications, dual-chamber cardiac pacing 800 IU/d plus calcium for all older adults at risk of falls and in patients residing in long-term care when they have vitamin D deficiency or with problems of gait or balance or who are otherwise at risk for falls Assessment and treatment Shoes with low heels and high surface contact area Trained individuals, removal or modification of identified hazards, installation of safety devices such as handrails on stairs and grab bars on bathrooms, antislip shoe devices, adequate lighting, absence of railings, and clutter Staff training and feedback; training in the use of appropriate assistive devices Recommendation Any remediable visual abnormalities should be treated, particularly cataracts; not to wear multifocal lenses while walking Endurance and flexibility (muscle and joint stretching techniques) training Training in the use of appropriate assistive devices Training in the use of appropriate assistive devices Camera-based, ambient sensors, and wearable sensors is associated with deaths in nursing home residents

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Table 4

Summary of the studies that examined the intervention with physical perfrmance and functional tests for prevention fall. Intervention with physical performance and functional tests

Reference

Population / Settings

Liu-Ambrose et al. (2019)

Participants were randomized to receive Among older adults receiving care at a fall usual care plus a home-based strength prevention clinic after a fall, a homebased strength and balance retraining and balance retraining exercise (n ¼ 173) or usual care, consisting of fall exercise program significantly reduced prevention care provided by the rate of subsequent falls compared a geriatrician (n ¼ 172). Both were with usual care provided by provided for 12 months. a geriatrician. Cross-sectional cohort study comprised Low gait speed was significantly The gait speed with cut-off 1.0 m/s could 108 elderly living in a small Norwegian associated with a history of multiple falls represent a useful tool for identifying municipality, born between 1936 and (odds ratio [OR] ¼ 3.70, 95% CI [1.18, individuals who are vulnerable but not 1938. Gait speed was dichotomized 11.65]). yet disabled and could benefit from fallusing a cut-off of 1 m/s. preventive exercise. Quasi-experimental study with repeated- This was followed by an 8-week A balance exercise program specifically measures, within subjects design. Older intervention period that included 16 targeting multisensory integration adults with a history of falls underwent sensory-challenge balance exercise mechanisms improved multisensory an 8-week baseline (control) period. sessions performed with computerized reweighting (MSR), balance, and lower balance training equipment. extremity strength. Long-term exercise is associated with Exercise randomized clinical trials (RCTs) The most used exercise was with intervention length of 1 year or a multicomponent training (e.g., aerobic a reduction in falls, injurious falls, and longer, performed among participants plus strength plus balance); mean probably fractures in older adults. 60 years or older (Systematic Review frequency was 3 times per week, about and Meta-analysis). 50 min per session, at a moderate intensity. Randomized clinical trials (RCTs) of fall- Exercise alone and various combinations Choice of fall-prevention intervention may prevention interventions for participants of interventions were associated with depend on patient and caregiver values aged 65 years and older (Systematic lower risk of injurious falls compared and preferences. Review and Meta-analysis). with usual care. The intervention group showed Gait velocity was assessed using the Twenty-four elderly (91.94.1 years old) were randomized. The intervention 5-m habitual gait and the timeup-and-go significantly improved TUG with single and dual tasks, rise from a chair and (TUG) tests with and without dual-task group performed a twice-weekly, balance performance (P 50 years old). Furthermore, they are often not included in screening programs (Taggarshe et al., 2013). These are usually on offer to patients over 50 years of age, with an exception for patients with family history (where screening is on offer from 40 or 10 years earlier than the youngest familial diagnosis). Also, younger patients often receive subtotal colectomies, however it is not clear if this is associated with longer survival times (Campos, 2017). In terms of survival, older patients who survive the first year postsurgery have the same survival time as younger patients. As stated previously, when making appropriate therapeutic decision, a comprehensive assessment should be taken into account not the patient’s chronological age. Same applies for postsurgical treatment, where it is reported that participation in multimodal rehabilitation programs shortened length of stay, and lowered readmission and reoperation rates both older and younger patients (Millan et al., 2015).

Conclusion GI cancer is an umbrella term for a collection of cancers that affect the digestive system. There are a total of 10 GI cancers, the most common of which include colorectal cancer and liver cancer. A key risk factor for GI cancers is older age, however, it is important to note that each GI cancer has its own set of independent risk factors and these risk factors differ across high, middle and low-income countries. Many of these risk factors are modifiable (e.g., smoking, diet, obesity, and alcohol consumption), and modification of these unhealthy behaviors has been recommended for GI cancer prevention. Few screening methods exist for GI cancers, with the exception of colorectal cancer for which several countries have adopted successful screening programs targeting older adults. There is an advanced knowledge and understanding of the diagnosis and treatment of all GI cancers. While age plays a role in determining the appropriate treatment course, it is not the only factor and the overall fitness of the patient to stand treatment is necessary, keeping in mind the need for shared decision-making. Recommendations are in place to improve the mental and physical health of GI cancer survivors through lifestyle modification. However, further research using a gold standard experimental design to evaluate the effectiveness of lifestyle interventions in cancer survivors is needed.

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Further Reading Acharya, A., Markar, S.R., Matar, M., et al., 2017. Use of tumor markers in gastrointestinal Cancers: Surgeon perceptions and cost-benefit trade-off analysis. Annals of Surgical Oncology 24, 1165–1173. https://doi.org/10.1245/s10434-016-5717-y. Danaei, G., Vander Hoorn, S., Lopez, A.D., et al., 2005. Causes of cancer in the world: Comparative risk assessment of nine behavioural and environmental risk factors. The Lancet 366, 1784–1793. https://doi.org/10.1016/S0140-6736(05)67725-2. Enzinger, P.C., Mayer, R.J., 2004. Gastrointestinal cancer in older patients. Seminars in Oncology 31, 206–219. Freelove, R., Walling, A.D., 2006. Pancreatic cancer: Diagnosis and management. American Family Physician 73, 485–492. World Cancer Research Fund, 2018. Continuous update project expert report 2018: Recommendations and public health and policy implications. https://www.wcrf.org/sites/default/ files/Cancer-Prevention-Recommendations-2018.pdf. (Accessed 16 December 2018).

Gene Therapy Olga Maslova, National University of Life and Environmental Sciences of Ukraine, Kyiv, Ukraine Alexander Koliada and Alexander Vaiserman, Chebotariov Institute of Gerontology NAMS of Ukraine, Kyiv, Ukraine © 2020 Elsevier Inc. All rights reserved.

Introduction Gene Therapy Technologies Viral Vectors Non-Viral Vectors Gene Editing Engineering of Chimeric Antigen Receptor T Cells Gene Therapy in Anti-Aging Research Metabolic Impairments Cardiovascular Diseases Musculoskeletal Disorders Alzheimer’s Disease Parkinson’s Disease Aging-Targeted Interventions Klotho Gene Therapy Telomerase Gene Therapy Conclusions References

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Glossary AAV Adeno-associated virus. CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat-associated protein-9 nuclease system) A genome editing tool capable of introducing sequence-specific breaks in double stranded DNA. GWAS (genome-wide association study) A method of identifying susceptibility loci for complex diseases by establishing statistical links between all or most SNP markers and a phenotype of interest. SNP (single nucleotide polymorphism) A single base pair variation in the DNA sequence between individuals.

Introduction Over the last years, most developed countries are characterized by rapidly increased life expectancy and population aging. These demographic processes are accompanied by rising incidence of age-related pathological conditions, including cardio-metabolic and neurodegenerative diseases, osteoporosis and cancer. Therefore, the search for new strategies for healthspan extension is currently a priority goal in biomedical research. Traditionally, pharmacological approach dominated in this research field. Development of supplements and medications specifically targeted at aging-related disorders is one of the most rapidly growing fields in modern biogerontology (Vaiserman and Marotta, 2016; Vaiserman and Lushchak, 2017). The modest benefits only may, however, be provided by pharmacological interventions. Therefore, more hopes are now pinned on stem cell and gene therapies. Nowadays, gene therapy is a most promising therapeutic option for treating genetic and acquired disorders. This is carried out by introducing the functional DNA fragments into the patient’s target cells to correct disease-causing mutations (Helal et al., 2017). Gene therapy-based applications allow to modulate gene expression in specific cells to treat particular pathological conditions. This modulation is performed by introducing exogenous nucleic acids such as DNA, mRNA, microRNA (miRNA), small interfering RNA (siRNA) and also antisense oligonucleotides (Yin et al., 2014). Presently, various gene therapy tools based on integration of foreign DNA into the host genome via transfer vectors, gene cloning, recombinant viruses, etc., and/or transcriptional/translational modulation of gene expression via RNA-interference are increasingly introduced and incorporated in the workflow of clinical laboratories worldwide (Ginn et al., 2018). These therapeutic strategies include, among others, gene augmentation (complementation of a defective gene product with a normal gene product), targeted disruption (knockout) of genes potentially involved in particular pathological pathways and gene editing to restore a normal gene product function (Wang and Gao, 2014; Naldini, 2015; Calos, 2017). In particular, direct in vivo gene transfer approach provides targeted delivery of the gene therapy vectors including adenoviral vectors, adeno-associated viral vectors and non-viral vectors such as cationic DNA-liposome complexes, to particular disease sites of the patient (Nayerossadat et al., 2012). Such a treatment mode may be a preferable therapeutic strategy in case of impossibility of

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using cell culture-based approaches for certain tissue types, for example when targeted cells (e.g., neurons) cannot be cultured in vitro in sufficient numbers or when cultured cells cannot be re-implanted effectively in patients. It is increasingly accepted that gene therapy approaches give the opportunity for both direct (e.g., by gene editing) and indirect (e.g., by viral or non-viral vectors) modulating the genome architecture and function. In preclinical studies, use of adenovirus (viral vectors) and plasmids (non-viral expression vectors) have been the most common treatment strategies to date. The genes delivered in such a way encode predominantly transcription factors, growth factors, antiinflammatory cytokines and, less frequently, cell signaling proteins, receptors and matrix proteins (Bellavia et al., 2017). Gene transfer offers additional advantages for the delivery of products with an intracellular site of action, including non-coding RNAs, transcription factors and proteins that need to be inserted into different cell compartments, for example, into the membrane (Evans and Huard, 2015). The techniques of gene editing such as transcription activator-like effector nuclease (TALEN) and CRISPR/Cas9 are most widely applied now due to their specificity for particular genetic conditions, such as the type of mutation inheritance, the targeting site within the gene and the possibility to target the mutation specifically (March et al., 2017). As of 2017, about 2600 clinical trials initiated to test the effectiveness of gene therapy in treating different pathological conditions have been already completed, are presently ongoing or were approved in 38 countries (Ginn et al., 2018). The applicability of gene-therapy approaches in treating skin, chondral and osteochondral defects, and also blood and cardiovascular diseases has proved to be most encouraging to date (Bellavia et al., 2017; Evans and Huard, 2015; March et al., 2017; Hulot et al., 2016; Urbinati et al., 2018). However, despite the promising results from early-phase clinical trials, in particular, in cardiology, subsequent large-scale clinical trials led to disappointing results, thereby forcing the field to re-evaluate currently used delivery systems, targets, vectors and endpoints (Hulot et al., 2016). Initially, gene therapy was established as a therapeutic approach aimed to cure monogenic diseases by bringing a normal copy of the deficient gene in the relevant cells. In fact, somatic gene therapy has a much wider potential. The gene therapy-based treatment strategy has moved now from a “gene correction” model to a “DNA as a drug” model. Therefore, this therapeutic approach is increasingly applied for treating polygenic complex diseases such as age-related chronic disorders. The therapeutic opportunities of gene therapy-based approaches are increasingly debated now in the context of biogerontological research. In the present chapter, recent advances in this rapidly developing research field are reviewed and discussed.

Gene Therapy Technologies Current gene therapy strategies include ex vivo and in vivo approaches (Fig. 1). In the ex vivo approach to gene therapy, the somatic cells of a patient are therapeutically modified outside the body in a laboratory setting and then transplanted back again. Throughout this procedure, a copy of the normal allele of the defective gene of interest is inserted through viral or non-viral gene delivery vectors into the cultured cells. Following the cultivation procedure, these cells are injected back into the patient. One of the major advantages of ex vivo gene therapy is the possibility to select and analyze the modified cells (van Haasteren et al., 2018). Other advantages include specificity, safety, and lack of immune response. However, ex vivo gene therapy was not a successful treatment option for lung, heart and brain disorders (Razi Soofiyani et al., 2013). In in vivo gene therapy, gene transfer is performed by direct injection of specific genetically engineered vectors into a patient’s blood stream, and in in situ gene therapy, genetic material is introduced

Fig. 1

Schematic representation of ex vivo and in vivo approaches in gene therapy.

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directly into a localized area to target specific tissue/organ. The introduced vectors may effectively enter target cells to induce shortterm or sustained gene expression. Main gene therapy approaches are described in more details in the subsections below.

Viral Vectors Viral vectors are widely used now in many clinical applications because of their capability to invade cells and deliver specifically manipulated genetic payloads to target cells for therapeutic purposes (Gruntman and Flotte, 2018). These vectors are commonly used because of their low immunogenicity, natural integration ability and other features. Among them, there are retroviral (gamma-retroviral and lentiviral) vectors, recombinant adenovirus vectors, herpesvirus vectors and oncolytic viral vectors. The clinical efficacy of gamma-retroviral and lentiviral vectors has been also reported in ex vivo hematopoietic stem cell (HSC) trials for some other single-gene disorders known to affect bone marrow, including X-linked severe combined immunodeficiency disease, Wiskott-Aldrich syndrome, and metachromatic leukodystrophy (Kohlscheen et al., 2017). Early studies of the in vivo applicability of recombinant adenoviral vectors were focused on the cystic fibrosis transmembrane conductance regulator gene transfer to treat cystic fibrosis respiratory epithelial cells (Gruntman and Flotte, 2018). Among various gene transfer platforms available for treating complex chronic disorders, recombinant adeno-associated viruses (AAVs), small (25-nm) viruses from the Parvoviridae family which are composed of a non-enveloped protein shell containing a linear single-stranded DNA genome, have currently emerged as vectors of choice for in vivo gene therapy because of their numerous eligible properties. These properties include safety, stability, poor immunogenicity, and also high efficiency of transduction of a broad range of target tissues (Colella et al., 2017). The number of clinical trials in that AAV vectors have been applied for in vivo gene transfer has steadily increased the past decade. These clinical trials were primarily designed to examine inherited blindness, coagulation disorders and neurodegenerative diseases (Colella et al., 2017). In recent years, the encouraging results on the efficiency and safety of the AAV gene transfer were also obtained in clinical trials for muscle, brain, retina and liver pathologies (Kaplitt, 2009; Auricchio et al., 2017; Kattenhorn et al., 2016; Aguti et al., 2018). In the context of anti-aging research, an important point is what AAV vectors may transduce both proliferating and non-dividing cells, and may maintain long-term (up to several years) the gene expression patterns in both small and large animal models of chronic disorders in tissues with very low proliferation rates (Jiang et al., 2006; Niemeyer et al., 2009). Over recent years, clinical trials of AAV vector-mediated gene transfer have provided the most encouraging results in the field and, most recently, to the market approval and introduction of AAV-based medications in Europe (Basner-Tschakarjan and Mingozzi, 2014). With further clinical development, however, it became increasingly clear that host immune response represents a serious problem for clinically applicable gene transfer with AAV vectors. Whereas over the last years a large amount of information was obtained on the interaction of AAV vectors with the human immune system, in particular, on the cytotoxic T cell responses directed against the AAV capsid (a protein shell of a virus), a lot of questions are still unanswered.

Non-Viral Vectors Non-viral vectors (both DNA and RNA) have only a limited ability to transfect many cell types because they usually tend to complex with delivery vehicles including cationic lipids, cationic polymers, etc., and also tend to be subjected to forced entry (e.g., hydrodynamic injection, electroporation, etc.) (Yin et al., 2014; Helal et al., 2017; Hardee et al., 2017). Non-viral gene transfer is commonly performed using microRNAs (miRNAs), short interfering RNAs (siRNAs), etc., as well as by naked plasmid DNA. Presently, non-viral DNA vectors are used less frequently than viral vectors, but this mode of gene therapy is regarded as very promising approach by many authors now. Plasmids are considered to be safer than viruses. They can be delivered more than once, have low integration risk, and can accommodate a long genetic payload (Hardee et al., 2017). Moreover, plasmids are cheap and easy to construct, produce and store. The use of non-viral vector systems has, however, some disadvantages. They are as follows: (1) additional complexity related to using DNA carrier vehicles; (2) relatively low transfection efficiency; (3) inflammation and/or gene silencing related to applying the naked CpG motifs; (4) potential difficulties surrounding the impacts of residual antibiotics and/or endotoxins (Hardee et al., 2017).

Gene Editing Gene editing (also called genome editing) refers to a group of technologies that give researchers the capability to directly alter an organism’s DNA. The gene editing technologies allow genetic material to be removed, added, or changed at certain locations in the genome. Four families of engineered nucleases are currently described (WareJoncas et al., 2018). These families include: (1) meganucleases (MEGAs), which are highly specific due to a large recognition site (dsDNA sequences of 12–40 base pairs); (2) zinc finger nucleases (ZFNs), fusion of a zinc finger DNA-binding domain to a DNA-cleavage domain; (3) transcription activator-like effector nucleases (TALENs), fusion of TALE DNA binding domain to a DNA-cleavage domain; (4) clustered regularly interspersed short palindromic repeats (CRISPRs), consisting in the delivery of Cas9 (an RNA-guided DNA endonuclease enzyme) and appropriate guide RNAs into the cell to cut DNA at a particular target site. Use of such systems allows target most DNA sequences with nucleotide-level precision (Salsman and Dellaire, 2017). The system consisting of Cas9 protein and the guide RNA (gRNA), commonly referred to as CRISPR/Cas9 system, has emerged as the most popular tool for genome editing (Mout et al., 2017; Wang et al., 2017; Hussain et al., 2019). It has been put in mammalian

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cells to specifically cut target genes, followed by repair of target genes via the host cell repair machinery. The repair can occur through two mechanisms. The first one is the non-homologous end joining (NHEJ) repair pathway that allows the cell to randomly insert or delete nucleotides at the CRISPR-mediated double-stranded DNA break site, resulting in gene coding sequence disruption. The second one is the homology-directed repair (HDR) pathway that provides insertion of a template DNA to correct mutations at the DNA break site. For therapeutic use, the CRISPR components need to be delivered into mammalian cells to enable gene modification in host cells (Mout et al., 2017; Wang et al., 2017).

Engineering of Chimeric Antigen Receptor T Cells Recently, gene and cell therapies were combined in revolutionizing method, the engineering of chimeric antigen receptor (CAR)-T cells. As of now, research is focused on improving the effectiveness, accessibility, and safety of CAR-T cell approaches. Main advantages and disadvantages of this strategy were described in several recent review papers (Wilkins et al., 2017; Jenkins et al., 2018). (CAR)-T cell therapy is usually regarded in the context of the broader adoptive cell therapy (ACT), a form of immunotherapy in that autologous cancer-cognate lymphocytes are expanded and modified ex vivo and re-infused in a patient’s circulation to combat the tumor (Yee, 2018; Met et al., 2019). More specifically, it involves the extraction of T cells and genetic modification of antigen receptors on the cell’s surface to target specific antigens produced on the surface of tumor cells. Currently, such therapeutic applications are mainly used to treat blood-related cancers.

Gene Therapy in Anti-Aging Research Investigation of the clinical potential of gene therapy-based technologies for combating age-related diseases was initiated only recently. In the following subsections, main findings from these studies will be summarized and discussed in the context of aging-associated pathological conditions and disorders, as well as of genetic pathways crucially involved in aging processes.

Metabolic Impairments Metabolic impairments are well-known to be critically involved in aging processes (Barzilai et al., 2012). Obesity and type 2 diabetes are commonly regarded now as important inducers of premature cellular senescence and aging (Burton and Faragher, 2018). Most research evidence for this came from the streptozotocin-induced diabetic rodent models. Streptozotocin is an agent known to destroy the insulin-producing beta cells in pancreas, thereby resulting in hypoinsulinemia and hyperglycemia in exposed animals. Since hyperglycemia originates in this model due to the hypoinsulinemia and in absence of peripheral insulin resistance, it most closely mimics type 1 diabetes, but may also be applied for inducing type 2 diabetes under certain conditions (Gheibi et al., 2017). In recent years, gene therapy approaches are increasingly implemented in treating streptozotocin-induced diabetes in rodents. In a mice model of streptozotocin-induced diabetes, diabetic mice treated with insulin and glucokinase using AAV1 vectors restored and maintained normoglycemia in skeletal muscle for more than 4 months after the streptozotocin administration. Moreover, these animals exhibited normalization of different metabolic parameters, glucose tolerance, and also food and fluid intake, thereby preventing secondary diabetic complications (Mas et al., 2006). Overexpression of TCFE3 (a transcription factor known to increase insulin sensitivity by activating insulin-signaling pathways) mediated by an adenovirus or AAV serotype 2 (AAV2) ameliorated hyperglycemia in a streptozotocin-induced diabetic mice by glucokinase upregulation in the liver (Kim et al., 2013). To express target genes in response to glucose specifically in hepatocytes of the streptozotocin-induced diabetic mice, Han and co-workers used a hepatocyte-specific and glucose-responsive synthetic promoter, SP23137 (Han et al., 2011). Intravenous administration of a recombinant adenovirus expressing furin-cleavable rat insulin under control of the SP23137 promoter led to remission of diabetes and normoglycemia maintained for more than 30 days after the administration. Delivery of a metabolically responsive insulin transgene to the liver of streptozotocin-diabetic mice with AAV8 restored near-normal blood sugar levels for over 1 month and also prevented anatomic, neurohistologic and functional changes revealed in diabetic mice (You et al., 2015). The correction of hyperglycemia in streptozotocin-diabetic mice via one intravenous systemic administration of a single-stranded serotype 8 pseudotyped AAV (ssAAV2/8) vector encoding the human proinsulin gene under a constitutive liver specific promoter was also reported (Gan et al., 2016). Moreover, the adenoviral vector-based delivery of a pancreatic transcription factor such as neurogenin-3 before the induction of diabetes by streptozotocin protected mice from developing hyperglycemia, thereby demonstrating the prophylactic potential for reducing or even eliminating the disease progression (Phillips and Kay, 2014). In a diabetic rat model, the evidence was also obtained that diabetic state may be effectively reversed by the insulin release from non-endocrine cells through gene therapy. The furin-cleavable human insulin was found to be expressed in the livers of autoimmune-diabetic rats (LEW.1AR1/ Ztm-iddm) and streptozotocin-induced diabetic rats following portal vein injection of INS-lentivirus (Elsner et al., 2012). During 5–7 days after the injection of the virus, the blood glucose level was normalized in the treated rats, and this glucose-lowering effect persisted for the 1-year observation period. Evidence for long-term efficiency of gene therapy was also obtained in a large-animal (dog) model of diabetes. A single intramuscular injection with AAV serotype 1 (AAV1) encoding for insulin and glucokinase led to normalization of fasting glycemia, normalized disposal of glucose after oral challenge and reduced glycosylated plasma proteins levels in diabetic dogs for more than four years after the gene transfer (Callejas et al., 2013). These outcomes were accompanied by recovery of body

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weight and improved long-term survival without any secondary complications. More recently, the same authors have reported a long-term (
8 years) follow-up after a single administration of these therapeutic vectors to diabetic dogs (Jaén et al., 2017). The signs of metabolic correction were found, including normalization of serum levels of cholesterol, triglycerides and fructosamine and substantial improvement in the response to oral glucose load. The persistence of vector genomes and therapeutic transgene expression were revealed over years after the vector delivery in multiple samples from treated dog muscles. Importantly, the successful multi-year control of glycemia was achieved in this study without any need of exogenous insulin administration.

Cardiovascular Diseases Gene therapy for cardiovascular disorders is the third most thoroughly investigated application in the field of gene therapy now, representing 8.4% of all gene therapy-based clinical trials according to the 2012 estimates (Scimia et al., 2014). Gene therapy is increasingly considered as a promising therapeutic option for treating atherosclerosis, a common ageassociated condition characterized by systemic oxidative stress and low grade chronic inflammation. Gene therapy strategies for this disease fall into two main categories: targeting genes causing premature atherosclerosis or targeting genes to stabilize vulnerable plaques or inflammation. Genes which are currently under investigation include ApoB, ApoC, LDL receptor, proprotein convertase subtilisin/kexin type 9, matrix metalloproteinase, monocyte chemotactic protein-1 and IL-10 (Misra, 2018). In animal models, delivery of genes encoding regulators of redox sensitive transcriptional factors (e.g., NF-kappa B, Nrf2, AP-1 etc.), antioxidant defense enzymes (e.g., superoxide dismutase, glutathione peroxidase, catalase and heme oxygenase-1) or endothelial nitric oxide synthase (eNOS) caused suppression of atherogenesis (Van-Assche et al., 2011). The evidence for efficiency of gene therapy in treating atherosclerosis came mostly from the rabbit models. For example, expression of apolipoprotein A-I (apoA-I) in the artery wall with a helper-dependent adenoviral (HDAd) vector retarded the development of atherosclerosis in hyperlipidemic rabbits (Flynn et al., 2011). The local HDAd-ApoAI vascular gene therapy promoted rapid regression of small-to-moderate-sized atherosclerotic lesions even when administered on a background of aggressive lowering of plasma cholesterol (Wacker et al., 2017). More recently, transduction of vascular endothelial cells with HDAd-ApoAI yielded at least 24 weeks of local apoA-I expression that durably reduced atherosclerotic lesion growth and intimal inflammation in severely hyperlipidemic rabbits (Wacker et al., 2018). However, despite promising results from basic research, the applicability of these strategies in clinics has proven to be challenging. The main problems include the inability of sustained local expression of these genes in target tissues and the development of immune responses and other side effects (Van-Assche et al., 2011). Gene therapy-based approaches are increasingly used now in the treatment of myocardial infarction (Scimia et al., 2014). In particular, these approaches are used to rejuvenate the autologous human cardiac stem/progenitor cells (hCPCs) used for this therapy. A serious obstacle to the practical applications of such treatment is that most hCPCs are dysfunctional (senescent) in elderly patients, who are most susceptible to cardiovascular pathology. Rejuvenating hCPCs from elderly patients is believed to be a way to overcome this problem. Recently, Khatiwala and co-workers used the pLenti X2 Blast/shp16 (w112–1) lentiviral plasmid containing the short hairpin RNA (shRNA, an artificial RNA molecule with a tight hairpin turn which may be applied to silence the target gene expression via RNA interference) insert for p16INK4A knockdown to rejuvenate the aging human cardiac progenitor cells via an upregulation of anti-oxidant and NFkB signal pathways (Khatiwala et al., 2018). The p16INK4A is a cyclin dependent kinase inhibitor known to play an important role in regulating the cell senescence. In this research, the authors examined whether knockdown of p16INK4A could rejuvenate aged hCPCs to a young phenotype. Both survival capability and cell proliferation have been shown to be significantly enhanced in hCPCs infected with a lentivirus expressing p16INK4A shRNA compared with control hCPCs. The knockdown of p16INK4A also induced antioxidant defense as indicated by decreased levels of ROS generation, and also resulted in upregulation of genes associated with cell senescence (p21CIP1), NFkB signal pathway (p65, IKBKB, HMOX1, etc.), apoptosis (BCL2 and MCL1), and antioxidant defense system (CYGB, PRDX1 and SRXN1). The authors concluded, based on these data, that implementation of gene therapy-based approaches can have the potential to improve clinical efficiency of autologous hCPC therapy in treatment of myocardial infarction. Angiogenesis which is known to play an important role in a broad range of pathological conditions, from myocardial ischemia to atherosclerosis, is regarded as one of the most promising targets for gene therapy of age-related cardiovascular diseases (Ambrose, 2017). In the study by Tafuro and co-workers (Tafuro et al., 2009), functional angiogenesis was promoted in both normoperfused and ischaemic skeletal muscle in adult mice by AAV allowing to regulate the expression of the vascular endothelial growth factor known to induce neovascularization of ischemic tissues. In the mice model, the neovascularization of ischemic tissues was shown to can be promoted by the gene delivery of the proangiogenic extracellular matrix (ECM) protein Del-1 (Zhong et al., 2003). Nakagami and Morishita (2009) also used the naked plasmid of hepatocyte growth factor as an angiogenic factor for peripheral arterial diseases, and reported its efficiency and safety in clinical trial. Some growth factors such as hepatocyte growth factor, fibroblast growth factors and vascular endothelial growth factors have already been tested in clinical trials. However, apart from demonstration of increased vascularity, very few results with clinical significance have been obtained due to, among others, problems associated with gene transfer efficiency and short duration of transgene expression (Ylä-Herttuala et al., 2017). These issues, including development of better and more specifically targeted delivery systems and search for more optimal growth factors, have to be addressed in future studies.

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Musculoskeletal Disorders Human aging is characterized by a progressive loss of muscle mass and function, commonly referred to as sarcopenia (Distefano and Goodpaster, 2018). Myostatin, a well-known negative regulator of muscle growth, is regarded as a potential mediator of sarcopenia as well as a promising therapeutic target in muscle-wasting disorders (White and LeBrasseur, 2014). Gene therapy approaches were widely applied to functional enhancement of muscle mass and improving glucose and fat metabolism by myostatin inhibition in rodent models. For example, myostatin inhibition by AAV-mediated gene delivery of myostatin propeptide, known to bind and inhibit myostatin, improved the growth of skeletal muscle in the transgenic diabetic db/db mice (Jiang et al., 2017). This therapy also had beneficial effects on lipid metabolism and glucose regulation, including significantly lower blood glucose and insulin levels and increased glucose tolerance and insulin sensitivity compared to the control animals. More recently, pre-treatment of rAAV-mediated expression of myostatin propeptide was shown to be able to facilitate the growth of skeletal muscle, and also to prevent hyperglycemia and hyperlipidemia, improve glucose metabolism and reduce the incidence of type 2 diabetes in C57BL/6 mice consuming high-fat diet (Yan et al., 2019). Moreover, AAV8-mediated myostatin propeptide gene delivery enhanced muscle growth in either normal or dystrophic (dystrophin-deficient) mdx mice and ameliorated dystrophic phenotypes in mdx mice (Qiao et al., 2008). Systemic myostatin inhibition by recombinant AAVs aimed to over-express a secretable dominant negative myostatin exclusively in the liver resulted in a significantly increased skeletal muscle mass and strength both in control C57Bl/6 mice and in mdx mice (Morine et al., 2010). A single intramuscular injection of naked plasmid DNA encoding a mutant myostatin propeptide, MProD76A, caused a significant increase in skeletal muscle mass in mice (Hu et al., 2010). This enhanced muscle growth occurred in consequence of myofiber hypertrophy, whereas no cardiac muscle hypertrophy or organomegaly was found in mice after inhibiting the myostatin pathway by plasmid-mediated MProD76A delivery.

Alzheimer’s Disease Alzheimer’s disease (AD) is a most common aging-associated neurodegenerative disease characterized by progressive deterioration of cognitive functions (dementia). Progression of AD is associated with the accumulation of neurofibrillary tangles and amyloid plaques (Magalhães et al., 2015). The present-day treatment for AD includes the administration of inhibitors of acetylcholinesterase to increasing the available acetylcholine in the AD patients’ brain by blocking degradation of this neurotransmitter by acetylcholinesterase (Douchamps and Mathis, 2017). Processes involved in pathogenesis of AD such as amyloid-beta (Ab) plaque formation and apoptosis have been targeted in preclinical studies. One therapeutic option for inhibiting the Ab plaque formation is to reduce Ab and tau levels in the brain. In a mice model of AD, the AAV-mediated knockdown of the Acat1 gene encoding the acyl-CoA: cholesterol acyltransferase 1 (ACAT1) has been demonstrated to decrease Ab levels (Murphy et al., 2013). Another therapeutic strategy for reducing Ab accumulation and treating AD is the inhibition of Ab plaque formation by the viral transfer of the gene encoding neprilysin, an enzyme known to be involved in Ab catabolism in the brain (Li et al., 2015). In pre-clinical studies, the delivery of the neprilysin/membrane metallo-endopeptidase (MME) gene by AAV9 vector through either direct injection into a hippocampus or cortex (Carty et al., 2013) or through intracardiac administration (Iwata et al., 2013) resulted in a significant reduction of Ab levels in the brain. In the later study, the improvement of amyloid burden was accompanied by the improvement in learning and memory (Iwata et al., 2013). In AD patients, lower circulating levels of leptin, an anorexigenic peptide hormone synthesized in adipocytes, have been reported, indicating its role in pathogenesis of disease (Magalhães et al., 2015). In an amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mouse model of AD, intra-cerebroventricular injection of a lentivirus vector expressing leptin protein in a self-inactivating HIV-1 vector led to a decreased levels of tau phosphorylation and Ab, and also improved synaptic density in treated mice (Pérez-González et al., 2014). The intrahippocampal injection of a F-spondin gene (a homolog of reelin, which is a signaling protein playing an important role in synaptic function) expressed by lentiviral vector resulted in an improved learning and memory, and also to reduced Ab levels (Hafez et al., 2012). In an aluminum-induced AD model, down-regulating the expression of caspase-3 gene using lentiviral vector-mediated caspase-3 short hairpin RNA led to reduced neural cell death and improvement in learning and memory in C57BL/6J mice (Zhang et al., 2014). In a rat model, intracerebral administration of a recombinant AAV vector expressing the human hypoxia-inducible factor 1gene (rAAV-HIF-1a) decreased the hippocampal neuronal apoptosis induced by Ab protein (Chai et al., 2014). Recombinant lentiviral vectors were used to overexpress the glial cell-derived neurotrophic factor (GDNF) gene in hippocampal astrocytes of 3xTg-AD mice (Revilla et al., 2014). Even although GDNF therapy had no significant effects on Ab or tau levels, treated mice demonstrated preserved learning and memory after 6 months of overexpressing GDNF compared to their control counterparts. A gene therapy-based approach was also used to modulate the expression of the insulin-like growth factor 2 (IGF2) previously shown to play an important role in memory consolidation in rodents. The AAV8IGF2-promoted overexpression of IGF2 in the hippocampus of aged wild-type mice resulted in enhanced dendritic spine formation and memory (Pascual-Lucas et al., 2014). In the APP Tg2576 mouse model of AD, the delivery of IGF2 or IGF1 by AAV system into hippocampus promoted dendritic spine formation, restored normal hippocampal excitatory synaptic transmission and rescued behavioral deficits in AD mice. More recently, AAV8 vector was used for the delivery of the ectodomain of neurotrophin receptor p75 (p75NTR), known to be a physiological protective factor against Ab in AD. Intramuscular delivery of AAV-p75ECD reduced brain amyloid burden, attenuated Tau hyperphosphorylation and neuroinflammation and also substantially improved the behavioral phenotype of APP/PS1 transgenic mice (Wang et al., 2016). Recently, clinical trials were initiated to evaluate the therapeutic potential of gene therapy approaches for the treatment of AD. These trials were focused on the nerve growth factor (NGF), an

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endogenous neurotrophic-factor protein previously shown to restore function and to protect degenerating cholinergic neurons in AD. In a phase1 trial, evidence was provided that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is well-tolerated and may produce long-term expression of an active form of NGF (Rafii et al., 2014). More recently, in the multicenter randomized clinical trial, AAV2-NGF delivery was confirmed to be well-tolerated but did not affect clinical outcomes or selected AD biomarkers (Rafii et al., 2018). So, further clinical trials are needed to determine optimal gene therapy-based treatment strategies for managing AD.

Parkinson’s Disease Parkinson’s disease (PD) is the second most common neurodegenerative disease and the most common movement disorder of aging. It is characterized by a loss of dopaminergic neurons in the substantia nigra and reduced dopamine levels in the striatum. The potential of gene therapy for treating PD was examined extensively and has already reached the stage of clinical trials. Three kinds of strategies are used in clinical studies of gene therapy in PD (Muramatsu, 2017):

• • •

Restoration of dopamine production in the putamen by introducing genes of dopamine-synthesizing enzymes; Protection of nigrostriatal projections by gene transfer of neurotrophic factors into the putamen and substantia nigra; Modulation of subthalamic nucleus neural activity by gene delivery of an enzyme to synthesize inhibitory transmitter yaminobutyric acid.

The gene therapy-based approaches showed their effectiveness in several Phase I clinical trials; the majority of them, however, failed to demonstrate improvements beyond the placebo effect when advanced to controlled, blinded Phase II trials (for review, see O’Connor and Boulis, 2015). The only Phase II clinical trial was efficient in which patients with PD were directly injected with AAV2-glutamic acid decarboxylase (GAD) into the subthalamic nucleus (LeWitt et al., 2011). Those PD patients who received AAV2-GAD exhibited improvement of symptoms over the control PD patients. In a long-term follow-up of a randomized AAV2GAD gene therapy trial for Parkinson’s disease, the same authors reported clinical benefits in PD patients, which persisted at 12 months after the bilateral delivery of AAV2-GAD (Niethammer et al., 2017). More recently, by determining mechanisms underlying these outcomes, it has been found that such gene therapy can reduce symptoms of PD by reorganizing functional brain connectivity (Niethammer et al., 2018). More specifically, those PD patients who received AAV2-GAD gene therapy, developed a unique treatment-dependent polysynaptic brain circuit termed by the authors as the GAD-related pattern (GADRP), which reflected the formation of novel polysynaptic functional pathways linking the subthalamic nucleus to motor cortical regions. Another open-label Phase 1/2 clinical trial was conducted to assess the efficiency of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring the local and continuous dopamine production in PD patients (Palfi et al., 2014). It has been shown that ProSavin is well tolerated and safe in patients with advanced PD. This treatment led to significant improvement in motor behavior from baseline at 1 year in all patients. PD patients from this open-label trial, who were injected with ProSavin into the putamen, have been followed up in the long term (Palfi et al., 2018). In this follow up, ProSavin continued to be well tolerated and safe in these patients, and moderate improvements in motor behavior over baseline continued to be reported in most of PD patients who might still be evaluated following five years of follow-up. A metabolic precursor of dopamine, Levodopa, which is a prescription medication in treating PD symptoms, is known to become less effective over time. It occurs perhaps due to progressive loss of aromatic L-amino acid decarboxylase (AADC), the enzyme converting levodopa into dopamine. Therefore, AADC is considered to be a promising candidate for gene therapy of PD. In a primate model of PD, the intrastriatal injection with an AAV2 vector containing the human AADC gene (AAV-hAADC) promoted a strong response to low-dose levodopa without any side effects. Therefore, Phase I clinical trials were designed to evaluate the safety and efficacy of gene therapy with AAV-hAADC for PD patients (Christine et al., 2009; Muramatsu et al., 2010). In a subsequent follow-up, the stable transgene expression and also the continued safety were observed over 4 years after the vector delivery (Mittermeyer et al., 2012). An improvement in a Unified Parkinson’s Disease Rating Scale (UPDRS) was revealed over the first 12 months, but it was slowly deteriorated during the following years of the follow-up.

Aging-Targeted Interventions In recent years, gene therapy-based interventions targeting aging process per se were developed. The main findings from these studies will be described in subsections below in more detail.

Klotho Gene Therapy One of the examples of pre-clinical studies targeted to investigate the potential of gene therapy-based approaches in anti-aging medicine is recent in vitro research aimed at upregulation by gene therapy of the Klotho gene (Chen et al., 2018). Considerable evidence indicates that Klotho protein encoded by this gene has substantial anti-aging and cognition-enhancing properties. It is known to increase the anti-oxidative stress defense, foster neuronal survival and promote remyelination of demyelinated axons. Evidence was also obtained that upregulation of this gene may alleviate the symptoms and also prevent the progression of some age-related neurodegenerative disorders including demyelinating diseases such as multiple sclerosis as well as Alzheimer’s disease.

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The CRISPR-dCas9 complex was used to investigate if single-guide RNA (sgRNA) targeting the Klotho promoter region may result in the transcriptional activation of the Klotho gene. In this study, both sgRNAs used were found to be able to increase Klotho expression at both gene and protein levels, suggesting, according to the authors, a therapeutic potential for enhancement of cognitive functions and treating aging-related demyelinating and neurodegenerative disorders, as well as chronic kidney disease and cancer. In the study by Zhou et al. (Zhou et al., 2018), lentiviral vectors encoding the full-length Klotho gene was used to deliver and sustain the expression of Klotho to determine its potential therapeutic effects in senescence-accelerated mouse prone-8 (SAMP8) mice. Three months after injection of the lentiviral vector, the expression of Klotho in the brain was found to be significantly increased in 10month-old SAMP8 mice. This change was accompanied by a reduction of neuronal loss, synaptic damage and memory deficits, and by increased levels of mitochondrial manganese-superoxide dismutase (Mn-SOD) and catalase (CAT) expression, suggestive of decreased oxidative stress. Moreover, the up-regulation of Klotho expression led to decreased Akt and Forkhead box class O1 (FoxO1) phosphorylation suggestive of inhibition of the Akt/FoxO1 pathway known to play an important role in many agingassociated processes.

Telomerase Gene Therapy In the field of anti-aging research, the transfer of the gene encoding the telomerase reverse transcriptase (hTERT) by specific plasmid vectors has been used most frequently. Telomere biology is one of the crucial contributory factors in aging and age-related disease risks, because telomeres progressively shorten during each round of mitosis in most human somatic cells, eventually leading to chromosomal instability and cell senescence. Telomeres may be elongated through action of telomerase, a specific enzyme that adds telomere repeats to the ends of chromosomes and thereby elongates telomeres. Telomerase is a ribonucleoprotein complex composed of hTERT gene and RNA template (hTR). The level of the telomerase activity in the cell is limited primarily by the level of hTERT expression. The hTERT is known to be expressed only in germ line cells, proliferative stem cells of renewal tissues, as well as in cancer cells. The hTERT expression in normal cells leads to reconstitute telomerase activity and to prevent the induction of senescence which likely contributes in specific tissues and locations to impairment of physiological functions and development of chronic pathological conditions with increasing age. Whereas expressing hTERT results in the maintenance of telomere length in certain cell types and is assumed to be a promising pro-longevity option, the blocking of replicative senescence would likely enhance the risk of developing cancer. However, the transient rejuvenation of cells might be advantageous in many cases. Ectopic expression of hTERT (i.e., the expression in cells in which the gene is not usually expressed) has been demonstrated to be able to immortalize many cell types including human skin fibroblasts and keratinocytes, muscle satellite (stem) cells, and also retinalpigmented, myometrial, vascular endothelial and breast epithelial cells in vitro (Shay and Wright, 2005; Kang and Park, 2007), and also to increase the healthspan and lifespan in vivo (Mendelsohn and Larrick, 2012). In pioneering work in this area, Bodnar and co-workers used two different hTRT expression constructs encoding the human telomerase catalytic subunit for the transfection of two telomerase-negative human cell types such as foreskin fibroblasts and retinal pigment epithelial cells (Bodnar et al., 1998). One construct was engineered for increase of translational efficiency by removal of the 50 and 30 untranslated regions of hTRT and creation of a Kozak consensus sequence, (gcc)gccRccAUGG, playing a key role in the initiation of the translation process in vertebrates. This engineered hTRT cDNA was cloned downstream of the myeloproliferative sarcoma virus (MPSV) promoter. Another construct consisted of the complete (native) hTRT cDNA cloned downstream of the SV40 promoter in pZeoSV plasmid vector. In contrast to control clones which were telomerase-negative and thereby exhibited telomere shortening and senescence, the telomerase-expressing clones showed reduced straining for beta-galactosidase, a known biomarker for cellular senescence, and also had elongated telomeres and divided vigorously. The telomerase-expressing clones had normal karyotypes and exceeded their normal replicative life span by at least twenty doublings. Subsequently, the potential of gene therapy-based approaches for “rejuvenating” tissue types and organ systems playing a key role in aging and pathogenesis of age-related diseases was shown. In the Rufer et al. (2001) study, the retroviral vectors have been used to transfer the hTERT gene into naïve CD8(þ) T lymphocytes whose replicative life span may be substantially limited by the loss of telomere repeats with cell divisions. Transduced T-cells expressed high levels of telomerase and either maintained or even elongated the telomere lengths in culture for a long period of time. Two of the transduced subclones maintained a normal cloning potency for more than 170 population doublings. Those T-cell clones which were transfected with control vectors, in contrast, exhibited progressive shortening of telomere lengths and stopped to proliferate after about 108 population doublings. The telomerase-positive T clones, moreover, had a normal 46,XY karyotype, maintained the cytotoxic properties, and exhibited very slight staining with the apoptotic marker such as annexin-V. In general, findings from this study demonstrate that ectopic hTERT gene expression may result in the extension of the replicative lifespan of human T lymphocytes. The telomerase activity was also reconstituted by the transfection of the telomerasenegative human osteoblasts with a vector pcDNA3 plasmid expressing hTERT complementary DNA (Yudoh et al., 2001). In contrast to the telomerase-negative control osteoblastic cells that exhibited telomere shortening and replicative senescence after 10–15 population doublings, the telomerase-expressing osteoblastic cells had lengthened telomeres and demonstrated continued osteoblastic features such as procollagen I C-terminal propeptide secretion and alkaline phosphatase activity for more than 30 population doublings. The feasibility of the telomerase gene therapy in anti-aging medicine was also confirmed in in vivo studies. In the study by Bernardes de Jesus et al. (2012), AAV9 vector was used to constitutive expression of the mouse TERT (mTERT) catalytic subunit in a variety of tissues of one- and two-year-old mice. This treatment resulted in a long-lasting (up to 8 months) 5- to15-fold increase of the level of mTERT expression and about a 5-fold increase of telomerase activity. These changes were expectedly associated with

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increased average telomere lengths in treated mice compared with control animals. Treatment of both one- and two-year old mice with AAV9-mTERT had significant beneficial effects on several age-related health parameters such as insulin sensitivity, neuromuscular coordination, osteoporosis, and also on some molecular biomarkers of aging. Moreover, the levels of insulin-like growth factor-1 (IGF-1), known to be gradually decreased with aging, were restored in AAV9-mTERT-treated two-year-old mice to levels characteristic of one-year-old animals. In addition, the median life spans of one- and two-year-old AAV9-mTERT-treated mice were increased by 24% and 13%, respectively. Importantly, these advantageous effects have not been revealed with a catalytically inactive TERT, indicative of requirement of telomerase activity. Remarkably, AAV9-mTERT-treated mice did not develop more tumors than their untreated littermates. The authors suggested, on the basis of these findings, that a cancer-promoting activity of telomerase may be substantially reduced when expressed in adult to old organisms using AAV vectors. However, since high-level TERT expression has been shown to be associated with oncogenic transformation in many other studies, its synthesis needs to be modified with caution, and transient expression of TERT could be a preferred treatment option in tissue engineering and adoptive stem cell therapy (Larrick and Mendelsohn, 2015).

Conclusions Gene therapy has the potential to provide benefits in preventing and treating various diseases, including aging-associated pathological conditions. Therapeutic efficacy of gene therapy-based applications is obviously dependent on understanding the targeted pathological processes. Clinical translation of such applications is certainly a long-time process that will involve many iterative cycles from bench to bedside required to address challenges encountered throughout the implementation of gene therapy as a novel therapeutic modality for treating age-related disorders. The major issue in this regard is choosing appropriate genes for therapeutic delivery. It is certainly much harder to target polygenic diseases than the monogenic ones, since simultaneous targeting a large number of genes may trigger cascades of unpredictable events. Current research is focused therefore on the development of means to target insertion of the gene of interest at a “safe harbor” locus of the cell’s genome to avoid the risk of insertional mutagenesis through the modification of non-target genes. An important challenge is also achieving the most complete transduction to the target tissue/organ and avoiding propagation into surrounding tissues. To overcome this issue, novel approaches for delivering therapeutic genes directly to target cells have been developed. The methods of gene delivery provide another important issue. Currently, the most common is the gene delivery approach based on viral vectors. This approach, however, is associated with a poor targeting efficiency, risk of inducing immune responses, low packaging ability for large DNA sequences and random integration into the human genome (Yan et al., 2019). Antisense oligonucleotides and siRNAs have also attracted substantial attention as potential therapeutics now, involving the use of miRNAs to regulate overexpressed genes (Misra, 2018). Presently, innovative non-inflammatory vectors capable to effectively propagate through tissues and having sufficient packaging space are actively developed. Using nanoparticles which are relatively small in size and do not incorporate into genome is regarded as an alternative strategy for gene transfer (Yan et al., 2018; Hu et al., 2018). Recently, mitochondrion modified to be capable to secrete therapeutic proteins was suggested to be a suitable gene delivery vector for anti-aging applications (at least, for post-mitotic cells) (Renteln, 2018). Extracellular vesicles (natural lipid particles released by many cell types) such as exosomes and microvesicles, which may mediate cell to cell communication via transferred contents including proteins, nucleic acids, and metabolites, were proposed as one more way to improve gene transfer with AAV vectors (György and Maguire, 2018). Based on the above data and considerations, it can be concluded that it is apparently premature to discuss the efficiency of gene therapy in anti-aging research at a clinical level. The dynamics of approval/cancellation of gene therapy-based medications by regulatory agencies across the world indicates the complexity and ambiguity of the issues above. However, after overcoming these issues, the implementation of innovative gene therapy-based approaches in biogerontological research may obviously open new horizons in anti-aging medicine.

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Geriatric Emergency and Prehospital Care Esra Ates Bulut and Ahmet Turan Isik, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey © 2020 Elsevier Inc. All rights reserved.

Introduction/Background Senior-Friendly Emergency Departments and Prehospital Care Conditions Frequently Encountered Special Considerations and Screening Tools Delirium and Dementia Falls Polypharmacy and Adverse Drug Effects Quality of Care Long Term Care Patients in ED Transitions of Care Palliative Care and End of Life Care Conclusion References Further Reading

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Introduction/Background Over the past 10 years, Americans 65 years and older increased from 37.2 million in 2006 to 49.2 million in 2016 and is estimated to proceed nearly double to 98 million in 2060. The age 85 and over population is reached 6.4 million in 2016 (Profile of Older Americans, 2017). About one in every seven (15.2%) of the population is classified as older person. Accordingly, there are many implications associated with aging on the health care system. On the other hand, chronological age does not always reflect physiological age. Most older adults have at least one chronic systemic disease and many have multiple conditions including disability, visual and auditory or cognitive impairments. Multiple diseases lead to concurrent use of multiple medications which can result in difficulty for review all medications and estimate adverse drug events (ADEs). Multimorbidity is associated with many adverse outcomes including falls, ADE, institutionalization, even death (Guiding Principles for the Care of Older Adults With Multimorbidity: An Approach for Clinicians, 2012). Also, a high burden of chronic disease can lead to problems with self-care, physical instability. Their functional status may vary from extremely fit to severe frail. Socioeconomic, psychological, and physical factors cause multidimensional state in elderly. Due to the complex conditions, older adults require more outpatient office visits and ambulatory care visits to hospital emergency departments (ED) than younger people. The ED is the most popular service to which older adults admit when they suffer from an illness (Shah et al., 2007). According to US National Center for Health Statistics, among people aged 75 and over, 27.4% had one or more visits to ED within the past 12 months compared to 20.5% among people ages 65–74, 18.1% among people ages 45–64, and 18.8% among people ages 18–44 in 2016 (Centers for Disease Control and Prevention, 2017). In addition, older people applied to the ED are more likely to need faster approach, more diagnostic testing and health care expenditure compared with their younger counterparts (Aminzadeh and Dalziel, 2002). Therefore, the ED not only plays a major role in improving care to the geriatric population, but is also the initial site of care maintaining a step for patients to the other levels of care.

Senior-Friendly Emergency Departments and Prehospital Care Age associated differences in health care use and economic burden to governments force to make new considerations on ED according to senior demands. Geriatric EDs began appearing in the United States in 2008 and have become increasingly common (Samaras et al., 2010). The classic approach to emergency medicine was aimed the rapid assessment and referral to appropriate centers or treatment of patients with a single-system acute problem. Older population frequently require emergency medical services (EMS). Patients who request EMS are directly transported to the ED in traditional care. Paramedical services response to all patients, and paramedical care is also major care provider for nursing home residents. Paramedics just stabilize patients on scene and transport them to the closest ED as prehospital care. However, paramedical services are designed to integrate primary and acute care to improve EMS system efficiency. Nontraditional paramedical care should contain first assessment of patients, referral to the most appropriate health center (e.g. trauma or stroke center) or treatment at the home environment (Duong et al., 2018). Paramedics with special geriatrics training can provide more than standard ambulance transfer, and can treat elderly patients with acute minor conditions in place without transport to ED.

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Most emergency health care providers have not been trained in particular approaches for older adults, and they are unfamiliar to geriatric syndromes and feel themselves uncomfortable while dealing with older patients (Grief, 2003). Furthermore, emergency physicians often don’t have preexisting relation with patients, and only evaluate patients’ chief complaint. A number of challenges face to emergency medicine to achieve better geriatric patient outcome. Older patients often present with atypical presentations and multimorbidities complicate diagnosis and treatment. They have increased risk for readmission, admission to intensive care unit (ICU), hospitalization and mortality (Singal et al., 1992). Complexity of older patients leads to emerge several conditions including introduce multiple medical, pharmacological, psychological, social and functional issues. These make challenges for a system design rapidly assess and resolve single acute problems. For this reason, the geriatric emergency care model incorporates factors including social isolation, polypharmacy, cognitive status, and functional disability (Sanders et al., 1996). The model of emergency and paramedic services to older patients should be designed for special necessities of this age group. EMS which involves geriatric care principles, achieves optimal outcomes and prevents short term readmissions. The specialized multidisciplinary team of care providers focused on the dynamics of the geriatric population can optimize ED visits, effectively coordinate care in a less costly, and organize resources for high-risk patients to prevent readmissions (Hwang and Morrison, 2007). In 2014, the American College of Emergency Physicians, the American Geriatrics Society (AGS), the Emergency Nurses Association, and the Society for Academic Emergency Medicine approved consensus-based geriatric ED guidelines (The American College of Emergency Physicians, 2014). This model reveals age associated differences in disorders and diagnoses, atypical presentation of diseases, physiology of aging, the complexity of management older adults, and the need to consider other issues beyond the presenting complaint (American College of Emergency Physicians, 2014). Many countries have developed geriatric/senior-friendly EDs. Senior-friendly EDs have four core domains: physical environment, social climate, hospital policies and procedures, health care system (Kelley et al., 2011). Physical environment should provide safety (prevention of falls, low-risk transport methods), maintenance of physical abilities (handrails on the walls, walking aids), preservation of attention and orientation (usage of restraint materials minimally, appropriate lightening, supplement hearing and vision). The care provided should be free of ageism and address issues of elder abuse. Emotional support and information sharing with caregivers or patients make social engagement. By using providers, including nurse practitioners, nurses, social workers, physician assistants, and physicians to coordinate care in the ED, create most conducive environment for elder patient’s care. The geriatric-trained ED staff and administration create multidisciplinary team focused on better practice. Hospital policy should include recruitment of qualified health care providers, screen all geriatric patients for high-risk features, and rational use of resources. Health care system organize continuum of services, reimbursement models according to older patients (The Senior Friendly Care Framework, 2017).

Conditions Frequently Encountered The most common ED presenting complaints included dyspnea, chest pain, lower extremity pain/injury and abdominal pain for older patients. Overall, 74.2% of patients were triaged as urgent or emergent. The most common diagnose was symptoms, signs, and ill-defined conditions (25%) which include syncope, malaise and fatigue. Thus, a quarter of older adults leave the ED without a definitive diagnosis. Injury and poisoning constituted 17.1% of diagnoses, was the second most common diagnosis. The following common diagnosis are related to circulatory, respiratory and digestive system (Latham and Ackroyd-Stolarz, 2014). Age is a well-known cardiovascular system risk factor, and 30% of the myocardial infarction occurs after 75 years (Thiemann et al., 2000). Approximately 20% of patients have shortness of breath and chest pain as chief complaints, additionally ECG can be nondiagnostic in 43% of patients older than 85 years. Due to the atypical presentations, difficulty in diagnose and worse outcomes, cardiac events should be considered in older adults admitted to ED (Alexander et al., 2007). Infectious diseases are one of the common causes of admission to ED. Elderly patients present with nonspecific clinical symptoms and nonspecific functional decline, making diagnosis difficult. The most frequent conditions are pneumonia, urinary tract infection, and sepsis (Marco et al., 1995). Polymicrobial infections, the propensity to develop organ failure and septic shock, blunted febrile responses, the high frequency and mortality of bacteremia should be considered in the elderly (Lee et al., 2007). Abdominal pain which have six- to eight-time higher mortality rates and twofold increased surgery rates compared of younger patients, is another main complaint in older adults. Leading causes of abdominal pain were nonspecific, urinary tract infection, bowel obstruction, gastroenteritis, and diverticulitis (Lewis et al., 2005). The nonspecific presentation of abdominal disease and high morbidity and mortality in older patients have revealed importance of computed tomography as a radiologic diagnosing test, which has a much higher sensitivity and specificity than the clinical examination in the evaluation of the older patient with abdominal pain (Hustey et al., 2005). However, because of the risk for contrast-induced nephropathy, ultrasonography and abdominal CT without contrast may be most appropriate radiologic method for patients at high risk for renal complications including chronic kidney disease, diabetes, chronic heart failure (Chronopoulos et al., 2010).

Special Considerations and Screening Tools Older adults, unlike their younger counterparts, are more likely to have cognitive impairment, falls, depression, functional impairment, depression, and to be taking multiple medications. These conditions make the evaluation and management of older patients more complex. Comprehensive geriatric assessment is the optimal method to identify older patients at high risk for adverse

Geriatric Emergency and Prehospital Care Table 1

• • • • • • • • • • •

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Principles of geriatric emergency medicine

Patient’s presentation is frequently complex. Common diseases present atypically in this age group. The confounding effects of comorbid diseases must be considered. Polypharmacy is common and may be a factor in presentation, diagnosis, and management. Recognition of the possibility of cognitive impairment is important. Some diagnostic tests may have different normal values. The likelihood of decreased physiologic reserve must be anticipated. Social support systems may not be adequate, and patients may need to rely on caregivers. Knowledge of baseline functional status is essential for evaluating new complaints. Health problems must be evaluated for associated psycho-social adjustment. The emergency department encounter is an opportunity to assess important conditions in the patient’s life.

Adapted from Sanders, A. B., Witzke, D. B., Jones, J. S., Richmond, K., and Kidd, P. (1996). Principles of care and application of the geriatric emergency care model. In: Sanders, A. B., (ed.) Emergency care of the elder person, pp. 59–93. St. Louis, MO: Beverly-Cracom Publications.

Table 2

Identification of seniors at-risk tool

Before the illness or injury that brought you to the Emergency, did you need someone to help you on a regular basis? Since the illness or injury that brought you to the Emergency, have you needed more help than usual to take care of yourself? Have you been hospitalized for one or more nights during the past 6 months (excluding a stay in the Emergency Department)? In general, do you see well? In general, do you have serious problems with your memory? Do you take more than three different medications every day? Adapted from McCusker, J., Bellavance, F., Cardin, S., Trepanier, S., Verdon, J., and Ardman, O. (1999). Detection of older people at increased risk of adverse health outcomes after an emergency visit: The ISAR screening tool. Journal of the American Geriatrics Society 47(10), 1229–1237.

outcomes and rehospitalization. However, the usual ED model does not focus on the special care older patients require. Principles of geriatric emergency medicine are summarized in Table 1 (Sanders et al., 1996). Functional assessment is important in the ED evaluation of many older patients. Subacute or acute functional decline may precipitate admission to the ED. Testing of measures for functional assessment is needed in older adults. Patients whose basic activities of daily living are affected generally require further evaluation or admission to the hospital (Gray et al., 2013). Therefore, emergency medicine practitioners need decision support systems to determine vulnerable older adults. These patients should receive comprehensive discharge planning that includes transitions with their patient-centered medical home, primary care provider, or appropriate specialty consultation, such as physical therapy or home care services. It is recommended all older adults, regardless of the presenting complaint should be screened using the “Identification of Seniors at Risk Tool (ISAR)” (Table 2) or a similar risk screening tool to identify patients at high risk (McCusker et al., 1999). Patients are considered to be at high risk, if there is more than one positive response in ISAR. In addition, multiple comorbidities, polypharmacy, functional and cognitive impairments who often present with subtle clinical symptoms and signs of acute illness, should be assessed separately in patients admitting to ED. The common encountered conditions including falls, cognitive and behavioral disorders, medication modifications, transitions of care, pain management and palliative care should be covered in the risky group to deliver high quality care. Evaluation and management of these conditions should be done according to concerns regarding the geriatric emergency principles (Hogan et al., 2010).

Delirium and Dementia Cognitive dysfunction may impair the ability of self-expression. Older adults tend to minimize symptoms, hiding the underlying serious condition. In order to learn the exact history of the patient, support should be obtained from the patients’ relatives. Moreover, acute mental status change may sometimes be the single presenting symptom of what turns out to be acute cardiovascular events. The Society for Academic Emergency Medicine (SAEM) Geriatric Task Force recommends mental status assessment for all older patients in the ED (Terrell et al., 2009). Furthermore, undiagnosed cognitive impairment and dementia are common in ED patients. The prevalence of delirium was reported increasingly up to 22% in elderly demented patients (Isik, 2018). Delirium is generally acute in onset and can be caused by medical conditions that are reversible. It causes increased mortality, morbidity, increased need for restraints, permanent long term functional and cognitive decline, and extended hospital length of stay subsequent need for nursing home placement (Isik, 2018). The Confusion Assessment Method (CAM) is practical and has a high specificity (100%) and sensitivity (86%) for the diagnosis of delirium (Monette et al., 2001). After exclusion of delirium, cognitive impairment may be evaluated by The Six Item Screener (Table 3) (Callahan et al., 2002) with a sensitivity of 94% and a specificity of 86% in the ED context when cutoff of  4 is accepted as impaired (Wilber et al., 2005).

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The six item screener

I would like to ask you some questions that ask you to use your memory. I am going to name three objects. Please wait until I say all three words, then repeat them. Remember what they are because I am going to ask you to name them again in a few minutes. Please repeat these words for me: APPLEdTABLEdPENNY. (Interviewer may repeat names 3 times if necessary but repetition not scored.) Did patient correctly repeat all three words? What is the year? What is the month? What day of the week is it? What were the three objects I asked you to remember? Apple Table Penny

Yes , Incorrect , , ,

No , Correct , , ,

, , ,

, , ,

Adapted from Callahan, C. M., Unverzagt, F. W., Hui, S. L., Perkins, A. J., and Hendrie, H. C. (2002). Six-item screener to identify cognitive impairment among potential subjects for clinical research. Medical Care 40(9), 771–781.

Falls Trauma is one of the leading causes of admission to ED in older patients, often caused by falls. 4%–6% of falls result to fractures; furthermore, 2%–10% of falls produce other major injuries requiring hospitalization or immobilization (Sanders, 1999). Such falls often leads to brain injuries and spine or hip fractures and make a huge burden on health care costs. On the other hand, traumatic injuries in elderly patients are often underestimated. Researchers found that elderly patients are often undertriaged, meaning they are not taken to a trauma center, even though their injuries are severe enough to warrant being seen in those facilities (Staudenmayer et al., 2013). Traumatic injury in the geriatric population is increasing in prevalence and is associated with higher mortality, complication rates, poorer overall functioning and early admission to long-term care facilities. Although falls has negative health outcomes, they are preventable geriatric syndromes that has multifactorial causes including balance, transfer, strength problems, medications, particularly psychoactive medications, and visual deficits, postural hypotension, and other cardiovascular and medical conditions (arthritis, stroke) (Carpenter et al., 2009). Because of the great heterogeneity of the causes, multifactorial or multicomponent approaches are recommended for fall prevention. Multifactorial interventions can be described as exercise, physical activity, medical assessment and management, medication adjustment, environmental modification, and education, visual supplement, cope with orthostatic hypotension and rhythm abnormalities (Geriatrics Society and British Geriatrics Society Panel on Prevention of Falls in Older Persons, 2011). Comprehensive evaluation is recommended to ED patients who fall, including an expanded history (e.g., Activities of Daily Living, environmental hazards, last eye examination), physical examination (Timed Up and Go Test, mental status examination), diagnostic studies and referral (geriatric assessment, social services, optometry, podiatry, physical therapy, occupational therapy) (Baraff et al., 1997). Slower Timed Up and Go (TUG) scores were found to be associated with a decline in functions and was a risk factor for recurrent falls (Russell et al., 2006). Although hospitals use different tools for fall assessment, predicting future falls in geriatric ED patients is challenging and there is no appropriate and valid tool (Oliver and Healy, 2009).

Polypharmacy and Adverse Drug Effects Older patients admitted to the ED take an average of 4.2 medications per day (ranging from 0 to 17 medications), with 91% using at least 1, and 13% receiving 8 or more. Moreover, they are at high risk of medication related adverse events due to multimorbidity and age-related changes in pharmacokinetics and pharmacodynamics (Hohl et al., 2001). Adverse drug events that lead to emergency department visits are clinically significant adverse events and result in increased health care resource utilization. Explicit criteria for potentially inappropriate medication use in older patients have been defined. Beers Criteria which is the most commonly used tool, become a widely accepted measure of quality of care for older adults in research studies (The American Geriatrics Society 2015 Beers Criteria Update Expert Panel, 2015). It is reported estimated 3.6% of these ED visits were because of medication adverse events according to the Beers criteria. Most commonly implicated medications categorized into three classes: oral anticoagulant or antiplatelet agents (warfarin, aspirin, and clopidogrel), antidiabetic agents (insulin, metformin, glyburide, and glipizide), and narrow therapeutic index agents (digoxin and phenytoin). 33.3% of adverse events from three medications warfarin, insulin, and digoxin (Budnitz et al., 2007). Regardless of presenting complaint, medication list of every geriatric patients should be reviewed, and emergency physicians should be aware of medication-related problems (American College of Emergency Physicians, 2014). Multidisciplinary approach should be given to patients taking more than five medications, any high-risk medications, or presenting with signs or symptoms of adverse drug events.

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Quality of Care Older adults are difficult to manage due to complex clinical conditions, higher rates of adverse outcomes. For this reason, improvement quality of care is challenging in geriatric patients admitted to EDs. Although, many EDs developed ways to assess the care for older adults, there is no validated and internationally accepted tool currently (Sinha et al., 2011). It is reported screening and prevention (new prescriptions and potential interactions, fall prevention, influenza and pneumococcal vaccination, functional assessment), discharge planning, and integration of community services were correlated with better quality of geriatric ED care as perceived by ED physician and nursing leaders (Carpenter et al., 2011). Well organized EDs have a professional multidisciplinary team to coordinate geriatric services, conduct high-risk screening, and have some form of medication assessment before discharge. Post discharge care plans for high risk patients in the ED should be organized. Communication with community physicians and postdischarge telephone follow-up are suggested.

Long Term Care Patients in ED The EDs play a vital role in providing acute care and access to the hospital care systems in every population, a substantial demand on the emergency department belongs to patients living in residential aged care facilities. This group represents the most vulnerable, frail population, with chronic diseases, atypical symptoms, multiple comorbidities, cognitive and functional impairment, and social problems. However, most referrals to the ED are potentially inappropriate or avoidable. Common reasons for ED visits are falls and fall-related injuries, respiratory tract diseases, cardiovascular illnesses. Long term care facility residents were triaged in emergent and urgent categories compared to other ED presentations. These patients underwent more diagnostic tests and interventions. This may contribute to adverse clinical outcomes as well as increased costs of care and prolonged length of stay in the ED. On the other hand, some of these patients have extremely poor survival after discharge. Instead of transferring to ED, appropriate and earlier palliative care should be done for patients who are seriously ill and die soon. Therefore, advance care planning including hospice or palliative care, and usage of existing resources for patients transferred with nonurgent symptoms, and assessment by their primary physicians could prevent unnecessary transfers (Dwyer et al., 2014).

Transitions of Care After the provision of care by the emergency providers, a decision is made to discharge home or admit to the hospital. For those discharged, follow-up can be in multiple ways, ranging from return to the ED to management by specialized geriatric management professionals in outpatient clinics. Optimizing transitions of care from the emergency department back to the community is receiving more and more attention due to the high rates of readmission to ED. Favorable outcomes depend not only on the care received in the ED, but also on the successful transition of care from the ED to the patient’s home. ED-based geriatric care can be improved through interventions with linkages to community-based services (Hastings and Heflin, 2005). Integrated community-based multidisciplinary care programs can reduce ED use. Additionally, comprehensive geriatric assessment and multidisciplinary intervention can improve health outcomes of older people at risk (Caplan et al., 2004). Although there is limited communication between hospital physicians and primary care physicians, flow of information improved quality of care. Lack of communication has been shown to adversely affect post-discharge health care (Kripalani et al., 2007). Accumulating evidence reveals variety of interventions ranging from staff education programs to comprehensive geriatric assessment, care coordination teams using a risk screen with referral model, home based services such as health visitors, telephone follow-up may be effective to improve clinical outcomes and reduce recurrent visits to ED (Hastings and Heflin, 2005). In addition, community paramedicine programs have been developed to treat patients without transport to emergency department; to identify and refer patients during emergency responses, to identify frequent users of prehospital services and emergency care to prevent unnecessary use (Shah et al., 2010). Further researches are needed to determine which processes of care for elders are advantageous in terms of utilization of resources and quality of care.

Palliative Care and End of Life Care The number of patients who live final stages of their life under the care of an emergency physician, are continually growing as the aging population increases. Therefore, appropriate end-of-life care in older adults is an important issue for geriatric ED care program. Palliative care is an interdisciplinary care (medicine, nursing, social work, chaplaincy, and other specialties when appropriate) that focuses on improving quality of life for persons of any age who are living with any serious illness and for their families. Palliative interventions enhance quality of life, reduce length of stay and health care expenditures. Core components of palliative care include the assessment and treatment of physical and psychological symptoms, and support for spiritual distress, expert communication to establish goals of care and assist with complex medical decision making, and coordination of care (NCP Guidelines, 2013). Researches are concluded that care of ill or dying patients is far from optimal, and when confronted with lifethreatening illness, the patient and family would be included in discussions, realistic estimates of outcome would be evaluated together, pain would be treated, and dying would not be prolonged (Anon., 1995). Caring for dying patients in ED is a challenging

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situation. First of all, the privacy of the patients and his relatives should be protected, and there is no place for monitors in the care of the actively dying patient. Dyspnea, anxiety and pain should be relieved. Patient’s current condition and prognosis should be discussed to the patient and their family. Decisions need to be made according to patient preferences. In case of impaired cognition, proxy decision maker could help decision making (American College of Surgeons, n.d.).

Conclusion The number of patients in need of emergency services is increasing. Due to the multimorbidity, atypical presentations, and physical, psychological, social complex states of older adults, the model of emergency to older patients should be designed for special necessities of this age group. The specialized multidisciplinary team of care providers focused on the dynamics of the geriatric population can optimize ED visits, effectively coordinate care less costly, and organize resources for high-risk patients to prevent readmissions.

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Marco, C.A., Schoenfeld, C.N., Hansen, K.N., Hexter, D.A., Stearns, D.A., Kelen, G.D., 1995. Fever in geriatric emergency patients: Clinical features associated with serious illness. Annals of Emergency Medicine 26 (1), 18–24. McCusker, J., Bellavance, F., Cardin, S., Trepanier, S., Verdon, J., Ardman, O., 1999. Detection of older people at increased risk of adverse health outcomes after an emergency visit: The ISAR screening tool. Journal of the American Geriatrics Society 47 (10), 1229–1237. Monette, J., Galbaud du Fort, G., Fung, S.H., Massoud, F., Moride, Y., Arsenault, L., et al., 2001. Evaluation of the confusion assessment method (CAM) as a screening tool for delirium in the emergency room. General Hospital Psychiatry 23 (1), 20–25. NCP Guidelines (2013) Clinical practice guidelines for quality palliative care. 3rd ed. Pittsburgh: National Consensus Project for Quality Palliative Care; https://www. nationalcoalitionhpc.org/ncp-guidelines-2013/ Oliver, D., Healy, F., 2009. Falls risk prediction tools for hospital inpatients: Do they work? Nursing Times 105 (7), 18–21. Panel on Prevention of Falls in Older Persons, American Geriatrics Society and British Geriatrics Society, 2011. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons. Journal of the American Geriatrics Society 59 (1), 148–157. Profile of Older Americans (2017) Administration on Aging website. https://www.acl.gov/sites/default/files/Aging%20and%20Disability%20in%20America/2017OlderAmericansProfile.pdf. Accessed October 2, 2018. Russell, M.A., Hill, K.D., Blackberry, I., Day, L.L., Dharmage, S.C., 2006. Falls risk and functional decline in older fallers discharged directly from emergency departments. The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences 61 (10), 1090–1095. Samaras, N., Chevalley, T., Samaras, D., Gold, G., 2010. Older patients in the emergency department: A review. Annals of Emergency Medicine 56 (3), 261–269. Sanders, A.B., 1999. Changing clinical practice in geriatric emergency medicine. Academic Emergency Medicine: Official Journal of the Society for Academic Emergency Medicine 6 (12), 1189–1193. Sanders, A.B., Witzke, D.B., Jones, J.S., Richmond, K., Kidd, P., 1996. Principles of care and application of the geriatric emergency care model. In: Sanders, A.B. (Ed.), Emergency care of the elder person. Beverly-Cracom Publications, St. Louis, MO, pp. 59–93. Shah, M.N., Bazarian, J.J., Lerner, E.B., Fairbanks, R.J., Barker, W.H., Auinger, P., et al., 2007. The epidemiology of emergency medical services use by older adults: An analysis of the National Hospital Ambulatory Medical Care Survey. Academic Emergency Medicine: Official Journal of the Society for Academic Emergency Medicine 14 (5), 441–447. Shah, M.N., Caprio, T.V., Swanson, P., Rajasekaran, K., Ellison, J.H., Smith, K., et al., 2010. A novel emergency medical services-based program to identify and assist older adults in a rural community. Journal of the American Geriatrics Society 58 (11), 2205–2211. Singal, B.M., Hedges, J.R., Rousseau, E.W., Sanders, A.B., Berstein, E., McNamara, R.M., et al., 1992. Geriatric patient emergency visits, part I: Comparison of visits by geriatric and younger patients. Annals of Emergency Medicine 21 (7), 802–807. Sinha, S.K., Bessman, E.S., Flomenbaum, N., Leff, B., 2011. A systematic review and qualitative analysis to inform the development of a new emergency department-based geriatric case management model. Annals of Emergency Medicine 57 (6), 672–682. Staudenmayer, K.L., Hsia, R.Y., Mann, N.C., Spain, D.A., Newgard, C.D., 2013. Triage of elderly trauma patients: A population-based perspective. Journal of the American College of Surgeons 217 (4), 569–576. Terrell, K.M., Hustey, F.M., Hwang, U., Gerson, L.W., Wenger, N.S., Miller, D.K., 2009. Quality indicators for geriatric emergency care. Academic Emergency Medicine: Official Journal of the Society for Academic Emergency Medicine 16 (5), 441–449. The American College of Emergency Physicians, The American Geriatrics Society, Emergency Nurses Association, the Society for Academic Emergency Medicine, 2014. Geriatric emergency department guidelines. Annals of Emergency Medicine 63 (5), e7–25. The American Geriatrics Society 2015 Beers Criteria Update Expert Panel, 2015. American Geriatrics Society 2015 updated beers criteria for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society 63 (11), 2227–2246. The Senior Friendly Care Framework (2017) Available at: https://www.rgptoronto.ca/wp-content/uploads/2017/12/sfCare_Framework.pdf. Accessed October 3, 2018 Thiemann, D.R., Coresh, J., Schulman, S.P., Gerstenblith, G., Oetgen, W.J., Powe, N.R., 2000. Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years. Circulation 101 (19), 2239–2246. Wilber, S.T., Lofgren, S.D., Mager, T.G., Blanda, M., Gerson, L.W., 2005. An evaluation of two screening tools for cognitive impairment in older emergency department patients. Academic Emergency Medicine: Official Journal of the Society for Academic Emergency Medicine 12 (7), 612–616.

Further Reading Adams, J.G., Gerson, L.W., 2003. A new model for emergency care of geriatric patients. Academic Emergency Medicine: Official Journal of the Society for Academic Emergency Medicine 10 (3), 271–274. Agarwal, G., Angeles, R., Pirrie, M., Marzanek, F., McLeod, B., Parascandalo, J., et al., 2017. Effectiveness of a community paramedic-led health assessment and education initiative in a seniors’ residence building: The Community Health Assessment Program through Emergency Medical Services (CHAP-EMS). BMC Emergency Medicine 17 (1), 8. Bayoumi, I., Dolovich, L., Hutchison, B., Holbrook, A., 2014. Medication-related emergency department visits and hospitalizations among older adults. Canadian Family Physician Medecin de famille Canadien 60 (4), e217–e222. Carpenter, C.R., Shelton, E., Fowler, S., Suffoletto, B., Platts-Mills, T.F., Rothman, R.E., et al., 2015. Risk factors and screening instruments to predict adverse outcomes for undifferentiated older emergency department patients: A systematic review and meta-analysis. Academic Emergency Medicine: Official Journal of the Society for Academic Emergency Medicine, vol. 22 (1), 1–21. Caterino, J.M., Karaman, R., Arora, V., Martin, J.L., Hiestand, B.C., 2009. Comparison of balance assessment modalities in emergency department elders: A pilot cross-sectional observational study. BMC Emergency Medicine 9, 19. Chen, Y.C., Fan, J.S., Chen, M.H., Hsu, T.F., Huang, H.H., Cheng, K.W., et al., 2014. Risk factors associated with adverse drug events among older adults in emergency department. European Journal of Internal Medicine 25 (1), 49–55. Kale, M.S., Ornstein, K.A., Smith, C.B., Kelley, A.S., 2016. End-of-life discussions with older adults. Journal of the American Geriatrics Society 64 (10), 1962–1967. Lee, J.S., Schwindt, G., Langevin, M., Moghabghab, R., Alibhai, S.M., Kiss, A., et al., 2008. Validation of the triage risk stratification tool to identify older persons at risk for hospital admission and returning to the emergency department. Journal of the American Geriatrics Society 56 (11), 2112–2117. Mason, S., Knowles, E., Colwell, B., Dixon, S., Wardrope, J., Gorringe, R., et al., 2007. Effectiveness of paramedic practitioners in attending 999 calls from elderly people in the community: Cluster randomised controlled trial. British Medical Journal (Clinical Research Ed.) 335 (7626), 919. McCusker, J., Cardin, S., Bellavance, F., Belzile, E., 2000. Return to the emergency department among elders: Patterns and predictors. Academic EMErgency Medicine: Official Journal of the Society for Academic Emergency Medicine 7 (3), 249–259. Mion, L.C., Palmer, R.M., Meldon, S.W., Bass, D.M., Singer, M.E., Payne, S.M., et al., 2003. Case finding and referral model for emergency department elders: A randomized clinical trial. Annals of Emergency Medicine 41 (1), 57–68. Snooks, H.A., Kingston, M.R., Anthony, R.E., Russell, I.T., 2013. New models of emergency prehospital care that avoid unnecessary conveyance to emergency department: Translation of research evidence into practice? The Scientific World Journal 2013, 182102. Stiffler, K.A., Finley, A., Midha, S., Wilber, S.T., 2013. Frailty assessment in the emergency department. The Journal of Emergency Medicine 45 (2), 291–298.

Geroscience Alexander Vaiserman, Chebotariov Institute of Gerontology NAMS of Ukraine, Kyiv, Ukraine Oleh Lushchak, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine © 2020 Elsevier Inc. All rights reserved.

Introduction Geroscience Hypothesis Anti-Aging Medicine Anti-Aging Pharmacological Intervention The Longevity Dividend Debate on Recognizing Aging as a Treatable Medical Condition Conclusions Acknowledgement References

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Introduction Life expectancy has been substantially extended in most developed societies over the last decades. Such improvement in longevity is to a large extent, attributable to continuous economic growth and improvements to the living environment, particularly advances in education, medicine and public healthcare practice (Lunenfeld and Stratton, 2013). This is mainly due to a significant reduction of infectious diseases as a leading cause of death due to wide-scale implementation of vaccination, disinfectants and antibiotics (de Magalhães, 2014). In elderly, the continuous decline in mortality during last decades is most likely due to increased awareness of healthy lifestyle behaviors, such as proper exercise and diets, reduction in excessive alcohol consumption and tobacco smoking (Vijg and de Grey, 2014). It is suggested that, while maintaining current trends, then about 20% of the global population will be over 60 years old by 2050 (Kennedy and Pennypacker, 2014). Thereby, most of present-day developed societies undergo rapid population aging and dwindling workforce participation, leading to serious financial pressure on the social security systems. This is all the more true because aging is the main risk factor for most chronic pathologies. Thus, current trend to rising life expectancy is not accompanied by the same trend toward the health span extension (Hung et al., 2011). The incidence of aging-related disorders, such as type 2 diabetes (T2D), cardiovascular and neurodegenerative diseases, osteoporosis and cancer rises to a large extent with increasing life expectancy in all developed societies. It has been recently estimated that more than 30 million people aged over 80 will reside in the United States by 2050. About half of these subjects will supposedly suffer from Alzheimer’s disease and about 3 million will be diagnosed with Parkinson’s disease (Petsko, 2008). In the coming years, the expected rise in prevalence of aging-associated pathological conditions will apparently have a strong negative impact on economic growth in many countries, including increasing financial and psychological burden for families and large pressure on the healthcare programs and costs (Beard and Bloom, 2015). Therefore, the priority task now is a development of effective programs of disease prevention and health promotion that target all major causes of morbidity in elderly population. The implementation of such programs can allow the minimization of financial pressure linked to population aging by providing that aging population stays sufficiently healthy until very old age (Lopreite and Mauro, 2017). In recent years, a considerable rise in the interest in biogerontological research is observed among both medical professionals and the general public, related to the world-wide demographic trend to increased proportion of older people in populations of developed countries (Le Bourg, 2013). The investigation aimed to promote life expectancy understandably raises doubt not only among the general public, but also among government regulators and policy makers. This concern is related to the growth of the older population and, as a consequence, to the rising prevalence of chronic pathologic conditions associated with aging. Studies in animal models have, however, demonstrated that artificial life extension is usually accompanied by delayed or reduced morbidity including cardiovascular disease, neurodegeneration and cancer (Fontana et al., 2010). For instance, calorie restriction (the most effective life-extending intervention by now), has been repeatedly confirmed to be able not only extend the life span, but also slow down the rate of age-related functional declines and delay the onset of chronic diseases in various animal models (Balasubramanian et al., 2017). There is also increasing epidemiological evidence which is consistent with findings from experimental studies. For example, in centenarian studies, it has been repeatedly reported that long-lived persons have not only exceptional life span but also usually remain free from chronic pathologies and disabilities to a very old age (Willcox et al., 2008).

Geroscience Hypothesis Over the past few decades, both basic and clinical research efforts in gerontology were focused on the compression of morbidity. These efforts are aimed at limiting morbidity to a short period near the end of life. If implemented, this would allow to reduce the burden of

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illness and disabilities owing to the delay in the age at onset of the most common age-associated pathological conditions (Seals et al., 2016). In recent years, a new field in biogerontological research termed “Geroscience” began to develop. This is interdisciplinary field of research aimed to distinguish the mechanistic links between aging and age-related disorders and focused primarily on health span extension (Sierra and Kohanski, 2017; Kennedy et al., 2014; Burch et al., 2014; Sierra, 2016). According to a “Geroscience hypothesis”, aging has to be manipulated in such a way that will allow delay the onset of most aging-associated chronic diseases in parallel, since all these pathological conditions share the same main underlying risk factor, i.e., age (Balasubramanian et al., 2017; Sierra and Kohanski, 2017). Extension of health span is the main focus of research activity aimed to achieve the “optimal longevity”, a condition defined as “living long, but with good health and quality of life” (Seals et al., 2016) including improved functioning, productivity and independence. Studies attempted to improve health span are presently focused on slowing the biological processes underlying aging such as cellular senescence, impaired proteostasis and stem cell function and maintenance, dysfunctions of mitochondria, deregulated sensing of cell energy status and growth pathways, oxidative and inflammatory stress and age-related decrease in stress resistance (López-Otín et al., 2013a). These processes affect each other to maintain cellular signaling pathways and to support homeostasis. The main compensatory mechanisms linking these processes became, however, exhausted after reaching a certain age and various aspects of aging are inevitably manifested, thereby enhancing the risk of various functional declines and progression of aging-related pathologies (Epel and Lithgow, 2014).

Anti-Aging Medicine The development of therapeutic options to combat various age-related functional declines and chronic illnesses is a primary goal of investigations in a rapidly developing research field which is commonly referred to as ‘anti-aging medicine’. This field of research first emerged two decades ago, is an intensively debated topic now (Kirkland, 2013; Flatt et al., 2013). The main aim of anti-aging research is promoting both health span and life span by specific exercise and nutritional regimes, as well as by specific biomedical interventions aimed at slowing down or delaying the processes that cause aging (Lara et al., 2016; da Costa et al., 2016). Traditionally, aging has been viewed as ‘natural’ and, as a consequence, unpreventable phenomenon. However, currently many experts in the field have distanced from such view, arguing that the idea that aging is inevitable part of human nature is quite doubtful (Mitteldorf and Fahy, 2018). Indeed, most evolutionary theories of aging postulate that this process originated as a by-product of basic evolutionary processes and has no specific function (Lemaître et al., 2015). If aging is not an obligatory component of life, then it can be manipulated like any other unnatural or pathological process. The primary assumption underlying investigation in the field of antiaging medicine is that age-related senescence can be considered as a consequence of pathophysiological processes that can be delayed, prevented or even reversed (Anton et al., 2005). Therefore, biotechnological innovations supposed to be potentially able to postpone or slow down different processes involved in regulating aging are increasingly implemented now in anti-aging medicine (Vijg and de Grey, 2014). Present-day technological developments continue to accelerate the rate of available data from various -omics technologies such as genomics, proteomics, transcriptomics, lipidomics and metabolomics (Cevenini et al., 2010). Through the widespread application of such technologies, a deeper understanding was gained about the basic molecular and cellular mechanisms underlying aging (López-Otín et al., 2013b). Basing on this novel knowledge, innovative therapeutic solutions aimed to counteract age-related functional impairments and pathological conditions are being developed. Among them, the gene therapy- and stem cell-based approaches are supposed to be most promising in the long term. Currently, however, numerous concerns and doubts remain widespread among both medical professionals and general public regarding the long-term safety of such therapeutic approaches. This is to a large extent because of insufficient knowledge about potential side effects of such technologies. Therefore, the use of more traditional and generally accepted pharmacological interventions is regarded as a reasonable alternative in anti-aging medicine now (Vaiserman et al., 2016).

Anti-Aging Pharmacological Intervention Further development of supplements and clinically approved drugs specifically targeted at aging-associated pathological conditions is one of the most rapidly growing fields in biogerontology. If the 1990s were the era of “genes for aging” in biogerontological research, the second decade of the 21st century is characterized by an explosion of interest in identifying novel powerful pharmacological interventions aimed at extending human health span (Melov, 2016). Over the last two decades, there has been an exponential rise in research of agents with potential for application in geriatric practice (Verdaguer et al., 2012). The first step in the process of novel drug development is a search for druggable molecular targets (Zhou and Huang, 2015). Therefore, experimental designs based on using gain-of-function or loss-of-function mutant phenotypes may be very useful to determine gene targets largely involved in aging processes (López-Otín et al., 2013a). In last years, these approaches have been widely used to identify genetic pathways related to aging and life expectancy, and novel drug classes specifically targeting these pathways are already under intensive development and investigation (López-Otín et al., 2013a; Moskalev et al., 2014). Such research developments present certainly a challenging task taking into account the extraordinary complexity of aging-associated processes. Significant progress has been gained, however, in this research area during last years. Several new classes of nutraceuticals and chemically synthesized substances

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have been recognized as having anti-aging potential. Medications and supplements that are capable of mimicking effects of calorie restriction, e.g., resveratrol, rapamycin and metformin, are considered to be among the most promising candidates in this regard now (Roth and Ingram, 2016). In previous studies, these compounds were demonstrated to be able to significantly (up to 25%–30%) extend life expectancy in various experimental models including yeast, worms, fruit flies and rodents (Vaiserman et al., 2016). A novel drug class which holds great promise in anti-aging research comprises agents specifically targeted to enzymes contributed to epigenetic regulation of gene expression such as histone deacetylase inhibitors, e.g., sodium butyrate, trichostatin A and suberoylanilide hydroxamic acid (Vaiserman and Pasyukova, 2012). Great hopes are placed in modern biogerontological research on the development of innovative biotechnological applications. One example is the nanotechnology-based approach for delivery of drugs for treating Parkinson’s and Alzheimer’s diseases (Cunha et al., 2016). The main advantage of nanomaterial drug delivery systems is their small size and, as a consequence, capability to penetrate the blood-brain barrier. One promising approach in biogerontology is assessment of anti-aging potential of drugs approved by the US Food and Drug Administration (FDA) and other regulatory agencies for treating particular chronic pathological conditions. Most promising drug classes in this regard include beta-blockers, statins, anti-inflammatory medications, b-adrenergic receptor inhibitors, reninangiotensin-aldosterone system inhibitors, thiazolidinediones, and also metformin (Seals et al., 2016). The safety of all these medications was confirmed in many clinical trials and applications. Several lines of evidence also indicate that treatment with these drugs can improve health status and well-being in elderly persons suffering from chronic pathological conditions (Seals and Melov, 2014). One important problem is, however, that these medications are not used now for treating age-associated disorders in the absence of their clinical manifestation. There are, nonetheless, compelling reasons to expect that these pharmaceuticals might theoretically be redirected to treating or preventing other conditions or syndromes that are generally associated with aging. Another essential issue is that majority of agents with potential anti-aging effects are multifunctional and targeted at multiple molecular pathways related to aging. Moreover, limited evidence only is available to indicate overall health benefits of these substances by now. Data from observational studies and clinical trials reporting the health outcomes of long-term consumption of such supplements and medications are rather inconsistent. Furthermore, available evidence demonstrates that uncontrolled intake of several compounds regarded as potential anti-aging agents can be useless and occasionally even detrimental. Good example is longterm intake of antioxidants. The consumption of substances with free radical-scavenging activities was considered for decades by many scholars and medical professionals as rationale option to promote health and well-being, as well as to prevent agingassociated pathological conditions such as inflammatory disorders, atherosclerosis, cardiovascular disease and tumors (Whayne et al., 2016). Observational studies of people who regularly consume synthetic antioxidants, however, have demonstrated that such consumption can cause rather ambiguous consequences. This ambiguity is evident, for example, from meta-analyses of observational studies and randomized controlled trials conducted by Bjelakovic and co-authors. Based on results from these metaanalyses, the authors concluded that long-term consumption of chemically synthesized antioxidants including b-carotene, vitamin A and vitamin E, may be associated with adverse health outcomes, in particular, enhanced rates of both cancer and all-cause mortality, especially in well-nourished populations (Bjelakovic et al., 2013, 2014). Another example of potential risk from intake of substances with anti-aging properties, e.g., mimetics of calorie restriction, is that their regular consumption can trigger insulin resistance. Such unfavorable side effects have been revealed, for example, in individuals who are treated with rapamycin which is considered to be one of the most promising anti-aging drugs now (Blagosklonny, 2012a). Treatment with this medication, among other inhibitors of mechanistic Target of Rapamycin (mTOR), has been shown to be associated with a 13%–50% higher risk of hyperglycemia and T2D (Vergès and Cariou, 2015). Insulin resistance-inducing effects have been repeatedly observed in persons treated with commonly used cholesterol-lowering drugs such as statins. The 18%–99% enhanced risk for development of T2D was revealed in five population-based studies and 9%–12% enhanced risk was found in two meta-analyses of randomized clinical trials of statins (Laakso and Kuusisto, 2017). To overcome this problem, i.e., to prevent insulin resistance and T2D development, the combined therapy of rapamycin and metformin was suggested (Kezic et al., 2018). This combined therapy with metformin would allow block abnormalities in the glucose metabolism caused by treatment with rapamycin through inhibition of gluconeogenesis by downregulated expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (Mendelsohn and Larrick, 2012). Such combined approach is suggested to be a more balanced therapeutic strategy than using the rapamycin alone, especially in healthy individuals. This example is a good illustration for more common therapeutic strategy consisting in using “cocktails” of different drugs with anti-aging properties for simultaneous impact on multiple molecular pathways and physiological processes in an organism (Ingram and Roth, 2015; Blagosklonny, 2017).

The Longevity Dividend The idea that the health span extension through slowing aging is the most efficient way to combat aging-associated dysfunctions and disorders is referred to as the “longevity dividend” in modern literature (Olshansky, 2016; O’Neill, 2017). Indeed, if it would be possible to retard the aging process per se, then that might allow prevent or delay age-related diseases rather than combating them one by one, which is a conventional approach in the current disease-based paradigm. Furthermore, the human life expectancy can be only slightly influenced by preventing certain pathological conditions only. It is because other diseases will, owing to the aging-associated comorbidity, substantially abolish the positive effects related to the prevention of particular target disease. It is also clear that one aging-associated disease may accelerate the onset of others (Bellantuono, 2018), and geriatric patients with multimorbidity are usually being treated with many drugs at once, often with unfavorable effects from multidrug abuse (Maher et al.,

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2014). Therefore, the simultaneous delay of clinical manifestation of all age-related diseases by slowing down basic aging processes could be much more efficient than preventing the particular chronic pathological conditions (Seals et al., 2016; Blagosklonny, 2017). It may be also suggested that such approach can result not only to substantial health advantages but also to larger socioeconomic benefits than the conventional approach in contemporary public health practice targeted to preventing certain disorders only (Martin, 2017). The economic advantages from enhancing health span in consequence of slowing down aging per se are expected to be about 7 trillion dollars during the next five decades in the US (Goldman et al., 2013).

Debate on Recognizing Aging as a Treatable Medical Condition Until recently, potential anti-aging agents were not recognized by FDA and other regulatory agencies as appropriate candidate drugs for clinical trials, since they did not recognize aging as a treatable medical condition. However, such opinion is considered as rather contradictory by many experts now (Bulterijs et al., 2015; Zhavoronkov and Moskalev, 2016). Indeed, aging is well known to be typically accompanied by health problems generally associated with clinical conditions such as hypertension, atherosclerosis, heart attacks, strokes, osteoporosis, atrophy of brain tissues causing dementia and loss of muscle mass (sarcopenia). All these conditions are recognized as clinically treatable disorders and require specific therapeutic interventions. Therefore, contentious debates have emerged now in both policy making and academic circles on whether or not aging process may be recognized as a disease (Bulterijs et al., 2015; Zhavoronkov and Moskalev, 2016; Gladyshev and Gladyshev, 2016). Perhaps, as a consequence of this intense discussion, the FDA’s position on this topic has recently become much less rigorous. A good example of such paradigm shift is approval by FDA of clinical trial specifically targeted at determining the efficiency of metformin, which is a first-line medication for the treatment of T2D now (Palmer and Strippoli, 2018), in reducing the risk for different aging-related disorders including cognitive impairments, cardiovascular diseases and cancer, in non-diabetic older individuals. This pharmacological agent was selected for clinical trial since it was shown previously to influence various pathways involved in aging such as oxidative damage, cellular senescence, inflammation, autophagy and apoptosis (Kulkarni et al., 2018). Moreover, type 2 diabetic patients treated with metformin showed higher longevity compared to gender- and age-matched control subjects without diabetes (Bannister et al., 2014). In this double-blind multicenter clinical trial named Targeting Aging with Metformin (TAME), 3000 volunteers aged 70 to 80 years will be treated with metformin for 5–7 years to assess whether this therapeutic agent is efficient in delaying the onset or preventing age-related pathologies (Niedernhofer et al., 2017; Barzilai et al., 2016). Such decision of FDA might be indicative for changes on the antiaging pharmacology from regulations for cosmetic products to regulations for development of medications specifically targeted at treatment and/or prevention of chronic disorders associated with aging (Gems, 2011). It would provide innovative regulatory opportunities for clinical trials of drugs specifically designed to slow down the processes related to aging. Furthermore, recognizing aging as a disease might motivate research funding agencies and individual donors to relocate more resources to biogerontology and translational research in anti-aging medicine.

Conclusions By summarizing the considerations discussed above, we can conclude that targeting aging process per se could be a far more efficient therapeutic option to delay or prevent age-related pathological conditions than therapeutic approaches that are specific to particular clinical conditions. Since population aging becomes an increasingly global phenomenon largely influencing various social and economic aspects in different countries, the implementation of geroscience-based approaches in public health practice can provide a promising alternative to conventional disease-centered medical model (Longo et al., 2015). The development of novel anti-aging drugs may apparently provide one of the most promising drug screening platforms in modern pharmacological industry, because a potential target group can include each adult person (Vaiserman and Marotta, 2016; Vaiserman and Lushchak, 2017). In presentday pharmaceutical market, several supplements are already widely promoted as ‘anti-aging pills’. One good example for this is resveratrol, a polyphenol found in grapes, chocolate, and certain berries and roots, which was repeatedly shown to be able to extend health span in different animal models (Aschemann-Witzel and Grunert, 2015). The recent marketing research indicates that most respondents would like to buy medications and supplements targeted to prevent or delay age-related declines in physical and mental functioning and progression of aging-associated diseases (Olshansky, 2016). According to the results of sociological surveys, there is currently a great hope across the globe for artificial extension of human health span and life span due to modern biotechnological achievements. Interestingly, these data are significantly different from the results of previous studies. Apparently, this was due to the fact that most previous questionings were based on the fallacious presupposition that human life extension may be achieved through extension of the period of frailty, cognitive and functional impairments and disability at the end of life. As a consequence of this false assumption, it is not surprising that cautious attitude to artificial life extension was revealed in these surveys. When the extended health span was postulated in the questionnaire design, the positive attitude to the human life extension was observed. For instance, in a recent survey conducted by Donner et al. (Donner et al., 2015), 20% of respondents expressed a desire to live by the age of 85 years, while 42% of respondents wanted that their life span would not be limited. The implementation of geroscience-based approaches into health care practice could greatly affect various aspects of social and economic life in different countries. Indeed, health life extension would substantially enhance the ratio of healthy (and workable) to unhealthy (and unworkable) people in consequence of delaying the onset of age-related chronic pathologies. Several authors concluded that such change of

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this ratio can cause decrease of biological age (i.e., elder subjects will become biologically younger) and enhancement of the age of disability, thereby increasing the age of retirement and income without raising payroll taxes (Blagosklonny, 2012b; Goldman, 2015). However, due to the extreme complexity and ambiguity of economic, social and ethical processes involved, various aspects of applying the health span- and life span-promoting interventions should certainly be extensively debated prior to their implementation in practice of public health services.

Acknowledgement The author would like to thank Oksana Zabuga for the assistance in preparing the manuscript.

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Gluten Intolerance and Sensitivity in the Elderly Antonio Carroccio, DiBiMIS University of Palermo, Palermo, Italy; and Giovanni Paolo II Hospital, ASP Agrigento, Italy Francesco La Blasca and Pasquale Mansueto, DiBiMIS University of Palermo, Palermo, Italy © 2020 Elsevier Inc. All rights reserved.

Celiac Disease Definition of the Disease Celiac Disease and the Elderly: Introduction to the Topic Epidemiology: Incidence and Prevalence Clinical Presentation of Celiac Disease in the Elderly Dermatitis Herpetiformis Autoimmune Diseases Linked to Celiac Disease Bone Diseases and Fractures Pathogenesis of pathological bone alterations in celiac disease Osteopenia/osteoporosis and risk of fractures in celiac disease Recommendations for BMD testing in celiac patients Treatment of osteopenia/osteoporosis in celiac patients Complicated Celiac Disease Spectrum Refractory celiac disease Malignancy in Celiac Disease Neurological Complications Cardiovascular Risk in Celiac Disease Diagnosis of Celiac Disease in the Elderly Dietary Treatment of Celiac Disease in the Elderly Conclusions Nonceliac Wheat Sensitivity: A New Clinical Condition Introduction Why Is There NCGS Interest in the Elderly Conclusions References Further Reading

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Celiac Disease Definition of the Disease Celiac disease (CD) is a chronic, immune-mediated enteropathy in genetically predisposed individuals caused by the ingestion of gluten-containing cereals. CD is further characterized by variable clinical presentation, specific serum autoantibody response and a variable degree of damage in the small intestinal mucosa. HLA molecules DQ2 (90%–95%) and DQ8 (5%–10%) are associated with CD, and in the continued presence of gluten the disease is self-perpetuating. Regarding clinical presentation, CD patients may complain of not only gastrointestinal (GI) symptoms, but also extraintestinal symptoms, and most importantly they may often be asymptomatic (“silent” CD). In recent years, several reports have suggested a major shift in the clinical presentation of CD with extraintestinal symptoms being more prevalent than “classical” GI symptoms. CD is also associated with several autoimmune diseases, usually thyroiditis and diabetes mellitus type 1. Currently, the only effective treatment available is a strict life-long gluten-free diet (GFD), which improves symptoms, nutritional status, and serologic and histologic changes (Murray et al., 2018).

Celiac Disease and the Elderly: Introduction to the Topic CD has been traditionally recognized in children and young adults, although recently diagnosis in the elderly population has increased. Studies report that about 20%–30% of celiac patients were first diagnosed in patients over 60 years of age in several countries such as Canada, the United States, and Northern Europe (Bathrellou et al., 2018). It remains uncertain whether the number of undetected cases in the elderly is due to diagnostic delay, or the development of CD at an advanced age, or both. Despite growing knowledge regarding CD, very little is known about this condition in the elderly. This lack of awareness, along with the lower frequency of typical symptoms in older celiac patients compared to younger patients (see below), leads to significant delays (up to 15–20 years) in the diagnosis of CD in this population, which in turn increases the morbidity and mortality. For example, the mild changes in the bowel habits of older CD patients may be easily attributed to functional changes in the intestinal track due to diseases such as irritable bowel syndrome (IBS) and/or

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mood disorders (anxiety, depression, etc.), or even be considered part of the normal aging process. In addition, symptoms in an elderly celiac patient, such as anemia, may lead to extensive evaluation to rule out colon cancer before CD is even considered. Finally, several other diseases must be considered in an elderly patient who has symptoms of malabsorption. Small intestine bacterial overgrowth, small bowel ischemia, and exocrine pancreatic insufficiency (in association with chronic pancreatitis or pancreatic cancer), may be more common in the elderly, and can sometimes appear with chronic malabsorption. These disorders can either mimic CD in an older patient or occur in elderly celiac patients due to their advanced age. Autoimmune enteropathy, albeit an extremely rare condition, has also been described in older patients. Nongranulomatous enterocolitis or self-limited enteritis may be seen in elderly patients too. Therefore, a complete and accurate differential diagnosis is the basis of the process, leading to CD diagnosis in the elderly (Collin et al., 2018). However, a diagnosis of CD in the elderly does not always mean diagnostic delay. A study by Collin et al. first illustrated this point. They found that 28% of patients with potential CD eventually developed various degrees of villous atrophy on follow-up endoscopy performed between 1 and 7 years after the initial negative endoscopy (Collin et al., 1993). Similarly, Vilppula et al. found five new cases among patients who had previously been seronegative; two had minor abdominal symptoms and three were asymptomatic (Vilppula et al., 2009). Thus, a negative test does not preclude the subsequent development of CD. When onset of CD occurs in elderly patients, there may be either GI symptoms (i.e., diarrhea, steatorrhea, and bloating), or more frequently weight loss and selective malabsorption of nutrients, such as iron, calcium, and fat-soluble vitamins (A, D, E, and K). The presence of autoimmune disorders, known to be associated with CD, should prompt the suspicion of CD especially in the elderly: in effect, the incidence of these disorders in CD increases with age. In the elderly the risk of CD-related intestinal lymphoma or other neoplastic processes seems to be higher. In both children and adults the only treatment for CD is a gluten-free diet (GFD), even if the response to diet in the elderly appears to be slower than in young patients (Cappello et al., 2016).

Epidemiology: Incidence and Prevalence Recent reports suggest a trend toward increased incidence of CD, particularly among elderly people. In 1960, only 4% of newly diagnosed CD patients were over 60 years of age (Green and Wollaeger, 1960). But later studies showed that 19%–34% of new cases of CD are diagnosed in this age group. For example, a population-based study, carried out on the residents of Olmsted County (Minnesota, United States), highlighted that the incidence of CD in individuals age > 60 years, in an observation period of 56 years (1950–2006), increased from 0.0 in 1950–59 to 15.1 in 2000–2001 (Murray et al., 2003). Similar results were found by Vilppula et al. The study was based on prevalence figures in randomly selected subjects > 55 (52–74) years of age who had undergone a clinical examination and serologic screening for CD in 2002. A second screening in the same population was carried out in 2005. Within 3 years the prevalence of biopsy-proven CD increased from 2.13% to 2.34%, and that of CD from 2.45% to 2.70%, including seropositive subjects for antitissue transglutaminase antibodies (tTGAs). The incidence of CD in 2002–05 was 0.23%, an annual incidence of 0.08% in this population (Vippula et al., 2009). Another survey of 2440 celiac patients in the United States reported that the proportion of CD patients diagnosed in the elderly is similar to that of patients diagnosed before 18 years of age (16% vs. 15%, respectively) (Patel et al., 2005). The estimated prevalence of CD is now about 1% in the Western world, and recent epidemiological data showed that CD is also a common disease in developing countries (Middle East, South Asia, Africa, and South America), with a prevalence similar to that in Western countries (Singh et al., 2018). Regards the elderly, a population-based study of individuals aged 45–76 years, showed that the prevalence of positive CD-related autoantibodies was 1.2% among unrecognized cases (Fasano et al., 2003). More recently, a Finnish study found a higher prevalence (2.13%) of histologically proven CD in the elderly (52–74 years) (Vippula et al., 2008). Tortora et al., retrospectively analyzed the prevalence of CD in an elderly population from 1970 to 2015, dividing patients into three age-groups (group A: 18–34 years; group B: 35–64 years; group C: > 65 years), and compared them regarding baseline anthropometric and serologic variables, clinical features at diagnosis, diagnostic mode, associated autoimmune diseases, and CD-related neoplastic complications. The authors reported 2812 CD diagnoses in adults, 2.5% of them > 65 years at diagnosis. Elderly CD patients had a higher risk of being diagnosed with malabsorption symptoms than younger patients, but without increased risk of autoimmune and neoplastic complications (Tortora et al., 2016). Similar to other autoimmune disorders, CD occurs more frequently in women compared with men, with a female to male ratio of 2:1. In contrast, CD is much more often diagnosed in elderly men, compared with elderly women, in whom the incidence increases until the age of 65 years and then starts to decline, while it continues to rise in men. Women are more symptomatic than men, so this may lead to earlier diagnosis and men may delay contacting healthcare professionals. In addition, women use health-care facilities more often than men, so they are more likely to be diagnosed with CD, and they are more likely to develop autoimmune disorders. Finally, an interplay between sex hormones and the gastrointestinal microbiota may also prevent men from developing CD (Murray et al., 2003).

Clinical Presentation of Celiac Disease in the Elderly In a proportion of older people the symptoms go back to childhood, but the diagnosis of CD was not made because they either did not present to health care workers or the diagnosis was missed only to be arrived at many years later. For unknown reasons, presentation of GI symptoms is less prominent in elderly celiac patients compared to younger patients. GI symptoms, when

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present, are mild, making the diagnosis difficult; diarrhea, abdominal pain, and weight loss are more commonly indicative of irritable bowel disease (IBS) than of CD in the elder patient. In contrast, constipation and obesity are more frequent in elderly patients than in younger patients. In this context, weight loss is unlikely to be associated with severe malabsorption in older individuals because prevalence of diarrhea is higher in younger patients than in older patients. But dyspepsia seems to be more prevalent in older individuals, which may contribute to weight loss given the high risk of malnutrition in sick older people. Some patients may not present with any intestinal symptoms at all (silent CD). In the aged population, anemia and deficiency of micronutrients may often represent the only symptoms. In particular, more than 60%–80% of elderly CD patients had anemia, due to iron deficiency, folic acid and vitamin B12 deficiency, and inflammation state, as demonstrated by elevated levels of serum ferritin and erythrocyte sedimentation rate. Lack of calcium and vitamin D are consequences of malnutrition, leading to osteopenia/osteoporosis (> 70% of patients), which contributes to the risk of fractures. Malnutrition can also be responsible for hypoalbuminemia, which can further lead to hypocalcemia, hypomagnesemia, ascites, and peripheral edema (Vivas et al., 2015; Kalkan et al., 2017).

Dermatitis Herpetiformis Dermatitis herpetiformis (DH) is considered to be a directly immune-mediated extraintestinal manifestation of CD (Reunala et al., 2018). In contrast to CD, the incidence of DH is decreasing. It was suggested that an early diagnosis and treatment of CD might lead to less DH. In contrast to CD, DH affects mostly men (male to female ratio of about 2:1), with an age of presentation ranging from 20 to 70 years (average age of presentation about 40 years of age) (Bolotin and Petronic-Rosic, 2011). The disease is characterized by pruritus and papulovesicular eruptions involving the surfaces of elbows, knees, buttocks, and scalp. Lesions can be limited to small areas or are diffused over the whole body, and can be present only intermittently, such that only excoriations (abrasive skin lesions) in characteristic areas might be present during a clinical examination. For this reason, clinicians should elicit any reports of chronic pruritus from patients with CD, and recommend dermatological evaluation in these patients (Collin et al., 2017). About 80% of DH patients show intestinal alterations consistent with CD in the endoscopic or histopathologic evaluation. However, only 20% of these patients initially have GI symptoms of CD. The diagnosis is performed by biopsy of the perilesional areas and the subsequent direct immunofluorescence of the sample, showing granular deposition of IgA in the dermal-epidermal junction and neutrophil infiltrates in the papillary dermis. In the exact region of a lesion or excoriated area, the pathological features of DH are disrupted and biopsy samples will only demonstrate nonspecific inflammatory changes, which is a major diagnostic issue. GFD is able to resolve the clinical picture, but slowly. Resolution of DH can take months or longer on GFD, and pharmacological therapy with dapsone or sulphapyridine is often necessary to rapidly improve symptoms. If ongoing symptoms prevent the termination of dapsone or sulphapyridine treatment, consistent with nonresponsive CD, the patient should be evaluated for ongoing gluten exposure (Antiga and Caproni, 2015). In general, the clinical course of DH does not differ between young and elderly patients. B-cell lymphoma in DH may more likely develop than in patients with CD, who typically develop enteropathy-associated T-cell lymphoma. A lower mortality rate in DH is an interesting feature (Viljama et al., 2006).

Autoimmune Diseases Linked to Celiac Disease Some investigators have reported that the risk of developing an autoimmune disease in patients with CD is directly related to the age at diagnosis, because of the duration of gluten exposure; while others believe that the duration of gluten exposure does not represent an important predictor of autoimmunity. However, the protective role of the GFD has been highlighted in some studies, where patients who strictly adhered to a GFD were found to acquire fewer autoimmune diseases than patients not compliant with the strict dietetic regimen (Diamanti et al., 2016). Hashimoto’s thyroiditis and Graves’ disease are the most frequent immune-mediated thyroid disorders, affecting elder celiac patients (up to 15%), especially hypothyroidism. In contrast, Type 1 diabetes has a lower prevalence (3%) (Kahaly et al., 2018). Autoimmune liver disease, such as autoimmune hepatitis, biliary cirrhosis, and sclerosing cholangitis, can also affect celiac patients; they do not benefit from GFD, but from immunosuppressive therapy. So-called “celiac” hepatitis is commonly associated with active CD (20% of cases), but in clinical practice it often remains unrecognized or is attributed to other causes, such as fatty liver disease. Although these abnormalities are generally subclinical, CD-related liver injury can progress to cirrhosis and liver failure. In epidemiological data, patients with CD have a twofold to sixfold increased risk of future liver disease, and an eightfold increased risk of death from liver cirrhosis. For these reasons clinical guidelines recommend an initial screening for abnormal liver function in newly diagnosed patients with CD, and routine liver function tests as part of CD follow-up. However, the pathogenesis of CD-related liver injury is unclear. It is unknown whether hepatitis originates from cross-reacting autoantibodies (as in DH), or is initiated by a transfer of cytokines and other inflammatory mediators from the small bowel through the portal vein into the liver. However, about 75% of CD patients with elevated liver enzymes respond well to gluten withdrawal (Marciano et al., 2016). Other autoimmune disorders related to CD in the elderly are primary hyperparathyroidism, Addison’s disease, rheumatic and connective tissue diseases (i.e., Sjögren’s syndrome, antiphospholipid syndrome, systemic lupus erythematosus, dermatomyositis, and juvenile idiopathic arthritis), and cardiological illnesses (i.e., autoimmune myocarditis, and idiopathic dilated cardiomyopathy, see below) (Lauret and Rodrigo, 2013).

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Bone Diseases and Fractures Pathogenesis of pathological bone alterations in celiac disease The etiology of pathological bone alterations in CD is likely to be multifactorial: (1) malabsorption of calcium, also a result of steatorrhoea, alterations in calcium-transport mechanisms (due to anatomical epithelial damage), and lack of vitamin D (i.e., reduced levels of vitamin D-dependent calcium-binding proteins), causing an increase in PTH, that stimulates osteoclast-mediated bone resorption. While serum calcium levels might increase with this compensatory effect, osteoclast stimulation leads to an alteration in bone microstructure; (2) decreased absorption of vitamin D. Dietary vitamin D, absorbed as a fat-soluble vitamin, along with dietary fat, and incorporated into chylomicrons, is secreted with bile and reabsorbed in the intestine. Steatorrhoea and intestinal mucosal lesion may impair the reabsorption of 25(OH)D undergoing enterohepatic circulation, thereby contributing to the development of hypovitaminosis D, especially during acute exacerbations of CD; vitamin D deficiency occurs in 64% of men and 71% of women with CD; (3) increased bone turnover, due to hypocalcemia and vitamin D insufficiency, which are associated with increased levels of serum PTH, which accelerates bone turnover, bone loss, and increases fracture risk; (4) high pro-inflammatory (TNF-alpha, IFN-gamma, IL-1, and IL-6) and low antiinflammatory (IL-18, and IL-12) cytokine levels. Osteotropic cytokines are involved in bone remodeling because they regulate the differentiation and activation of osteoblasts and osteoclasts. In inflammatory diseases, including CD, the chronic release of pro-inflammatory cytokines is well-known; (5) OPG (osteoprotegerin)/RANKL (receptor activator of nuclear factor-kB ligand, which stimulates osteoclast activity) ratio is significantly lower in individuals with CD, due to decreased secretion of osteoprotegerin, and positively correlate with low bone mineral density (BMD). Potential autoantibodies could also block the inhibitory effect of OPG on RANKL, but this is controversial; (6) sex hormone alterations. CD has been associated with alterations in sex hormones in women due to periods of amenorrhea or early menopause, as well as in men due to a reversible androgen resistance. These alterations might contribute to osteoporosis; (7) malnutrition. Diet plays an important role in proper bone mineralization. Generally, a diet based on gluten-free products is low in nutrients: minerals including calcium, and vitamins. The calcium supply in the diet of patients with CD is reduced even more due to a decreased intake of milk and dairy products in an effort to avoid lactose. Secondary lactose intolerance, resulting from decreased lactase production by the damaged villi, is common in patients with CD. Additionally, naturally gluten-free products are often low in calcium, iron, zinc, magnesium, vitamins (B group vitamins and vitamin D) and fiber. Very few gluten-free products are enriched with calcium as their wheat containing counterparts; however, it is possible to obtain good-quality calcium-enriched bread of pleasant sensory characteristics and high-calcium content, which according to the World Health Organization could be considered an excellent source of calcium (Di Stefano et al., 2013).

Osteopenia/osteoporosis and risk of fractures in celiac disease Reduction in bone mass is the most common metabolic bone disorder in CD. The prevalence of osteopenia or osteoporosis measured by dual-energy x-ray absorptiometry (DEXA) among patients with CD is reported to be as high as 38%–72% at diagnosis, and decreases by 50% during follow-up in adult patients after adherence to a strict GFD. The risk of low BMD among adults with newly diagnosed CD is higher with increased age, lower body mass index, and more years after menopause. Furthermore, low BMD is more common in classical and untreated CD but can be present in asymptomatic individuals with CD. Conversely, a fourfold increase in the prevalence of CD has been found in patients with osteoporosis. Low BMD likely leads to increased risk of fractures. Studies evaluating the risk of fracture in patients with CD are heterogeneous in design and controversial in results. A meta-analysis confirmed an almost twofold increase in risk of fractures (both axial and peripheral) in patients with CD. Some studies suggest that the risk of fractures is more pronounced in patients with CD who have gastrointestinal symptoms (chronic diarrhea or malabsorption), compared with those diagnosed because of CD-associated conditions and with minimal symptoms. In addition, CD has been linked to an increased risk of fractures before and after diagnosis, probably due to poor compliance to GFD (Duerksen et al., 2018).

Recommendations for BMD testing in celiac patients It seems reasonable to perform bone DEXA on adult CD patients in high-risk situations: postmenopausal women, men > 55 years, those with known osteopenia/osteoporosis before CD diagnosis, previous osteoporotic fracture, weight loss > 10%, and low body weight. Further studies are required to identify the efficacy and cost-effectiveness of performing DEXA on all adult CD patients at diagnosis, and to identify the follow-up frequency of performing such analysis. Testing of BMD should be performed after 1 year of treatment before deciding on further management. If the results of BMD testing are normal at diagnosis, follow-up BMD testing might be considered 2 to 3 years after starting a GFD (Rios et al., 2013).

Treatment of osteopenia/osteoporosis in celiac patients Gluten-free diet GFD is the most important approach offering protection. A strict and lifelong GFD can help recover normal bone density when a diagnosis of CD is made in children and adolescents; however, there is no evidence that an optimal peak bone mass level can be achieved or that it can be maintained for many years, as happens in healthy individuals. An early start of treatment for pediatric

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patients with CD ensures significantly higher bone metabolism rates because the treatment reverses the inflammatory process and prevents impairment of bone mass acquisition during the most important period for its acquisition (Jerich et al., 2017). In the case of adult and elderly CD patients diagnosed with bones disease, a GFD is still considered the most rational treatment approach. Nevertheless, a GFD rarely normalizes BMD in these patients (Casella et al., 2012). A recent study indicated that, despite longterm strict adherence to GFD, 74% of patients displayed low BMD; among these, 24% showed osteoporosis and 76% osteopenia (Larussa et al., 2012). Therefore, nutritional supplementation should be considered for patients with CD. Nutritional supplementation Some patients with CD may not be able to meet the recommended daily intake level for calcium and vitamin D through GFD alone, and supplements may be indicated. Multiple forms of calcium supplements are available; medical conditions, such as lactose intolerance, impaired gastric acid secretion, and high-risk for kidney stone formation, should be taken into consideration before selection of a calcium supplement. Currently, the dominant anions in the calcium supplement market worldwide are citrate and carbonate. Calcium citrate is better absorbed than calcium carbonate, causing a greater rise in serum calcium and a greater fall in serum PTH. Moreover, calcium citrate is absorbed regardless of gastric acidity; thus, individuals producing less gastric acids or taking drugs that lower acidity in the stomach, like proton pump inhibitors, H2 blockers, and antacids, like many older patients, may best utilize this salt form (Southerlan and Valentine, 2001). Other treatment In some special situations, such as severe osteoporosis, it might be useful to begin treatment with hormone replacement therapy (postmenopausal women), or bisphosphonates; however, there are no systematic data on the efficacy of bisphosphonates or other drugs (i.e., teriparatide) commonly used for osteoporosis in patients with CD (Kumar et al., 2013; Mana et al., 2017). Additionally, a well-balanced diet and consumption of dairy products or alternatively low-lactose or lactose-free products should be encouraged; education on the importance of lifestyle changes, such as regular exercise, smoking cessation, and limiting alcohol intake should be provided; and a dietitian must be part of the health care team to monitor the patient’s nutritional status and compliance of a balanced diet (Southerlan and Valentine, 2001).

Complicated Celiac Disease Spectrum Refractory CD (RCD), Ulcerative JejunoIleitis (UJI), and Enteropathy-Associated T cell Lymphoma (EATL) represent a biological continuum and are estimated to affect only a few cases in adult CD. However, even though rare, complications of CD can occur even many years after the diagnosis of CD and have a high mortality rate. The risk of complications in patients with CD is linked to a series of factors, such as age at diagnosis of CD, the diagnostic delay of CD, the strictness of the GFD, the clinical form of CD and the homozygosity for DQ2 (Biagi et al., 2014a, b).

Refractory celiac disease Refractory CD (RCD) has been defined as a significant malabsorption, associated with progressive weight loss and significant deficiencies of nutrients and electrolytes, in a CD patient with severe enteropathy who has had a lack of initial response to a GFD or recurrence of symptoms despite strict adherence to the GFD. This complication develops in about 5% of cases (Malamu and Cellier, 2015; Rishi et al., 2016). However, the most common cause of unresponsiveness in CD is gluten contamination of the diet. Even minute amounts of gluten used in pills, capsules, envelope adhesive, modified food starch, preservatives, and stabilizers can prevent healing of the intestine resulting in the persistence of symptoms (Leonard et al., 2017). Other conditions that should be ruled out before the diagnosis of RCD, especially in older patients, include microscopic colitis, small bacterial overgrowth, lactose intolerance, IBS and pancreatic insufficiency. There are also rare enteropathies which can mimic CD pathology and may cause apparent failure of response to treatment. These include self-limited enteritis, autoimmune enteropathy, collagenous sprue and even NSAID injury (Nijeboer et al., 2013). RCD can be classified into 2 types: polyclonal, or RCD I, and monoclonal, with aberrant phenotype of lymphocytes, or RCD II. Duodenal histology show partial villous atrophy and increased number of intraepithelial lymphocytes, with normal immunophenotype, characterized by CD3 and CD8 expression, in type RCD I, villous atrophy and abnormal intraepithelial lymphocytes, characterized by expression of CD3, but mostly CD8-, in type RCD II. Overall survival is about 80% for RCD I, and about 45% for RCD II. Main causes of death are refractory state in RCD I, EATL in RCD II. Age > 65 years is considered a negative prognostic factor for survival (Rishi et al., 2016). Because of their frequent nutrient deficiencies, patients with RCD should be encouraged to take vitamin supplements and calcium. Although the benefit of GFD in RCD is unknown, its use is widely recommended. It has been suggested that nutritional support and GFD may be all that is necessary to maintain remission in selected patients with RCD1. Total parenteral nutrition may be required in approximately 28%–60% of patients. Use of prednisone, budesonide, or a combination of glucocorticoids and a corticosteroid-sparing agent, such as azathioprine, has shown promise in the treatment of RCD1, and often results in resolution of symptoms as well as mucosal healing. In contrast, patients with RCD2 do not respond that well, and although symptomatic relief may occur in a significant number (75%), mucosal remission is rarely achieved, and at the same time the progression to EATL is not prevented. In addition to corticosteroids, several other treatment options have been investigated (i.e., oral cyclosporine, alemtuzumab, an anti-CD52 monoclonal antibody, infliximab, and highdose chemotherapy followed by autologous stem cell transplant), and may be effective in some RCD patients (Woodward, 2016).

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Malignancy in Celiac Disease Occurrence of malignancy is higher in elder celiac patients, particularly in those age 60–80 years. Lymphomas and adenocarcinomas of the gastrointestinal track are more frequent in patients with CD, and even those with silent disease showed a higher mortality rate (Freeman, 2009). EATL have the strongest association with CD (4%), with multifocal and ulcerative lesions, and a high rate of bowel perforation, sometimes the initial presentation of disease (Ondrejka and Jagadeesh, 2016). Non-Hodgkin lymphomas (NHL) and gastrointestinal adenocarcinomas are also more common in celiac patients than expected (Elfström et al., 2011; Zullo et al., 2017). Patients with CD carry an increased risk of colon cancer. This has to be borne in mind in elderly celiac patients, because this cancer is very common, and its overall incidence is increasing in the older age groups. In those with CD who have or develop iron deficiency anemia, especially in later life, the possibility of concurrent colon cancer should always be considered. If iron deficiency anemia is not reversed by a GFD and supplements, the presence of colon cancer should be suspected (Dahlerup et al., 2015). Interestingly, the risk of breast, endometrial and ovarian cancer is reduced in celiac patients (Ludvigsson et al., 2012). GFD has a protective effect on risk of malignancy in celiac patients, and poor dietary compliance increases the risk of EATL (Silano et al., 2008). A previous study showed that the risk of NHL decreased in the United States in patients diagnosed from 1975 to 2004. The development and widespread application in the last two decades of serologic markers that have enabled more younger individuals with mild or atypical symptoms to be diagnosed and to start early treatment of CD can reasonably explain the declining risk of NHL (Gao et al., 2009).

Neurological Complications Neurological complications of CD are ataxia of nonalcoholic origin, peripheral neuropathy, brain atrophy, cognitive impairment, and memory disturbances, the treatment of which can be very problematic because equilibrium disorders increase the risk of falls, and thus, the risk of bone fractures, already high for the low BMD of these patients. Unfortunately, neurological conditions are often irreversible in spite of the introduction of a GFD. Mean onset of ataxia of nonalcoholic origin and peripheral neuropathy occurs at 55 years. However, it seems that overall elderly patients with CD are not at increased risk for dementia compared to the general population (Casella et al., 2016).

Cardiovascular Risk in Celiac Disease Most studies show an increased mortality rate in celiac patients, especially older patients, which has not always been attributed to the increased cancer risk in this age group (Corrao et al., 2001). Some studies have shown an increased risk of ischemic heart disease, and death resulting from ischemia or cardiovascular disease (CVD), but this point of view is still controversial. The idea that CD might modulate CVD risk was first raised by Whorwell et al., who found a 40% reduction in mortality owing to ischemic heart disease in people with diagnosed CD compared with the general population. This study proposed an apparent protective effect of CD as a result of malabsorption of dietary lipids (Whorwell et al., 1976). In a population-based study from the United Kingdom, the investigators reported lower rates of hypertension and hyperlipidemia in patients with CD than in the general population. However, in this study the reported prevalence of hypertension and hyperlipidemia in the control group was substantially higher than age-adjusted rates in populations of the United Kingdom, and the risk of stroke and coronary artery disease was similar in CD patients to that of the control population (West et al., 2004). Interestingly, according to a study conducted in the United States, type 2 diabetes mellitus and metabolic syndrome are less prevalent in adults with CD before and after gluten-free diet initiation, compared with the general population and matched controls, and the risk does not increase after CD diagnosis, despite a rise in body mass index (BMI). Therefore, the overall cardiovascular mortality risk does not seem to be elevated in CD (Kabbani et al., 2013). However, Tortora et al., evaluating consecutive patients with newly diagnosed CD for waist circumference, BMI, blood pressure, lipid profile (HDL cholesterol, triglycerides), levels of blood glucose and diagnosis of metabolic syndrome, demonstrated a high risk of metabolic syndrome 1 year after starting a gluten-free diet, suggesting that an in-depth nutritional assessment must be undertaken for all patients with CD (Tortora et al., 2015). Abdul Sultan et al. demonstrated that by 10 years after diagnosis, people with CD have no major excess risk of cancer, digestive disease or respiratory disease, or cardiovascular mortality compared with the general population. Those with CD had a slightly lower cumulative incidence of cardiovascular death following diagnosis. Patients with CD had a 0.15% excess risk of dying from non-Hodgkin’s lymphoma up to 10 years post diagnosis (Abdul Sultan et al., 2015). More frequent CVD related to CD are idiopathic dilated cardiomyopathy (5.7%), heart failure, arrhythmias (atrial fibrillation), and QT interval prolongation. Possible reasons for these associations might be malabsorption of nutrients (¼ low circulating concentrations of folate and/or high serum concentrations of homocysteine), low-grade chronic inflammation, antiangiogenic effect of tTGAs, and GFD not in healthy balance: fats, carbohydrates, and fiber. It could be reasonable to suspect CD in patients suffering from CVD, especially idiopathic dilated cardiomyopathy, given the evident favorable effect caused by a GFD on myocardial performance (Santoro et al., 2017; Ciaccio et al., 2017; Emilsson et al., 2012).

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Diagnosis of Celiac Disease in the Elderly As stated above, clinical diagnosis of CD in the elderly can be quite challenging, not only for family doctors but also for gastroenterologists. This may be due in part to the low index of suspicion for CD in the elderly, subtle clinical symptoms, and distraction by more threatening conditions, such as malignancies. However, in general elderly celiac patients are probably just as likely to have serologic and histologic abnormalities as younger patients, and the HLA association with CD also persists in this age group. Therefore, CD diagnosis in the elderly is based on the same guidelines as in young people. Diagnosis is linked to the presence of anti(deamidated) gliadin antibodies (AGAs, DGPs), endomysial antibodies (EMAs), or tTGAs. Moreover, the presence of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis, and the response (clinical and histological) to GFD are also used for diagnosis. However, we must consider the high incidence of false serologic test results for serum antibodies in older patients, even though available data all point to the accuracy of EMAs at all ages, including in the elderly. Thus, these data suggest that a negative EMA test result may be a way of excluding CD in an older patient in whom clinical features are suggestive. While one might hesitate to subject a very elderly patient with multiple comorbidities to intestinal biopsy as a primary test for CD, older patients are more likely to undergo endoscopy to exclude other causes of their symptoms and to have their first diagnosis made by duodenal biopsies rather than serology (Lau and Sanders, 2017). Titer of tTGAs and improvement of histologic lesions on GFD are inversely related to age. Presence of high antibody titers (10 times normal levels) appears in less than half of the adult cases, with more “seronegative” cases. Recent studies have shown that in more than 50% of adults, villous atrophy does not improve on GFD unless biopsy is performed after 2 years of an adequate diet (Wahab et al., 2002). In contrast, recovery of the mucosa occurs in the vast majority (95%) of children, in the first 2 years after the diagnosis (Sugai et al., 2006). The main cause of this lack of mucosal recovery in adults could be the continuous and inadvertent ingestion of small amounts of gluten. This cause is likely to be more frequent in adults, since the daily diets of children are more closely monitored (Vivas et al., 2015). Population-based screening for CD is not supported. Identification of CD in clinical practice is driven by testing symptomatic patients or by case finding. Case finding is defined as the practice of testing individuals who are at an increased risk for the disease, due primarily to the presence of conditions associated with CD (i.e., family history of CD, gluten-related symptoms, autoimmune diseases). Case finding has been reported to increase CD diagnosis by 32–43-fold in the primary care setting; however, there is increasing suspicion that case finding may not be effective, and may have poor diagnostic accuracy in identifying CD (Turner, 2018).

Dietary Treatment of Celiac Disease in the Elderly Casella et al., evaluating the adherence to the GFD, assessed according to interview, CD-related serology, and duodenal histology, demonstrated a capacity of older individuals to cope with a GFD as efficiently as younger individuals and to obtain the same serologic and histologic improvement, although older participants reported symptomatic relief less frequently than younger individuals. In no case was this symptom persistence attributable to RCD, and it was in most cases judged to be attributable to associated functional syndromes (Casella et al., 2012). A possible explanation for the lower symptomatic relief in older individuals is that a GFD is, in general, perceived as burdensome and is often associated with a perception of poor subjective health and depression. It is plausible that depressed mood may further reduce the perception of health in older individuals facing a major change in lifestyle (Vilppula et al., 2011). Despite the high rate of dietary compliance reported, management of CD in older patients has specific challenges. First, patients usually have a life-time of dietary habits that are hard to break. They may also have limited financial or social resources and limited mobility restricting their ability to travel to gluten-free suppliers. Elderly patients may be residing in assisted living facilities where it may be difficult to provide them with a GFD. Additional issues relate to impaired vision limiting their ability to read ingredient lists which are often minute in size. Therefore, community support is important and family members should be recruited and probably should participate in the patient’s dietary consultation. Direct communication between the dietitian and the director of food services at the patient’s institution, if institutionalized, are likely necessary to achieve a GFD (Borghini et al., 2016). In the very elderly or debilitated patient who has relatively minor symptoms, consideration of not treating the patient by GFD may have some rationale; however, it should be noted that patients can often have a dramatic improvement in chronic symptoms, even non-GI, after adherence to a GFD, and the opportunity for this recovery should not be ignored (Rashtak and Murray, 2009). Finally, the risk of overweight is present after commencing GFD, and weight maintenance counseling should be an integral part of celiac dietary education (Bascuñán et al., 2017).

Conclusions CD is a common disorder not only in the young but also in the elderly. Despite a paucity of symptoms (i.e., diarrhea and weight loss), CD has been increasingly recognized in the elderly. Other presentations in the elderly include iron deficiency anemia, autoimmune disorders, bone diseases, malignant intestinal disease, and idiopathic dilated cardiomyopathy. It may linger for many years before the diagnosis, causing subtle or quite troubling symptoms and it may present for the first time with serious fatal complications. A greater awareness of the incidence and clinical presentation of CD in the elderly is essential to prevent long delays in the diagnosis. Although for these patients the GFD offers effective clinical management, elderly patients sometimes do not adhere to the diet, particularly in view of making radical changes to the preexisting diet, as well as coping with the complications of longstanding malabsorption. Micronutrients, such as calcium and vitamins, should be part of a modified GFD for

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elderly patients. A comprehensive, multidisciplinary approach to management of CD should result in reduced morbidity in these patients. A management approach tailored to the particular challenges presented by elderly celiac patients is crucial to their success.

Nonceliac Wheat Sensitivity: A New Clinical Condition Introduction In the last decade we have seen an increasing interest in gluten-free foods, and consequently an increasing market. The boom of the gluten-free market has gone beyond the need for a GFD for CD. The industry has repeatedly championed this market, with retail sales in the USA going from $0.9 billion in the year 2006, to over $10 billion in the year 2015, and is projected to reach $24 billion by the year 2020 (Aziz, 2018). It is very probable that this trend is strongly supported by commercial messages, but after initial skepticism, the scientific community has begun to consider the possibility that a percentage of people who avoid gluten-containing foods and who report problems when they eat wheat products, suffer from a gluten-related disease, different from celiac disease or wheat allergy. In the year 2009, Elena Verdù and coll., in a seminal study, proposed a theory for investigating and understanding gastro-intestinal symptoms associated with gluten in functional bowel diseases and organic disease (Verdu et al., 2009). The Authors hypothesized that even in the absence of fully developed celiac disease, gluten can induce symptoms similar to functional bowel diseases. They suggested that gluten can cause symptoms in sensitive individuals, with a mechanism involving host genotype, diet, and intestinal microbiota; they hypothesized that this could be one of the most common pathogenic mechanisms for “functional” gastrointestinal conditions. The concept of “gluten-sensitivity” rather than CD, has challenged physicians and investigators over the years. Data published in 1980 and 2000 suggested the existence of a syndrome caused by the ingestion of gluten in a subset of patients who did not have CD or WA, even though it has been suggested that some of these patients might be affected by “potential CD” (Kaukinen et al., 2000; Cooper et al., 1980). In 2011 an international panel of experts participated in a consensus meeting and defined “nonceliac gluten sensitivity” (NCGS) as “a nonallergic and nonautoimmune condition in which the consumption of gluten can lead to symptoms similar to those seen in CD.” The consensus statement suggested that clinical symptoms can overlap with CD or WA, respond to a GFD, and worsen on gluten reintroduction, but patients must be characterized by negative CD antibodies (absence of antitransglutaminase, antiendomysial, or de-aminated gliadin peptide antibodies, with the exception, perhaps, of antigliadin antibodies) and normal duodenal histology. In summary, the hallmarks for NCGS diagnosis are clinical improvement on a GFD in the absence of CD specific serum antibodies and intestinal mucosal abnormalities (Sapone et al., 2012). NCGS is characterized by symptoms and signs that usually occur soon after gluten ingestion, improving or disappearing (within hours or a few days) with gluten withdrawal and relapsing following its reintroduction. Clinical presentation of GS is a combination of symptoms identical to those of “Irritable Bowel Syndrome” (IBS) (e.g., bloating, abdominal pain, bowel habit abnormalities), and systemic manifestations (e.g., foggy mind, headache, fatigue, depression, joint and muscle pain, leg or arm numbness, dermatitis, anemia) (Aziz and Sanders, 2012; Volta et al., 2012; Carroccio et al., 2012). Table 1 summarizes some of the symptoms reported by patients suffering from NCGS. From an “internist or gastroenterology point of view,” the most frequent possible association is seen between NCGS and IBS (Catassi et al., 2017); this is relevant as the prevalence of IBS has been estimated to be between 10% and 20% (Dalrymple and Table 1

List of symptoms reported in patients with Non-Celiac-Wheat-Sensitivity

Gastrointestinal symptoms

Neurological-psychiatric symptoms

Other symptoms

Abdominal pain Bloating Diarrhea Constipation Alternating bowel movements Nausea Vomiting Hematochezia Anal fissures

Foggy mind Tiredness Headache Depression Numbness in arms, legs, fingers Hyposthenia Loss of balance Disturbed sleep pattern Mood swings

Eczema Skin rash Joint pain Muscle pain Menstrual disorders Anemia Weight loss Weight increase Puffiness Interstitial cystitis Ingrown hairs Dyspareunia Recurrent (not microbial) vaginitis

Data from the literature and our own experience. Modified from Carroccio, A., Mansueto, P., D’Alcamo, A., Iacono, G., Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review. The American Journal of Gastroenterology 108 (2013): 1845–1852.

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Bullock, 2008; Lovell and Ford, 2012), and approximately 50% of patients with gastrointestinal complaints seen in primary care have IBS-type symptoms (Canavan et al., 2014). Furthermore, patients with IBS report impaired quality of life, and there is an associated economic and societal cost (Whitehead et al., 2002). On the other hand, it is noteworthy that the patients have always reported that food plays an important role in their IBS-type symptoms with estimates of up to 80% of patients having postprandial symptomology, and up to 40% reporting specific “food intolerance” (Böhn et al., 2013; McKenzie et al., 2016). In this context, there has been increasing interest in recent years in dietary interventions for functional gastrointestinal disorders, and the gluten-free diet has been demonstrated as an efficacious treatment, in patients with diarrhea due to IBS (Wahnschaffe et al., 2001, 2007; Vazquez-Roque et al., 2013; Azi et al., 2016). Due to the lack of diagnostic tests for NCGS, diagnosis is essentially made by exclusion (especially of CD and wheat allergy). This clinical condition is basically a self-reported disease and, as a consequence, there is wide variability in prevalence figures; however, three studies from Europe had similar findings, with self-reported NCGS prevalence slightly higher than 10% in the general population (Aziz et al., 2014; van Gil et al., 2016; Carroccio et al., 2017a). NCGS epidemiology, however, seems to be concordant in median age and sex: it has been reported that GS onset is at an age between 20 and 40 years and it is more prevalent in females than in males (male to female ratio ranging between 1:2.5 and 1:8) (Volta et al., 2012; Carroccio et al., 2012). To establish a gold standard for the NCGS diagnosis, a consensus meeting of experts recommended a double-blind placebo controlled (DBPC) method using 8 g of gluten (Catassi et al., 2013). However, this is difficult to undertake in daily clinical practice.

Why Is There NCGS Interest in the Elderly According to the above epidemiology data, elderly subjects are not included among the population at risk for NCGS. However, NCGS can be associated with a higher frequency of osteoporosis and autoimmune diseases, both conditions frequent in the elderly. In particular, a pilot study including only 75 NCGS patients demonstrated that 35 of them (46.6%) had osteopenia or osteoporosis (Carroccio et al., 2014). In this study, low Bone Mineral Density (BMD) was related to low body mass index (BMI) and multiple food sensitivity. Many patients suffering from NCGS, in our experience, suffer from multiple food hypersensitivity and exclude several foods from the diet; this can lead to a low daily intake of dietary calcium, as already demonstrated. Since the mean age of the patients included in this pilot study was 36 years, the consequence of an inadequate diet on BMD, until elderly, could be dramatic. And this is a possible scenario as NCGS seems to be a persistent condition (Carroccio et al., 2017b). Regarding the association between NCGS and autoimmune diseases, in a retrospective study involving more than 100 NCGS patients, these patients had an associated autoimmune disease in 29% of the cases (for comparison, it was 21% in patients with celiac disease), and both these groups had a higher frequency than control patients suffering from IBS (Carroccio et al., 2015). In detail, NCGS patients in that study had one or more of the following diseases: Hashimoto’s thyroiditis (29 cases), psoriasis (4 cases), type 1 diabetes (4 cases), mixed connective tissue disease (1 case), and ankylosing spondylitis (1 case).

Conclusions NCGS seems to be a very frequent condition in the general population. Although it commonly affects young or middle age subjects, its presence should also be considered in the elderly, and especially in patients with gastrointestinal symptoms (mainly IBS-like). An accurate diagnosis of NCGS can be difficult and cumbersome, but it can help elderly patients both in improving gastrointestinal symptoms, and in searching for and treating possible associated diseases.

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Wahnschaffe, U., Ullrich, R., Riecken, E.O., Schulzke, J.D., 2001. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology 121, 1329–1338. Wahnschaffe, U., Schulzke, J.D., Zeitz, M., Ullrich, R., 2007. Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Clinical Gastroenterology and Hepatology 5, 844–850. West, J., Logan, R.F., Card, T.R., Smith, C., Hubbard, R., 2004. Risk of vascular disease in adults with diagnosed coeliac disease: A population-based study. Alimentary Pharmacology & Therapeutics 20, 73–79. Whitehead, W.E., Palsson, O., Jone, K.R., 2002. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: What are the causes and implications? Gastroenterology 122, 1140–1156. Whorwell, P.J., Alderson, M.R., Foster, K.J., Wright, R., 1976. 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Further Reading Carroccio, A., Mansueto, P., D’Alcamo, A., Iacono, G., 2013. Non-celiac wheat sensitivity as an allergic condition: Personal experience and narrative review. The American Journal of Gastroenterology 108, 1845–1852.

Growth Hormone and Mammalian Aging Diana Van Heemst and Evie van der Spoel, Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands Andrzej Bartke, Southern Illinois University School of Medicine, Springfield, IL, United States © 2020 Elsevier Inc. All rights reserved.

Introduction Mice With Suppressed GH Signaling Are Long-Lived GH Influences Aging by Multiple Mechanisms Longevity Benefits of Reduced GH Signaling Are Associated With Various Trade-Offs Trade-Offs Between GH-Dependent Traits and Longevity Are Not Limited to Mutant Mice Living in Laboratory Conditions The Somatotropic Axis Is Involved in Developmental Programming of Aging and Longevity Effects of GH Deficiency and Resistance on Human Aging and Longevity Somatotropic Axis and Human Aging: Evidence From Epidemiological Studies Somatotropic Axis and Human Aging: Evidence From Genetic Studies Somatotropic Axis and Human Aging: Evidence From Extreme Longevity GH as Anti-Aging Therapy? References

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Glossary Congenital trait A trait which is inborn or inherited. Evolutionary fitness A measure of reproductive success which is equal to the average contribution to the gene pool of the next generation by individuals of a given genotype or phenotype under prevailing environmental conditions. Familial trait A trait which clusters in families. Growth hormone deficiency (GHD) A medical condition resulting from inadequate secretion of growth hormone (GH) from the anterior pituitary gland. Growth hormone resistance A medical condition resulting from inadequate GH receptor signaling due to GH receptor deficiency or postreceptor defects. Mechanistic target of rapamycin (mTOR) A target of the (originally anti-fungal) drug rapamycin, which arrests G1 to S cell phase progression in mammalian T-lymphocytes, thus suppressing the immune system. Somatotropic axis A hypothalamic–pituitary axis comprising the secretion of growth hormone (GH; somatotropin) from the somatotropes of the pituitary gland into the circulation to stimulate the production of insulin-like growth factor 1 (IGF-1; somatomedin-1) by the liver (and other tissues). Pleiotropic effects Two or more seemingly unrelated effects that result from the same determinant. Sporadic trait A trait that is acquired, occurring occasionally in single individuals.

Introduction The rate of aging and longevity are linked to growth, the underlying anabolic processes, and adult body size. Evidence for these links includes correlations among body size, metabolic rate, and lifespan, as well as the remarkably conserved role of insulin/insulin-like growth factors, and target of rapamycin signaling pathways in the control of aging and the mechanistic role of byproducts of oxidative metabolism in age-related changes in macromolecules. In mammals, growth hormone (GH), a protein hormone secreted by the anterior pituitary, is the key regulator of somatic growth and adult body size. In addition to its direct and insulin-like growth factor-1 (IGF-1)-mediated effects on growth, GH exerts pleiotropic effects on metabolism, body composition, and the function of different organ systems. Studies in mice with mutations affecting GH signaling led to the realization that GH also has a major role in the control of aging (details and references in the next section of this article). Apparently, the stimulatory actions of GH on growth, maturation, and metabolism involve significant costs in terms of stress resistance, maintenance, repair, rate of aging, and, ultimately, longevity. These unexpected costs of the processes of growth and development also apply to other mammalian species. However, the impact of GH signals on aging and lifespan in humans is much more subtle than in the laboratory populations of mice. In this article, we will briefly review the highlights of studies in mice with GH-related mutations and discuss mechanisms of GH actions on aging. We will also consider the relationship of results obtained in genetically altered laboratory mice to evolutionary

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Overview of consequences of genetic alterations in genes from the somatotropic axis on mouse longevity.

Genetic alteration

Main endocrine feature

Longevity

GHRH KO GHRHR mutation Pit-1 mutation Prop-1 mutation GHR KO whole body GHR KO liver GHR KO Skeletal muscle GHR KO Heart muscle GHR KO Adipose tissue Overexpression transgenic GH

Isolated GH-deficiency Isolated GH-deficiency (Little mice) Combined GH, TSH, prolactin-deficiency (Snell dwarf) Combined GH, TSH, prolactin-deficient (Ames dwarf) GH-resistance Selective GH-resistance Selective GH-resistance Selective GH-resistance Selective GH-resistance GH overproduction

[ [ [ [ [ z [ _ only [ _ only z Y

fitness under natural conditions and to life-course strategy tradeoffs. We will then review evidence that GH actions are involved in the control of human aging and longevity.

Mice With Suppressed GH Signaling Are Long-Lived Major extension of longevity was demonstrated in mice lacking GH or GH receptors as a result of spontaneous mutations or targeted gene disruption. This included animals lacking hypothalamic GH releasing hormone (GHRH), a key stimulator of GH biosynthesis and release (Alba and Salvatori, 2004; Sun et al., 2013), mice lacking functional receptors of GHRH (Godfrey et al., 1993; Flurkey et al., 2001) or GH (Zhou et al., 1997; Coschigano et al., 2003), and mice with mutations blocking differentiation of GH-producing cells during fetal development (Li et al., 1990; Sornson et al., 1996; Brown-Borg et al., 1996; Flurkey et al., 2002) (Table 1). Increases in average longevity of GH-deficient and GH-resistant mice were detected in both females and males and, importantly, were associated with increases in maximal longevity. The exact magnitude of longevity extension in these mutants depends on the mutation, genetic background, sex, and composition of the diet, is generally no less than 30%, and in some studies exceeded 50%. It deserves emphasis that among various mutations and pharmacological interventions that were shown to extend mouse longevity, only fairly severe (40%) calorie restriction caused comparably large extension of longevity and none achieved large gains in lifespan without compromising reproduction. Studies of multiple phenotypic characteristics that normally change with age (glucose homeostasis, cognitive function, muscle strength, balance, immune function, collagen structure) (Flurkey et al., 2001; Bartke, 2011; Arum et al., 2013) and analysis of the shape of survival curves (Koopman et al., 2016) indicate that these GH-related mutants age at a slower rate and have a longer “healthspan.” In other words, at a given chronological age, they appear to be biologically younger than their normal (“wild type”) siblings and are less likely to be affected by disease or disability. To probe the role of different GH target tissues in the extension of longevity in GHR
/
mice, List and his colleagues produced new lines of mice in which the GHR gene was disrupted selectively in the liver, the skeletal and heart muscle, or the adipose tissue (List et al., 2013, 2014, 2015, 2019; Duran-Ortiz et al., 2018). Results of longevity studies in these animals indicated that inducing GH resistance selectively in the muscle tissue can increase lifespan (List et al., 2015), while fat- or liver-specific GHR disruption does not (List et al., 2014; Duran-Ortiz et al., 2018) (Table 1). Several studies addressed the issue of relative importance of early life (developmental) vs. adult GH signaling in the control of aging and lifespan. These studies will be discussed later in this article. We will also explore the role of GH in the developmental programming of aging, the evolutionary implications of genes exerting pro-aging effects and trade-offs among growth, reproduction, and aging. Interestingly, transgenic mice overexpressing GH have reduced longevity (Wolf et al., 1993). Consistent with the role of GH in the control of aging in mice, significant extension of longevity was also reported in animals with germline or adult disruption of the pregnancy associated plasma protein A (PAPP-A) (Conover and Bale, 2007; Bale et al., 2017), reduced number of IGF-1 receptors due to heterozygous knockout of the Igf1r gene (Holzenberger et al., 2003), and germline disruption of S6 kinase1 (S6K1) (Selman et al., 2009; Table 1). PAPP-A is a protease that degrades IGF-1 binding proteins (IGFBPs) and thus regulates local (tissue) bioavailability of IGF-1. Consequently, the disruption of PAPP-A would be expected to protect IGFBPs, and particularly IGFBP4, and thus reduce the amount of active (“bioavailable”) IGF-1. GH and IGF-1 are upstream regulators of the mechanistic target of rapamycin (mTOR) and S6K1 mediates the actions of the mTORC1 complex.

GH Influences Aging by Multiple Mechanisms Following the demonstration that absence of GH signals can lead to a remarkable extension of longevity, much work was directed at identifying the mechanisms that could explain the impact of GH deficiency or resistance on aging (reviewed in Brown-Borg, 2015; Aguiar-Oliveira and Bartke, 2019; Basu et al., 2018; Bartke et al., 2013). The picture which emerges from these studies

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Fig. 1 Network of potential mechanism contributing to the link between reduced GH signaling and increased healthspan and longevity. Adapted from Bartke, A., Sun, L.Y., Longo, V. (2013). Somatotropic signaling: Trade-offs between growth, reproductive development, and longevity. Physiological Reviews 93(2), 571–598; PMID: 23589828, with permission from the publisher.

includes profound changes in the profiles of gene expression in different organs leading to beneficial alteration in IGF-1 (Bartke et al., 2013; Bartke and Brown-Borg, 2004), mTORC1 (Dominick et al., 2017), and mTORC2 (Dominick et al., 2017; Fang et al., 2018) signaling, anti-oxidant defense mechanisms (Brown-Borg, 2015; Bartke and Brown-Borg, 2004; Sanz et al., 2002; BrownBorg et al., 2012), stress resistance (Bartke, 2011; Bokov et al., 2009; Salmon et al., 2005; Murakami et al., 2003), burden of senescent cells (Stout et al., 2014), inflammatory processes in the brain and in the peripheral tissues (Hascup et al., 2016; Masternak et al., 2012; Wang et al., 2006), glucose homeostasis (Bartke et al., 2013), stem cell maintenance (Ratajczak et al., 2010), and other characteristics known to influence aging, risk of age-related disease, and longevity (Fig. 1). These alterations can be grouped by the three categories of hallmarks of aging; causes of damage, responses to damage, and consequences of damage (Lopez-Otin et al., 2013). This indicates that reduced GH signaling influences the aging process at multiple levels. These mechanisms are interacting, forming a complex network of physiological changes, compensatory adjustments, and feedback loops (Aguiar-Oliveira and Bartke, 2019; Bartke et al., 2013). We believe that it is this network that is responsible for the development of the “longevous” phenotype of these animals and for the life extension, and, thus, can be viewed as “the mechanism” linking GH signaling with trajectories of aging. It should be pointed out that a conclusive proof of the direct cause:effect relationship between any of the phenotypic characteristics of GH-deficient or GH-resistant mutants and extension of their healthspan and lifespan is difficult to obtain. In most cases, we must rely on comparisons with animals subjected to calorie restriction or other anti-aging interventions or the known effects of signaling pathways, cytokines, growth factors, and blood plasma components, and on epidemiological findings. For example, reduced insulin levels and enhanced insulin sensitivity are among the most consistent effects of mutations of disrupting GH signaling and resemble the effects of calorie restriction in numerous species, while increases in circulating levels of glucose and insulin are known to be detrimental. Moreover, reduced insulin sensitivity (insulin resistance) is a key feature of the metabolic syndrome and an established risk factor for chronic age-related diseases. In light of what is known about the role of oxidative damage and genome maintenance in the control of aging (MacRae et al., 2015; Milholland et al., 2017), association of reduced GH signaling with reduced ROS production, enhanced antioxidant defenses, and reduced oxidative damage to DNA (BrownBorg et al., 2012), and with improved DNA repair capacity (Dominick et al., 2017), strongly implies a causal role of these changes in the extension of longevity. The importance of some of the mechanisms believed to link reduced GH signaling to extended longevity is also supported by results of silencing specific genes or by pharmacological suppression of specific signaling pathways. Genetic suppression of insulin production in Ins1
/
and Ins2þ/
mice leads to enhancement of insulin sensitivity and extension of female lifespan (Templeman et al., 2017). Consuming food containing rapamycin inhibits mTORC1 signaling and extends longevity (Miller et al., 2014). Still, positive identification of mechanisms responsible for slower aging and longer life of GHrelated mutants is difficult. Many phenotypic characteristics associated with extension of longevity can be interpreted as either mechanisms or symptoms of delayed and/or slower aging. For example, enhanced insulin sensitivity and its persistence into advanced age in long-lived mutants could be seen as one of the reasons they live longer or as a sign that at a given chronological age, they are biologically younger than their normal siblings. In fact, we believe that both interpretations are valid and improvement of insulin signaling represents both a mechanism and a symptom of slower aging. In one of our studies of hepatic gene expression, we attempted to disentangle the relative importance of these factors by including normal controls of comparable biological age as the mutants (Panici et al., 2009).

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Fig. 2 Pace-of-lifedFast pace-of-life causes most of an organism’s available energy to be directed to growth and reproduction at a cost of relative neglect of maintenance and repair, while organisms with slower pace-of-life exhibit opposite characteristics.

Longevity Benefits of Reduced GH Signaling Are Associated With Various Trade-Offs It is interesting to ask why the beneficial characteristics of long-lived GH-related mutants have not been naturally selected to be present in all members of the species. The most probable explanation is that this is due to the trade-offs between longevity and evolutionary fitness, that is the probability of producing offspring which survive and reproduce under prevailing environmental conditions. The overall life course strategy of mice and other small mammals involves rapid growth, early maturation, and rapid production of numerous offspring with limited investments into care of the young. These features of a fast “pace-of-life” (Salzman et al., 2018; Ricklefs and Wikelski, 2002) demand directing most of the available energy to growth and reproduction at a cost of relative neglect of maintenance and repair leading to early aging and short lifespan (Fig. 2). According to this view, animals with a slower pace of life exhibit opposite characteristics (slower growth, later maturation, and fewer offspring, with a major investment in their care) and live longer. The effects of GH deficiency or resistance include drastic reductions in postnatal growth rate and adult body size, delay of puberty, and decreases in litter size and other indices of fecundity. This corresponds to the features of organisms with a slower pace of life and, thus, provides a plausible explanation of their extended longevity. In other words, comparisons between mutant and genetically normal (“wild-type”) animals and comparisons between long-lived and short-lived species indicate that the rate of aging reflects trade-offs with processes involved in somatic growth and reproduction. We speculate that individual variations in growth and associated trade-offs may be important for survival of the species under natural, that is somewhat unpredictable, environmental conditions. Thus, in seasons or years in which climatic conditions ensure plentiful food, rapid growth, early reproduction, and producing multiple offspring would represent the optimal strategy in spite of the associated acceleration of aging. In contrast, when environmental conditions are sub-optimal and availability of food is limited, improved stress resistance and extended longevity might allow reducing early reproductive effort and postponing reproduction until the conditions improve, enhancing the chances of offspring for survival. These theoretical predictions would seem to agree with the evidence for delayed reproductive aging in long-lived GH-related mutants (Schneider et al., 2014, 2017; Bachelot et al., 2002; Saccon et al., 2017). The extreme phenotypes of GH-deficient, GH-resistant, or other genetically altered laboratory animals are unlikely to provide competitive advantage for survival and reproduction under natural conditions (Giorgio et al., 2012). However, studies of these animals allow elucidation of genetic and endocrine regulation processes clearly relevant to survival of the species in the “real world” such as genome maintenance, stress resistance, and xenobiotic detoxification. We suggest that individual differences within the range of natural variations in these traits may represent a spectrum of survival and reproductive strategies that facilitates survival of the population in the changing environment.

Trade-Offs Between GH-Dependent Traits and Longevity Are Not Limited to Mutant Mice Living in Laboratory Conditions The striking negative association between GH signaling and longevity discovered in studies of GH-deficient, GH-resistant, and GHoverexpressing mice is counterintuitive and prompts a number of important questions:

• • •

Are GH actions related to longevity in mice not bearing mutations with a major impact on endocrine function and growth? Does GH influence aging and longevity in species from other taxonomic groups? Is the relationship of GH to aging limited to animals living in a “protected” laboratory environment with constant access to high quality food and minimal (if any) exposure to pathogens and parasites?

These questions can be answered by relating data on longevity to adult body size and other GH-dependent traits. Negative association of longevity with body size has been found in comparisons of mice from different strains or selected lines (Miller et al., 2000; Wirth-Dzieciolowska and Czuminska, 2000), as well as in individual animals from a genetically heterogeneous population (Miller

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et al., 2002). Negative associations of body size and longevity have been described in other mammalian species, including rats (Rollo, 2002), domestic dogs (Patronek et al., 1997), and horses, that is other rodents as well as carnivores and ungulates (Brosnahan and Paradis, 2003). In fact, much shorter survival of large as compared to small dogs provides one of the most striking and best documented examples of the negative association of growth and longevity. In both dogs and genetically normal (“wild type”) mice, longevity has been related not only to adult body size but also to circulating levels of insulin like growth factor-1 (IGF-1) (Miller et al., 2002; Greer et al., 2011). IGF-1 is a key mediator of GH actions on somatic growth and circulating IGF-1 levels are derived primarily from GH-driven production in the liver. Relationship of human longevity to GH signaling, IGF-1 levels, and adult body size will be discussed later in this article. Paradoxically, in comparisons between, rather than within species, it is almost always the larger animals that live longer. Thus, whales and elephants live longer than horses or cows and much longer than cats, dogs, or most small rodents. Intriguingly, IGF-1 levels were reported to be generally lower, rather than higher, in larger species (Swanson and Dantzer, 2014), and recent genomic analysis uncovered reduced IGF-1 signaling in the Brandt’s bat, a species living much longer than its body size would predict (Seim et al., 2013). Perhaps aging and longevity are causally related to the pace-of-life (as discussed earlier in this article) rather than to body size. This could explain why primates (monkeys, apes, and humans) live much longer than ungulates of comparable or even much larger size. Late puberty, a relatively small number of offspring, and a very long period of offspring dependence on the mother and the family/social groups are norms of the life history in primates and other long-lived mammals.

The Somatotropic Axis Is Involved in Developmental Programming of Aging and Longevity Results of recent studies in rodents with hereditary GH deficiency provided evidence that actions of GH during the peri-pubertal period of rapid somatic growth are important for determination of longevity and characteristics believed to represent mechanisms of aging. Panici and his colleagues reported that treating juvenile (two-weeks-old) Ames dwarf mice with GH for a period of 6 weeks greatly shortens their longevity (Panici et al., 2010). Several years later, Sadagurski et al. (2015) and Sun et al. (2017) reported that in addition to reducing longevity, this regimen of GH replacement therapy partially or completely normalizes many adult characteristics related to mechanisms of aging. Normalization occurred with circulating levels of glucose, insulin, adiponectin, and ketone bodies, markers of gliosis in the hypothalamus (brain region importantly involved in the control of metabolism), expression of hepatic genes related to stress responses’ and xenobiotic detoxification, metabolic rate, and metabolic substrate utilization (Sadagurski et al., 2015; Sun et al., 2017). More recently, Podlutsky and his colleagues showed that early life GH treatment of Lewis dwarf rats reduces their radiation resistance by interfering with the capacity for DNA repair (Podlutsky et al., 2017). In agreement with the role of early life GH signaling in the control of aging, implied by these observations, Ashpole et al. reported that knockdown of IGF-1 in female mice at 10 days after birth can extend their longevity (Ashpole et al., 2017). Intriguingly, data supporting the role of early life somatotropic signaling in the control of longevity were obtained also in wild animals living in their natural environment. Higher juvenile IGF-1 levels in spotted hyenas predicted reduced longevity as well as early onset of reproduction (Lewin et al., 2017). Evidence for a role of GH and IGF-1 actions during development in determining adult phenotype and longevity provides novel mechanistic insights into the broader issue of developmental origins of adult health and disease (DOHaD). Importantly, it also expands the significance of early life events to include their impact on the trajectory of aging. When considering the role of early life somatotropic signaling in the control of aging, it is important to emphasize that the role of GH and IGF-1 in shaping the trajectory of aging and the life expectancy is not limited to the period of rapid growth. Growth hormone has important effects on metabolism, body composition, and multiple physiological functions in adult organisms and somatotropic signaling (GH and IGF-1) is importantly related to the origin and progression of cancer. Direct proof that GH actions limited to the adult period can influence longevity was provided by the recent study of Junnila and his colleagues, showing that conditional GHR gene deletion induced at the age of 6 weeks made female mice live longer (Junnila et al., 2016). Moreover, Ashpole et al. reported extension of longevity of female mice by knockdown of IGF-1 gene at 5 months of age (Ashpole et al., 2017).

Effects of GH Deficiency and Resistance on Human Aging and Longevity Because of its severe impact on development, growth, maturation, and adult stature, congenital GH deficiency is the principal indicator for GH replacement therapy (Gharib et al., 2003). Striking and consistent effects of injections of recombinant human GH (hGH) on the growth, attainment of developmental landmarks and final stature in GH-deficient children are well documented (Zanelli and Rogol, 2018). These effects are seen as beneficial and are perceived as outweighing any possible risks (Cohen et al., 2002; Bell et al., 2010; Kemp et al., 2005; Cook and Rose, 2012). However, findings from GH-deficient individuals that have not been treated with GH and from individuals with genetic GH resistance suggest that absence or severe reduction of GH signals may favor extension of healthspan in people as it does in laboratory mice, although longevity does not appear to be increased. Early studies of people with various syndromes resulting in dwarfism produced controversial findings. In a cohort of GHdeficient individuals living in Switzerland, longevity was reduced presumably due to increased incidence of cardiovascular disease (Besson et al., 2003). However, some individuals with hypopituitarism (including GH deficiency) due to mutations of the Prop1 gene who live on the Island of Krk in the Adriatic Sea (the “little people” of Krk), were reported to reach 80s and even 90s, a very

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advanced age for their birth cohort (Krzisnik et al., 2010). Studies of people with GH resistance due to mutations of the GH receptor gene by Dr. Laron (the discoverer of this syndrome now known as Laron syndrome) indicated that they are protected from cancer and their life expectancy is normal or, perhaps, extended (Laron, 2011). More recent studies of a large cohort of individuals with congenital GH receptor-deficiency (GHRD) living in Ecuador revealed remarkable protection from cancer and diabetes with no deaths recorded from either disease and only one case of cancer among 99 subjects (Guevara-Aguirre et al., 2011). Complete absence of diabetes in this cohort of GHRD subjects was associated with, and likely due to, enhanced insulin sensitivity and increased levels of adiponectin in spite of increased percentage of body fat (Guevara-Aguirre et al., 2011). Compared to their unaffected relatives, GHRD subjects had lower blood glucose levels and greatly reduced plasma insulin without significant changes in tolerance to oral glucose load. It is interesting that the long-lived mice with targeted deletion of GH receptors exhibit strikingly similar metabolic characteristics: increased adiposity, greatly enhanced insulin sensitivity with very low insulin and slightly reduced or “low normal” glucose, increased adiponectin, and greatly enhanced insulin (but not glucose) tolerance (Bartke et al., 2013; Masternak et al., 2009). Enhanced insulin sensitivity has been linked to extension of healthspan and lifespan in several kinds of long-lived mutant mice and to familial longevity, as well as exceptionally long survival in humans (Wijsman et al., 2011). However, longevity of GHRD subjects is not affected. Presumably, any benefits they may derive from improved glucose homeostasis and reduced insulin levels may be outweighed by other causes of mortality not related to this aspect of metabolic health. It should also be mentioned that GHRD subjects from the Middle East studied by Laron and his colleagues sometimes do develop diabetes (Laron, 2015). It is unclear whether these differences are due to different mutations underlying GHRD in these two cohorts, to diet, and other lifestyle differences or to other causes. Cardiovascular disease accounted for a similar proportion of deaths among the Ecuadorian GHRD subjects as in their non-affected relatives, but the dwarfs were more likely to die from cardiac disease and less likely to die from stroke. Among GHRD subjects, most deaths after the age of 10 were due to causes considered not to be age-related, including accidents, problems resulting from alcohol consumption, and convulsive disorders (Guevara-Aguirre et al., 2011). While the etiology of convulsive disorders in these subjects remains unexplained, recent studies of brain structure and function showed that GHRD subjects have improved memory along with various structural and functional brain characteristics resembling chronologically younger, unaffected individuals (Nashiro et al., 2017). It is intriguing that GHR
/
mice also retain youthful levels of cognitive function at the age when cognitive function of their normal siblings is in decline (Kinney et al., 2001). A great amount of information on the role of GH in human aging is available from the studies of Drs. Aguiar-Oliveira and Salvatori in a large cohort of individuals with isolated GH deficiency (IGHD) who had not been treated with GH. This cohort located in the Itabaianinha county in northeastern Brazil has now been studied for over 25 years and continues to be followed by monitoring their health and analyzing various morphological and functional aspects of their phenotype. The results have been summarized in several recent review articles (Aguiar-Oliveira and Bartke, 2019; Aguiar-Oliveira et al., 2017, 2018). IGHD in the Itabaianinha county dwarfs is due to mutations in the GHRH receptor gene which is transmitted as a recessive trait (Salvatori et al., 1999). The affected (homozygous) individuals are characterized by extremely short stature with near normal body proportions and characteristic “doll-like” facial features. They are cognitively normal, healthy and fertile, and maintain physical fitness, high energy levels, and ability to work into advanced age. Moreover, they generally look younger than their chronological age. Their average age at death is not significantly different from that of their non-affected relatives or unrelated members of the community (Table 2), but some IGHD individuals reached a very advanced age, including one female subject who recently died at the age of 103. In spite of increased adiposity and systolic blood pressure, as well as serum cholesterol levels that would be considered unfavorable, IGHD individuals from this cohort are remarkably protected from premature/accelerated atherosclerosis (Menezes Oliveira et al., 2006). Importantly, despite improvements in lipid profile and body composition, treatment with GH led to a progressive increase in intima-media thickness and in the number of atherosclerotic carotid plaques i.e. emergence of atherosclerosis. While the skeletal muscle mass is reduced, as expected with severe suppression of GH signals, muscle strength and conduction velocity are superior to those of non-affected controls (Andrade-Guimaraes et al., 2019). In terms of cancer incidence, they differ from individuals with GHRD by being susceptible to skin cancers (but not melanoma) with one case of a fatal outcome (Marinho et al., 2018). Similar to the finding in the Ecuadorian cohort of Laron dwarfs, causes of death include issues other than age-related disease or degenerative

Table 2

Overview of consequences of genetic alterations in genes from the somatotropic axis on human longevity.

Genetic alteration

Geographic region

Main endocrine feature

Longevity Pathology

GH-1 gene deletion Prop-1 gene mutation GHR mutation GHR mutation GHRHR mutation

Switzerland Krk island, Croatia Middle East Ecuador Itabaianinha county, Brazil NA

Isolated GH-deficiency Combined GH, TSH, and prolactin-deficiency GH-resistance (Laron syndrome) GH-resistance (Laron syndrome) Isolated GH-deficiency

Y [?

Increased cardiovascular disease Not reported

z z z

Protected from cancer Protected from cancer and diabetes Protected from premature arteriosclerosis and most cancers Increased cardiovascular disease, diabetes, and some cancers

Pituitary tumor

GH overproduction (acromegaly; Y gigantism)

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changes. Some of the accidental deaths appeared to have been related to the elderly IGHD subjects undertaking risky tasks that do not seem to be age-appropriate, and possibly stem from their high energy levels. Thus, it can be concluded that both syndromes of congenital deficiency of GH signaling (GHRD and IGHD) result in significant protection from age-related chronic disease but not or very little impact on longevity due to an increased number of deaths from accidents and other causes which are less common in the general population. In spite of these similarities, the phenotypes of individuals with theses syndromes or GHD of different etiology are not identical. In addition to differences between the underlying mutations, these differences could be due to genetic background, lifestyle factors, and differential impact on somatotropic signaling during development. Individuals with IGHD due to defects in GHRH action have functional GH receptors and, thus, can respond to placental and maternal somatotropic hormones transported through the placenta and perhaps also through milk and the relatively “leaky” gastrointestinal tract of the infant. In contrast, absence of GH receptors in GHRD individuals presumably precludes these biological effects. It is also of possible consequence that in the Itabaianinha county dwarfs, GH appears to be not entirely absent, but rather secreted only in extremely small amounts (Salvatori et al., 1999, 2006). It can be speculated that this level of GH secretion may be sufficient to protect them from the deleterious effects of GHD seen in other cohorts (Dattani, 2005; Savage et al., 1993; Oliveira-Neto et al., 2011; Barreto et al., 2009; Valenca et al., 2016, 2012; Laron et al., 2012). On the other end of the spectrum, acromegaly, which is characterized by high GH secretion and elevated IGF-1 levels, has been associated with increased mortality (Dekkers et al., 2008), again mimicking results from mice.

Somatotropic Axis and Human Aging: Evidence From Epidemiological Studies As discussed above, untreated Itabaianinha county dwarfs with congenital isolated GH deficiency have preserved muscle strength and do not display premature atherosclerosis or premature cognitive decline despite the presence of (cardiovascular) risk factors such as increases in visceral obesity, systolic blood pressure, and serum levels of total and LDL cholesterol (reviewed in AguiarOliveira et al., 2017). However, patients with sporadic (childhood or adult onset) GH deficiency do display more cardiovascular disease and decreased cognitive functioning (reviewed in de Boer et al., 1995), as well as increased mortality (Stochholm et al., 2007). It is however uncertain whether the increases in morbidity and mortality observed in these studies are due to GH deficiency per se, the treatment thereof, or other hormonal, (patho)physiological or lifestyle differences following the onset of GH deficiency. It is well known that during regular human aging GH secretion and circulating levels of IGF-1 gradually fall, a phenomenon known as somatopause (Iranmanesh et al., 1991). Because of the resemblance of the age-associated changes in body composition, bone mineral density, risk of cardiovascular disease, and cognitive decline, to those of GH deficiency, it has been hypothesized that age-related decreases in GH secretion and circulating IGF-1 levels may play a causal role in age-related disease and mortality. Conversely, it can be hypothesized that age-related decreases in GH secretion and circulating IGF-1 levels reflect an adaptive response to accumulated damage that serves to direct energy away from growth related processes toward maintenance and repair in order to reduce risk of disease. To address these hypotheses, numerous epidemiological studies have investigated associations between circulating levels of the individual components of the somatotropic axis with risk of the different common diseases of old age, notably risk of diabetes, risk of cardiovascular disease, risk of dementia, and risk of cancer, and with mortality. Different parameters of the somatotropic axis were evaluated in different studies, including GH, IGF-1, and IGF binding proteins. Growth hormone, which is produced by the somatotroph cells of the adenohypophysis is secreted in a pulsatile manner. Fig. 3 presents a scheme of the feedforward and feedback regulation within the somatotropic axis. The secretion of GH is primarily under the control of growth hormone releasing hormone (GHRH) and somatostatin (SST), two hypothalamic peptide hormones which are secreted into the hypophyseal portal circulation. Although GHRH can also be detected in serum, the majority of the circulatory GHRH is produced by the gut. GH can exert its actions directly, via the GHR, as well as indirectly, via the production of IGF-1 in the liver. Because of its pulsatile mode of secretion and short half-life, reliable estimates of GH secretion can only be obtained from blood sampled frequently over a period of 24 h. Due to the invasive nature of frequent blood sampling, as well as the high costs associated with serial hormone measurements, studies with reliable measures of GH are by design limited in sample size (Roelfsema and Veldhuis, 2016). Fig. 4 presents a 24-h concentration profile of one healthy older individual. Circulating IGF-1 levels are far more stable and consequently IGF-1 is the parameter most often measured in larger, epidemiologic studies. Although IGF-1 can also be produced locally, most circulatory IGF-1 is derived from (GH-mediated) production by the liver. The majority of circulating IGF-1 is bound to IGF binding proteins (IGFBPs), a family comprising six members of which IGFBP3 is most abundant. Binding of IGF-1 to IGFBPs affects the activity and half-life of IGF-1. It has been estimated that only 1% of circulating IGF-1 is in its biologically active free form. The IGF-1/IGFBP3 molar ratio is considered a measure of IGF-1 bioavailability. Epidemiological studies on the relation between circulating levels of the somatotropic axis components with risk of diabetes have yielded contradictory results. In an analysis of the DETECT and SHIP studies (comprising 7777 individuals without diabetes), a U-shaped relationship was observed between total IGF-1 and risk of diabetes (Schneider et al., 2011). However, this study did not take levels of IGFBP3 into account. In the prospective Cardiovascular Health Study (comprising 3133 individuals without diabetes) higher levels of IGFBP3 (but not IGF-1) were found to be associated with a higher risk of incident diabetes in older women but not men (Aneke-Nash et al., 2017). In a meta-analysis of the relation between total IGF-1 and risk of CVD, a U-shaped relationship was observed indicating that both low and high IGF-1 levels are associated with increased risk of CVD (Jing et al., 2015). Circulating IGF1 was observed to be positively associated with risk for several common cancers, including breast cancer (Endogenous et al.,

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Fig. 3 Key parameters of the somatotropic axisdGrowth hormone releasing hormone (GHRH) and somatostatin (SST) are produced by the hypothalamus in the brain. GHRH stimulates and SST inhibits the secretion of growth hormone (GH) from the pituitary. GH provides negative feedback to the hypothalamus via stimulation of SST and stimulates the production of insulin-like growth factor 1 (IGF-1) by the liver. The majority of circulating IGF-1 is bound to IGF binding proteins (IGFBPs), a family comprising six members of which IGFBP3 is most abundant. Figures of tissues/organs were adapted from Servier Medical Art, available from: https://smart.servier.com/ [cited 2019 Apr 4].

Fig. 4 GH concentration profile over 24 h of one healthy older individual from the Switchbox StudydConcentrations of growth hormone (GH) measured every 10 min, starting at 09:00 in the morning, during 24 h. Pulses are indicated by the arrows, basal secretion by the dotted line and pulsatile secretion by the vertical line. Number and timing of pulses differ per person. In general, GH secretion is stimulated during sleep hours. Adapted from van der Spoel, E., Jansen, S.W., Akintola, A.A. et al. (2016). Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity. Aging Cell 15(6), 1126–1131; PMID: 27605408, with permission from the publisher.

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2010), prostate cancer (Travis et al., 2016), and advanced colorectal cancer (Yoon et al., 2015). Individuals with Alzheimer’s disease (AD) were found to have lower circulating levels of total IGF-1 and IGFBP3 than cognitively intact individuals (Westwood et al., 2014; Hertze et al., 2014; Duron et al., 2012). Results from a meta-analysis indicate that also in non-demented older individuals, total IGF-1 levels were positively correlated with global cognitive functioning (Arwert et al., 2005). Taken together, these results indicate that relations between circulating IGF-1 and disease in old age are often not linear and that the direction of the association may be different for different age-related diseases. In line with the above, a U-shaped relationship between circulating total IGF-1 and mortality was observed in a meta-analysis of population-based studies (comprising 14,906 participants) indicating that both low and high IGF-1 concentrations are associated with increased mortality in the general population (Burgers et al., 2011). In this meta-analysis, also low (but not high) IGFBP3 was associated with mortality (Burgers et al., 2011). Studies on circulating IGF-1 and mortality in extreme old age have yielded contradictory results, as in some studies lower IGF-1 was associated with increased mortality (Arai et al., 2008), while in others lower IGF-1 or lower IGF-1/IGFBP3 ratio were associated with better survival (Milman et al., 2014). It should, however, be kept in mind that circulating IGF-1 levels are only one of the parameters of a complex system. For example, without data concerning expression and sensitivity of the IGF-1 receptor it is unknown to what extent IGF-1 levels reflect IGF-1 deficiency or resistance in a given population or age stratum. Moreover, reported associations of circulating IGF-1 with morbidity and mortality may not reflect true cause: effect relationships as these might be due to (residual) confounding or reverse causation. As an example of confounding, cigarette smoking may affect circulating levels of IGF-1 and/or IGFBP3 as well as risk of disease and mortality. As an example of reverse causation, disease and impeding death may be associated with poor nutritional state and immobility, which may result in lower levels of IGF-1. To address some of these caveats, it would be interesting to not only study associations of absolute levels of IGF-1 with disease and mortality, but also how these levels change over time, e.g. to model IGF-1 trajectories. Using this approach, it was found that in old age, tight regulation of IGF-1 levels was a stronger predictor of mortality than absolute IGF-1 levels (Sanders et al., 2018).

Somatotropic Axis and Human Aging: Evidence From Genetic Studies Genetic association studies are another approach to study causality. After the discovery of the important role of GH/IGF-1/insulin signaling in longevity in model organisms, selected naturally occurring genetic variants in components of the human GH/IGF-1/ insulin pathway have been tested for associations with (old age) mortality and longevity in several candidate gene association studies. Although in different studies associations with longevity and survival have been observed for specific candidate genes from the GH/IGF-1/insulin pathway (Bonafe et al., 2003) or combinations thereof (van Heemst et al., 2005), the associations of genetic variation in the FOXO3 gene with longevity have been most consistently and widely replicated across different studies (Willcox et al., 2008; Anselmi et al., 2009; Flachsbart et al., 2009; Li et al., 2009; Soerensen et al., 2010; Di Bona et al., 2014). In addition to these candidate gene studies, FOXO3 candidacy was confirmed in unbiased genome-wide association (GWA) studies for longevity (Broer et al., 2015). Interestingly, along with other genetic determinants, genetic variation in FOXO3 was also identified in GWA studies of circulating IGF-1 levels (Broer et al., 2015). In contrast to the other genetic determinants identified in these genome-wide association (GWA) studies of circulating IGF-1, genetic variation in FOXO3 was found to be linked to risk of Alzheimer’s disease (Williams et al., 2018).

Somatotropic Axis and Human Aging: Evidence From Extreme Longevity Another strategy to assess the importance of the somatotropic axis in human aging and longevity is to compare key parameters of the somatotropic axis between long-lived individuals and controls. Such comparisons have been performed for different parameters using various study designs. One such study design is to compare a group of rare individuals that have successfully reached an extremely advanced age, such as centenarians, to groups of individuals of other ages, such as adults (< 50 years of age) or aged individuals (75–99 years). Using this design, an age-related decline was observed of IGFBP3 over these three age categories, while IGF-1 was higher in the group of adults but did not differ between the groups of aged individuals and centenarians (Paolisso et al., 1997). Another study found an age-related decrease in levels of free IGF-1 that extended into extreme old age (Bonafe et al., 2003). Moreover, IGFBP3 gene polymorphism was shown to be associated with longevity in Chinese nonagenarians and centenarians (He et al., 2014). The drawbacks of such cross-sectional designs are that it is not possible to disentangle whether the differences observed between different age groups are caused by differences between birth cohorts, selective survival or whether these reflect ageinduced changes. An alternative design is to study different generations from long-lived families. This study design has been applied to both centenarians as well as to nonagenarian siblings and comprises comparisons of their middle-aged offspring with a control group that is matched for age and other appropriate characteristics and that lacks a family history of longevity. Using this design, it was found that female Ashkenazi Jewish centenarians’ offspring displayed several signs of relative IGF-1 resistance, including higher circulating levels of IGF-1 and a somewhat shorter stature (Suh et al., 2008). When Italian centenarians’ offspring were compared to an age-matched control group, lower levels of total IGF-1, IGF-1 bioactivity, and the IGF-1/IGFBP-3 ratio were observed (Vitale et al., 2012). In participants of the Dutch Leiden Longevity Study, it was found by analysis of 24-h GH profiles that GH secretion was lower and more tightly controlled in the offspring of long-lived families as compared to the offsprings’ partners who were

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included as an environmentally and age-matched control group (van der Spoel et al., 2016). Interestingly, these differences were observed in the absence of differences in circulating levels of IGF-1 or IGFBP3 between groups of offspring of long-lived families and the offsprings’ partners (Rozing et al., 2009). Taken together, the results from these different studies have revealed differences in the somatotropic axis in familial human longevity, although the exact nature of observed differences may differ between studies, and likely also between the different families included in a particular study. Future work will be needed to identify possible differences in the responses to endogenous GH that could be related to longevity. Polymorphism in multiple genes, including IGF-1 and IGFBP3 (He et al., 2014; Kaplan et al., 2011), has been related to responses to therapy with recombinant GH (Chen et al., 2018). In parallel studies in mice, more research is needed to unravel the molecular pathways and mechanisms via which the somatotropic axis may impact human aging and longevity.

GH as Anti-Aging Therapy? There are striking clinical similarities between many of the adverse changes which occur with aging and those of adult onset GH deficiency, including those that occur in body composition, muscle strength, bone mineral density, and physical performance. These similarities, together with the observed age-related decrease in GH secretion and circulating IGF-I levels, have prompted the question whether aging is a GH deficiency syndrome that could be treated with GH as an ‘anti-aging’ therapy. The advent of recombinant human growth hormone has led to a number of studies in which older individuals were treated with hGH alone or in combination with sex steroids or physical training to assess effects of hGH as an ‘anti-aging’ therapy on various endpoints. In the first study on hGH treatment in older men, it was found that the hGH-treated group exhibited decreases in total fat mass in conjunction with increases in IGF-1, lean body mass, bone mineral density at the lumbar spine (but not at the radius or proximal femur), and skin fold thickness (Rudman et al., 1990). The effects of hGH treatment on body composition were corroborated in subsequent studies (Liu et al., 2007). In men, treatment with hGH combined with testosterone resulted in a stronger decrease in fat mass than treatment with hGH alone (Giannoulis et al., 2006). Beneficial effects on body composition were also observed in older men and women upon hGH treatment in combination with physical training (Lange et al., 2000). However, despite the beneficial effects on body composition, treatment with hGH did not result in increased muscle strength, neither in older adults, nor in young adults (Hermansen et al., 2017). In older men, treatment of hGH combined with testosterone resulted in an only marginal increase in muscle strength (Blackman et al., 2002). In older women, improvements in muscle strength were absent, also when hGH treatment was combined with estrogens (Blackman et al., 2002). Moreover, hGH therapy was found not to improve bone mineral density, although a decrease in fracture risk was observed in post-menopausal women with age-related osteoporosis (Barake et al., 2018; Atkinson et al., 2017) In addition to the limitations in efficacy as discussed above, there is considerable controversy as to the safety of hGH treatment in older adults without GH deficiency, as treatment with hGH is associated with a high incidence of adverse effects (Liu et al., 2007). Persons treated with hGH displayed a significantly higher risk for soft tissue edema, arthralgias, carpal tunnel syndrome, and gynecomastia. In addition, hGH treatment was associated with a somewhat higher risk of insulin resistance which may accelerate the onset of diabetes mellitus. Another concern as to the long term safety of hGH treatment is the possibility that elevated levels of IGF-1 may cause an increased risk of cancer. However, despite its limited efficacy and high risk of adverse events, and based on the reversal of age-related changes in body composition upon hGH treatment, its use as an anti-aging therapy has been widely advocated and the distribution and marketing of GH as anti-aging therapy has grown into a multimillion-dollar industry (Perls et al., 2005). Moreover, it is estimated that about one-third of the sales of hGH in the United States may be for “off-label” illegal use as an anti-aging therapy (Perls et al., 2005). Another final concern as to the long term safety of hGH treatment is that the decreases in GH secretion and circulating IGF-I levels that are observed with aging may well be protective. The data discussed earlier in this chapter regarding extension of health span and lifespan in mice with mutations resulting in GH resistance or deficiency bolster this hypothesis. Also consistent with this hypothesis, although the data from epidemiological studies are somewhat more controversial, the human data on congenital GH deficiency and resistance, as well as the association of genetic variation in components of the GH/insulin/IGF-1 axis with human longevity and the data concerning GH secretion and/or IGF-1 levels in offspring of long-lived individuals discussed earlier in this chapter, do not support the use the hGH as an antiaging therapy.

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Gut Microbiota and Aging: Targets and Anti-aging Interventions B Singh, ICARdIndian Veterinary Research Institute, Regional Station, Palampur, India R Catanzaro, University of Catania, Catania, Italy G Mal, ICARdIndian Veterinary Research Institute, Regional Station, Palampur. India SK Gautam, Sun-Yat Sen University, Shenzhen, China Mohania, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India F He, Sichuan University, Chengdu, People’s Republic of China H Yadav, Wake Forest School of Medicine, Winston-Salem, NC, United States L Bissi, San Babila Clinic, Healthy Aging Unit by Cell-Energy Modulation Biotech (CMB), Milano, Italy F Marotta, ReGenera R&D International for Aging Intervention, Milano, Italy; and VCC Preventive Medical Promotion Foundation, Beijing, China © 2020 Elsevier Inc. All rights reserved.

Introduction Aging and Gut Microbiota: Between Physiology and Disease-Accelerated Process Relationship Between Diet and Gut Microbiota Gut Microbial and Microbial Metabolite Connection of Aging Host Aging-Microbial Connection Microbiota-Mitochondrial Crosstalk and Aging Cognition, Neurodegenerative Diseases and Aging Eyes Bone, Aging and Gut Microbiota Signaling Muscle Aging and Gut Microbiota Immune-Aging vis-a`-vis Gut Microbiota Gut Microbiome in Skin Homeostasis and Aging Microbiota-Mitochondrial Crosstalk and Aging Centenarians and Gut Microbiota: A Different Story? The Probiotics and Postbiotic Interventions to Decelerate Aging Perspective and Conclusions Acknowledgements References Further Readings

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Introduction Aging and Gut Microbiota: Between Physiology and Disease-Accelerated Process Aging process has a complex, multifactorial dynamics where we know a number of causative factors, phenomena or epiphenomena (Fig. 1), though all are not fully unveiled. The biomedical sciences have achieved a great deal of progress in understanding the nutrients-gene interactions, host-microbe relationship, and basic mechanisms of aging, and controlling age-associated health issues such as cardiac failure, metabolic and lifestyle-associated chronic diseases and also cancer (Yu et al., 2010). Focusing on function of gut microbiota in aging, and speculating the strategies to alter aging through interventions in gut ecosystem is a major focus of recent biological sciences. The microbes have coevolved with humans for millennia and inhabit virtually all the mucosal sites in body. The human body in particular, is a normal niche hosting around 30 trillion cells living in symbiosis with multiple microbial communities. The human gut microbiota has coevolved by means of only two major phyla: Bacteroidetes, and Firmicutes, which account for
20%
80% of all gut bacteria, respectively; with minor populations of Actinobacteria (
3%), Proteobacteria (
1%), and Verrucomicrobia (
0.1%) (Lloyd-Price et al., 2016). State-of-the-art high-throughput sequencing technology has revealed that human genome contains genetic elements of microorganism and viruses inhabiting them, thus representing a major analytic advancement when studying gut microbiota. The symbiosis is so intimate that majority of herbivores depend overwhelmingly on their microbial symbionts for activation of immunity and immune functions, protection against enteropathogens, extracting nutrients and energy from diet, and detoxification of anti-nutritional plant metabolites. This has led to commercial utilization of gut microbiota for commercial applications (Singh et al., 2001, 2008). This perfectly reconciles with the wider view of human evolution, that is, the “holobiont” concept with its intrinsic relevance to human variation and personalized characteristics, the “evolving inner self” as elegantly outlined by Kundu et al. (2017). A well-described literature is available on establishment of human microbiota since development in utero to birth

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Fig. 1 The causative factors of accelerated aging. Environmental factors, genetic factors, biotic and abiotic stress, consistent exposure to hazards, sedentary life style, smoking, junk food habits, noise pollution and poor nutritional status accentuate the process of inopportune aging.

of infant, age- and health-associated alterations in composition, and perturbations in structural and functional repertoire of normal microbiota that offer opportunities to dominate pathogens and spoilage microorganisms (Singh et al., 2013).

Relationship Between Diet and Gut Microbiota Diverse colonizing gut microbiota is important for greater resilience, increased immunity, metabolic potential and resisting to diseases. Of note, the quantity and quality of diet impact microbial communities and determines the types of microorganisms in gastrointestinal (GI) tract. Also, the gut microbes assist host derive the nutrients from indigestible plant materials and prevent from the toxicity induced by plant metabolites and their gut intermediary metabolites (Singh et al., 2003, 2008; Sharma et al., 2017; Cortés-Martín et al., 2018). The diets in certain rural regions are richer in different plant sources. Phytometabolites such as polyphenols including resveratrol, curcumin, catechins and phytoestrogens present in food and fodder sources are documented for their therapeutic and antiaging effects (Singh et al., 2003; Shimojo et al., 2018; Skrypnik and Suliburska, 2018). Apples, blueberries, pistachios and artichokes are known to increase gut bifidobacteria in humans. The Hadza tribes, the hunter gatherer tribes of Tanzania, for instance, eating vegetarian diets harbor sundry microbiota with diverse metabolic activities (Smits et al., 2017). The tribes depend on different diets in different seasons, and the gut microbial composition varies drastically with seasons in response to the diets. Although the mechanisms are not fully clear as yet, when considering the often observed vitamins malabsorptive condition in aging, it is noteworthy mentioning the study of Valentini et al. (2015) which showed that probiotic strains could positively boost the populations of bifidobacteria with concomitant increase in levels of folate and vitamin B12 in older individuals. By interplaying with low molecular weight molecules produced by the indigenous microbiota, dietary components exert a fundamental epigenetic role in health and disease (Kumar et al., 2013, 2017; Paul et al., 2015). The relevant impact of such interaction in contributing to a aging well phenotype is shown in family cohort of nonagenarian and centenarian siblings (Rea et al., 2015). The “epigenetic view-angle” of dietary lifestyle, now more than ever calls for a proper dietary plan in elderly. A large study addressing the metagenomics understanding of the association between butyrate-generating bacteria and functional capacity is supported by metagenomics findings in older adults (
78 years) has clearly shown that community-dwelling elders had more butyrate-producing bacteria and microbial diversity unlike institutionalized elderly (Claesson et al., 2012). As an example, higher levels of fiber intake and production of SCFAs by the microbiota, is known to stimulate the intestinal production of regulatory lymphocytes with anti-inflammatory properties (Asarat et al., 2016) as has been demonstrated in recent study of colon cancer (O’Keefe et al., 2015) whose incidence increases by aging.

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Gut Microbial and Microbial Metabolite Connection of Aging The gut microbes exert beneficial effects (Fig. 2) by producing a variety of metabolites such as short chain fatty acids (SCFAs) (acetate, propionate and butyrate) from dietary fiber, organic acids that maintain low luminal pH, promoting and regulating mucus production, supporting gut barrier integrity. The gut microbiota has as strong impact on energy homeostasis in the colon. The gut microbes regulate host production of several signaling molecules such as serotonin (5-HT), hormones and neurotransmitters. The SCFAs have varying effects in different tissues. They are utilized by enterocytes as energy sources and contribute to 5%–10% of total energy requirement of human body (Donohoe et al., 2011; Makki et al., 2018). The acetate is used as substrate for hepatic lipogenesis, cholesterol synthesis and prevents liver carcinogenesis (Makki et al., 2018). Propionate is important component of hepatic gluconeogenesis, regulation of cholesterol synthesis, and prevents development of cancer. The butyrate acts as epigenetic regulator of cellular genome (Kumar et al., 2013), and activates intestinal gluconeogenesis gene expression through cAMP-dependent mechanism. Decline in the levels of gut microbial SCFAs is associated with some pathophysiological conditions such as neuro-immune activation. The decline in population of butyrate-producing bacteria is provide opportunities to establish bacterial consortia that promote degradation of mucin, thereby increasing the likelihood of entry of pathobionts into gut mucosa, which raises the susceptibility to inflammatory diseases such as IBD, Crohn’s diseases, ulcerative colitis and gut-related diseases in old ages. Reduced level of propionate and propionate-producing bacteria affects intestinal gluconeogenesis and gut-brain neural circuit via GPR-41 (De Vadder et al., 2014).

Host Aging-Microbial Connection Studies have revealed that there are dominant species in human microbiota which maintain a constant profile throughout life. Nonetheless, under certain conditions, abnormalities may also arise in proportion and composition of different taxa. All these

Fig. 2 A generalized overview of pro-health attributes of commensal microbiota and their anti-aging affects through multiple effects and modes of actions. The GI microbiota play important role in controlling immunity, food intake, lipid accumulation, production of SCFAs, insulin signaling, regulation of dental and bone mass, and protecting against lifestyle and metabolic disorders.

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are characterized by expression of pro-inflammatory responses which are also shared by the so-called senescence-associated secretory phenotype (SASP) (Gurau et al., 2018). This is why the hectically growing investigations on microbiota may prove to be a cornucopia of advanced information in understanding aging process and planning of tailored interventions as also our group has already envisaged (Vaiserman et al., 2017). Advancing age is characterized by imbalance in gut, skin and genitourinary microbiota (dysbiosis), increase in permeability of intestine, a condition known as leaky gut that facilitates passage of some microorganisms, endotoxin and other microbial metabolites (e.g., indoxyl sulfate) into blood circulatory system (Singh et al., 2013; Grosicki et al., 2018). Very recently, it is demonstrated that compared to healthy young people (20–35 years), the circulating microbiome in older subjects (60–75 years), showed a different clustered b-diversity anda-diversity (chao1, P ¼ .001) as well as phylogenetic diversity (in terms of relative abundance of the phyla Bacteroidetes, Spirochaetes, SR1, bacteria TM7, and Tenericutes) (Buford et al., 2018). Interestingly, a significant positive correlation appeared between IGF1 and Bacteroidetes, Spirochaetes SR1 and TM7 and a robust inverse correlation between IL6 and TNFa with Bacteroidetes. Besides direct effect of on organs, the aging has adverse effects on bacterial consortia that produce beneficial metabolites such as butyrate from enteric fermentation of dietary fiber (Rampelli et al., 2013; Jeffery et al., 2016), and an increase in pathogenic proteobacteria (e.g., Enterobacteriaceae). Taking together, the aging process may lead to increased intestinal permeability owing to decrease in integrity of epithelial tight junctions (Thevaranjan et al., 2017). This paucisymptomatic phenomenon leads to translocation of microbial byproducts such as Gram-negative bacteria-derived lipopolysaccharides (LPS) that could be detected in bloodstream in aged persons (Ghosh et al., 2015). The variety of beneficial phyla such as bifidobacteria changes from childhood. Whereas Bifidobacterium longum, B. bifidum are and B. breve, usually dominate in infants, B. adolescents and B. catenulatum, and B. longum prevail in elderly people (Matsuki et al., 2004). On the other hand, low detection of B. bifidum and B. breve as revealed by culture-dependent techniques in aged individuals (Chaplin et al., 2015), support above inferences. Probiotics and their metabolites, functional foods and FMT are effective in restoring healthy gut microbiota, thereby offer potential benefits in preventing or curing the diseases where conventional therapies have failed (Kumar et al., 2016; Singh et al., 2017). Given that normal microbiota plays a fundamental role in most aspects of human health and disease, it is envisioned that novel alternative interventions such as probiotics, postbiotics, fecal microbiota transplantation (FMT) would be the futuristic therapeutic interventions for managing the well-being of older individuals. Concerning the role of gut microbiota in health and diseases, and aging, several queries are still unanswered. For instance, it is not clear whether aging is a disease mediated by gut dysbiosis, or can it be delayed using timely nutritional or therapeutic interventions (Nagpal et al., 2018). However, whether rejuvenation or modulation of gut microbiota with multi-targeted inventions, could prevent frailty is yet to be unraveled in the perspective of elder individuals (Mello et al., 2016). A most recent aging theory and model do consider that genes of host itself, commensal microbiota and some non-living genetic elements affect longevity and life span of host organism (Tetz and Tetz, 2018).

Microbiota-Mitochondrial Crosstalk and Aging Zooming to the intracellular level, aging is invariably associated with decreased mitochondrial efficiency and a less effective antioxidant enzymatic machinery. This affects apoptosis, genome instability, relentless inflammation and metabolic functions. One of the main reasons of such mitochondria decay resides in the age-related declining of mitochondria number and around 40% decrease of electron transport chain (ETC) efficiency (Markaki et al., 2018). Overall, these finding pose a robust ground for the comprehensive longevity regulating hypothesis by the integration of the three genetics (nuclear DNA, mitochondrial DNA and gut microbiome) (Garagnani et al., 2014). Mitochondrial numbers may be related with several systemic signaling pathways including insulin-resistance. In this context, the gut microbiota has emerged as essential component regulating insulin signaling and mitochondrial biogenesis-associated energy. Given a common prokaryotic ancestry, it is not surprising that it does exist a significant cross-talk between the gut bacterial community and the mitochondria. It was recently shown that energy efficiency in rats is dependent on the source of milk they were fed. This is likely to be in relation with the butyrate-producing gut microbiota and their diversity. Notably, the butyrate can directly gain access, especially through inside colonocytes (Donohoe et al., 2011), into the TCA cycle and reduce the NADþ versus NADH ratio, thus leading to increased mitochondrial biogenesis. Gut microbiota may also conjure up to directly altering ETC and affect energy metabolism. Indeed, in the gut there is a dynamic equilibrium between some enteric bacteria (E. coli, and Salmonella spp.) which are strong producers of hydrogen sulfide inhibiting ETC cytochrome oxidase and other species which can breakdown it and make it available for the colonocytes mitochondrial respiratory chain. During aging process, as noted in mice models, the level of mitophagy, that is, the process that selectively degrades damaged mitochondria, decreases up to 70% (“Garb-aging”) (Franceschi et al., 2017). This may particularly affect the dendrite gyrus area regulating learning and memory (Petsophonsakul et al., 2017). Hence, this may be one of the candidate mechanisms in neurodegenerative diseases (Hou et al., 2018; Wee et al., 2018), and may open interventional avenues with gut ecosystem manipulation.

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Cognition, Neurodegenerative Diseases and Aging Eyes Numerous factors including genetic, environmental and dietary signals affect the composition of gut microbiota which are important constituents of a bi-directional gut brain axis. The dysbiosis can cause neuropsychiatric disorders such as autism, depression, anxiety, anorexia nervosa and, most notably, neurodegenerative diseases (Quigley, 2017), such as Parkinson’s disease (PD) and Alzheimer’s disease. The gut microbes contribute to maturation of enteric nervous system, GI physiologic functions and circulatory system (De Vadder et al., 2018) as well as for microglia in the CNS (Erny et al., 2015). The ubiquitous nature of PD explains why abnormally aggregated a-synuclein, a typical cerebral hallmark of the disease, is also observed in peripheral autonomic and enteric nervous system in GI tract which contains more neurons in the gut than in the spinal cord. Intestinal dysbiosis with lowered LPSbinding and SCFAs (lower Prevotella and butyrate-producing bacteria) have been reported in PD (Unger et al., 2016; Hasegawa et al., 2015). Although the main clinical phenotype o PD has been often reported to be associated with low count of Bifidobacterium (Minato et al., 2017), this finding has been questioned by other research groups (Keshavarzian et al., 2015; Hasegawa et al., 2015). Increased Enterobacteriaceae, Lactobacillus gasseri subgroup, duration-related increase counting of Lachnospiraceae have been variably, but not robustly reported features in PD (Hopfner et al., 2017; Scheperjans et al., 2015) so far, given the complex interfering factors such as: geographical area, stage of the disease, diet, concurrent medications and dominant symptom phenotype (Hill-Burns et al., 2017; Li et al., 2017). Generally speaking, the neuronal cells are differentially susceptible to aging. Based on examination of postmortem, and molecular signals examinations in 480 brain cell samples of individuals with age from 16 to 106 years, it is inferred that compared to neurons, the glia cells are affected most by brain aging. Glia cells (astrocytes and oligodendrocytes) present in hippocampus and substantia nigra, but not the neuron-specific genes, were found to shift their patterns of gene expression upon aging (Soreq et al., 2017). Patients with different degrees of cognitive impairment and brain amyloidosis as ascertained by specific imaging are found to be colonized by more proinflammatory gut microbes as compared to age-matched controls (Cattaneo et al., 2017). Under abnormal gut (and oral) ecosystem, the abundant Gram-negative bacilli (Bacteroides fragilis and E. coli) may secrete a constant flow of pro-inflammatory neurotoxins such as endotoxins, exotoxins, lipooligosaccharides and lipopolysaccharides, amyloids, and small non-coding RNAs. In this regard, Zhao et al. (2017) has shown presence of bacterial LPS in AD hippocampus lysates with up to a 26-fold increase in its amount found in most advanced cases as compared to healthy controls. It is likely that microbial amyloid, generated at gut level, primes the innate immune system by igniting an inflammatory priming cascade linked to M cells via the mediation of epithelial Toll Like Receptors localized at Peyer patches. This phenomenon opens the way to a possible hematogenous route routes (Powell et al., 2017), which would eventually elicit a detrimental reactive response to neuronal amyloids in the brain. Recently, Xu and Wang (2016) have identified 56 microbial metabolites strongly associated with “cognitive decline” in AD and 45 with AD susceptibility, in particular, d-proline and several secondary bile acids. These promising data suggest that targeting bacteria producing d-proline may provide an attractive alternative therapeutic approach in removing amyloids from brain, therefore reversing or inhibiting cognitive decline in AD. Further, microbiota-modifiable markers were also represented by several secondary bile acids which are potent inhibitors of apoptosis whereas anti-apoptotic interventions seem to be potentially beneficial in AD. Prebiotics, probiotics, dietary interventions, FMT and antibiotics possess the rationale for foreseeing an epigenetic intervention on gut microbial community (Lye et al., 2018). Therapeutic strategies to neurodegenerative disease have the potential to be tailorshaped as to switching off detrimental noxious molecules-generating bacterial species while fostering salutogenic ones for preventive and, ideally, adjunctive therapy after disease onset (Sampson et al., 2016). Promising data are coming from experimental studies showing how a multi-strain supplementation to middle-age rats would improve some memory tests and related behavioral flexibility paralleled by ex vivo 1H nuclear magnetic resonance spectroscopy analyses proving region-specific changes in brain metabolites (O’Hagan et al., 2017). Accordingly, it is of great interest what just reported by Huang et al. (2018), that also in a senescence-accelerated model, administrating Lactobacillus paracasei PS23 would improve anxiety behavior and brain redox balance, modulating levels of neural monoamines and their metabolites in the striatum and hippocampus, increasing brain derived neurotrophic factor and dopamine. Another gut microbiota-brain area to explore and amenable to intervention is represented by aberrant autoimmune responses, given that a large quantity of human peptides binding to HLA-II alleles mimic gut bacteria (mostly Firmicutes and Proteobacteria), and likely to be auto-immunogenic with potential brain-tropism (Negi et al., 2017). Efforts to affect neuroprotective mast cells activity by gut microbiota interventions might also represent a new avenue to pursue (Girolamo et al., 2017). Although there is no data exploring the effect of gut microbiota in age-related sleep disorders, a recent clinical work recruiting healthy elderly, reported that a higher proportions of certain gut microbial entailing phyla such as Verrucomicrobia and Lentisphaerae had correlation with better sleep quality and cognitive flexibility healthy older adults. Also, it was postulated that further studies are needed to scientifically validate these findings (Anderson et al., 2017). In this succession, a surprisingly beneficial effect on restoring a youth melatonin chronobiorythm was noted in healthy elderly by a phytomarine compound, while testing it on in vitro stem cell and redox enhancing properties, have prompted us to focus our studies on effect of the compounds on gut microbiota (Pathak et al., 2018). As gut microbiota contribute to immune-mediated ocular disease, targeting gut microbiota for ocular health is an emerging areas of scientific inputs. Age-related macular degeneration (AMD) is an age-related and a leading cause of vision loss among humans aging above 50 years and older. The disease progresses faster in some subjects and may lead to loss of vision in both the eyes. The mouse

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retina represents a good model of age-related macular degeneration (AMD), being susceptible to inflammatory metabolic dysfunction, dietary abnormalities and cigarette. A quick note of role of gut microbiota in aging ophthalmologic field is of top concern. An experimental work on mice administered a high-glycemia (HG) diet, resulted in many AMD features (AMDf). Switching from the HG to the low-glycemia (LG) diet late in life was found to arrest or reverse some AMDf (Rowan et al., 2017). More recently, the same research group has further deepened this area of research suggesting a more definite pathogenic role played by gut microbes such as clusters belonging to Ruminococcaceae and Lachnospiraceae, and some strains of microbial families including Clostridiaceae, Mogibacteriaceae and Turicibacteraceae (Rowan and Taylor, 2018). Interestingly, Beli et al. (2018) have shown that intermittent fasting enabled gut microbiota modification bringing to increased beneficial production of metabolites from increased levels of Firmicutes, and decreased Bacteroidetes and Verrucomicrobia, thus preventing diabetic retinopathy in db/db mice models as compared to ad-libitum-fed ones. The fine mechanisms of microbial interplay in this area are not clear as yet. It is expected that strategies that target intestinal bacteria mediating propagation of ocular inflammatory diseases, could lead to develop interventions to manage ocular health (Lin, 2018).

Bone, Aging and Gut Microbiota Signaling Loss of bone mass with advancing age is a common phenomenon with the characteristic deletion of minerals such as calcium and phosphorus, the bone density loses gradually, and the bones become porous and weak. These metabolic events in health and disease have been found to be related also to gut microbiota (Skrypnik and Suliburska, 2018). Elevated osteoblast and osteocytes apoptosis and reduced number of osteoblasts, change in muscle-bone interaction are the characteristic features of age-associated changes in skeletal system. Moreover, the changes in gut microbiota associated with aging process are likely to trigger fat infiltration into bone, thus clustering a shared dysfunction of muscle, bone and adipose tissue (osteosarcopenic obesity) (Agrawal et al., 2015). This is mediated by increased levels of oxidative stress in bone cells, decreased bone mass and increased osteoblast/osteocyte apoptosis by activation of p53/p66shc signaling cascade. Aging-associated dysbiosis could be advocated for to explain the stimulation of osteoclast differentiation and resorptive activity via proinflammatory T helper 17 (TH17) involvement. This would lead to a decrease in overall bone mass (Ohlsson and Sjögren, 2015), although gut microbiota interplay with brain-controlled hormonal factors is also envisaged (Quach and Britton, 2017). Probiotics (L. reuteri and L. gasseri) confer various immunomodulatory properties, ameliorate inflammatory conditions and offer bone-health benefits as inferred from in vitro studies, experimental model animals and human trials (Collins et al., 2017). Probiotic Lactobacillus acidophilus fed to experimental ovariectomized (ovx) mice was found to enhance trabecular as well as cortical bone microarchitecture with simultaneous increase in mineral density and heterogeneity of bones. The effect was attributed to immunomodulatory effects of the probiotic strain, suppressing expression of osteoclastogenic factors (IL-6, IL-17, TNF-a and RANKL), and augmented expression of anti-osteoclastogenic factors (IL-10, IFNg) (Dar et al., 2018a).Bacillus clausii, another probiotic strain could inhibit bone loss in postmenopausal osteoporotic murine models by skewing Treg-Th17 cell equilibrium, and promoting anti-osteoclastogenic Treg cell development (Dar et al., 2018b). Though auxiliary studies are warranted to improve the efficacy of probiotics to improve bone mineral density (BMD), prevent age-associated osteoporosis in humans, a randomized, placebo-controlled, double-blind, clinical trial utilizing L. reuteri ATCCPTA 6475 showed that probiotic strain could diminish bone loss in older women with low BMD (Nilsson et al., 2018). As gut microbiota affect bone homeostasis by interacting with immune and bone sells, regulating nutrient absorption, modulating production of gut serotonin, mediation of IGF-pathway, restoring gut microbiota by probiotics and postbiotics might reduce production of inflammatory cytokines which ultimately leads to change in bone density. Although still under study, prebiotics may beneficially act by inducing a microbial fermentation (Wallace et al., 2017), leading to enhanced production of SCFAs and a concurrent reduction in gut luminal pH. This would also improve the colonic bioavailability of calcium and optimize mineral release into the lumen (Whisner and Weaver, 2017).

Muscle Aging and Gut Microbiota Muscular aging is associated with reduction in muscle mass and function and multifactorial condition called as sarcopenia leading to loss of independence and quality of life. A spectrum of structural and functional changes such as frailty and disabilities are noted in advancing aging in humans and animals. Especially, the muscle wasting commences in the fourth decade of human life leading to frailty and disabilities. The muscle mass decrease rate is around 3%–8% after the age of 30, which further increases beyond 60 years of age (Holloszy, 2000). The diseases associated with muscle aging and dysfunction include insulin resistance, T2DM, oxidative damage, autophagy, hypertension and hyperlipidemia, reduction in mitochondrial biogenesis and ATP production, morbidity and mortality as a consequence of supervening complications. Available data suggest a cross-talk between gut microbiota and skeletal muscle health with gut microbiota overall affecting skeletal muscle bioenergetic pathways. For instance, the extracellular vesicles secreted by gut microbes can cross the intestinal barriers and directly induce insulin resistance while deranging glucose metabolism in skeletal muscle as one of the pathogenetic mechanisms of T2D (Choi et al., 2015). Gut microorganisms are indeed recognized as potential contributors of age-dependent loss in muscle mass and function resulting in enhanced susceptibility to infectious agents and tumorigenesis. The muscle aging can be partly prevented with lifestyle

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interventions, sustained or life-long active physical activities and calorie-restriction. The probiotics and their metabolites have beneficial effects on muscle health as shown in animals raised for food production. A probiotic mixture of L. reuteri and L. gasseri, but not other species, administered to cachectic leukemic mice showing dysbiosis, was found to show a significant decrease in inflammatory cytokines such as IL-6, IL-4 along with monocyte chemoattractant protein-1 (MCP-1), together reduced expression of atrophy markers including MuRF1, Atrogin-1, LC3 and Cathepsin. These phenomena were associated with an increased tibialis anterior muscle mass. Overall, these inferences imply that gut microbes could serve as a novel therapeutic target in the management of leukemia-associated inflammation and related muscular disorders (Bindels et al., 2012). Moreover, the functional-enhancement effects were also demonstrated in healthy young mice when fed L. plantarum supplementation where a significant increase in lean mass and function (grip strength and swim time) were noticed (Chen et al., 2016). L. plantarum supplementation was found to reduce white adipose tissue while increasing muscle mass and gastrocnemius muscle type I fiber with better performance (forelimb grip strength and swimming time to exhaustion). Gut microbiota manipulation by this intervention was also paralleled by reduced blood lactate, ammonia, CK, and increased glucose metabolism. This is an important area of research when considering that glucose homeostasis has a propensity towards disequilibrium with increasing age (van den Beld et al., 2018). Together with a marked reductions in Lactobacillus (
8-fold less) (van Tongeren et al., 2005), an age-related decrease in gut Bifidobacterium content may underlie increases in circulating endotoxin that are shown to induce skeletal muscle atrophy (Morales et al., 2015). The prebiotics, such as fiber oligofructose, may positively affect skeletal muscle health as shown by reducing the levels of inflammatory molecules and improving muscle mass in obese mice (Cani et al., 2009). Moreover, it is noteworthy reporting that, Lee et al. (2016) has shown that a specific strain of L. reuteri, namely L. reuteri BM36301, producing anti-inflammatory metabolites, could help in maintaining low weight gain by 36% less than the control mice with heavier testicles, and significantly higher serum testosterone levels. On clinical ground, there are promising data showing that supplementation with inulin and fructooligosaccharides may improve muscle strength (handgrip) and endurance in frail older adults (Buigues et al., 2016). Intriguingly, a muscle (exercise)gut microbiota relationship seems to have a bidirectional beneficial interplay. In that, for instance, few years ago Clarke et al. (2014), has retrieved an enhanced gut microbial diversity, reductions in levels of plasma endotoxin and inflammatory markers among professional players compared to less active (control) groups (Clarke et al., 2014). Estaki et al. (2016) have found that cardiorespiratory fitness was significantly associated to
20% of variation in gut bacterial alpha diversity. The above data offer a rationale for a robust role of some specific butyrate-producing taxa among more aerobically fit individuals. So, it seems plausible to infer that regular physical exercise “per se” may counteract the age-related decline in butyrate-producing microbiota and lactobacillus levels (Denou et al., 2016).

Immune-Aging vis-a`-vis Gut Microbiota The dynamically changing intestinal microbiota implies a constant patrolling and check points through interaction of epithelial microfold M cells, as well as dendritic cells. Over this complex system, the immune system plays like a mandatory intermediate to health and disease, wherever located (Jain et al., 2012). It is known that aging process affects innate immunity, with decreased natural killer cells activity, adaptive immunity, and antigen-specific IgA antibody and cellular immune responses (Malaguarnera et al., 2010). When studying 148 healthy adults, divided into 3 groups of progressively older age, it was found out that in elderly group, the presence of Akkermansia was positively correlated with IgA levels and the percent of CD8þ T cells, and negatively correlated with the percent of CD4þ T cells and CD4þ/CD8þ ratio (Shen et al., 2018). Earlier, we had shown that a symbiotic mixture containing Saccharomyces boulardii lysate supplementation in otherwise healthy elderly, but with poor immune-competence (exhibiting NK cell activity < 10%), had a significant improvement in NK cell activity (Naito et al., 2014). Immunosenescence has also been beneficially treated by orally-administered Lactococcus lactis subsp. lactis by stimulating the plasmacytoid dendritic cells (pDCs). Indeed, pDCs, play an important role in viral infection, and oral administration of LC-Plasma showed prophylactic effects against viral infection in mice as well as humans. Long term oral intake of LC-plasma prevents immune-senescence and other senescence types at organ levels, indicating that that LC-Plasma could be a functional dietary microbial supplement for slowing-down the processes of aging (Tsuji et al., 2018). To address a potential probiotic anti-inflammatory intervention, a detailed in vitro study on fecal batch cultures, supplemented with B-GOS, inulin, B. bifidum, L. acidophilus and Ba. coagulans, showed a significant inhibition of LPS induced TNF-a (Liu et al., 2016). At the same time this symbiotic mixture through a positive (saccharolytic fermentation) microbial shift, increased IL-10 production, by stimulating the bifidobacteria. Vulevic et al. (2015) has shown that a 5.5 g of GOS mixture for 10 weeks administered to elderly persons (age 65–80 years) had significantly increased bacteroides and bifidobacteria, with higher IL-10, IL-8, natural killer cell activity and C-reactive protein, together with a lower IL-1b.

Gut Microbiome in Skin Homeostasis and Aging Skin is the largest organ situated in interface with body and environment and serves as an effective barrier with manifold functions including protection of internal organs, maintaining body temperature, protecting body against injuries caused by biotic

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(infections, tumor and cancer), and abiotic stressors such as ultraviolet radiations (UVR), thermal stress and pollutants. To comply with this, the skin undergoes constant epidermal turnover. While doing so, the skin supports a delicate ecosystem of microbial populations. The skin microbiota interacts with internal environment, thereby imbalance the healthy body state. Skin aging is a visible process. The skin becomes dry lusterless and rough. The aging skin starts developing wrinkles and black spots, called as age spots. The skin diseases, such as acne, psoriasis and atopic dermatitis also lead to faster aging of skin. Recently, there is surge of interest in studying the skin microbiota, and exploring benefits of microbial therapies to improve skin health. It is likely that gut microbiota influences skin homeostasis by immunological signaling pathways (O’Neill et al., 2016). Although the fine molecules and mechanisms are to be fully explored as yet, it seems that antiinflammatory responses are promoted at a skin level by some gut microbiota strains (Bacteroides fragilis, Faecalibacterium prausnitzii) producing retinoic acid, and polysaccharide A and Clostridium cluster IV and XI, both recruiting regulatory T cells, lymphocytes (Forbes et al., 2015). The SCFA shave a beneficial role by inhibiting inflammatory cells, translocation and local cytokine release together with inhibition of histone deacetylase and NF-kB signaling inactivation. Thus, dysbiosis, it is plausible that besides other physio-pathological factors affecting the aging skin, gut microbiota imbalance may play and additional detrimental role (Salem et al., 2018). For instance, while a proper wound healing is promoted by efficient gut microbiota production of SCFAs (Meijer et al., 2010), this may be severely hampered when dysbiosis-related overgrowth of filamentous bacteria, triggering the accumulation of pro-inflammatory Th17 and Th1 cells supervenes. The probiotics protect or enhance epithelial barrier function via modulating tight-junction barrier. This has led to concept of use of probiotics for skin health by killing or competitive exclusion of inimical dermal pathogens, reinforcement of skin epithelial barrier, promoting fibroblast and epithelial cell migration and activity. Studies have recommended use of probiotic lactic acid bacteria and postbiotics to enhance cutaneous immune responses (Sultana et al., 2013), and maintain dermal health and prevent premature skin aging (Kimoto-Nira, 2018). In cases of disrupted intestinal barriers such as in antibiotic or proton pump inhibitors users, obesity, metabolic syndrome, coeliac disease, chronic stress, aging progression per se’ and so forth, gut bacteria and its metabolites may enter into the bloodstream, accumulate in the skin and they have been isolated from the plasma of psoriatic patients (O’Neill et al., 2016). Experimental studies supplementing Lactobacillus reuteri (Levkovich et al., 2013) have shown a significant increase of dermal thickness, and folliculogenesis in mice. A more recent clinical trialusing L. brevis SBC8803 has proven to improve two typical age-associated skin features, that is, corneal hydration and trans-epithelial water loss (TEWL) (Ogawa et al., 2016) while another using Lactobacillus paracasei NCC2461 supplementation (Guéniche et al., 2013) either TEWL and higher transforming growth factor beta-related reduced skin sensitivity was reported. The microbial species such as Bifidobacterium, Lactobacillus sp., Staphylococcus sp., Streptococcus sp., can prevent acne, while Bifidobacterium, Lactobacillus sp., Staphylococcus epidermidis and Vitreoscilla filiformis might be used to treat can treat atopic dermatitis (Mottin and Suyenaga, 2018).

Microbiota-Mitochondrial Crosstalk and Aging While studying a complex metabolic remodeling in a representative Italian longevity cohort in view of identifying biological markers of exceptional longevity, it was found that the longevity phenotype was affected by remarkable variations in the gut microbiome with increased excretion of phenylacetylglutamine and p-cresol sulfate in urine of centenarians as compared to other elderly people (Collino et al., 2013). It appeared that centenarians had lower contribution of Clostridium cluster XIVa, and relatives abundance of symbiotic species with anti-inflammatory properties together with a relative increase of facultative anaerobes including Proteobacteria. Interestingly, Bifidobacterium longum BBMN68 and B. adolescentis BBMN23 isolated from healthy centenarians were found to improve both innate and acquired immunity in mice (Yang et al., 2009).

Centenarians and Gut Microbiota: A Different Story? By screening gut microbiota in European young adults, elderly, and centenarians, Biagi et al. (2010, 2017) has shown that unlike what was thought in the past, a linear relation with age till a significant variation is not observed in centenarians. Indeed, population of successful agers shows unexpected features such as high diversity in species composition (Santoro et al., 2018), an overgrowth of expected health-promoting species (Akkermansia, Christensenellaceae and Bifidobacterium) (Biagi et al., 2017). The breakdown picture of the later showing that B. longum was abundant in Italian centenarians, followed by B. adolescentis and B. bifidum (Drago et al., 2012), and predominantly B. dentium was dominant in Chinese centenarians (Wang et al., 2015). While studying a complex metabolic remodeling in a representative Italian longevity cohort in view of identifying biological markers of exceptional longevity (Collino et al., 2013) it was found that the longevity phenotype was affected by remarkable variations in the gut microbiome with increased excretion of phenylacetylglutamine and p-cresol sulfate in urine of centenarians as compared to elderly. It appeared that in centenarians there was a lower contribution of Clostridium cluster XIVa, and relatives abundance of symbiotic species with antiinflammatory properties together with a relative increase of facultative anaerobes including proteobacteria. Of intriguing interest is also a bit dated report showing that Bifidobacterium longum BBMN68 and Bifidobacterium

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adolescentis BBMN23 isolated from healthy centenarians proved to significantly improve both innate and acquired immunity in mice (Yang et al., 2009). Increasingly evidence is accumulating suggesting the beneficial effects of supplementation with bifidobacteria for health promoting metabolites including SCFAs, conjugated linoleic acid and bacteriocins, as documented also by ongoing large urinary free fatty acid metabolomics studies by Dr. Huang at VCC premises (data in house, ongoing). A recent study carried out in Drosophila melanogaster reveals that a formulation entailing probiotics (L. plantarum NCIMB8826, L. fermentum NCIMB5221, and Bifidobacterium longum spp. infantis NCIMB702255), and symbiotic (trifala-containing Emblicaoficinalis, Terminalia bellirica and Terminalia chebula), could extend longevity by alleviating inflammation, oxidative stress and preventing damage to mitochondrial integrity (Westfall et al., 2018).

The Probiotics and Postbiotic Interventions to Decelerate Aging The metabolomics and nutrigenomics studies and powerful analytical tools have suggested that nutrients affect gene expression at various cellular and molecular levels, which means that diet is important factor not only for nutrition, but also for preventing host from stress and diseases. Notably, the targets of probiotics, postbiotics and dietary ingredients are same that is, restoring or maintaining the homeostasis of GI ecosystem, which can be of more importance during old age. The probiotics originating from humans, especially from centenarians or elderly subjects are envisaged to be the ideal microbial additives for healthier aging. The revolutionary high-throughput sequencing analyses, metabolomic and in silico analytical studies have shown that diversity of gut, skin as well as genitourinary microbiota differs significantly in young and older individuals. The studies also show that compared to non-vegetarian and junk-foods, the plant-origin diets are crucial for increasing the number, metabolic capacity as well as variety of core gut microbiota. Of note, the dietary fiber is important as energy source for the anaerobic bacteria residing in colon. The microorganisms alone are not involved in healthy or adverse effects on the host. In addition, the microorganisms metabolize the dietary component and to alleviate toxic effects (Singh et al., 2016, 2017), or produce metabolites that have therapeutic relevance. A rigorous randomized, double-blind, placebo-controlled, crossover study conducted in elderly people, showed that a probiotic intervention with a multi-strain lactobacilli-bifidobacteria intervention could shift the gut microbiota, bringing about a beneficial curbing of the inflammatory cytokine intraluminal asset (Spaiser et al., 2015). Dietary components slow down the process of aging through multiple mechanisms (Fig. 3). The 6-gingerol, and 6-shogaol extracted from (Zinziber officinale Roscoe) in were found to increase stress tolerance, reduce levels of ROS, and promote the levels of stress resistance proteins (HSP-16.2), and SOD-3in Caenorhabditis elegans, showing that above ingredients from medicinal plant Zinziber officinale Roscoe could extend the lifespan in humans (Lee et al., 2018a, 2018b).

Perspective and Conclusions Aging and senescence are inevitable and complex processes that are regulated by several genetic and environmental factors. As gut microbiota modulate age-related physiological and metabolic processes, sarcopenia, immunity, behavioral and cognitive functions, the potential of gut microbiota to manage human health has salutary relevance in humans. The realization that probiotics can express their beneficial effects at distant sites from their habitat or site of inoculation into an individual has raised the possibilities for treatment of diseases by microbial therapy. This has led to the concept of developing recombinant probiotics for use as delivery vehicles of vaccines, curtailing bacterial and protozoal pathogens and improving cognitive health. The efforts should be to enhance population and functional repertoire of the gut microorganisms by possible interventions (Box 1). Studies should focus on framework for deciphering fundamental cellular and molecular mechanisms existing between normal microbiota and host health, the processes regulating maintenance of integrity of gut microbiota, and thereafter evolving strategies for use of probiotics in conjunction with plant-origin dietary supplements to maintain health in elderly stages. Forging ahead, it is evident that we, at the moment, don’t have complete understanding of the mechanisms underlying the changes that lead to aging. Owing to the fact that aging populations are increasing in developed and developing countries, more investments have to be made to take care of old people population. The strategies that are effective, safer and acceptable to wider populations should be developed. Vegetarian diets such as polyphenol-enriched foods and their gut microbial metabolites could exert anti-senescence effects in humans, and improve diversity and metabolic properties of the gut microorganisms. However, there are still many issues that need scientific attention. Are probiotics and gut microbes alone able to delay aging? Are only gut-targeted microbial therapies able to delay aging? Are microorganisms intended for human applications safe when included in the diet of aged persons or patients with weaker immunity? In conclusion, the gut microbiota has emerged as a important regulator of physiology and a key player in maintaining human health. The probiotics and postbiotics represent futuristic therapeutic avenues ameliorating diseases that contribute towards accelerated human aging. Despite the fact the findings concerning success of FMT, designer probiotics and postbiotics are still in infancy,

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Fig. 3 A diagrammatic presentation of plant metabolites and their gut metabolic products with anti-aging effects. Sometimes the gut microbial metabolic products are more active than their precursor.

Box 1 The general strategies to improve structural and functional efficacy of the gut microbial ecosystem

• • • • • • •

Eat diverse range of vegetarian diets entailing tree nuts and fruits Prefer fermented foods (yoghurts, kimchi, kefir, tempeh and ethnic fermented foods) containing live microbes to supporting butyrate-producing bacteria such as Clostridiales, Roseburia, Lachnospiraceae, and Erysipelotrichaceae Include clean raw vegetables and fruits should in diet to harbor environmental microorganisms, if you don’t have problems in digesting vegetables and fiber Consume vegetable fibrous diets to promote diverse gut microbiota Avoid excess artificial sweeteners and avoidable use of antibiotics as they deter the gut microorganisms Promoting breast-feeding in infants as to enrich infant gut microbiota (vaginal delivery and breast-feeding are associated to best healthier gut microbiota status, and maintenance in infants as opposed to formula-fed infants with higher abundance of Escherichia coli, C. difficile, bacteroides, and lactobacillus Avoid optional cesarean births, as babies born naturally through birth canal contain more diverse gut and genitourinary microbial populations

there are positive speculations concerning their applications in gut-related ailments, metabolic diseases and colorectal cancer, controlling cognitive health and preventing aging. The benefits of manipulating gut microbiota by probiotics are substantially supported by trials conducted in cell lines, models animals some in silico speculations. The findings should be validated in humans following strict guideline, before recommending them for human applications.

Acknowledgements This work was supported in part by ReGenera R&D International for Aging Intervention, Milan-Beijing, Italy-China and San Babila Clinic, Vitality Therapeutics, Gender Healthy Aging, CMB Unit, Milano, Italy. The funding bodies had no role in work design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Further Readings Vaiserman, A.M. (Ed.), 2016. Anti-aging Drugs: From basic research to clinical practice. Royal Society of Chemistry, Cambridge. Catanzaro, R., Anzalone, M.G., Milazzo, M., et al., 2015. The gut microbiota and its correlations with the central nervous system disorders. Panminerva Medica 57 (3), 127–143. Choi, J., Hur, T.Y., Hong, Y., 2018. Influence of altered gut microbiota composition on aging and aging-related diseases. Journal of Lifestyle and Medicine 8 (1), 1–7. Cho, S.S., Finocchiaro, T. (Eds.), 2012. Handbook of Prebiotics and Probiotics Ingredients: Health Benefits and Food Applications. CRC Press, Taylor & Francis. Illuzzi, N., Galli, R., Kushugulova, A., et al., 2014. Expanding the Metchnikoff postulate: Oral health is crucial in a successful global aging management strategy. Rejuvenation Research 17 (2), 172–175. Matsumoto, T., Yamaoka, Y. (Eds.), 2019. Microbiota: Current Research and Emerging Trends. Caister Academic Press. Metugriachuk, Y., Marotta, F., Pavasuthipaisit, K., et al., 2006. The aging gut motility decay: May symbiotics be acting as “implantable” biologic pace-makers? Rejuvenation Research 9 (2), 342–345. Summer. Nagpal, R., Kumar, M., Yadav, A.K., et al., 2016. Gut microbiota in health and disease: an overview focused on metabolic inflammation. Benefical Microbes 7 (2), 181–194. https:// doi.org/10.3920/bm2015.0062. Oliveira, M., Serrano, I. (Eds.), 2015. The Challenges of Antibiotic Resistance in the Development of New Therapeutics. Book Series: Frontiers in Antimicrobial Agents. Bentham eBooks. Otles, S. (Ed.), 2013. Probiotics and Prebiotics in Food, Nutrition and Health. Taylor & Francis. ur-Rahman, A. (Ed.), 2014. Frontiers in Clinical Drug Research-Anti Infectives. Bentham eBooks. Vaiserman, A.M., Marotta, F., 2016. Longevity-promoting pharmaceuticals: Is it a time for implementation? Trends in Pharmacological Sciences 37, 331–333. https://doi.org/ 10.1016/j.tips.2016.02.003.

Gut Microbiota and Healthy Aging Le´a Siegwald, Nestlé Research, Lausanne, Switzerland Harald Bru¨ssow, KU Leuven, Lab of Gene Technology, Heverlee, Belgium © 2020 Elsevier Inc. All rights reserved.

Healthy Lifespan, Diet, and Microbiota From Leeuwenhoek to Metagenome Sequencing Metchnikoff and His Followers Gut Microbiota Changes With Age Probiotics Interventions in Elderly: Complementing the Microbiota? Microbial Treatments of Antibiotic-Associated Diarrhea and Clostridium Difficile Infection Prebiotics Interventions: Feeding the Microbiota? Synbiotics: The Best of Both Worlds? A more Holistic Approach: Whole Diet Interventions Outlook References

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Healthy Lifespan, Diet, and Microbiota “The idea is to die young as late as possible.” This quote, attributed to the anthropologist Ashley Montagu, reflects a paradox of our time. Staying in a youthful state is seen as a societal goal, in contrast to earlier historical periods where old age was venerated for its life experience, sagacity, and serenity. This admiration for the elderly in former times had a sound biological basis: they survived a dangerous environment where food preparation was associated with substantial risks, and they were largely responsible for health and childcare. Indeed, studies exploring population data up until the 19th century in Sweden demonstrated the impact of the presence of a grandmother for the survival of children: the effect was inversely proportional to the distance in kilometers separating grandmother and grandchildren (Lahdenpera et al., 2004). Family structures and societies drastically changed after the industrial revolution. In industrialized countries, safe food is now provided by the food industry, while health care is in the hands of health professionals. Better nutrition, easier and safer working conditions, and medical progress have (at least in the developed parts of the world) led to a substantial increase in life expectancy through both reducing childhood mortality and extending lifespan. Geneticists are even discussing whether there is a biologically defined maximal age for humans or whether the upper age limit will further creep upwards in the future (Geddes, 2016). The extended lifespan has drastically changed the population pyramid in developed societies, posing enormous economic challenges. If the increasing lifespan is not mirrored by an increased “health span,” older individuals can become a burden for society by consuming a disproportionate part of social services. Thus, it is of crucial importance to also enhance the human health span. The question now is what targeted interventions can contribute to healthy aging? There is certainly a genetic basis for a long life and health span. Even if better characterization of the link between genomic background, health, and longevity was to be made in the future, it is not clear whether such findings will lead to targeted interventions since changing the hardwired human genetic code will be technically and ethically challenging. Elucidation of critical control pathways in healthy aging might lead to pharmacological interventions, which are currently mostly restricted to treating specific detrimental conditions and not designed as a preventive solution to sustain health. Therefore, research on healthy aging has concentrated on diet. The rationale for targeting diet is clear-cut: as better nutrition has contributed to lifespan extension, it seems plausible to associate it with health-span extension as well. In addition, both undernutrition and overnutrition are clearly associated with compromised health outcome and drastically shortened life expectancy (Foreman et al., 2018). The diet-lifespan question has taken an interesting turn with the realization that calorie restriction is linked to an extended lifespan over an astonishing range of animal life forms (Heilbronn and Ravussin, 2003). The insight gained by molecular biologists from intervention studies in shorter-lived animal species will continue in stimulating this fertile research area. Human studies have so far demonstrated the feasibility of calorie restriction interventions and shown positive effects on mood and biomarkers of health (Martin et al., 2016). The diet-lifespan discussion has more recently extended to the gut microbiome field. Microbiologists have redefined the concept of the human self by showing that we are, in fact, a super-organism colonized with a perplexing diversity of microbial life. This “other genome” might represent 100-fold more genes than our own genome, adding substantially to our metabolic capacities. This realization has important implications for the diet-healthy aging discussion. If diet influences the composition of the human microbiomedthere is some indication that indeed it doesdand if the metabolism of the gut microbiome influences human physiology and nutritiondand there is again some data that point into that directiondthen we would have a handle to influence healthy aging with specific diets. One could identify dietary components that favor specific microbes (prebiotics) or add viruses

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that suppress specific microbes (see entry “Bacteriophage Therapy” in this Encyclopedia) or one could directly add beneficial microbes (probiotics, fecal transplantation). There is some supportive evidence for these approaches, but also substantial hype. The present entry critically evaluates the available data from the diet/gut microbiota/healthy aging field.

From Leeuwenhoek to Metagenome Sequencing The discovery that humans are colonized by a large number of microbes goes back to 1683, when Leeuwenhoek described “animalcules” (Latin for tiny animals) with the first microscope. However, a better characterization of these commensal life forms in humans had to await in vitro cultivation of these microbes in the late 19th century. Then by sequencing the 16S ribosomal DNA from the gut microbiota and analyzing it with bioinformatics tools, microbiologists could extend the identification of bacteria and archaea beyond cultivable microbes, revealing an unsuspected complexity of the human-associated microbiota. When conducting metagenome sequencing of whole DNA and RNA from size-fractionated gut samples, we can now extend this analysis not only to eukaryotic microbes and viruses, but also to microbial metabolism further supported by metabolome analysis. However, these new techniques also come at a price: they produce large and complex datasets on ecosystems for which the fundamental laws of interaction and evolution are largely ignored. For the gut microbiome, we are still in a descriptive phase where factors such as interindividual differences, development across lifetime, and the impact of factors like geography, ethnicity, diet, disease and medication are under investigation. Substantial functional redundancies for metabolic pathways between different gut microbes confound associations between microbial organisms and their physiological impact on humans. Stochastic elements might further complicate the equations of human-microbial interaction. While a rapid development of bioinformatics and statistical analyses have allowed to cope with complex datasets created by sequencing, too many studies are still purely descriptive, and too few studies test working hypotheses, which could guide the understanding of microbiota-host interaction.

Metchnikoff and His Followers Interestingly, a more than 100 year-old hypothesis proposed by Elie Metchinkoff, a Russian biologist, still dominates the diet/ gut microbiota/healthy aging field. Metchnikoff distinguished three types of microbes in the human gut. First, there are diseasecausing microbes that transiently colonize the gut causing acute food intoxication and infectious diseases, which he suggested to reduce by boiling food and drinks. Secondly, he hypothesized noxious bacteria that transform the food we consume into toxic metabolites, which poison the gut over longer terms and which he held responsible for the detrimental aspects of the aging process. Thirdly, he envisioned beneficial microbes that provide metabolites to the gut that contribute to human health and the prolongation of life, as he so titled his influential book published in 1908. Metchnikoff even associated specific bacterial groups with these opposite physiological effects. He attributed the age-inducing effects to proteolytic gut bacteria that lead to putrefaction in the gut and the production of toxic bacterial metabolites. Beneficial bacteria were, in his view, saccharolytic bacteria that transform carbohydrate compounds by microbial fermentation processes into beneficial metabolic end products like lactic acid. He argued that the latter process can be furthered by the consumption of fermented milk products and backed it with the observation that populations consuming high amounts of fermented milk products also showed increased longevity. Metchnikoff’s hypothesis stimulated modern research into the diet-gut microbiota interaction. A recent study published in Nature investigated the gut microbiota of 10 healthy adults who switched from a plant-based to an animal-based diet (David et al., 2014). In striking agreement with Metchnikoff’s hypothesis, the gut microbiota composition showed characteristic changes after only 4 days of food change in this cross-over study. Upon animal product consumption, the microbiota changed to bacteria that are bile-resistant and associated with amino acid fermentation (Alistipes, Bilophila, Bacteroides), while under a plant-based diet, saccharolytic bacteria increased (Roseburia, Eubacterium rectale, Ruminococcus bromii, Faecalibacterium prausnitzii). Clear data have also been obtained from intervention studies with resistant starch in healthy adults from three continents, who all showed increases in E. rectale and R. bromii (Abell et al., 2008). Inulin, fructo- or galacto-oligosaccharide feeding led to increases in stool Bifidobacterium in both adults and children, which was partially associated with moderate health benefits. Milk oligosaccharides also led to significant fecal Bifidobacterium increases in infants (Simeoni et al., 2016). Less clear were the results from observational studies; only small effects were detected when comparing the stool microbiota in vegetarian and omnivorous subjects from case-control studies in various regions of the world (India, Slovenia, Germany, United States). Likewise, the Dutch LifeLines-DEEP study investigating the stool microbiome in more than 1000 participants for an association with 126 factors described only an association with a few food items characterized by high polyphenol content (coffee, tea, red wine) and gut microbiome, but none with a vegetarian diet. Notably, only 19% of the variation in the microbiome between the individual participants were explained by the investigated factors in this large study (Zhernakova et al., 2016). This figure points to a substantial interindividual variation of microbiota composition, which remained unexplained. It is even not clear to what extent stochastic, nondeterministic effects influence stool microbiota composition, leaving gut microbiota and health associations a difficult task.

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Gut Microbiota Changes With Age What then is actually the available evidence for gut microbiota changes with old age and its possible association with health and disease? Until the mid-1990s, studies addressed this question with cultivation methodology and reported decreases of bifidobacteria and increases of clostridia, lactobacilli, streptococci and enterobacteria with increasing age, while Bacteroidetes remained stable (Bouhnik et al., 1992). Subsequent cultivation studies revealed no consistent pattern: the small number of subjects and substantial interindividual variation prevented clear conclusions. Even when increasing the number of participants to 85 young adults and 145 healthy elderlies in four European countries and using oligonucleotide probes, no consistent pattern was seen: Elderlies from France and Sweden showed no age-related changes; German elderlies displayed increases in Eubacterium-Clostridium and BacteroidesPrevotella with age; while Italian elderlies revealed a decrease of these bacteria (Mueller et al., 2006). A study using qPCR technology showed a lower Firmicutes to Bacteroidetes ratio in infants and elderlies than in young adults from France (Mariat et al., 2009). Likewise, the ELDERMET study, which used 16S rRNA sequencing for 161 Irish subjects, demonstrated an overall increase in Bacteroidetes and a decrease in Firmicutes when compared to nine younger controls, but both bacteria groups varied over wide ranges (3%–94%) with respect to relative abundance (Claesson et al., 2012). In view of this wide variation, researchers looked for differences in more defined elderly subgroups like centenarians. An earlier Italian study revealed no major composition changes between centenarians, elderlies, and young adults, but noted in the centenarians a greater number of pathobionts associated with the concept of “inflammaging,” an increased inflammatory status in very old age (Biagi et al., 2010). Subsequent metabonomics studies revealed several microbial antiinflammatory pathways in Italian centenarians, demonstrating a remodeling of lipid and amino acid pathways and an activation of antioxidative response (Collino et al., 2013). A pilot metagenome analysis in the Italian elderly population demonstrated a loss in detection of genes for short chain fatty acid synthesis, decreases in saccharolytic potential, and increases in tryptophan and branchedchain amino acid metabolism (Rampelli et al., 2013a). When including 105–109 year old “super-centenarians,” the Italian authors found a shrinkage of the core gut microbiota and an acquisition of subdominant fraction of longevity-associated bacteria (Eggertella, Akkermansia) (Biagi et al., 2016). Some studies in Chinese centenarians revealed both age-related and diet-related gut microbiota changes that differed from the Italian observations (Wang et al., 2015), while others showed a partial overlap in microbiota shifts with the Italian centenarians (Kong et al., 2016). A large Chinese study involving more than 1000 healthy Chinese subjects between 3 and 100 years showed major gut microbiota changes in young adults, but no significant changes in older age groups except for a gradual decrease in bifidobacteria (Bian et al., 2017). Japanese elderlies showed an increase in Bacteroidetes and centenarians an additional increase in Proteobacteria (Odamaki et al., 2016), which were also increased in elderlies from Korea (Park et al., 2015). While some common trends were seen across these studies from different geographical areas, no clear conclusions can yet be drawn. Part of this ambiguity might be due to the lack of stratification in function of health status, as revealed by inclusion of centenarians. Indeed, two opposing trends become apparent in these subjects; on one side, they represent the extreme of age-associated “degenerative changes” of the gut microbiota, while on the other, centenarians represent survivors and are thus likely enriched in longevity-associated gut microbiota. It is therefore logical to further stratify the populations of interest by comparatively investigating the microbiota of healthy and frail elderlies of comparable chronological age. Indeed, the relationship between frailty and gut microbiota is also established independently of age. For instance, the twin gut microbiota studies revealed increased Eubacterium and Eggerthella and decreased F. prausnitzii abundance in frail individuals when compared with community-living younger adults (Jackson et al., 2016). Likewise, Bacteroides-Prevotella, F. prausnitzii, and Clostridium clostridiiformi were lower in hospitalized elderly patients compared to community-living elderlies (n ¼ 38, 35 respectively). Finally, a 10-fold decrease in Lactobacillus/Enterococcus and 10-fold increase in Enterobacteriaceae was seen in retirement homes residents showing high frailty scores compared to residents with low frailty (Bartosch et al., 2004). In the ELDERMET study, the community-dwelling elderlies differed from the long-stay home residents in Bacteroidetes and Firmicutes proportions. Lachnospiraceae were enriched in the community group, which also displayed higher fecal levels of short-chain fatty acids (Claesson et al., 2012). One covariate strongly correlated to those differences were the diet, which was generally different between the two groups (high fat/low fiber in the residents and moderate fat/high fiber in the community group). Looking at the duration of care for longstay individuals, diet changes were established after 1 month; however, clear change of microbiota towards the long-stay type could only be characterized after a year of care. One should keep in mind that comparisons of community versus institutionalized elderlies are further complicated by other differences that impact gut physiology, namely mastication and swallowing difficulties, salivation insufficiency, and constipation problems, which are all greater in long-stay residents than in community living elderlies. In the ELDERMET dataset, iterative binary clustering of identified gene sets associated distinctive microbiota constellations with aging. This Irish population revealed a reduced core module in elderlies dominated by Bacteroides. A diversity-associated module characterized by high microbiota diversity and Coprococcus, Prevotella and Catenibacteria was associated with a healthy high-fiber diet. A microbiota characterized by Anaerotruncus, Desulfovibrio and Coprobacillus was found in less healthy, long-term residents (Jeffery et al., 2016). Significant changes in the gut commensal bacteria composition (“dysbiosis”) was associated with mortality in a 2-year follow-up of hospitalized Italian elderlies. Interestingly, multimorbidity and frailty was not associated with dysbiosis, while polypharmacy had a significant impact. Notably, proton pump inhibitors, antipsychotic, and antidepressant drugs had the strongest effects (Ticinesi et al., 2017) concurring with recent in vitro drug effects on microbial in vitro growth (Maier et al., 2018). Antibiotic

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treatment in the elderly with nucleic acid synthesis inhibitors had a strong effect on fecal Bifidobacterium numbers, while cell envelope inhibitors impacted mostly Lactobacillus (O’Sullivan et al., 2013).

Probiotics Interventions in Elderly: Complementing the Microbiota? “The philosophers have only interpreted the world in various ways. The point, however, is to change it”; this remark of Marx applies also to microbiota research. Beyond describing age-related microbiota constellations, it is important to design intervention strategies that induce gut microbiota changes, which are associated with beneficial health effects. Based on the ideas of Metchnikoff, the introduction of dairy bacteria into the human diet was the earliest approach, which also attracted, and still does, substantial interest from the food industry. The interest first focused on lactobacilli, which are major starter bacteria in the dairy industry, and on bifidobacteria, which are the major gut bacteria of the breast-fed infant. The Japanese microbiologist Shirota already developed in the 1930s a Lactobacillus casei strain that was introduced as a dairy drink supplement on the Japanese market, and has now become an established multibillion dollar business in Japan and elsewhere. This idea was taken up by a number of Western food companies in the 1990s, leading to a wide range of probiotic products, mostly marketed as a health-promoting yogurt with claims of gut health support, including digestion as well as gut comfort, and reinforcement of immunity. The definition of probiotics has evolved over the last 50 years, comprising initially a “live food supplement, which beneficially affects the host by improving its intestinal microbial balance” (Gibson and Roberfroid, 1995). Due to the reported gut microbiota dysbiosis and the associated immune-senescence developing with old age, such a concept is of special interest to the elderly. While some progress has been made, a break-through for probiotic use in the elderly population has not yet been achieved. The reason is several-fold: on one side, only a few intervention trials with probiotics have been conducted in elderlies and many of them enrolled only modest, or even small, numbers of subjects, which limited the power of these trials to observe significant changes in the gut microbiota in a population characterized by high interindividual variability. Furthermore, not all trials were placebo-controlled, and a number of conclusions were drawn from subgroup analyses. Primary outcomes were mostly impact on the gut microbiota composition or some immune parameters, with no evident hypotheses drawn to link the two, and few medically relevant effects were documented. Questions about the efficacy of oral probiotic application are not new. A study conducted 25 years ago already showed that while about 30% of an orally applied Bifidobacterium survived gastrointestinal passage, a major in vivo amplification was not observed. Fecal titers were only maintained as long as the probiotic was consumed. One week after stopping the probiotic application, the Bifidobacterium could not any longer be detected in the stool (Bouhnik et al., 1992). The effect of oral probiotics on the gut microbiota is not well defined because of the complex interactions and interdependency of organisms in that ecosystem. For example, in a placebo-controlled Finnish study with elderlies who received a Bifidobacterium longum probiotic, an increased fecal bifidobacterial count was detected. However, this increase did not concern the applied B. longum probiotic, but two other Bifidobacterium species (Lahtinen et al., 2009). Likewise, in a study with elderlies from New Zealand who received a probiotic of a Bifidobacterium lactis strain at three different doses, only a modest 0.5 log increase in fecal bifidobacteria was demonstrated in the treatment over the control group. Notably, no difference was seen whether a high, medium, or low dose of the probiotic was applied, which raises questions about the pharmacokinetics of oral probiotic application (Ahmed et al., 2007). In the probiotic recipients, fecal lactobacilli and enterococci were also increased and enterobacteria decreased, indicating cascading reactions in the gut microbiota, which are not always well considered nor described. Surprisingly, elderlies both from Finland and New Zealand showed high preintervention titers of nearly 1010 bifidobacteria per gram stool, which might have prevented further significant increases over this level. In a follow-up cross-over study, the Finnish group compared a probiotic cheese containing Lactobacillus rhamnosus and Lactobacillus acidophilus strains versus the same cheese without probiotics (Lahtinen et al., 2012). With these lactobacilli probiotics, the researchers observed a transient fecal increase of the orally applied probiotic strains, while overall gut microbiota changes were not observed. Fecal IgA, calprotectin, or defensin levels were measured as immunological outcome parameters, but no changes with probiotic application were seen. Subgroup analysis showed a decrease in fecal Clostridium difficile with probiotics. An Italian study investigated the impact of feeding a probiotic biscuit containing B. longum and Lactobacillus helveticus. Compared to control biscuit feeding, no significant difference in gut microbiota composition was found neither for the probiotics nor other gut bacteria (Rampelli et al., 2013b). Another small cross-over trial enrolling US elderlies compared a probiotic mixture consisting of Lactobacillus gasseri, B. longum and Bifidobacterium bifidum versus placebo. As assessed by qPCR, fecal bifidobacteria increased and E. coli decreased during probiotic treatment and a less inflammatory cytokine profile was observed, but without amelioration of gastrointestinal function such as transit (Spaiser et al., 2015). The RISTOMED trial in elderly Europeans reported reduced erythrocyte sedimentation rate, plasma cholesterol, and blood glucose levels with a probiotic intervention compared to baseline. Addition of a complex probiotic mixture consisting of lactobacilli and bifidobacteria to the diet improved folate and vitamin B12 levels in the probiotic recipients without, however, causing significant gut microbiota changes. Only in a subgroup of participants with low grade inflammation at baseline was the increase in folate and vitamin B12 correlated with increases in bifidobacteria, of which some strains can indeed produce vitamin B12 (Valentini et al., 2015). One study explored a distinct probiotic candidate, namely Bacillus subtilis spores. In a relatively larger, placebo-controlled French trial, this probiotic showed no effect on the incidence of common infectious diseases in elderlies. A subgroup was investigated for laboratory parameters and showed increases in fecal spores and fecal and salivary IgA, but no effect on cytokines in the probiotic treatment group (Lefevre et al., 2015).

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Clinically relevant effects were rarely reported in probiotic trials with elderlies. As for probiotic studies in young adults, one might argue that such trials need defined groups of patients with specific disease conditions to demonstrate health effects. Along this argument, Chinese researchers treated mild dyslipidaemic elderly subjects with a B. bifidum probiotic, which indeed showed a decrease in total cholesterol and low-density lipoprotein cholesterol levels after intervention (Wang et al., 2018). In another study, Japanese elderlies who were fed via enteral tubes received either B. longum or placebo and underwent influenza vaccination. The authors observed a significant probiotic-specific Bifidobacterium increase in the stool of the test patients, but only nonsignificant changes in immune parameters and vaccine response (Akatsu et al., 2013). In another placebo-controlled trial, elderly residents from Japan received the L. casei Shirota probiotic strain during a winter season displaying a norovirus outbreak. Probiotic recipients showed a fecal titer increase of the probiotic, and an additional small increase in bifidobacteria, which correlated with increased fecal acetic acid levels. Norovirus diarrhea occurred with similar frequency and with similar symptomatology in both groups, but probiotic recipients showed a trend for lesser fever reactions (Nagata et al., 2011). The authors repeated this study in another Japanese elderly home and confirmed the increase in bifidobacterial and lactobacilli and the decrease in facultative pathogens in the stool of placebo recipients, as well as a decrease in fecal pH. Beneficial effects on constipation (mostly caused by an increase of constipation in the placebo group) and fever (liberally defined as  37 C) were observed in the probiotic recipients (Nagata et al., 2016). No clear conclusions can yet be drawn from the published studies for the impact of probiotics on the commensal microbiota composition in elderly. Notably, a detailed microbiome study in US elderlies, who were treated orally with the probiotic L. rhamnosus strain GG, showed no impact on the overall gut microbiota composition by 16S rRNA profiling. However, the transcription of genes involved in bacterial motility and adhesion from Bifidobacterium and the butyrate producers Eubacterium and Roseburia were increased by probiotic application (Eloe-Fadrosh et al., 2015), demonstrating that more subtle, but still physiologically relevant, effects can be achieved with probiotics. The World Health Organization (WHO) definition of probiotics is now, “live microorganisms which when administered in adequate amounts confer a health benefit on the host.” This definition removed the improvement of intestinal microbial balance as a probiotic selection criteria. Therefore, intervention studies using probiotics should aim to build stronger bridges between the added functionality of the probiotic to the commensal microbiota function and its impact on the host health. Focusing on functional pathways linking the probiotic to the host metabolism are thus of great importance. This definition enlarges the scope of the functionality of probiotics, which can be independent of microbiota modulation. Indeed, a direct effect on the epithelium and underlying immune system can be considered. Moreover, it is important to note that no apparent impact on bacterial composition and communities does not exclude an effect on microbial metabolic function, and thus an impact on host health.

Microbial Treatments of Antibiotic-Associated Diarrhea and Clostridium Difficile Infection Antibiotic-associated diarrhea (AAD) is a particular problem in elderly subjects and occurs in 2%–25% of patients, depending on the type of antibiotic used. AAD is normally a self-limiting disease and thought to be the result of a disruption of the physiological gut microbiota by the applied antibiotic. A subgroup of AAD cases are associated with C. difficile infection (CDI), which can lead to recurrent, difficult to treat diarrheal episodes or even pseudomembranous colitis or a toxic megacolon, both associated with high fatality rates. Interventions that help to reestablish the gut microbiota (probiotics, prebiotics) could potentially alleviate the undesired side-effects of antibiotics and therefore help against AAD/CDI. Indeed, a US study in 200 antibiotic-treated elderlies demonstrated a twofold reduction in the rate of AAD in patients treated with plain yogurt compared to placebo (Beniwal et al., 2003). Similar results were seen in Canadian elderlies treated with a fermented milk containing L. acidophilus and L. casei (Beausoleil et al., 2007). A German study enrolling 680 antibiotic-treated elderlies demonstrated an even higher threefold reduction of AAD and a suppression of CDI with L. casei Shirota over placebo recipients (Stockenhuber et al., 2008). Another study with 135 antibiotic-treated elderlies from United Kingdom, who received probiotics (L. casei and two yogurt starters Lactobacillus bulgaricus and Streptococcus thermophilus) or placebo, reported very similar probiotic efficacy (Hickson et al., 2007). Nevertheless, one should consider that the probiotic effects remains strain-specific. Indeed, while these studies suggest a consistent, reproducible, and clinically relevant result against a well-defined medical condition with probiotics, a large UK study enrolling nearly 3000 elderly, antibiotic-treated patients demonstrated no difference in AAD occurrence, diarrhea duration, diarrhea symptoms, or CDI occurrence between patients receiving probiotic or placebo (Allen et al., 2013). The probiotic preparation was as high-titered as in the trials providing positive outcomes and contained two L. acidophilus strains and two Bifidobacterium species (B. lactis and B. bifidum). The viability of the probiotic at the moment of application was verified. The discrepancy between these studies remains thus unexplained, with the only notable differences being that the larger negative study did not use L. casei as a probiotic. Recurrent CDI is difficult to treat. As in the case of AAD, a dysbiosis of the gut microbiota by antibiotic treatment is considered to be the underlying cause. It was therefore logical to use fecal microbiota transplantation (FMT) from healthy donors as a therapeutic approach. A widely quoted Dutch study reported an 81% cure rate after the first fecal infusion compared to 31% cure rate with standard therapy (van Nood et al., 2013). The observation was reproduced in a larger Canadian trial, where fresh and frozen stool material from healthy donors was used, achieved similar cure rates (Lee et al., 2016). Several microbiological studies documented that the clinical efficacy of FMT was accompanied by an increase in Bacteroidetes and Clostridium and a decrease in Proteobacteria in the treated patients, such that the gut microbiota of the patients approached the microbiota composition of the healthy donors directly after the transfer, followed by later diversification. FMT is now an FDA-recognized treatment mode for CDI. However, such an

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approach poses logistic (stool banking) and safety (donor screening for pathogens) problems. It would therefore be desirable to replace whole stool transfer by a transfer of a better-defined strain cocktail, yet with the risk of missing biologically active strains. However, the outlook is not too bleak. Thirty years ago, a Danish group had already developed a cocktail of 10 fecal bacterial commensals, which showed efficacy in treatment of CDI that was associated with three Bacteroides species (Tvede and Rask-Madsen, 1989). Efficacy of CDI treatment with a synthetic microbiome consisting of 33 defined strains was recently demonstrated in the “RePOOPulating” project (Petrof et al., 2013). An alternative approach is a Firmicutes spore preparation obtained from ethanol-treated stools of healthy donors, which showed favorable results in an open, single arm trial (Khanna et al., 2016). An interim analysis of a controlled trial could unfortunately not document a difference to the placebo group (Hudson et al., 2017). In contrast, spores from a single nontoxigenic C. difficile strain demonstrated efficacy against recurrence of CDI in a controlled, multicenter trial (Gerding et al., 2015). Recently, a new facet was added to this question by a pilot study demonstrating that the transfer of a sterile fecal filtrate also showed treatment efficacy in CDI patients. The filtrate contained bacterial DNA, bacteriocins, metabolites, human proteins, and bacteriophages (Ott et al., 2017). Possibly, transferred bacterial viruses contributed via predator-prey dynamics to the reestablishment of an equilibrated gut microbiota in CDI patients. A virome sequencing analysis in CDI patients receiving standard FMT demonstrated that responders consistently exhibited higher levels of donor-derived tailed phages (Caudovirales) and Microviridae that may prey on Proteobacteria (Zuo et al., 2018). It is tempting to associate these phages with the decrease of Proteobacteria observed after FMT, but the data are still too preliminary to allow firm conclusions. FMT is a treatment mode that consistently showed high efficacy in the treatment of CDI; what is now needed is a mechanistic understanding of its mode of action, which will then allow the use of better-defined microbial agents for clinical interventions.

Prebiotics Interventions: Feeding the Microbiota? Another way to enhance beneficial bacterial activity in the gut is to use specific ingredients that are substrates for bacteria of interest in order to boost their growth. This concept of prebiotics gained interest in the mid-20th century when several research groups found that nondigestible oligosaccharides of human milk or vegetables represent the bifidus factor (now commonly named “bifidogenic effect”), which stimulates the growth of bifidobacteria (Gyorgy et al., 1954; Kanao et al., 1965). Knowing that dietary fibers are the main nutrients for saccharolytic bacteria, diets rich in fibers have been associated with healthy aging (Gopinath et al., 2016). Knowing that fiber intake is below recommendations in most populations and particularly in elderlies, supplementation with fiber was recommended to boost saccharolytic bacteria (Cuervo et al., 2013). Prebiotics are generally carbohydrates that are not digested by the host, nor absorbed in the small intestine. When reaching the colon, they are fermented by certain groups of gut bacteria. In 1995, Gibson and Roberfroid defined prebiotics for the first time as ingredients that should have the following properties (Gibson and Roberfroid, 1995):

• • • •

Resist digestion and upper gastrointestinal tract absorption Promote selectively beneficial commensal bacteria by fermentation Change the colonic microbiota towards a “healthier composition” End products of fiber fermentation by these bacteria should be beneficial for the host

The most common and most studied prebiotics are nondigestible oligosaccharides with varying degrees of polymerization, such as fructo-oligosaccharides (FOS, derivatives from fructose-containing carbohydrates like inulin) and galacto-oligosaccharides (GOS, derivatives from lactose). Over the last 20 years, prebiotic interventions in elderly people were mainly focused on nondigestible oligosaccharides for their well-described bifidogenic effect, and beneficial clinical effects were focused on gut transit time, since constipation is a common problem in the elderly population. Intervention studies with inulin showed an increase in stool bifidobacteria as well as a laxative effect (Kleessen et al., 1997; Marteau et al., 2011). However, the increase of fermentation activity from fiber degradation was also clearly linked to an increase of gut discomfort. The administered dose varied several-fold from one study to another, and it is currently not clear whether beneficial effects can still be maintained at lower prebiotic doses that would avoid gut discomfort and flatulence. Therefore the dose effect should be carefully taken into account in further trials. Several studies using FOS showed a decrease of low-grade inflammation (Guigoz et al., 2002; Schiffrin et al., 2007), which was caused by the antiinflammatory properties of the increased short chain fatty acid (SCFAs) production by the gut bacteria. The observed benefits were limited to the length of intervention, with a return to baseline after a month of follow-up (Bouhnik et al., 2007). Fewer interventions were done using GOS, which was better tolerated in terms of gut comfort and also showed an increase in bifidobacteria and sometimes lactobacilli and concomitant decreases of blood inflammatory markers (Vulevic et al., 2008; Vulevic et al., 2015; Walton et al., 2012). Other oligosaccharides such as xylooligosaccharides (XOS) could also be of interest for the elderly population. One interesting intervention study of XOS in adults (Finegold et al., 2014) highlighted a boost of Akkermansia together with a bifidogenic effect. Akkermansia muciniphila, the only species known in this genus, is a commensal bacteria, which degrades the mucus layer and is of growing interest in microbiome research for its antiinflammatory properties and impact on host metabolism. Several intervention studies using oligosaccharides also showed an increase of F. prausnitzii (Ramirez-Farias et al., 2009; Dewulf et al., 2012), one of the main commensal gut bacteria and butyrate producers. Since Akkermansia and Faecalibacterium have been reported with lower abundance in elderly compared to younger adults and have been linked to health effects, more research needs to be done to design prebiotics trials that go beyond the widely sought bifidogenic effect to favor other potentially beneficial bacteria.

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As for probiotics, few prebiotic intervention studies have established clear mechanisms that link prebiotic supplementation with microbiota changes and health outcomes. One growing health interest in the elderly population is mineral absorption. Positive effects of prebiotics have been observed in several clinical trials (Coxam, 2007), especially in postmenopausal women. One of the suggested mechanism is linked to increase of SCFAs, which reduces intestinal pH and therefore potentially increases the solubility of minerals like calcium and magnesium, as demonstrated in several preclinical studies. Also, immunosenescence could potentially be improved by prebiotic supplementation since hospitalized, enterally-fed elderly patients showed an improved vaccine response when being fed a specifically designed prebiotic formula (Nagafuchi et al., 2015; Akatsu et al., 2016). Other ingredients like resistant starch (RS), which is often lacking in elderly diet, have been evaluated for their beneficial effects on the gut microbiota. A recent intervention trial in elderly and middle-aged participants demonstrated a bifidogenic effect of RS together with a moderate increase of butyrate in the stools of elderly subjects. Bifidobacterium cannot produce butyrate, but the authors hypothesized cross-feeding mechanisms of ruminococci by resistant starch breakdown products produced by bifidobacteria. Likewise, butyrate-producing Firmicutes were crossfed with acetate and lactate produced by Bifidobacterium. Those findings were associated with better insulin management in the elderly group, therefore confirming the potential of some form of RS as a prebiotic. However, such results cannot be generalized to all RS because of their important structural variability: more research is needed to associate chemical structure of RS, and prebiotics in general, and their prebiotic effects (Zaman and Sarbini, 2016). Gut microbiota changes are mainly measured in feces used as a proxy of what happens in the whole gut, but experimental evidence that stool faithfully represents the intestinal microbiota in humans is scarce. Prebiotics that are fermented in different regions of the intestine might stimulate distinct components of the microbiota. Different prebiotics could be combined, potentially resulting in synergistic stimulation of several microbiota components and prolong the benefit all along the colon. For example, FOS are rapidly fermented and would therefore be more active in the proximal parts of the large intestine, whereas inulin or RS are slowly fermented and therefore more active in the distal parts of the large intestine, as demonstrated in a preclinical trial (Rodríguez-Cabezas et al., 2010). In 2017, the definition of prebiotics was extended to noncarbohydrate ingredients by the International Scientific Association for Probiotics and Prebiotics (Gibson et al., 2017). This opened the door for the introduction of new ingredients as potential prebiotics, such as polyphenols. Those compounds are naturally present in plant-derived foods such as fruits, cereals, coffee, tea, and wine. In the small intestine, they are not digested and minimally absorbed (5%–10%). In the large intestine, they are either degraded by the colonic microbiota into absorbable metabolites or excreted. Phytoestrogen polyphenols have been of particular interest in aging research: from the parent compounds, they can be degraded in equol, enterolignans, and urolithins by some members of the gut microbiota. Those metabolites display antioxidative and antiinflammatory properties and have been positively associated with the management of age-related conditions, such as menopausal symptoms, cognitive decline, and bone and cardiovascular diseases (Landete et al., 2017). In view of their potential estrogen-like activity, there is some debate whether phytoestrogens qualify as a new generation of prebiotics (Rietjens et al., 2017). Polyphenols are highly variable in terms of structure, bioactivity, and stability; therefore not all polyphenols are processed similarly by the host and its gut microbiota (Tresserra-Rimbau et al., 2018). Bolca et al. introduced the term “metabotypes” to distinguish between different capacities of polyphenol metabolism, usually caused by a difference in microbiota composition (Bolca et al., 2013; Gaya et al., 2016). This interindividual variability in response to polyphenols has also been observed in fecal suspension from healthy elderlies incubated with quercetin (Tamura et al., 2017). Such a variability has also been observed in RS interventions (Venkataraman et al., 2016), where it was clearly linked to microbiota composition. The biological effects of prebiotics on the gut microbiota are therefore strongly dependent on the individual bacterial composition of the microbiota from the recipient, in addition to the prebiotic dose. Therefore, prebiotic intervention studies aiming to illustrate biological activity should consider the specific prebiotics-microbiota interactions and stratify the study population according to their baseline community composition.

Synbiotics: The Best of Both Worlds? Synbiotics combine prebiotics and probiotics, providing a nutritional push by the prebiotic to the applied probiotic to improve its survival throughout the GI tract. Elderlies received a mix of B. bifidum and B. lactis together with a chicory-derived inulin and a FOS mix, which improved the gut transit of the probiotic and also increased endogenous bifidobacteria (Bartosch et al., 2005). The beneficial effect of B. lactis on immune response was stronger when supplemented in low-fat milk rich in GOS (Chiang et al., 2000). B. longum combined with inulin and FOS increased bifidobacterial and, in parallel, butyrate production (Macfarlane et al., 2013). A mix of FOS with L. acidophilus and B. bifidum showed a beneficial effect on HDL cholesterol and reduction in fasting glycemia in type 2 diabetes patients (Moroti et al., 2012). Application of L. rhamnosus with FOS and fermented cow milk induced modest increases in blood IL-1b, IL-6, and IL-8 (Amati et al., 2010). However, most of those studies use a symbiotic versus placebo study design and not a symbiotic versus probiotic versus prebiotic group design. In a trial with a synbiotic yogurt containing FOS and L. rhamnosus LGG, improvement in constipation was mainly attributed to FOS, whereas the LGG probiotic did not seem to have a significant impact (Granata et al., 2013). Synergistic effects can thus not be deduced from these trials, which are usually only validated in vitro (Likotrafiti et al., 2016).

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A more Holistic Approach: Whole Diet Interventions Since changes in gut microbiota of elderlies have been strongly correlated with diet in the ELDERMET cohort, newer initiatives are considering a more holistic picture by evaluating the impact of a whole balanced diet on the gut microbiota composition and on healthy aging. Italian elderlies following a typical Mediterranean diet showed lower signs of cognitive decline, better independency, and better blood biochemical parameters than Italian elderlies following a nonspecified diet. The NU-AGE project is a follow up of the ELDERMET study, where the impact of a Mediterranean diet on the gut microbiota, metabolic measures, inflammatory blood markers, and health status will be investigated in a cohort of 1250 European subjects 65 years and older (Santoro et al., 2014). Data will be revealing, but gut microbiota data are not yet published at the writing of this entry.

Outlook Metchnikoff’s hypothesis linking the metabolism of gut bacteria with the aging process has been extremely fruitful. The mere fact that recent research reports in leading scientific journals have corroborated aspects of his reasoning indicates that basic aspects of his hypothesis have stood the test of time (David et al., 2014). Indeed, his ideas on the “Prolongation of Life” have become a statistical reality in industrialized countries over the last century: better food together with better health care and safer working and living conditions have contributed to this development. Yogurt is still a favorite vehicle for probiotic supplements, lactic acid bacteria still constitute the majority of investigated probiotic bacteria and a diet favoring saccharolytic gut bacteria is still considered as means of promoting health and healthy aging. Thanks to the high-throughput DNA sequencing and analysis revolutions, we can now define the gut microbiota composition in finer detail to support those hypotheses. However, a potential danger of these technologies is the data flood they generate with still very limited understanding of the ecosystem they describe. Indeed, we must ask whether the perplexing diversity of the gut microbiota composition as seen in its high interindividual variability prevents a better understanding of the microbiota-health connection. Current research is still mostly descriptive, merely associating microbiota changes with health outcomes, and we have only limited knowledge about the underlying causal relationships. Instead of focusing only on bacterial composition, considering the gut microbiota through the lens of secreted bacterial metabolic products might reveal better associations with host physiology and pathology, leading to more targeted interventions. Progress along this line has already been achieved both with diet change interventions in humans, as well as in mechanistic studies, for example evaluating the pathways of bacterial-produced SCFAs and their impact on the host physiology in animal experiments (De Vadder et al., 2014). Including metabolome analyses will likely provide mechanistic insights on the microbiome-human interaction in the gut, and will introduce new interventions possibilities such as postbiotics, by directly using the metabolic byproducts of the gut microbiome (Aguilar-Toalá et al., 2018). While we cannot see the forest for the trees yet, one can only hope that this new era of a more mechanism-oriented research will be supported by robust analytical methods. Indeed, only a proper integration of those streams of data will allow to draw a holistic picture of the gut microbiome and the host physiology as a whole ecosystem, allowing to design dietary interventions as microbiome engineering for human health.

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Wang, F., Yu, T., Huang, G., Cai, D., Liang, X., Su, H., et al., 2015. Gut microbiota community and its assembly associated with age and diet in Chinese centenarians. Journal of Microbiology and Biotechnology 25 (8), 1195–1204. Wang, K., Yu, X., Li, Y., Guo, Y., Ge, L., Pu, F., et al., 2018. Bifidobacterium bifidum TMC3115 can characteristically influence glucose and lipid profile and intestinal microbiota in the middle-aged and elderly. Probiotics Antimicrob Proteins. Zaman, S.A., Sarbini, S.R., 2016. The potential of resistant starch as a prebiotic. Critical Reviews in Biotechnology 36 (3), 578–584. Zhernakova, A., Kurilshikov, A., Bonder, M.J., Tigchelaar, E.F., Schirmer, M., Vatanen, T., et al., 2016. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352 (6285), 565–569. Zuo, T., Wong, S.H., Lam, K., Lui, R., Cheung, K., Tang, W., et al., 2018. Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome. Gut 67 (4), 634–643.

Health and Social Care Services Organization for Older Adults Natalie McNeela, University Hospital of North Midlands, Stoke-on-Trent, United Kingdom Amit Arora, University Hospital of North Midlands, Stoke-on-Trent, and Midlands Partnership Foundation Trust, Stafford, United Kingdom; and Keele University, Keele, United Kingdom Peter Crome, European Geriatric Medicine, Genoa, Italy; University College London, London, United Kingdom; and Keele University, Keele, United Kingdom © 2020 Elsevier Inc. All rights reserved.

Introduction Structure of National Health Service (NHS): A UK Perspective Chronic Disease Management and the Role of Primary Care Frailty Polypharmacy Management of Complex Patients Deconditioning Hospital Avoidance Community Care: Geriatrics and Primary Care History of Social Care in the United Kingdom Health and Social Care Interface Challenges of Social Care International Perspective Future of Health and Social Care Conclusion References Further Reading

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Glossary Clinical Commissioning Groups A group of clinicians responsible for planning and funding health services within their local area. Comprehensive Geriatric Assessment Multidisciplinary assessment of an older adult comprising medical, psychological, functional and social assessments. The gold standard approach to managing an older adult with frailty. Deconditioning A decline in physical, functional and psychological abilities as a result of prolonged bed rest and inactivity. Frailty A state of vulnerability but to loss of body reserves. It is associated with but not caused by aging. Polypharmacy The act of prescribing multiple medications. No formal agreement on the number of medications exists but usually classed as those on four to six medications a day. In older adults this increases the risk of side effects and adverse events. Telemedicine Remote delivery of health or social care using telecommunications. Workhouse A workhouse was a building for the destitute poor where housing was provided in exchange for hard labor. Workhouses also contained a medical wing where providing basic medical care and long term care for patients often with chronic disease and mental illness. At the close of the workhouse, many buildings became the new public hospital.

Introduction Geriatrics (alternatively called geriatric medicine) is the medical speciality concerned with health of older adults. The name was coined by Ignatz Leo Nascher, an Austrian-American physician, in 1909 by combining the words ‘geri’ meaning old and ‘iatrics’ the study of illness, to highlight differences between illness in older patients and normal aging (Nascher, 1909). It was further developed in the United Kingdom by Marjory Warren, often called the mother of geriatrics, when working at West Middlesex County Hospital. Tasked with treating several hundred, predominantly older adult, inpatients at a local former workhouse, she focused on treatment of their medical condition and rehabilitation to facilitate discharge home. Her paper, ‘Care of chronic sick’ (Warren, 1943), advocated a geriatric medicine approach to care highlighting the importance of reeducation and speaking to families regarding on-going care at home.

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Box 1 Branches of geriatric medicine/areas of interest for geriatricians Frailty Falls Incontinence Orthogeriatrics POPs (proactive care of older patients) Movement disorders Dementia Community geriatrics Rehabilitation and re-enablement End of life care, in collaboration with palliative care

Assessment of patients on admission to hospital. Completion of CGA with aim of facilitating rapid discharge Assessment and management of patients presenting with falls predominantly within multidisciplinary falls clinics Assessment and management of older adults with urinary and fecal incontinence Assessment of patients admitted with a fractured neck of femur. Coordinated assessment along with orthopedics and anesthetics to facilitate surgery within 48 h and early mobilization Similar to orthogeriatrics, for older adults admitted to surgery. Started at Guys and St Thomas’ hospital London Management of patients with Parkinson’s disease and similar movement disorders. Often in collaboration with neurology Management of patients with dementia and delirium Assessment of patients within the community setting including care homes Intensive rehabilitation and discharge planning following acute disease, stroke or fractured neck of femur Management of patients approaching the end of their life, in the hospital or community

Geriatrics, or care of older adults, as it is now often called has expanded since then and is now the largest speciality in the United Kingdom within the discipline of medicine. The basic mantra of advocating for older adults has not changed since its infancy and the ideas of assessment, treatment and rehabilitation are core principles for the speciality. The gold standard of care in geriatric medicine is the Comprehensive Geriatric Assessment, a multidisciplinary assessment utilizing medical, nursing and therapy professionals. The Comprehensive Geriatric Assessment is a thorough review of the complete person and has been consistently shown to reduce mortality at 6 months and progression to 24 h care along with improved cognitive function (Ellis et al., 2011; Parker et al., 2018). While it has come a long way since its inception, geriatric medicine is an expanding speciality (Box 1) and the patient group is changing. With the demographic changes, and as a result of improvements in medicine, antibiotics and sanitation, people are living longer (which is a cause for celebration) but often living with a longer list of medical conditions and medication and frequently require societal support. Adaption and cohesion between health and social care is therefore more important than ever to meet the needs of this patient population.

Structure of National Health Service (NHS): A UK Perspective The National Health Service (NHS) was devised in 1948 by Aneurin Bevin, then government minister for health, with the core principles of care that meets the needs of everyone, free at the point of delivery and based on clinical need, not the ability to pay (Gov.uk, 2015). It has since devolved into four separate entities, NHS England, Scotland, Wales and Northern Ireland (NHS England, 2016), with the aim to ensure each meets the needs of their own local community by utilizing local resources. Devolved nations have developed their own methods of health delivery. For example, in England, the funding to provider organizations is delegated to the local Clinical Commissioning Groups which are primarily run by groups of local General Practitioners (primary care physicians). Clinical Commissioning Groups allocate the budget between primary and secondary care according to their local demographics needs. Similar mechanisms of allocation exist in other devolved nations with in the United Kingdom. While the NHS has changed a lot in the last 70 years, further adaption is needed to meet the needs of an aging population. At inception, the NHS mainly treated acute illnesses prevalent then in society, while now it must not only treat the acute presentations but also chronic diseases and the consequences of living longer, as well as adopting newer medicines and technology. Life expectancy at the birth of the NHS in the 1950 census stood at 66 for males and 72 for females, increasing to 79 and 82 respectively in 2011 (Office for National Statistics, 2015). While the trend does continue to rise for life expectancy, there has been a reduced rate of growth in life expectancy since 2010, and 2018 was a significant year as life expectancy did not increase for either males or females, remaining at 79.6 and 83.2 respectively (Office for National Statistics, 2019). A significant portion of this latter trend is thought to be an increased discrepancy in life expectancy between the least and most deprived regions, a worrying trend requiring further investigation (Iacobucci, 2019). To meet the needs of this changing population, the UK Government has released a new NHS Long Term Plan for England (NHS, 2019a). This sets out the future vision for the NHS within three domains: ‘making sure everyone gets the best start in life’, ‘delivering world class care for major health problems’ and ‘supporting people to age well’. Within this final section is a particular focus on place of care by increasing funding for primary care and community services especially with regard to rapid community response teams. Dementia care and care of older adults in care homes is recognized as an increasingly important issue and should receive particular attention from policy makers.

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Chronic Disease Management and the Role of Primary Care Geriatrics has traditionally been a speciality tasked with management of chronic disease often in combination with other diseases in older people, with regular monitoring of the patient to ensure they remain stable. While the disease in question cannot be cured, treatment is intended to prevent deterioration, and preserve quality of life and functional abilities. For fairly stable patients, primary care remains best placed to monitor chronic disease. Most chronic diseases progress slowly over years requiring subtle management adjustments. Primary care has the advantage of a long-term relationship with the patient allowing recognition of subtle deteriorations missed by those who only review irregularly. The expectations on primary care for chronic disease review was formally documented in the GP contract via the Quality and Outcomes Framework (QOF) (NHS, 2019b). QOF is an annual incentive for GP practices from the Department of Health and Social Care in United Kingdom and aims to reward considered best practice within primary care with monetary rewards by assigning ‘points’ if certain standards are met. Eighteen chronic diseases have been identified of particular importance further expanded into a total of 69 subdivisions (Box 2). It aims to ensure that the patient is reviewed and leaves an audit trail of the management of each condition.

Frailty Frailty is a state of vulnerability, and though not the same as chronic disease and multimorbidity, they often coexists (British Geriatric Society, 2014). A person has frailty rather than is frail, an important distinction to make if only for the negative connotations of the word ‘frail’. Vulnerability means a lesser considered stressor, such as urinary tract infection or move to new location, can lead to significant deterioration in the functional state of the patient, lasting longer than a similar deterioration would in a healthy individual. Given that these older adults are often living just above the independence line, this stressor often leads to new care needs or temporary placement in 24 h care facility. If not, the risk is that the patient will be admitted hospital, with exposure to all the risks associated with secondary care admission (Fig. 1). Frailty is not static and an individual can move between different stages. The different stages have been categorized by many frailty identification tools. For example, one commonly used tool is the Rockwood’s Clinical Frailty Scale (Rockwood et al., 2005) (Fig. 2). This classifies function ability on a scale of 1–7, from elite athlete at 1 to severe frailty or complete dependence on other individuals at 7. Of particular interest are those classed as ‘vulnerable’ or ‘mildly frail’, stages 4 and 5 respectively. Vulnerable adults are not yet dependent on others for activities of daily living (ADLs), while mildly frail individuals require help with higher order ADLs. There is growing evidence that interventions here can reverse or slow down progression of frailty (Travers et al., 2019). Physical activity and resistance training shows good results but more research especially into physiological changes such as sarcopenia and immune aging is required.

Polypharmacy Multiple conditions may often require multiple treatments. The Health Survey for England 2016 Prescribed Medications report (NHS, 2017) reported on the number of prescribed medications for the entire population. As expected older adults are more likely

Box 2 List of QOF chronic disease domains Atrial fibrillation Secondary prevention of coronary heart disease Heart failure Hypertension Peripheral arterial disease Stroke and transient ischaemic attack Diabetes Asthma Chronic obstructive pulmonary disease (COPD) Dementia Depression Mental health Cancer Chronic kidney disease Epilepsy Osteoporosis: secondary prevention of fragility fractures Rheumatoid arthritis Palliative care

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Vulnerability of frail older adults to falls with a sudden change in health status after a minor illness. Used with permission by Dr A Clegg.

Fig. 2 Clinical Frailty Scale*. *1. Canadian Study on Health & Aging, Revised 2008; 2. Rockwood, K., et al. (2005). A global clinical measure of fitness and frailty in elderly people. Canadian Medical Association Journal 173, 489–495.

to be taking prescribed medications with over 90% of the over 75s on one or more medication. When looking at those on five or more medication this increases from 9% in the 45–54 age group to 56% in the over 85s. The term used to describe this is polypharmacy and is especially important in older adults. While no standard definition exists it is usually accepted as patients prescribed over 4–6 separate medications a day. Reasons for this include multiple comorbidities and the single organ focus that has driven health care developments in recent years. While legitimately prescribed for a certain condition, increased medication burden is not without its danger with side effects, drug-drug interactions and associated iatrogenic hospital admissions. A study in America in 2011 estimated almost 100,000 admissions a year due to adverse drug reactions with nearly half of those in the over 80 age group (Budnitz et al., 2011). Four drugs were implicated in 67% of admissions, these being warfarin, oral antiplatelet agents, insulin and oral hypoglycemic medication. Perceived high risk medication contributed to less than 2% of admissions indicating that it is the everyday, frequently prescribed medications that are causing patients harm. Garfinkel has evaluated the safety of deprescribing with a longitudinal study in Israel (Garfinkel, 2018). This study assessed older, community dwelling, adults prescribed six or more medication. The participants were divided between treatment and current practice arms, with the treatment arm undergoing a Comprehensive Geriatric Assessment in the community and medication review. Results demonstrated that the number of prescriptions in the treatment arm reduced by three or more compared to less than 2 in the

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current practice group. Importantly there was no difference in hospitalizations or mortality between the groups, with the deprescribing arm showing a nonsignificant improvement in mortality. The treatment arm also noted significantly less deterioration in mental state, sleep quality, appetite, and sphincter control with improved quality of life for those in the last years of life. However it is also important not to be too negative about medication which should not be withheld on grounds of biological age alone. Withholding appropriate prescriptions can cause more harm than over-prescribing for an unwell patient and should be equally avoided. For example, an older diabetic patient may not need strict glycemic control but may be hospitalized with hyperglycemia and hyperosmolar hyperglycemic state if not treated at all. To aid with prescribing and deprescribing in the elderly multiple tools have been created from Beers (American Geriatrics Society 2012 Beers Criteria Update Expert Panel, 2012) deprescribing list in 1991 updated in 2012, predominantly for the American market, to the STOPP/START criteria (Gallagher et al., 2008) favored by the United Kingdom and Ireland. These offer recommendations based on best evidence available but as with all people, the older adult group is heterogeneous and the recommendations may not be suitable for all patients. One to one of the skills of the geriatrician is creating that balance with the patient and their personal health plan at the center.

Management of Complex Patients With all their complexities one of the questions to be asked is who should treat these patients? Single organ specialists may be appropriate in the acute phase but balancing multiple comorbidities requires a more holistic, generalist approach. Coupled to this is a lack of evidence based medicine for this age group. Clinical trials usually rely on single organ disease and exclude older adults on age and or comorbidity (Fernando et al., 2014) forcing the clinician to extrapolate from the available clinical data or in some cases simply guess the treatment will work. The second consideration is where these patients will be treated. The nature of chronic disease suggests lack of cure and need for the patient to adapt and live with their condition. As such the burden of treatment usually falls on primary care or community teams with the aim of hospital avoidance where possible (The King’s Fund, 2010). While community care may be the ideal solution, primary care cannot be expected to possess the knowledge to manage all chronic disease in the elderly and in certain situations hospital admission may still be the best option for the patient. Many patients get admitted to acute hospitals when their needs could have been met in the community if the right facilities were available. Equally many patients have their stay in hospitals extended inappropriately due to a variety of reasons. This results in harms associated with inappropriately prolonged hospitalization leading to deconditioning and need for increased social care on discharge.

Deconditioning Deconditioning syndrome can be defined as a decline in physical, functional and psychological abilities as a result of prolonged bed rest and inactivity. Usually, seen in hospital inpatients it is not uncommon in older adults in care homes and those living alone with care support. It can affect anyone irrespective of age but in older adults it starts earlier, is more common, more severe, and can often be irreversible. For many this Hospital Acquired Functional Decline could be so severe that it could lead to premature institutionalization in a care home or even death. Deconditioning has been known about for a long time with an article by Richard Asher in 1947 discussing the effects of prolonged bed rest (Asher, 1947), but more recently the word ‘Deconditioning’ has been rejuvenated with the first ever National campaign to highlight awareness about harms of unnecessarily prolonged bed rest during hospitalization. ‘Time to Move: Sit Up, Get Dressed, Keep Moving’: National Deconditioning Awareness and Prevention Campaign; aimed at staff and public (Arora, 2017) and #EndPJparalysis (2018) have been immensely successful in raising awareness and have generated action to try to reverse the unintended harms, a hospital admission can have on an older patient. These campaigns focus on reducing the burden of admission but it is better to prevent deconditioning occurring at all (Fig. 3 and Box 3).

Hospital Avoidance Within the wider scope of chronic disease and frailty management are hospital avoidance strategies. Hospital avoidance mainly focuses on older adults presenting to secondary care as an emergency who do not require admission. Many local areas in the United Kingdom have created their own strategy with the two most popular being community assessment or front of house teams based in Emergency departments (Arora et al., 2018). Hospital avoidance can best be described using the example of a fall. An older adult presenting with a fall and unable to mobilize will call the emergency services. If not hurt a hospital avoidance community team, usually consisting of paramedic or trained nurse and occupational therapist, will assess the patient in their own environment. Quick interventions and suitable social arrangements can be timely arranged and the patient never sets foot in hospital.

PREVENTING DECONDITIONING AND ENABLING INDEPENDENCE FOR OLDER PEOPLE

A Campaign For Deconditioning Awarenessd“Sit up. Get dressed. keep on moving.”.

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Box 3 Potential harms of hospitalization for frail older adults Deconditioning syndrome including Incontinence Immobility Increased risks of institutionalization Malnutrition Pressure damage and ulcers Psychological deterioration Social isolation, depression, loss of self esteem Delirium Hospital acquired infections, e.g. hospital acquired pneumonia, Clostridium difficile diarrhea Thromboembolic events Premature decisions about future care needs in wrong setting

However if the patient does suffer an injury, such as distal radial fracture, they will still need to be assessed in the Emergency department for an X-ray and cast. The easy option here would be to admit due to fracture and increased care needs but this risks exposing the patient to hospital acquired infections and other harms associated with hospitalization like deconditioning. A timely intervention however could stop the admission, complete a comprehensive geriatric assessment and safely discharge back to the community with appropriate social input. Appropriate patient selection is vitally important for hospital avoidance strategies to work and patients should not be denied secondary care treatment simply to keep them out of hospital. There are varying levels of success but when it does work, the patient gains a full holistic review with medical treatment and social review all without setting foot in hospital. Clear lines of corporate and clinical governance and accountability are important when developing these services.

Community Care: Geriatrics and Primary Care Along with primary care, the medical speciality ideally suited for community assessment is geriatrics. Historically domiciliary visits were a routine part of a geriatrician’s job plan but these fell out of favor as clinicians were pulled back in to hospital with the aim of reducing length of stay and clinic waiting lists. Over the last few years however, community geriatrics has reemerged as a subspeciality in its own right with hospitals again employing doctors solely for the role of a community geriatrician. Community geriatricians provide an important role in community management of frail, older adults. Often these are the patients with the highest need for specialist care yet cannot travel for a hospital appointment and do not wish to be admitted. Community geriatricians review these older adults for their acute illness and by visiting their own home gain a rare insight into the everyday challenges patients are facing in their a normal life. Along with frailty, community geriatricians also manage chronic disease and conduct advanced care planning for older patients. Chronic disease management here aims to reduce symptoms as opposed to improve life expectancy. Medication reviews improve quality of life by reducing tablet burden and medication side effects along with financial gain for Clinical Commissioning Groups by reduced prescriptions. For those approaching the end of life advanced care planning is often instigated. This is a voluntary act but when completed sets out the patient’s wishes for end of life care. Many people wish to die at home or in a hospice if under palliative care (Office of National Statistics, 2016) yet all too often terminally ill patients are still admitted to hospital for active treatment in the last days of their life. Advanced care planning may be a tough discussion for some but vitally important for many patients. Reviewing where the patient is most comfortable or what matters to them improves these discussions, along with giving the doctor a true assessment of the patient’s needs in this stage of their life. Community geriatricians can act as an interface between primary and secondary care, linking with the primary care physician and community nursing teams for coordinated patient care. Geriatricians in the United Kingdom are trained in dementia and delirium care and so reviewing community patients with these conditions even if they have another acute presentation is useful. For patients recently discharged, the community geriatrician can act as a liaison officer between primary and secondary care and relaying information about the last admission and providing expert knowledge regarding the secondary care plan. Likewise primary care can relay information such as family dynamics which may not be obvious to the geriatrician. This close relationship is essential for coordinated and efficient patient care of this complex patient group. Another area of community practice to be considered is preventative care. Here primary care with their close proximity to their patients are best suited to provide. Each local area has its own demographics and challenges and the local primary care team will be acutely aware of this. A classic example of preventative medicine is the annual flu vaccine drive. Winter 2017–18 was a particularly high flu season predominantly affecting older adults and leading to increased need to seek medical attention and increased mortality. Fifty-four

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per 100,000 GP appointments were due to influenza in 2017–18 compared to 13 per 100,000 in 2016–17 in England rising to 74.5 per 100,000 in Wales with similarly raised hospital admissions (Public Health England, 2016). There was increased mortality with 15,000 extra deaths attributed to flu in England alone. Few treatments exist and so focus is mainly on vaccination to prevent influenza infection. Primary care practices, local pharmacies and community nursing teams are best suited to this due to location and opportunistic approach when reviewing patients for another reason.

History of Social Care in the United Kingdom With aging and frailty comes increased need for functional assistance for activity of daily living. Traditionally this has been within the family unit with couples living with their parents after marriage and raising children within a multigenerational living arrangement. Traditional gender roles led to the male working while the female tended to house and children. An older adult would remain at home with the younger generation providing care if required. This changed over the 20th century with increased wages and affordable housing leading to couples preferring to move in together after marriage and start a family. Gender roles have since evolved with both members working and sharing chores removing the traditional caretaker role. This along with increased life expectancy, though not increased disease-free life expectancy, led to a need for social care outside of family or charities. The origins of today’s social care lie in a 1942 paper by Sir William Beveridge entitled ‘Social Insurance and Allied Services’ which set out an insurance system for health and social care. It was then expanded upon in the 1948 National Assistance Act (law) (National Assistance Act 1948 c. 29 (Regnal. 11 and 12 Geo 6)) which led to the creation of the ‘Welfare State’ and importantly the creation of the NHS. Social care was included but unlike the NHS which was ‘free at the point of need’, social care was provided by local authorities who could charge for their services. The law stipulated the need to care for the ‘disabled, sick, aged or other persons’ but mainly was within 24 h residential care with no community care. Revisions in the 1980s with the 1988 Griffiths review and 1989 white paper ‘Caring for People’, expanded into the 1990 Community Act (law) (National Health Service and Community care act 1990 c. 19) (King’s Fund, 2006). These papers changed social care as the local authority became the care manager but not necessarily the person providing the care. It also importantly highlighted the lack of community care and how budgets could be better spent keeping older adults at home with a package of care rather than immediate residential care placement. The latest law in play currently in the United Kingdom is the Care Act which came into effect in May 2014 (Care Act 2014 c.23). The Care Act reaffirms the role of the local authority to provide care and a guarantee that everyone who requests can be assessed for care even if they later will not qualify. While encouraging a competitive care market, it also pledges that older adults will be provided with options for different care providers to choose the one they wish. Carer burden is acknowledged as a key concern with the promise to identify carers who needs are not being met.

Health and Social Care Interface A recurring theme across the multiple advice papers and government laws is a need for better cohesion between health and social care. Chronic disease exacerbations and frailty are predictable events and so is the need for increased care during these exacerbations. Failure to address these deteriorations with increased care often results in hospital admissions when adequate care could have kept the patient at home. Before this is explored further, it is important to be aware of the different levels of care available. A package of care is when a carer comes to the person’s home at set times of the day. Within the local authority care arrangement this is generally limited up to two carers calling up to four times a day. The calls vary from 15 min, often in the middle of the day, to 1 h, usually the morning call. Carers help with activities of daily living to facilitate independent living at home. The next level of care is potentially a sheltered living facility where a person moves into an apartment in a specially designed building. A warden is on site at all times and each apartment has an alarm to call for help. Carers may still call in to the flat to provide the same care as above with up to six calls a day. Although popular and often overbooked, sheltered living is rarely offered by local authorities and are usually privately arranged. Finally there is 24 h care which in the United Kingdom is further divided in to residential and nursing care. Here the resident has their own room with in a communal living setting. Carers are on site at all times to provide full care to the patient with no limit on number of calls. The decision of residential or nursing care is often confusing to the lay person. Residential homes are staffed with carers full time, trained in personal care but not nursing training. For residential care, a level of mobility is required usually able to mobilize or transfer with the assistance of one person. Healthcare needs are provided by visiting community teams allowing much of the traditional nursing care undertaken in nursing homes to be completed in the residential home. Any person requiring closer monitoring or assistance of two people for transfers usually requires a nursing home. Here personal care is again provided by carers, though there should be funding for increased staffing numbers and more frequent interaction with the service users. There is also a nurse on site at all times for nursing needs be it wounds, pressure care or complex medication. Older

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adults with severe and very severe frailty on the Clinical Frailty Scale (Rockwood et al., 2005) usually require nursing home care if in 24 h care. Twenty-four hour care is mainly provided by the private sector and funded either privately by the person themselves or via the local authority. In addition there is a third route called Continuing Healthcare or Funded Nursing Care whereby the NHS will either pay for all care or fund the nursing care required respectively (Department of Health and Social Care, 2018). Developed for patients requiring support due to a ‘primary health need’ as opposed to a social care need it has strict criteria to be met meaning full Continuing Healthcare is rarely granted. For patients admitted to hospital, the Comprehensive Geriatric Assessment can be used to assess care needs. Physiotherapy and occupational therapy assessments are of particular importance here as they focus on the patient’s mobility and ability to successfully navigate their own environment respectively. The combination of chronic disease, deconditioning and frailty results in patients often discharged at lower baselines than admission. These assessments therefore give an accurate judgment of the patient’s current function. Timing of social assessments is vital to gain accurate assessment of the patient’s current baseline but not delay discharge. To the patient, a delayed discharge risks further deconditioning, risk of hospital acquired infections and psychological deterioration. Wider economic issues exist due to a well patient occupying acute bed preventing new acute admissions. The government has recognized the issue and now the NHS can charge local authorities for each day delayed to encourage prompt discharges. To speed up the discharge process, many health care systems have arranged their own supported discharge teams with care often provided for 4–6 weeks on discharge while the social care assessments are being arranged. Frequently therapists are included in these teams, ensuring rehabilitation continues on discharge. The other favored option is emergency placement in a nursing home especially for older adults with expected complex care needs awaiting a Continuing Healthcare review. Useful for patients expected to need long term 24 h care, it should not simply be used for older adults to be discharged home for fear of the same deconditioning experienced in hospital. Hospital discharges are fairly well established with multiple systems in place and social teams present within the hospital. However in many circumstances the older person needs an increased care arrangement but not necessarily a hospital admission and here the cohesion is not always as clear. Systems are in place but variation exists between different local authorities and it is not always clear who to call for this. he ideal situation is a personalized care plan (NICE Guidance, 2015) for each older adult which has been recommended by the National Institute for Health and Care Excellence, the agency involved in suggesting best practice care and discussing healthcare issues in England and Wales. They recommend all older adults have a detailed review of their care needs with a trained individual, normally a trained nurse or social worker. An individualized care plan is then created discussing current care needs and those to be expected in the event of a sudden deterioration. Crucially, each person has a named care coordinator as a first point of contact for help who is aware of the case and has the ability to liaise with other agencies for the person. They also can signpost the patient or arrange review by medical or therapy teams for rapid intervention in the event of health deterioration (Fig. 4).

Challenges of Social Care The social work sector is under immense pressure. An aging population along with increased numbers of older adults living along at home has led to pressure on the system as never before. Local authorities are under pressure due to budget constraints and need to remain within budgets, a constraint the NHS can avoid due to emergency health funds. Many have described the social sector as at a ‘tipping point’ (King’s Fund, 2018) and how it will continue to provide this care for future generations remains yet to be seen. The UK population is growing, with the current population of 65 million expected to reach 70 million by 2030 and 73 million by 2040 while those of a pensionable age are predicted to increase from 12.4 million to 16.3 million by 2041 (UK Parliament, 2014). Healthy aging however has not increased and although people are living longer, they are living longer with chronic diseases and frailty. It is therefore reasonable to presume the length of time older adults with frailty will require for care will also increase. The care service is already struggling to meet the needs of all their service uses and longer life expectancy means an already stretched service will suffer increased pressure for the foreseeable future. There is also severe financial pressure to provide care within an already stretched local authority. On average in the United Kingdom, social care consumes 43% of a local authorities budget, amounting to £20.4 billion nationally (National Audit Office, 2018). In 2011, the UK coalition government implemented a policy of austerity to reduce the national deficit. While the social budget remained a protected expenditure and emergency budgets were later released, it has still suffered a true monetary reduction of 28%. NHS contribution has partly countered this, increasing their contribution by 25% via Continuing Healthcare and Funded Nursing Care to help fund nursing care for complex patients (Fig. 5). All of the above leads to increased financial pressure to meet the care budget. Social care underwent a change in the 1990 Community Act (National Health Service and Community care act 1990 c. 19) when the local authority became a care manager as opposed to service provider. Private, for profit, providers tender for the care contracts either in the community or 24 h care. Competition is encouraged to help keep costs low but the care providers do require payment and financial constraints risk some older adults not receiving the care they are entitled. Care is set out rigidly in a care plan, following the assessment and agreed

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Fig. 4 Integrated personalized care for people with long term conditions, older People living with frailty and people with dementia. www.england. nhs.uk. Copyright © 2018, Friedhelm Albrecht.

need from the original social worker assessment. A deterioration in frailty level should initiate an increased care response ideally in accordance with the patient’s own personalized care plan for frailty and many carers would wish to instigate this. However, due to funding and finite care calls available, a care agency is not always able to meet this. A solution would be protected empty slots to cover emergency care, but the care agencies are already overbooked and the local authority simply does not have the budget to fund this.

International Perspective The issue of balancing health and social care is not related to the United Kingdom only, but largely all over the developed world. Each country has a different health and social care arrangement, but the trend of an aging population and reduced birth rate is a common factor. A move into chronic disease and frailty as opposed to infections is experienced across the developed world and with improvements in life expectancy and public health will soon also be a problem for the developing world. As to be expected, with medical advancements, the percentage spent on health worldwide has been increasing. In the year 2000, the world on average spent 8.4% of their Gross Domestic Product on healthcare, increasing to 9.9% in 2015 (World Health Organization, 2016). Most countries across Europe, Australia and America see this upward trend in increased healthcare expenditure. The increased spend is not universal with reduced spend in some countries including Eritrea and Bhutan, however these are the exception and most other countries rich and poor have had to increased their expenditure. Large healthcare budget does not equate to full access. The United Kingdom and Canada among others offer universal healthcare funded fully through taxes. Most other countries offer a combination of private and public healthcare with Australia a classic example of this approach. In Australia universal healthcare is provided via the Medicare Benefits Scheme mainly funded by Federal and State Governments (The Commonwealth Fund, 2016a). However nearly 50% of Australian citizens have private health insurance which provides more options for hospitals and quicker referral times for nonemergency consultations. Australian citizens are actively encouraged to buy private health care through tax rebates and levy on higher earners. Other countries have an almost fully insurance system, with the United States being the classic example. Medicare is provided to those with no insurance, but most people are expected to have private cover. In 2016, 67.2% of Americans had private healthcare with a further 16.3% in receipt of Medicare (The Commonwealth Fund, 2016b). However 8.6% of Americans had no insurance which equates to 27.3 million people with no insurance. It is easy to see how older adults gain access to healthcare in publically funded systems such as United Kingdom and Canada, and via the public system of Medicare in Australia. In United States, elderly people aged over 65 are exempt from the

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Health and Social Care Spend in UK in 2016 Total Spend

Public

Healthcare

£202.5bn £157.6bn £152.4bn

Curative Care

Inpatient

£109.6bn

£68.4bn Day Case

£96.6bn Outpatient

£50.1bn Preventative Care

£10.3bn Medical Goods

£26.5bn Administration and other

£9.6bn Long term Care (Health)

Home care

£17.1bn

£35.5bn Inpatient (for total see above) Long term Care (Social)

£10.9bn Private

£44.9bn

Insurance Private sector (predominantly for contributes to health healthcare) and social care across the spectrum £7.2bn Non-Profit Sector

£7.5bn Personal out of pocket payments

£30.3bn Fig. 5 Health and Social Health Spend in the United Kingdom in 2016. Adapted with permission from Appleby, J. (2019). What does the UK spend on Health and Social Care? British Medical Journal 365, l1619.

need for private healthcare with 95% eligible for the publically funded Medicare and Medicaid (National Research Council (US) Panel on Statistics for an Aging Population, 1988). Medicare consists of two branches: ‘Hospital Insurance’ to cover hospital admissions, care facilities and home carers, and ‘Supplementary Medical Insurance’ to cover outpatient services and the cost of the physician. However this rarely covers mental health, and coverage for other services such as medication and dental work is also often not covered (Osborn et al., 2017). Twenty three percent of older adults in the United States reported forgoing an appointment or prescription due to costs, increasing to 31% in those classed as ‘high need’ (multiple chronic conditions or need assistance with activity of daily living), compared to less than 5% for countries with universal healthcare.

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Future of Health and Social Care With all the challenges and aging population, what is to be expected in the future of health and social care? One area which can help is technology and telemedicine is already used by many older adults. Fall pendant alarms have been around for a few years and originally required the older person to manually activate the alarm. While useful, this requires the person to have intact cognition to press the alarm, neglecting those with cognitive impairment or loss of consciousness from the fall. The next generation fall alarms now automatically trigger on sensing a fall, removing the need for the patient to manually activate. Some have even trialed inflatable cushions which act as safety bags as in cars. Telemedicine is now expanding with private companies developing health apps on smart phones monitoring anything from blood sugars to blood pressure that automatically send the information to a chosen healthcare provider. For older adults, telemedicine can send medication reminders to improve concordance along with reminders to move and keep active (Florence, 2019). It is still in its infancy but telemedicine is expected to play a larger role in health and social care in the future. With regard to both, health and social care, robotics and Artificial Intelligence (AI) inevitability will play a role. Robotics exist currently to improve mobility such as transferring out of a chair, or to help with cleaning and vacuuming. Prototypes also exist of robotics to transfer off a toilet and help with feeding. A Parliamentary review suggested implementation of robotics within social care may save up to £6 billion annually (Houses of Parliament, 2018). For the future of health and social care integration, multiple models are being trialed. One of the best known is the Greater Manchester Health and Social care partnership (Greater Manchester, Health and Social Care Partnership, 2019) (DEVO-MANC) where the health and social care budget has been combined. A total of £6 billion was granted to Greater Manchester to fund both health and social care. The project is currently in its third phase with results yet to be seen if full devolution and combined health and social care improves care for older adults (Walshe et al., 2018).

Conclusion Geriatric medicine is a complex speciality treating any condition experienced in the over 65s. From its infancy it has specialized in management of chronic disease and rehabilitation and as the population has grown with increased number of chronic diseases, it has evolved into a speciality dealing with multiple comorbidities in older adults. While geriatric medicine has always appreciated the interaction between health and social care, never believing them to be separate entities, this has not always played out in practice across the components of health and social care systems. The outer phenotype of chronic disease or frailty can easily be assessed as ‘social’ leading older adults away from a geriatric review and Comprehensive Geriatric Assessment. Missed diagnoses and lack of rehabilitation risk exacerbating a deconditioning to a new normal for the patient of severe disability. Health and social care services have finally reached a stage where integration is accepted as one of the key solutions to manage complex conditions. A personalized patient passport created for each patient with frailty outlines their treatment plans and social support escalation. Coordinated hospital discharges transition the older adult from hospital to community care seamlessly. Finally a named care coordinator oversees, providing the person with one number to call to seek help and reduce the need for emergency admissions simply due to care deterioration. By complete integration and implementation of the above each older person can hopefully receive the gold standard health and social care. Older people deserve no less.

References #EndPJparalysis, 2018. https://www.endpjparalysis.com (accessed 12.04.19). American Geriatrics Society 2012 Beers Criteria Update Expert Panel, 2012. American Geriatrics Society Updated Beers Criteria for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society 60 (4), 616–631. Arora, A., 2017. Time to move: Get up, get dressed, keep moving. BGS Newsletter 60, 20. Arora, A., Holmes, E., Morris, A.M., Norton, J., Bates, T., 2018. Admission avoidance in emergency departmentdWhat works for frail older people: The exemplar front door (EFD) initiative. Age and Ageing 47 (Suppl 3), iii31–iii42. Asher, R., 1947. The dangers of going to bed. British Medical Journal 2, 967. British Geriatric Society, 2014. Introduction to frailty, fit for frailty. Best practice guide. https://www.bgs.org.uk/sites/default/files/content/resources/files/2018-05-14/fff2_short.pdf (accessed 12.04.19). Budnitz, D., Lovegrove, M., Shehab, N., Richards, C., 2011. Emergence hospitalisations for adverse drug events in older Americans. The New England Journal of Medicine 365, 2002–2012. Department of Health and Social Care, 2018. National framework for NHS continuing healthcare and NHS-funded nursing care. October 2018 (revised). https://assets.publishing. service.gov.uk/government/uploads/system/uploads/attachment_data/file/746063/20181001_National_Framework_for_CHC_and_FNC_-_October_2018_Revised.pdf (accessed 12.04.19). Ellis, G., Whitehead, M.A., O’Neil, D., Langhorne, P., Robinson, D., 2011. Comprehensive geriatric assessment for older adults admitted to hospital. Cochrane Database of Systematic Reviews (7), CD006211. Fernando, P., Arora, A., Editorial, C.P., 2014. Inclusion of older people in interventional clinical trials. The Clinical Investigator 4 (1), 87–99. Florence, 2019. https://www.getflorence.co.uk/ (accessed 12.04.19). Gallagher, P., Ryan, C., Byrne, S., Kennedy, J., O’Mahony, D., 2008. STOPP (screening tool of older person’s prescriptions) and START (screening tool to alert doctors to right treatment). Consensus validation. International Journal of Clinical Pharmacology and Therapeutics 46 (2), 72–83.

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Garfinkel, D., 2018. Poly-de-prescribing to treat polypharmacy. Therapeutic Advances in Drug Safety 9 (1), 25–43. Gov.uk, 2015. Guidance: NHS constitution for England. https://www.gov.uk/government/publications/the-nhs-constitution-for-england (accessed 12.04.19). Greater Manchester, Health and Social Care Partnership, 2019. Let’s take charge of our health together. http://www.gmhsc.org.uk/our-plans/ (accessed 12.04.19). Houses of Parliament, 2018. Parliamentary office of science and technology: Robotics in social care. https://researchbriefings.parliament.uk/ResearchBriefing/Summary/POST-PN0591 (accessed 12.04.19). Iacobucci, G., 2019. Life expectancy gap between rich and poor in England widens. BMJ 364, l1492. King’s Fund, 2006. Securing good care; taking a long term view. https://www.kingsfund.org.uk/sites/default/files/field/field_publication_file/securing-good-care-for-older-peoplewanless-2006.pdf (accessed 12.04.19). King’s Fund, 2018. Key challenges facing the adult social care sector in England. https://www.kingsfund.org.uk/sites/default/files/2018-12/Key-challenges-facing-the-adult-socialcare-sector-in-England.pdf (accessed 12.04.19). Nascher, J.L., 1909. Geriatrics. New York Medical Journal 90, 358–359. National Audit Office, 2018. Adult social care at a glance. https://www.nao.org.uk/wp-content/uploads/2018/07/Adult-social-care-at-a-glance.pdf (accessed 12.04.19). National Research Council (US) Panel on Statistics for an Aging Population, 1988. The aging population in the twenty-first century. National Academies Press, Washington, DC. NHS, 2017. Digital: Health survey for England 2016 prescribed medications. http://healthsurvey.hscic.gov.uk/media/63790/HSE2016-pres-med.pdf (accessed 12.04.19). NHS, 2019a. The NHS long term plan. https://www.longtermplan.nhs.uk/wp-content/uploads/2019/01/nhs-long-term-plan.pdf (accessed 12.04.19). NHS, 2019b. Digital: Quality and outcomes framework. https://qof.digital.nhs.uk/ (accessed 12.04.19). NHS England, 2016. Devolution: What does it mean from an NHS England perspective? https://www.england.nhs.uk/commissioning/wp-content/uploads/sites/12/2016/05/ devolution-publication.pdf (accessed 12.04.19). NICE Guidance, 2015. Older people with social care needs and multiple long-term conditions. https://www.nice.org.uk/guidance/ng22/evidence/full-guideline-552742669 (accessed 12.04.19). Office for National Statistics, 2015. How has life expectancy changed over time. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/lifeexpectancies/ articles/howhaslifeexpectancychangedovertime/2015-09-09 (accessed 12.04.19). Office for National Statistics, 2019. Quarterly mortality report, England: October to December 2018 and year-end review. https://www.ons.gov.uk/peoplepopulationandcommunity/ birthsdeathsandmarriages/deaths/articles/quarterlymortalityreports/octobertodecember2018andyearendreview (accessed 12.04.19). Office of National Statistics, 2016. National Survery of Bereaved People (VOICES): England, 2015. Quality of care delivered in the last 3 months of life for adults who died in England. https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthcaresystem/bulletins/nationalsurveyofbereavedpeoplevoices/england2015#preferences-and-choiceat-the-end-of-life (accessed 19.03.19). Osborn, R., Doty, M.M., Moulds, D., Sarnak, D.O., Shah, A., 2017 Dec. Older Americans were sicker and faced more financial barriers to health care than counterparts in other countries. Health Affairs 36 (12), 2123–2132. Parker, S.G., McCue, P., Phelps, K., et al., 2018. What is comprehensive geriatric assessment (CGA)? An umbrella review. Age and Ageing 47 (1), 149–155. Public Health England, 2016. Surveillance of influenza and other respiratory viruses in the UK: Winter 2017 to 2018. https://assets.publishing.service.gov.uk/government/uploads/ system/uploads/attachment_data/file/740606/Surveillance_of_influenza_and_other_respiratory_viruses_in_the_UK_2017_to_2018.pdf (accessed 12.04.19). Rockwood, K., Song, X., MacKnight, C., et al., 2005. A global clinical measure of fitness and frailty in elderly people. Canadian Medical Association Journal 173 (5), 489–495. The Commonwealth Fund, 2016a. International healthcare system profiles; Country Australia. https://international.commonwealthfund.org/countries/australia/ (accessed 12.04.19). The Commonwealth Fund, 2016b. International healthcare system profiles. Country United States of America. https://international.commonwealthfund.org/countries/united_states/ (accessed 12.04.19). The King’s Fund, 2010. Avoiding hospital admissions. Lessons from evidence and experience: Seminar highlights. https://www.kingsfund.org.uk/sites/default/files/field/field_ publication_file/avoiding-hospital-admissions-lessons-from-evidence-experience-ham-imison-jennings-oct10.pdf (accessed 12.04.19). Travers, J., Romero-Ortuno, R., Bailey, J., Cooney, M.T., 2019. Delaying and reversing frailty: A systemative review of primary care interventions. The British Journal of General Practice 69 (678), e61–e69. UK Parliament (2014) Social indicator. Researchbriefings.files.parliment.uk/documents/RP13-16/RP13-16.pdf (accessed 12.04.19) Walshe, K., Lorne, C., Coleman, A., McDonald, R., Turner, A., 2018. Devolving health and social care: Learning from Greater Manchester. The University of Manchester, Manchester. Warren, M.W., 1943. Care of chronic sick. British Medical Journal 2 (4329), 822–823. World Health Organization, 2016. Global health expenditure database. http://apps.who.int/nha/database/Select/Indicators/en (accessed 12.04.19).

Further Reading Cochrane review of Comprehensive geriatric assessment: Ellis, G., Whitehead, M.A., O’Neil, D., Langhorne, P., Robinson, D., 2011. Comprehensive geriatric assessment for older adults admitted to hospital Cochrane Database of Systematic Reviews (7), CD006211. Clinical frailty scale: Rockwood, K., Song, X., MacKnight, C., et al., 2005. A global clinical measure of fitness and frailty in elderly people Canadian Medical Association Journal 173 (5), 489–495. Deprescribing and polypharmacy: Garfinkel, D., 2018. Poly-de-prescribing to treat polypharmacy Therapeutic Advances in Drug Safety 9 (1), 25–43.

Heart Failure in Older Patients Krzysztof Rewiuk and Tomasz Grodzicki, Jagiellonian University Medical College, Cracow, Poland © 2020 Elsevier Inc. All rights reserved.

Epidemiology Diagnosis Treatment References Further Reading Relevant Websites

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Epidemiology Heart failure (HF) is a multifaceted clinical condition in which functional and structural heart dysfunction leads to other systems deterioration as the brain, kidneys, liver, lungs bones and muscles and significantly affecting everyday life. The progressive nature of that chronic condition significantly affects quality of life, with a high risk of mortality and hospitalization, especially among the older people (Cleland et al., 2011; Oudejans et al., 2012; Kannel, 2000). The majority of HF cases in adults are a consequence of former arterial hypertension, and coronary heart disease (CHD) (Mosterd and Hoes, 2007). Due to population aging, the age-associated occurrence of that diseases the incidence of HF surges with advanced age. Ironically, advances in CHD treatment like better survival in acute myocardial infarction (MI) due to the development of invasive strategies such as angioplasty as well as widespread cardioverter implantation post MI contribute to the epidemic of HF in older adults (Najafi et al., 2009). Finally, the results of the multiple epidemiologic observations show an increasing proportion of patients with HF who were over 80 years old. As can be expected, elderly subjects with HF present not only heart dysfunction but also coexisting multimorbidity (Mogensen et al., 2011; Skalska et al., 2014) and functional limitations concurrently with social and economic problems (Sanchez et al., 2011; Komajda et al., 2009; Rodriguez-Pascual et al., 2012). Comorbidity is a specific feature of older HF patients across the world due to the nature of that disease and exerts a great impact on the morbidity, physical and functional status and increased mortality (Mogensen et al., 2011; Skalska et al., 2014). These findings emphasize the need for careful assessment and treatment of diseases other than HF. The presence of at least one geriatric condition such as dementia, depression, falls or incontinence was found in 43% of the patients hospitalized for HF (Chaudhry et al., 2010) and in 52% of those hospitalized due to decompensated HF (Martin-Sanchez et al., 2012). Moreover, limitations in basic activities of daily living (ADL) were present in 11% of HF subjects in the NHANES (The National Health and Nutrition Examination Survey) study and 17% of HF patients in the Health and Retirement Study (HRS) (Wong et al., 2011; Gure et al., 2008). Impairment in at least one of the IADL activities was found in half of the patients with the history of HF hospitalization which was similar to the results of HRS. Disability in IADL in Polish study POLSENIOR was found in 25% of patients with the history of HF hospitalization, while in HRS, it was noted in 10% of HF subjects (Skalska et al., 2014; Gure et al., 2008). The most frequently described functional limitations were problems with shopping, traveling or household chores. Cognitive impairment has been shown to be present in 20%–30% of HF older subjects and some studies suggested that dementia was more frequent in HF patients in comparison to subjects free from cardiovascular diseases (Gure et al., 2008). Of note, cognitive impairment significantly influences self-care and cooperation with patients and increases risk of nonadherence, rehospitalization, and death (Chaudhry et al., 2010). Depression is another of geriatric giants presented frequently in HF patients related to the patients’ age, functional limitations and severity of HF and it strongly influences quality of life, drug compliance or weight control (DeWolfe et al., 2012). Taking into account observations indicating the high prevalence of functional limitations, dementia, depression or frailty in the geriatric patients with HF and its’ relationship with indicators of poor prognosis such as hospitalizations or death rate it seems mandatory to include comprehensive geriatric assessment (CGA) to standards of care on HF patients. Of note, the Multidimensional Prognostic Index based on a CGA was found to be a reliable predictor of short-term mortality in older HF patients (Pilotto et al., 2010).

Diagnosis The clinical manifestation of HF in older patients could be difficult to interpret due to numerous concomitant diseases and altered behavior of patients. The most common symptoms of HF, in essence nonspecific, like: breathlessness, reduced exercise tolerance, fatigue, tiredness may be either actually triggered or incorrectly attributed to coexisting pathology of respiratory, musculoskeletal, endocrine system, anemia, or even depression. Urinary tract diseases may affect the presence of nycturia, and renal failure, as well as venous insufficiency may be responsible for the presence of lower limb edema. In the study of Oudejans et al. (2011) only 46% of

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older patients who had presented with symptoms of breathlessness, fatigue or ankle swelling have later confirmed the diagnosis of HF. The main predictors of HF in this population were in fact: male sex, older age, nocturnal dyspnea, absence of wheezing (as exclusion of bronchial obstruction), loss of appetite and lower body mass index. On the other hand limited physical activity could mask the presence of exercise dyspnea or tachycardia. In cited study only 32% of patients presented typical signs (tachycardia, tachypnea, pulmonary rales, pleural effusion, elevated jugular venous pressure, peripheral edema, or hepatomegaly) in physical examination. However, it should be strongly emphasized that the above mentioned symptoms and signs cannot be treated as a normal phenomenon in older adults and each time an attempt should be made to explain their etiology. Objective confirmation of heart failure is performed by means of echocardiography and/or determination of the level of natriuretic peptides (Ponikowski et al., 2016). The diagnostic value of both methods is limited in elderly patients. Achieving a good quality echocardiographic image may be difficult due to patient obesity, emphysema or difficulty in maintaining the patient’s proper body position during the examination. However, determining the global left ventricular systolic function usually does not present a special difficulty. A much more serious problem is the interpretation of heart function in conditions of heart failure with preserved systolic function (HFpEF). The assessment of mitral inflow and mitral ring motion, usually used for this purpose, cannot be used to assess the left ventricular diastolic function under conditions of atrial fibrillation (AF) frequently present in elderly patients. Indirect indications of left ventricular impaired relaxation include hypertrophy of the left ventricle and enlargement of the left atrium (in the absence of atrial fibrillation or important valve disease) (Ponikowski et al., 2016). It should be also noted that echocardiographic norms have been developed on the basis of observations of younger patients, and in the case of the older population, the indexing of individual parameters to the patient’s body surface is of particular importance (Manzano et al., 2012). Determination of the level of natriuretic peptides, markers of increased heart wall stress, was introduced into the medical practice as a simple way to confirm cardiac etiology of dyspnea. European Society of Cardiology (ESC) Guidelines propose the levels of 125 pg/mL for N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and 35 pg/mL for brain natriuretic peptide (BNP) in chronic condition or 300 pg/mL for NT-proBNP and 100 pg/mL for BNP in patients with acute symptoms as cut-off points for HF diagnosis (Ponikowski et al., 2016). Unfortunately, the concentration of these substances in the blood serum of healthy subjects increases with age (Wang et al., 2002) and the cut-off point for the elderly population has not yet been determined. Moreover, diseases such as atrial fibrillation, kidney failure or chronic obstructive pulmonary disease as well as cachexia can affect the level of natriuretic peptides, making it difficult to interpret the obtained result. It seems that NT-proBNP is more accurate in confirmation of HF in older patients (Costello-Boerrigter et al., 2006). One of the simpler tests useful in the diagnosis of HF is a resting electrocardiography (ECG) test. The correct recording, without the features of arrhythmia and conduction disturbances, cardiac cavities hypertrophy or ischemic changes, makes the diagnosis of HF unlikely, although it does not exclude it completely (e.g., in the case of paroxysmal AF). Summing up, the diagnosis of HF in older adults is based on the combined interpretation of symptoms, signs and additional tests taking into account the accompanying diseases as well as somatic and mental functional state of the patient. A negative result of one of the above aspects should not in itself constitute grounds for ruling out the diagnosis. In case of HF confirmation, it is necessary to perform a number of additional tests (unless they have been carried out earlier in the course of diagnostics). The list of tests recommended by ESC includes ECG, chest X-ray, hemoglobin and WBC, sodium, potassium, urea, creatinine (with estimated GFR), liver function tests, glucose, HbA1c, TSH, ferritin, TIBC (Ponikowski et al., 2016). Among them, thyroid function tests and iron deficiency/anemia tests are particularly important in elderly patients. Recently, attention was drawn to the fact that in elderly people an important indicator of recurrent hospitalizations and the risk of death are the presence of memory disturbances, muscle weakness, depression and disability (Green and Maurer, 2013). For this reason, it is advisable to perform a comprehensive geriatric assessment for any older patient diagnosed with HF. HF diagnostic diagram in elderly patients is presented in Fig. 1.

Treatment Similarly to the diagnosis, also the treatment of older patients with HF is characterized by some differences in comparison with the younger population. The basic difficulties that should be taken into account when planning an older person’s treatment include: comorbidity, connected polypharmacy risk, altered drug pharmacokinetics, and diminished patient cooperation in the case of cognitive impairment as well as economic or social limitations (Guerra et al., 2017). Nevertheless international guidelines do not treat old age as an indication or contraindication to any specific method of pharmacotherapy, paying attention only to the necessity of gradual inclusion and slow increase of doses of individual drugs, more frequent monitoring of treatment effects, avoidance of polypharmacy and consideration of withdrawal of drugs that do not bring a patient-perceived beneficial effect (Ponikowski et al., 2016). Most of the data on which the current heart failure with reduced ejection fraction (HFrEF) treatment standards are based is derived from large randomized trials in which elderly patients were insufficiently represented. The mean age of patients included to HFrEF trials in years 1987–2014 was 62 years (Burnett et al., 2017). Even in studies aimed at elderly patients, the pre-existing exclusion criteria caused that their participants do not reflect the real population of older people. Generally, analysis of data from randomized trials shows that beneficial effect of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in HFrEF is consistent in all age subgroups (Guerra et al., 2017). Moreover, the absolute benefit of using these drugs may be higher in older patients, as their risk of cardiovascular death or exacerbation of

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Signs and/or symptoms suggesting HF

Natriuretic peptides NT-proBNP > 125pg/ml BNP> 35pg/ml

HF unlikely, consider other diagnosis

no

no

Echocardiography EF 65 years (mean age 71) was The Losartan Heart Failure Survival Study (ELITE II) comparing the efficacy and safety of losartan and captopril. The study did not show differences in the effectiveness of both drugs, although ARB was better tolerated (Pitt et al., 2000). Nevertheless, current recommendations indicate a clear advantage of ARB only in the case of ACE inhibitors intolerance. When starting treatment with drugs acting via renin-angiotensin-aldosterone (RAA) axis, the physician should remember about the risk of orthostatic hypotension, deterioration of kidney function and hyperkalemia, in particular in dehydrated patients and those using other drugs affecting renal function. The only one study exclusively confirming the effectiveness and safety of the beta-blocker in the elderly population (mean age 76 years) was Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure (SENIORS) showing a 14% reduction in total mortality and hospitalization from cardiovascular causes in the nebivolol treatment group compared to placebo (Flather et al., 2005). In the remaining studies, the percentage of patients over 65 years of age did not exceed 45%, however, comparison of subgroups of younger and older patients did not indicate differences in the safety and efficacy of the treatment (Guerra et al., 2017). Again, it should be emphasized that the inclusion of the drug should start at a low dose and its up titration should be gradual to avoid the risk of substantial bradycardia. Effectiveness of spironolactone and eplerenone was confirmed in particular studies, showing no difference between patients younger and older than 65 years (Pitt et al., 1999; Zannad et al., 2011). Therapy with these drugs in older age require closer monitoring of renal function and hyperkalemia.

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Newer drugs like ivabradine and sacubitril/valsartan have been studied in individual studies in HFrEF, including respectively 30% and 50% of participants over 65 years. In both cases, the beneficial effect of the drug was independent of the age of the subjects (Tavazzi et al., 2013; McMurray et al., 2014). Diuretics are used in HF to eliminate the symptoms of congestion, their effect is limited to reducing symptoms and improving the comfort of life without affecting the distant prognosis (Ponikowski et al., 2016). The dose of diuretic should be as low as possible and regularly modified depending on the hydration status of the patient. Hypokalemia caused by these drugs may be the cause of life-threatening cardiac arrhythmias, and hyponatremia or dehydration itself may lead to confusion and delirium. The group of drugs clearly more often used in elderly patients are digitalis. We have one clinical trial evaluating the efficacy and safety of digoxin, indicating a reduction in the frequency of hospitalizations without a significant impact on patients’ mortality. Subanalysis indicates the possibility of lower mortality among patients with lower serum levels of digoxin (0.5–0.9 ng/mL) (Adams et al., 2016). Although these results come from the era before the widespread introduction of currently routinely used drugs, digoxin still has its place in symptomatic therapy, especially in patients with concurrent AF. Cardiac resynchronization therapy (CRT) reduce all-cause mortality and HF hospitalization as well as improve New York Heart Association (NYHA) class and quality of live in patients with symptomatic HFrEF, ejection fraction  35%, wide QRS duration (Ponikowski et al., 2016). Although elderly patients were inadequately represented in CRT trials, posthoc analyses show that beneficial effect of this therapy is consistent all across age spectrum. Data from The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) suggest that among patients with NYHA I-II class benefit could be even more important in older patients (Penn et al., 2011). In contrast, implantable cardioverter-defibrillator (ICD) decrease the risk of sudden cardiac death at the expense of the patient’s quality of life. Therefore, it should be remembered that indications for ICD implantation do not include patients in functional class IV and with expected survival time below 1 year. Despite the results of the meta-analysis of Santangeli et al. (2010), and the DANISH study (Køber et al., 2016) indicating the lack of benefits from ICD implantation in patients > 60 years of age, another meta-analyses (Kong et al., 2011; Earley et al., 2014) did not show a difference in benefits dependent on the age of patients. However, it should be remembered that the percentage of sudden cardiac deaths decreases in this age group in favor of deaths with a noncardiac cause, which ultimately limits the benefits of the treatment. Although current international guidelines state that carefully selected patients > 70 years of age may be considered for cardiac transplantation (Mehra et al., 2016), the limited availability of donors in practice reduce the use of this treatment method. Instead, we observe in this group an increasing use of left ventricle assist devices (LVAD) as a target therapy rather than a bridging therapy. Data on the effectiveness and safety of mechanical support in the oldest age group are inconsistent (Rose et al., 2001; Kirklin et al., 2017). It seems, however, that age should not in itself constitute contraindications for LVAD therapy, provided that the indications and the risk of surgery are clearly defined. Even more than half of HF elderly patients are presented with HFpEF. So far, none of the large randomized trials confirm the effect of drugs used in HF to reduce mortality in these population. Nebivolol, candesartan, digoxin and spironolactone were able to reduce HF hospitalization in HFpEF patients without AF. Guidelines underline the need of symptoms amelioration with use of diuretics (Ponikowski et al., 2016). The guidelines point to the benefits of the support from a multidisciplinary therapeutic team including geriatrician and the need to involve family or caregivers in the therapeutic process of an elderly HF patient (Ponikowski et al., 2016). Palliative care should be gradually introduced at an early stage of the disease. A decision to alter the focus of care from changing the distant prognosis to optimizing quality of life should be made in discussion with the patient. Specific therapy ameliorating symptoms in end-phase of HF includes, among others: morphine, oxygen therapy, diuretics, inotropic agents and requires decision regarding the withdrawal of antihypertensive drugs to maintain sufficient oxygenation and reduce the risk of falls. The holistic approach also refers to the psychological and spiritual aspects of patient care and supports the family and caregivers during illness and mourning. Details of palliative care in HF including decisions on abandoning resuscitation efforts and deactivation of ICD are discussed in the relevant document (Jaarsma et al., 2009).

References Adams, K.F., Butler, J., Patterson, J.H., et al., 2016. Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial. European Journal of Heart Failure 18, 1072–1081. Burnett, H., Earley, A., Voors, A.A., et al., 2017. Thirty years of evidence on the efficacy of drug treatments for chronic heart failure with reduced ejection fraction: A network metaanalysis. Circulation: Heart Failure 10 (1) pii: e003529. Chaudhry, S.I., Wang, Y., Gill, T.M., Krumholz, H.M., 2010. Geriatric conditions and subsequent mortality in older patients with heart failure. Journal of the American College of Cardiology 55, 309–316. Cleland, J.G., McDonagh, T., Rigby, A.S., et al., 2011. The national heart failure audit for England and Wales 2008–2009. Heart 97, 876–886. Costello-Boerrigter, L.C., Boerrigter, G., Redfield, M.M., et al., 2006. Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in the general community: determinants and detection of left ventricular dysfunction. Journal of the American College of Cardiology 47, 345–353. DeWolfe, A., Gogichaishvili, I., Nozadze, N., et al., 2012. Depression and quality of life among heart failure patients in Georgia, Eastern Europe. Congestive Heart Failure 18, 107–111. Earley, A., Persson, R., Garlitski, A.C., Balk, E.M., Uhlig, K., 2014. Effectiveness of implantable cardioverter defibrillators for primary prevention of sudden cardiac death in subgroups: A systematic review. Annals of Internal Medicine 160, 111–121. Flather, M.D., Shibata, M.C., Coats, A.J.S., et al., 2005. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). European Heart Journal 26, 215–225.

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Green, P., Maurer, M.S., 2013. Geriatric assessment of older adults with heart failure: An essential tool in planning of care. The American Journal of Medicine 126, 93–94. Guerra, F., Brambatti, M., Matassini, M.V., Capucci, A., 2017. Current therapeutic options for heart failure in elderly patients. BioMed Research International 2017, 1483873. Gure, T.R., Kabeto, M.U., Blaum, C.S., Langa, K.M., 2008. Degree of disability and patterns of caregiving among older Americans with congestive heart failure. Journal of General Internal Medicine 23, 70–76. Jaarsma, T., Beattie, J.M., Ryder, M., et al., 2009. Palliative care in heart failure: A position statement from the palliative care workshop of the Heart Failure Association of the European Society of Cardiology. European Journal of Heart Failure 11, 433–443. Kannel, W.B., 2000. Incidence and epidemiology of heart failure. Heart Failure Reviews 5, 167–173. Kirklin, J.K., Pagani, F.D., Kormos, R.L., 2017. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. The Journal of Heart and Lung Transplantation 36, 1080–1086. Køber, L., Thune, J.J., Nielsen, J.C., et al., 2016. Defibrillator implantation in patients with nonischemic systolic heart failure. NEJM 375, 1221–1230. Komajda, M., Hanon, O., Hochadel, M., et al., 2009. Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II. European Heart Journal 30, 478–486. Kong, M.H., Al-Khatib, S.M., Sanders, G.D., Hasselblad, V., Peterson, E.D., 2011. Use of implantable cardioverter-defibrillators for primary prevention in older patients: A systematic literature review and meta-analysis. Cardiology Journal 18, 503–514. Manzano, L., Escobar, C., Cleland, J.G.F., Flather, M., 2012. Diagnosis of elderly patients with heart failure. European Journal of Heart Failure 14, 1097–1103. Martin-Sanchez, F.J., Gil, V., Llorens, P., et al., 2012. Barthel Index-Enhanced Feedback for Effective Cardiac Treatment (BI-EFFECT) study: Contribution of the Barthel Index to the Heart Failure Risk Scoring System model in elderly adults with acute heart failure in the emergency department. Journal of the American Geriatrics Society 60, 493–498. McMurray, J.J.V., Packer, M., Desai, A.S., et al., 2014. Angiotensin neprilysin inhibition versus enalapril in heart failure. NEJM 371, 993–1004. Mehra, M.R., Canter, C.E., Hannan, M.M., et al., 2016. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. The Journal of Heart and Lung Transplantation 35, 1–23. Mogensen, U.M., Ersboll, M., Andersen, M., et al., 2011. Clinical characteristics and major comorbidities in heart failure patients more than 85 years of age compared with younger age groups. European Journal of Heart Failure 13, 1216–1223. Mosterd, A., Hoes, A.W., 2007. Clinical epidemiology of heart failure. Heart 93, 1137–1146. Najafi, F., Jamrozik, K., Dobson, A.J., 2009. Understanding the ‘epidemic of heart failure’: a systematic review of trends in determinants of heart failure. European Journal of Heart Failure 11, 472–479. Oudejans, I., Mosterd, A., Bloemen, J.A., et al., 2011. Clinical evaluation of geriatric outpatients with suspected heart failure: Value of symptoms, signs, and additional tests. European Journal of Heart Failure 13, 518–527. Oudejans, I., Mosterd, A., Zuithoff, N.P., Hoes, A.W., 2012. Comorbidity drives mortality in newly diagnosed heart failure: A study among geriatric outpatients. Journal of Cardiac Failure 18, 47–52. Penn, J., Goldenberg, I., Moss, A.J., et al., 2011. Improved outcome with preventive cardiac resynchronization therapy in the elderly: A MADIT-CRT substudy. Journal of Cardiovascular Electrophysiology 22, 892–897. Pilotto, A., Addante, F., Franceschi, M., et al., 2010. Multidimensional prognostic index based on a comprehensive geriatric assessment predicts short-term mortality in older patients with heart failure. Circulation. Heart Failure 3, 14–20. Pitt, B., Zannad, F., Remme, W.J., et al., 1999. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. NEJM 341, 709–717. Pitt, B., Poole-Wilson, P.A., Segal, R., et al., 2000. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trialdThe losartan heart failure survival study ELITE II. Lancet 355, 1582–1587. Ponikowski, P., Voors, A.A., Anker, S.D., et al., 2016. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Journal of Heart Failure 18, 891–975. Rodriguez-Pascual, C., Vilches-Moraga, A., Paredes-Galan, E., et al., 2012. Comprehensive geriatric assessment and hospital mortality among older adults with decompensated heart failure. American Heart Journal 164, 756–762. Rose, E.A., Gelijns, A.C., Moskowitz, A.J., et al., 2001. Long-term use of a left ventricular assist device for end-stage heart failure. NEJM 345, 1435–1443. Sanchez, E., Vidan, M.T., Serra, J.A., Fernandez-Aviles, F., Bueno, H., 2011. Prevalence of geriatric syndromes and impact on clinical and functional outcomes in older patients with acute cardiac diseases. Heart 97, 1602–1606. Santangeli, P., Di Biase, L., Dello Russo, A., et al., 2010. Meta-analysis: Age and effectiveness of prophylactic implantable cardioverter defibrillators. Annals of Internal Medicine 153, 592–599. Skalska, A., Wizner, B., Wie˛ cek, A., et al., 2014. Reduced functionality in everyday activities of patients with self-reported heart failure hospitalization – Population-based study results. International Journal of Cardiology 20 (176), 423–429. Tavazzi, L., Swedberg, K., Komajda, M., et al., 2013. Efficacy and safety of ivabradine in chronic heart failure across the age spectrum: Insights from the SHIFT study. European Journal of Heart Failure 15, 1296–1303. Wang, T.J., Larson, M.G., Levy, D., et al., 2002. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. The American Journal of Cardiology 90, 254–258. Wong, C.Y., Chaudhry, S.I., Desai, M.M., Krumholz, H.M., 2011. Trends in comorbidity, disability, and polypharmacy in heart failure. The American Journal of Medicine 124, 136–143. Zannad, F., McMurray, J.J.V., Krum, H., et al., 2011. Eplerenone in patients with systolic heart failure and mild symptoms. NEJM 364, 11–21.

Further Reading Metra, M., Teerlink, J.R., 2017. Heart failure. Lancet 390 (10106), 1981–1995. van Riet, E.E., Hoes, A.W., Wagenaar, K.P., Limburg, A., Landman, M.A., Rutten, F.H., 2016. Epidemiology of heart failure: The prevalence of heart failure and ventricular dysfunction in older adults over time: A systematic review. European Journal of Heart Failure 18, 242–252.

Relevant Websites http://learn.escardio.org/heart-failure/homepagedHeart Failure Association of European Society of Cardiology e-learning platform. https://www.heartfailurematters.org/en_GB/dHeart Failure Association of European Society of Cardiology website for patients. https://www.bhf.org.uk/informationsupport/conditions/heart-failuredBritish Heart Foundation page.

History of Life-Extensionism Ilia Stambler, Bar Ilan University, Ramat Gan, Israel © 2020 Elsevier Inc. All rights reserved.

Definitions Ancient Sources Medical Alchemy and Iatrochemistry Early Physiology Gerocomia and the Hygienists Late NineteenthdEarly 20th Century. The Emergence of Gerontology and Geriatrics Endocrine Rejuvenation The Aftermath of WWII. From Organotherapy to Replacement Medicine. From Physiology to Molecular Biology and Cybernetics The Present Time: Expansion and Public Involvement Acknowledgment References Further Reading

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Definitions Life-extensionism can be defined by a belief in the possibility and desirability of a significant prolongation of healthy human life, chiefly aspiring to the extension of life and health through amelioration of degenerative aging processes, but also by other means. Proponents of life-extensionism have commonly built on contemporary scientific and technological achievements to project and facilitate further improvements and increases of life span, life expectancy and health in old age. Furthermore, the desire to prolong healthy human life has often constituted a strong motivation for biomedical research and discovery. Thus, the pursuit of healthy life extension (or life-extensionism) has constituted an inseparable and crucial element in the history of biomedicine (Stambler, 2014). The precise definition of “life-extensionism” is difficult. The term “life-extensionism” is relatively recent, and its precise origins are uncertain, most likely emerging in the 1920s (Campbell, 1929). But, of course, the terms “life extension” (or “prolongation of life” in earlier texts) or “rejuvenation” that may hopefully lead to prolongation of healthy life, are very old. The prolongation of life and rejuvenation were pursued by alchemy (Gruman, 1966) and gerocomia (Galen, 1725) in the Middle Ages, and by experimental gerontology (Metchnikoff, 1961), geriatric therapy (Nascher, 1914), geroscience (Sierra and Kohanski, 2017) and antiaging medicine (Gardner, 1948) in our time. Obviously, they are not the same. In the second half of the 20th century, the advocates of healthy life extension were alternatively called prolongevitists (a term apparently coined in the 1960s (Gruman, 1966)), life-extensionists, immortalists (Harrington, 1969) or transhumanists (Huxley, 1957)ddepending on the context and levels of expectationsdand did not seem to have an agreed title before that. In view of the great terminological diversity and uncertainty, the term “life-extensionist” can be operationally defined to designate “proponents of healthy life extension” who seek various and often conflicting ways in which this common and definitive aspiration may be achieved. Though the term “life-extensionism” literally implies just the desire for the extension of life, the integral concomitant aspiration has always been the extension of health in old age, and thus these aspirations are historically inseparable. Even though a formal definition is difficult, it may be helpful to describe the history of the pursuit of longer and healthier life (or “life-extensionism”) using the above terms, as they relate to particular historical periods and particular regional and national contexts.

Ancient Sources One of the earliest representations of rejuvenation and life extension, as well as one of the earliest known works of literature, is the Sumero-Babylonian Epic of Gilgamesh, a story about the hero’s struggle with death (the most complete version has been dated from c. 1300 BC to 650 BC, but the story possibly originated as early as about 3000 BC). The Epic of Gilgamesh provides one of the most ancient descriptions of the search for life and health-prolonging (immortalizing) medicinal remedies (Thompson, 1928). There are striking parallels between the description of the immortalizing plant and the story of the extremely long-lived Utnapishtim in the epic of Gilgamesh and the biblical stories (with the composition sometimes dated from c. 1300 BC to 450 BC) about the “tree of life” and about the extreme longevity of antediluvian patriarchs (Genesis 2:9, 3:22–24, 5:1–32). These biblical stories too can be seen as representative of the ancient yearning for extended healthy longevity (Stambler, 2017). In Ancient Egypt too, the pursuit of longevity (even immortality) was a defining cultural and ideological feature. In one of the earliest known Egyptian medical papyruses, The Edwin Smith Surgical Papyrus (commonly dated to the period of the New Kingdom of Egypt, c. 1500 BC), there is a “Recipe for Transforming an Old Man into a Youth” using bruised and dried hemayet-fruit (with

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recent identifications varying from fenugreek to almond) (Breasted, 1930). In yet another ancient Egyptian medical papyrus, The Ebers Papyrus (c. 1500–1600 BC), there are antiaging cosmetic remedies to prevent the graying of hair (e.g., by the use of honey, onion water, donkey liver and crocodile fat), and to stimulate hair growth (for example by the use of flaxseed oil, gazelle excrements and snake fat). Actual treatment of aging was also mentioned: “When you examine a person . whose heart is weak as when old age comes upon him, you say: ‘This is an accumulation of diseased juices,’ the person should not arrogantly dismiss the disease or trust in weak remedies” (Joachim, 1890). It may be argued that many pioneering technologies of the Egyptians, from pyramid construction to embalming and surgery, emerged from the pervasive drive for life extension (or “immortality”). This aspiration has been also strong in the Indian historical tradition. In the Rigveda, one of the earliest known Vedic collections of India (c. 1700–1100 BC), the entire Book 9 is composed of hymns praising the immortality-giving “Soma” plant (Griffith, 1896). Recent identifications of “Soma” range from fly-agaric, ephedra and cannabis, to sacred lotus, heather and honey. The Indian medical tradition has been infused with the search for longer and healthier life. Thus Ayurveda, “the science of long life,” includes a special field of “Rasayana” dedicated entirely to the search for rejuvenation. Thus, according to one of the earliest Ayurvedic texts, the Sushruta Samhita (Sushruta’s Compilation of Knowledge, c. 800–300 BC), human life can be normally prolonged to 100 years. Yet, with the use of certain Rasayana remedies (such as Brahmi Rasayana and Vidanga-Kalpa), life can be prolonged to 500 or 800 years (Bhishagratna, 1907). The pursuit of rejuvenation and life extension are also present in another foundational text of Ayurveda, the Charaka Samhita (Charaka’s Compilation of Knowledge, c. 300–100 BC). Also according to the Charaka Samhita, the normal human life-span is 100 years. Yet, the users of certain medicines, such as Amalaka Rasayana and Amalakayasa Brahma Rasayana, could live many hundreds of years (Van Loon, 2003). In the Avesta, the sacred text of the Iranian Zoroastrian religion (with estimated dates of origin ranging from 1200 BC to 200 BC), during the rule of the mythical king Jamshid (Yima), people knew no disease, aging and death (Darmesteter, 1880). The legendary “cup of Jamshid” was said to be a container for the elixir of immortality and at the same time a means for information retrieval (scrying/remote viewing). According to Ferdowsi’s (CE 940–1020) Shah Nameh, Jamshid became proud and his reign of prosperity and longevity was terminated by the demonic king Zahhak. In China, especially in the Taoist tradition, the pursuit of longevity, even unlimited longevity, has always been an all-pervasive aspiration, since the inception of the nation. According to Chinese legend, the Yellow Emperor, Huangdi (Huang-ti), fabled to have originated many fields of Chinese culture c. 2600–2700 BC, also possessed the secret of extreme longevity. One of the foundational texts of Chinese Traditional MedicinedHuangdi Neijingdthe Inner Canon of the Yellow Emperor, includes many recipes aimed to promote longevity. The Yellow Emperor, Huangdi should not be confused with China’s first historical emperor and seeker of immortality, Qin Shi Huang-di (259–210 BC) who ordered a documented search of an elixir of immortality and funded alchemists and providers of rejuvenating nostrums, some of which presumably contained toxic substances, such as cinnabar and mercury, and allegedly contributed to his early death. Some of the formative figures of Chinese alchemy included Wei Boyang (Wei Po-Yang) the author of Ts’an T’ung Ch’i [“The akinness of the three”, i.e. of the alchemical processes, the Book of Changes, and the Taoist doctrines] (c. CE 142), and Ko Hung (Ge Hong), the author of Pao-p’u tzu [[Book of the] Master Who Embraces Simplicity] (c. CE 320) (Gruman, 1966). The search for rejuvenating and life-prolonging medical remedies, as well as life-prolonging life-style and exercise, has continued in China for centuries, to the present, with the very symbol of “longevity” being one of the most venerated cultural symbols in China.

Medical Alchemy and Iatrochemistry One of the fields that is most commonly associated with the pursuit of life extension is alchemy, or more specifically the medical application of alchemy. The world “al-kimia” is of Arabic origin, “al” being the Arabic definite article, and the etymology of “kimia” being uncertain, with hypotheses ranging from the “Khemia” (“the land of black earth,” the old name of Egypt); “khymatos” (pouring/infusing in Greek); “khymos (the Greek word for juice), etc. Strongly influenced by Greek scholarship, Muslim (Arab and Persian) adepts laid the foundations for alchemy and its medical applications, as could be seen from the etymology of many contemporary medical and chemical terms. Thus, the word “elixir” comes from the Arabic “al-iksir” (dry medicinal powder), as well as many other terms currently found in modern science, such as realgar (“raj al-har”), nushadir, alcohol (“al-kuhul”) and others. Numerous Muslim alchemists expressed explicit interest in life extension. Thus, one of the founding figures of Muslim alchemy is considered to be Abu M usa Jabir ibn Hayyan (also known as Jabir in Arabic and Geber in Latin, c. 721–815) whose theory of elements profoundly influenced both the Islamic and European (Latin-Christian) alchemy. Jabir believed that prolongation of healthy life may be achieved by a balancing or equilibration of “elements” (“natures”) in the human body, “This equilibrium once obtained, they will no longer be subject to change, alteration or modification and neither they nor their children ever will perish” (Gruman, 1966). Also according to the alchemist Ibn-Bishrun (c. CE 1000), quoted by the Tunisian historian Ibn Khaldoun (1332–1406): “Man suffers from the disharmony of his component elements. If his elements were in complete harmony and thus not effected by accidents and inner contradictions, the soul would not be able to leave his body” (Stambler, 2017). The word “alchemy” apparently took root in Europe in the 12th century, the first European alchemical text presumably being translated from Arabic to Latin by Robert of Chester in 1144, entitled Liber de compositione alchimiae (the book of alchemical composition). The preservation of balance of particular elements (natures or humors) has become the foundational principle for the scholastic theory of life extension also for the European alchemy. Among the notable proponents of this theory were the Italian theological and alchemist Thomas Aquinas (1225–1274), the English philosopher and alchemist Roger Bacon (who treated on

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life extension in his Opus Majus, 1266) and the German friar and alchemist Albertus Magnus (1193–1280) who wrote about the prolongation of life in On Youth and Old Age and On Life and Death, the Italian physician Arnaldus de Villa Nova (c. 1240– 1311) and the 15th century (rather legendary) German Benedictine monk Basil Valentine. Yet, the person who is most strongly associated with the wedding of alchemy and medicine is Paracelsus (Phillippus Aureolus Theophrastus Bombastus von Hohenheim, 1493–1541). In fact, this renowned Swiss alchemist, occultist and physician is commonly considered as the founder of medical chemistry (iatrochemistry, from the Greek “Iatros”dDoctor). Like most other alchemists, he believed that human life can be prolonged well into centuries, or even “as long as Methuselah” and sought the quinta essentia that would have “the power to change us, to renew us, and to restore us” and that would “transform the body, removing its harmful parts, its crudity, its incompleteness, and transform everything into a pure, noble and indestructible being” (Waite, 1894). Paracelsus suggested quite a few elixirs for rejuvenation (Lloyd, 1883). One of the more famous was Paracelsus’ “Elixir Proprietatis” (proprietary elixir), containing myrrh, aloe and saffron, that could be found in pharmacopeias and pharmacies as late as the end of the 19th century. Judging from Paracelsus’ 48 years life-span, the elixirs were not particularly effective (the prevailing version of his death, however, was that he was murdered, and against such a cause of death surely no pharmacological remedies would avail).

Early Physiology The alchemy played a foundational role in the inception not only of medical chemistry, but also physiology. Thus, the Swiss physician Albrecht von Haller (1708–77), commonly acknowledged as a pioneer of physiology, was strongly interested in alchemy and rejuvenation. In the 8th volume of Albrecht von Haller’s monumental Elementa Physiologiae Corporis Humani (Physiological Elements of the Human Body, 1757–66), a large section “Decrementum” is dedicated to aging and longevity (Haller, 1778). In that section, Haller treated of age-related deterioration of various organs and humors, comparative longevity of plants, animals and humans, possibilities of rejuvenation (synonymous with regeneration of organs) and causes of longevity (including climate and diet). A list of super-centenarians, some of whom were said to live nearly two centuries and even more, was included to show that such tremendous life spans are reasonably attainable. Haller’s “Acid elixir” (Elixir Acidum Halleri, composed of a mixture of sulfuric acid and alcoholdof uncertain safety) was still to be found in the German Pharmacopeia of 1872. Haller apparently was influenced in his pursuit of longevity and rejuvenation by his teacher, the Dutch physician Herman Boerhaave (1668–1738), yet another pioneer of physiology (introducing, among other notions, the concept of hemodynamic equilibrium). In Elementa Chemiae (1724), Boerhaave presented five different processes for making Paracelsus’ Elixir Proprietatis, and highly recommended its efficacy (Lloyd, 1883). Boerhaave was also famous for his attempt to rejuvenate Amsterdam’s burgomaster by ordering him to sleep between two young persons (using the practice of “Shunamitism” after King David’s example, as described in 1 Kings 1:2). Boerhaave fostered the interest in these subjects in yet another of his famous pupils and assistants, the DutchAustrian physician Gerard van Swieten (1700–72). Aging and longevity were among the major topics of van Swieten’s fivevolume commentary on Boerhaave’s Aphorismi, but perhaps van Swieten’s most renowned apology of healthy life extension was his Oratio de senum valetudine tuenda (Oration on the care of health of the aged, published in 1778, first presented in 1763). Another crucial figure in the succession of rejuvenators from Paracelsus to Boerhaave was the Dutch (Flemish) physician Jan Baptist van Helmont (1579–1644), the author of “pneumatic”/gas chemistry and one of the most prominent philosophers of vitalism. Van Helmont’s elixir (as presented in the London Pharmacopoeia of 1770, though of uncertain authenticity) consisted of “Any fixed alkaline salt [such as potassium carbonate, K2CO3], Socotrine Aloes, Saffron, Myrrh, Sal Ammoniac [ammonium chloride, NH4Cl], Mountain wine [vinum album/white wine]” which one needed to “macerate without heat, for a week or longer, then filter through paper” (Lloyd, 1883). Notably, in the works of early physiologists, the search for “elixirs” coexisted with a routine practice of medicine and hygienic recommendation, though there were differences of emphasis in different authors.

Gerocomia and the Hygienists While medical alchemy and its descendant, the “iatrochemistry” or medical chemistry, were mainly concerned with finding medicinal means for healthy life extension, with rather radical aspirations, another powerful and ancient branch in the history of life-extensionism, and a more modest one, was more concerned with life style improvements to achieve healthy longevitydthe so-called “gerocomia” (Freeman, 1938). The term “gerocomia” (“gerocomica” or “gerontocomia” from the Greek “care for the aged”) was used at least since the time of Galen (Aelius/Claudius Galenus, c. CE 129–217). Galen used this term in his De tuenda Sanitate. Gerontocomia (5th book On the Preservation of Health. Gerontocomia). Galen’s authority was still recognized as late as the 18th century by another prominent proponent of gerocomiadSir John Floyer (1649–1734) in Medicina gerocomica, or, The Galenic art of preserving old men’s healths (1725) (Galen, 1725). Indeed, the term “Gerocomia” was commonly used from antiquity through the 18th century. Even without an explicit association with the field of “gerocomia,” principles for the “care of the aged” were expounded by ancient Greek physicians and scholars (Grmek, 1958). The “father of medicine”dHippocrates (c. 460d 370 BC) gave prescriptions for healthy longevity, such as “exertion, food, drink, sleep, sexual activity, in moderation” (Smith, 1994). Aristotle (384–322 BC) advised on moderation for the preservation of health in old age, for example in his treatises On Length and Shortness of Life and On Youth, Old Age, Life and Death, and Respiration (Barnes, 1984). The Romans carried on this tradition. Thus, On Old Age (De Senectute) by Cicero (106–43 BC)

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called to “fight” the infirmities and feebleness produced by aging. “We must stand up against old age and make up for its drawbacks by taking pains” Cicero wrote. “We must fight it as we should an illness. We must look after our health, use moderate exercise, take just enough food and drink to recruit, but not to overload, our strength. Nor is it the body alone that must be supported, but the intellect and soul much more” (Cicero, 1900). This statement may provide a short summary of the advice given by most works on the “care of old age” in Greco-Roman antiquity. The tradition continued through the middle ages to the early modern period. One of the more influential works on gerocomia was written by the Italian professor Gabriele Zerbi (1445–1505) entitled Gerontocomia, scilicet de senium cura atque victu (1489, “Gerontocomia, or, care and nutrition for old age,” written in Rome upon the request of Pope Innocent VIII, 1432–92). Further prominent proponents of this art were the Italian long-lived writer Luigi Cornaro (1467–1566), the author of Discorso sulla vita sobria (Discourse on a sober life, 1566), the Flemish Jesuit priest Leonardus Lessius (1554–1623, the author of A Treatise of Health and Long LifedHygiasticon, 1613) (Anon., 1743) and the German scholar Johann Heinrich Cohausen (1665–1750) who wrote Tentaminum physico-medicorum curiosa decas de vita humana theoretice et practice per pharmaciam prolonganda (Curioous physico-medical theoretical and practical attempts to prolong the decades of human life by pharmacological means, 1699) and Hermippus Redivivus or the Sage’s Triumph over Old Age and the Grave (1742, including the advice about chaste proximity to young maidens) (Cohausen, 1748). Indeed, the main defining recommendation for the attainment of healthy life extension, throughout the entire gerocomia tradition, was moderation, especially moderation in food and sexual moderation (Shapin and Martyn, 2000). This tradition has parallels in oriental traditions. In the words of Lao-Tse, the great teacher of Taoism (c. 6th century BC), “For regulating the human in our constitution and rendering the proper service to the heavenly, there is nothing like moderation” (Tzu, 1891). These concepts of gerocomia, formed the basis for the ideology and practice of early modern hygienists who strove to extend longevity and preserve health in old age. Perhaps the most notable in this hygienic tradition was Christoph Wilhelm Hufeland (1762–1836), the renowned German hygienist, physician to the King of Prussia, Friedrich Wilhelm III, and to Goethe and Schiller. In his book Macrobiotics or the Art of Prolonging Human Life (1796), Hufeland coined a particular term for life extensiond“macrobiotics” which has survived to the present (Wilson, 1867). Hufeland specifically distinguished the art of life extension from the general medical art that commonly aims to treat individual diseases and symptoms and mainly considers short term effects. As Hufeland wrote: “The object of medical art is health; that of the macrobiotic, long life. The means employed in the medical art are regulated according to the present state of the body and its variations; those of the macrobiotic, by general principles.” Some of the general principles that determine human longevity, according to Hufeland, include: “the innate quantity of vital power,” “firmness of organization of the vital organs,” and the rates of “consumption” vs. “renovation” (“restoration” or “regeneration”) of the vital force and of the organs. Moderation, in Hufeland, is an absolutely vital means for the conservation of vital power: “the more intensively a being lives, the more will its life lose its extension”; “strengthening, carried too far, may tend to accelerate life, and consequently, to shorten its duration.” Similar principles were professed by several European hygienists of the 18th century, such as the German-Latvian proponent of healthy life extension, Johann Bernhard Fischer (1685–1772), who served as “Archiatrus” (head of the ministry of medicine) of the Russian Empire and published the book On Old Age, its Degrees and Diseases (De Senior Eiusque Gradibus et Morbis, 1754, republished in 1760). The traditions of longevity hygiene of the 18th century laid the foundations for the emergence of “Medicine for the aged” (médecine de vieillards) in France in the 19th century, and “Geriatrics” in the early 20th century in the United States.

Late NineteenthdEarly 20th Century. The Emergence of Gerontology and Geriatrics In the early modern period, the pursuit of life prolongation was professed not only in the works of physicians and hygienists, like Luigi Cornaro, Johann Cohausen and Christoph Wilhelm Hufeland, but also philosophers such as Francis Bacon, René Descartes, Benjamin Franklin and Nicolas Condorcet (Gruman, 1966). However, the beginning of the true (or late) modern period in this endeavor can be traced to the end of the 19th century to beginning of the 20th century, to the so called “fin-de-siècle” period, denoted as an “end of an epoch” and characterized by the rise of scientific optimism and therapeutic activism, fostering the ideas of life extension (Stambler, 2014). By the end of the 19th century and in the first quarter of the 20th century, France was notably an epicenter of this intellectual movement. In the 19th century, major contributions to the study of aging were made by French pathologists (Thane, 2001). Working in the Parisian hospices for the elderlydthe Salpêtrière for women and the Bicêtre for mendCharles-Louis DurandFardel (1815–99) and Jean-Martin Charcot (1825–93) and their followers, carefully investigated the pathological tissue changes in old age: changes of the lungs, the brain, and the blood vessels (Stearns, 1976). This work was summarized in treatises, such as Durand-Fardel’s Traité clinique et pratique des maladies des vieillards (Clinical and practical treatise on the diseases of the aged, 1854) and Charcot’s Leçons sur les maladies des vieillards et les maladies chroniques (Lectures on Senile and Chronic Diseases, 1868). Some of the notable French physicians working in “medicine for the aged” following Durand-Fardel and Charcot, were Henri Cazalis (1840–1909), who coined the maxim “the man is as old as his arteries,” Jules Boy-Teissier (1858–1908) and Yves Delage (1854–1920). Some hygienic measures were suggested by the authors to alleviate the suffering of the aged (such as Charcot’s baths). However, the mid-19th century medicine for the aged was quite limited in its means of combating senescence, hence any explicit hopes for a significant life extension are absent from these writings. Nonetheless, the work of the French physicians laid the foundations for the understanding of the pathology and physiology of senescence and outlined measures of intervention.

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Around the mid-19th century, further significant advances were also made in the theoretical conceptualization of aging and the possibility of life extension by French biologists and physicians. Thus, one of the most prominent French researchers of longevity of the mid-19th century, the physician Marie-Jean-Pierre Flourens (1794–1867) asserted that the duration of growth multiplied a certain number of times determines the ordinary and extreme duration of life (the latter was estimated at 150 years) (1854) (Flourens, 1855). One of the first modern scientific theories of aging was proposed by Édouard Robin of the French Academy of Sciences in 1853, who posited that aging is due to body “mineralization” or accumulation of “alkaline residues,” “calcification” or “ossification.” Robin’s theory considered lactic acid and “vegetable acids” as possible means to dissolve the “mineral matters” and thus prolong life (Robin, 1854). Perhaps an even more substantial impetus was given by the Therapeutic Activist approach, advanced by Louis Pasteur (1822–95) and Claude Bernard (1813–78). This approach arguably influenced the advent of modern life-extensionism in fin-de-siècle France. Thus, the foremost researcher of life extension at the turn of the 20th century, the Nobel Prize winning biologist and the author of the concept of “gerontology” Elie Metchnikoff (1845–1916), was Pasteur’s protégé and député at Institut Pasteur. Another crucial contemporary proponent of life extension, Charles-Édouard Brown-Séquard (1817–94), the president of the French Biological Society, one of the founders of modern endocrinology and the inventor of rejuvenative hormone replacement therapy, was Claude Bernard’s pupil and successor at Collège de France. Brown-Séquard suggested that through the supplementation of deficient hormones, bodily equilibrium can be restored, youth returned, and life prolonged. In his seminal experiment of 1889 with self-injections of animal sex gland extracts (from dogs and guinea pigs), Brown-Séquard reported mental and physical reinvigorating effects (Brown-Séquard, 1889). Though the effects proved to be short-lasting and widely disputed at that time, these were arguably the first scientific attempts at hormone replacement therapy for rejuvenation, introducing longevity and rejuvenation research as an integral part of scientific discourse, and in fact establishing the field of therapeutic endocrinology. Another critical figure for the life-extensionist intellectual movement, Elie Metchnikoff, formulated a pioneering and highly influential scientific theory of aging, based on histological observations (c. 1900) (Stambler, 2015). According to this theory, the body was divided into “noble” or “functional” elements (mainly the parenchymal tissues, such as the heart and the brain) and “primitive” or “harmful” elements (such as the “devouring phagocytes” and intoxicating putrefactive microflora). The former needed to be strengthened or replenished, the latter destroyed or attenuated. Thus, the body was seen as a sort of a mechanical balance, with weights added or removed as needed to keep the balance steady. Based on this theory, several practical methods were suggested by Metchnikoff to attenuate the “harmful elements,” strengthen the “noble elements” and reestablish the balance, among them small doses of stimulating cytotoxic sera (to strengthen parenchymal tissues or “the noble elements”), and probiotic diets (to attenuate the destructive and toxic intestinal microflora or “the harmful elements”) (Metchnikoff, 1961) These suggestions arguably laid the foundation for the fields of systemic immunotherapy and microbiome studies. Generally, the works of CharlesÉdouard Brown-Séquard and Elie Metchnikoff can be seen as foundational for the emerging modern field of scientific biogerontology. The studies of aging took place across Europe, though with a notable concentration in France. Yet, at the turn of the 20th century, another prominent epicenter of this research was in the United States. The works of the early 20th century American physiciansdDr. Ignatz Leo Nascher (1863–1944, born in Vienna and brought to New York as an infant), Dr. Malford Wilcox Thewlis (1889–1956) and Dr. Francis Everett Townsend (1867–1960)dset the foundations for clinical geriatrics. In these authors too, the possibility of a significant life extension was affirmed and extensive further basic and clinical research was proposed as a first precondition to achieve this task. In the writings of the founder of geriatrics (and the author of the term “geriatrics” c. 1909), Ignatz Leo Nascher, the life-extensionist sentiment is strong. Nascher believed that “as a humanitarian it is [the physician’s] duty to prolong life as long as there is life and to relieve distress wherever he may find it” (1914) (Nascher, 1914). Interestingly, Nascher conceded the prevalence of European research on aging and longevity at that time, “in this direction the French and German investigators are far ahead of their American confreres,” yet expressed the hope for a stronger development in the United States, which came true. Further, the studies of calorie restriction as a means of life extension by Clive Maine McCay (1898–1967) of Cornell University, Ithaca, New York, strengthened the traditional hygienic relation between moderate nutrition and healthy longevity (McCay, 1935). Nascher, McCay and several other early 20th century American longevity researchers, such as Charles Manning Child (1869–1954), Jacques Loeb (1859–1924), Alexis Carrel (1873–1944), Raymond Pearl (1879–1941) and others, were extremely cautious regarding the immediate prospects for life extension. Yet, they believed that with a more profound understanding of the mechanisms of aging, potential rejuvenative and life-extending means might be found.

Endocrine Rejuvenation Yet, another stream in the life-extensionist movement was more “practice-oriented” hoping for immediate and rather far-reaching rejuvenating and life-extending results. In the early 20th century well until WWII most of such hopes were pinned on endocrine supplementation and stimulation, and this entire stream received the name “endocrine rejuvenation.” Though there were much earlier precedents, in both Western and Eastern medical traditions, the most recognizable founding figure of this stream was Charles-Édouard Brown-Séquard, famous for his rejuvenation experiments with dogs’ and guinea pigs’ sex gland extracts. Yet he had a cohort of prominent followers. One of the most famous (even notorious) was the Parisian physician Serge Voronoff (1866–1951)done of the pioneers of xeno-transplantation, conducted for rejuvenation purposes. His signature method was the

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transplantation (“grafting”) into humans of animal (mainly male ape) sex gland tissues, as he believed that the deterioration of aging is mainly due to a lack of balance or failure of endocrine function which could be reestablished by transplanting the sex gland tissue (Voronoff, 1925). Beside Voronoff, a cohort of French pioneers of endocrine rejuvenation (mainly practicing sex gland tissue transplantations and various other means of endocrine stimulation) included Placide Mauclaire, Lois Dartigues, Raymond Petit, Léopold Lévi, Henri de Rothschild, and others, forming a “school.” Similarly, in the German-speaking world, from the beginning of the 20th century and through the 1920s, the “endocrine rejuvenation” movement flourished. The practitioners utilized a wide variety of organotherapeutic (endocrine gland) supplements, gland transplants or gland stimulants (predominantly those of the sex glands). In this area, Austria was another seedbed, leading the way with the pioneering works of the Viennese physician Eugen Steinach (1861–1944) on sexual rejuvenation, most famously the “Steinach procedure.” The procedure involved spermatic cord vasoligation, as the suppression of sperm-producing activity was supposed to stimulate sex-hormone-producing activity, allegedly leading to increasing the blood flow and other reinvigorating effects (Steinach and Loebel, 1940). Steinach was followed by a host of other Austrian rejuvenatorsdKarl Doppler, Robert Lichtenstern, Paul Kammerer, Erwin Last, August Bier, Emerich Ullmann, Otto Kauders, and othersdperforming the “Steinach Procedure” by the hundreds and thousands, as well as other modified versions of sexual stimulation. Sigmund Freud (1856–1939) was enthusiastic enough about Steinach’s rejuvenating operation to have it performed on himself in 1923 by the surgeon Victor Blum. In Germany too, in the first quarter of the 20th century, the endocrine rejuvenation movement boomed, though perhaps to a lesser extent than in Austria, exemplified by the works of the physicians Jürgen Harms, Peter Schmidt, Richard Mühsam and Ludwig Levy-Lenz. Indeed, in the 1920s, Steinach’s procedure was widely applied all across the world. In Germany and Austria, however, the application of Steinach’s operation was among the widest. Beside operative interventions, by the late 1920s, hormonal preparations for rejuvenation also became an object of keen interest in Germany and Austria. Sex gland extracts and stimulants for men and women enjoyed by far the greatest vogue in the rejuvenation business (Romeis, 1931). There was also strong interest in this area across the Atlantic. Americans were among the first to conduct operations on sex glandsdvasectomy and sex gland transplantationsdfor rejuvenative and other therapeutic purposes. Among the prominent users of “rejuvenative” vasectomy and vasoligation techniques were Harry Clay Sharp and Harry Benjamin. Rejuvenation by transplantation of sex gland tissues (male and female) were also practiced in the US. Some of the first practitioners included: Victor Darwin Lespinasse, Levi Jay Hammond and Howard Anderson Sutton, George Frank Lydston, Max Thorek, and Leo Leonidas Stanley. Endocrine extracts were also popular in the United States, even before Charles-Édouard Brown-Séquard’s experiment (as attested by Brown-Séquard himself). Endocrine rejuvenation surgery and supplementation were also practiced in other countries. For example, in Russia, the rejuvenative extract “spermin” was produced by Alexander Poehl of St. Petersburg (1850–1908). Thus “endocrine rejuvenation” formed a global therapeutic movement. In later assessments, however, reductionist rejuvenation techniques did not appear to live up to their promise (Hamilton, 1986). For the endocrine “grafting” methods, the problem of graft rejection by the host organism appeared almost insurmountable. On the other hand, replacing, supplementing or stimulating a single endocrine gland did not appear to durably forestall the deterioration of the entire organism, with a particular lack of evidence for efficacy in elderly patients, and no conclusive evidence for extending either the life span or health span by such means were established (Romeis, 1931). Consequently, a recoil from immediate rejuvenation attempts occurred, accompanied by a recoil from their underlying mechanism and reductionism. Hence, the “endocrine rejuvenation” movement was largely abandoned and even discredited. Still, it represented a significant chapter in the history of life-extensionism.

The Aftermath of WWII. From Organotherapy to Replacement Medicine. From Physiology to Molecular Biology and Cybernetics Toward WWII the interest in rejuvenation attempts strongly subsided, and virtually disappeared during the war. The aftermath of WWII (roughly since the 1950s) may mark a transition in the history of life-extensionism: In the period c. 1930–50, earlier theories of aging and rejuvenation practices were thoroughly and critically reevaluated, and foundations for generically new ones established. By the 1950s, the hopes for immediate, far reaching rejuvenation, mainly through endocrine interventions, so rampant in the early 20th century, were virtually abandoned. Instead, great expectations for future life extension were pinned on continuous fundamental aging research, informed by the explosive scientific and technological advances of the mid-century: replacement medicine, molecular biology and cybernetics. Thus, a trend can be observed toward and after the 1950s: a marked decrease of interest in immediate rejuvenation and increase of interest in biological theories of aging that endeavored first to fully elucidate its mechanisms and thereafter pinpoint targets for intervention. The means suggested for potential life extension shifted their focus. The geographic focus also notably shifted, demonstrating the increasing, even dominant, presence of the United States. In therapeutic approaches, the central emphasis was gradually placed on antioxidants, following Denham Harman’s seminal work of 1956, delineating the “free radical theory of aging” (Harman, 1956). The rejuvenative opotherapy or organotherapy of the 1900s–1920s, using animal organ extracts or derivatives as the chief means of supplementation, gave birth to synthetic hormone replacements developed during the 1930s–1950s. In the late 1950s to early 1960s, hormonal therapy appears to resume its prominence in aging therapy, when synthetic hormones cheapened and became more widely available. Thus, the declining levels of 17-ketosteroids, and their particular forms, such as Dehydroepiandrosterone (DHEA), Androsterone and Estrone, were said to play a crucial role in aging by the American inventor of oral contraceptives,

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Gregory Pincus, whose group sought to develop steroid supplementation regimens designed to restore their patterns to youthful levels (1955) (Rubin et al., 1955). In the 1960s, in the United States, thyroxine (a thyroid hormone) was popularized for antiaging by Charles Brusch and Murray Israel, estrogen and progesterone by Robert Wilson, and thymosin (a thymus hormone) by Allan Goldstein. Hormone levels of the hypothalamus (such as dopamine and growth hormone-releasing hormone) were assigned a crucial role in the onset of aging by the American researchers William Donner Denckla and Caleb Finch (c. 1975), who referred to the hypothalamus as a hormonal “aging clock” (Finch, 1975). This echoed the work of the Russian-Soviet researcher of aging, Vladimir Dilman (1925–94), on the sensitivity threshold elevation theory of aging and impairment of homeostasis as the main cause of aging and the role of the hypothalamus as “the large biological clock” (1958) (Dilman, 1958). Not only hormones, but entire organs became targets for supplementation and replacement. The timeline of transplantation medicine was continuous and should necessarily include the original rejuvenation attempts of the 1920s–1930s through sex gland transplantation (Serge Voronoff), “artificial revival” by resuscitation devices (Sergey Bryukhonenko) and embryonic/juvenile cell transplants and tissue transplants (Alexis Carrel). However, in the 1950s, transplantation surgery advanced drastically, following a deeper understanding of immune rejection and tolerance mechanisms. In the 1950s–1960s, transplantations were conducted for a great array of organs, mainly by American surgeons. There were transplanted the human kidney (1954), heart valve (1955), bone-marrow containing adult stem cells (1956). There followed the transplantation of the liver (1963), lung (1963), hand (1964), pancreas (1966), and heart (1967). Head was transplanted in a monkey in 1963 in the United States, and earlier in a dog in 1956 in the USSR. Moreover, in the late 1950s to early 1960s, the possibilities of growing desired organs and tissues outside of the body by directing the differentiation of “totipotent” cells or regenerating tissues within the body, were being raised. The means of cryopreservation for transplanted organs also developed dramatically following WWII. In the 1950s, the advances in prosthetics, bionics and resuscitation technology paralleled those in live tissue transplantation. Landmarks in the field included the artificial heart valve development (1951), the first successful cardiac pace-making electro-stimulators (1952), the heart and lung machine (1953), and the artificial kidney (1955). In 1956, hyperbaric oxygen pressure chambers were successfully applied as an aid in cardiac surgery and resuscitation. In the late 1950s to early 1960s there emerged the first practical artificial hip replacements (1962), the first prototypes of biosensors and artificial blood (1962), a computer-controlled arm (1963), and synthetic skin (1965) (Stambler, 2014). The advances of the 1950s–1960s in live tissue transplantation and prosthetics were so momentous that many, and mainly in the United States, began to speak about the possibility of replacing all worn-out body tissues and organs (including parts of the nervous/brain tissue) through biological or bionic replacement parts. Some researchers cautioned that transplantations could impair the delicate body balance (Comfort, 1963). Still, the anticipation of unlimited tissue replacements was rampant and widely envisioned as a feasible way to a significant (even radical) life extension (Ettinger, 1964). These popular themes that emerged with great force in the late 1950s to early 1960sdthe unlimited potential of organic and bionic replacements, tailor-made culture of organs and tissues for transplantation, and cryopreservationdhave continued to be discussed and developed in life-extensionist literature up to the present time. The 1950s may also represent a demarcation period with regard to theories of aging, which were transformed by contemporary scientific and technological advances, particularly by the emergence of molecular biology and cybernetics. Here too, the US was in the lead. The theories of aging developed in the 1920s through 1940s gave way to generically new ones in the 1950s. No single cause, such as hormonal imbalance or auto-intoxication, was any longer believed to be the main cause of aging, but perhaps only a single (and minor) one. New damaging agents were being sought. In the 1920s–1940s, a dominant theory of aging was the entropic transformation and condensation of cell colloids (mainly proteins), forming flocculates and precipitates that clog the cell machinery. Yet, there was a great uncertainty of the colloids’ molecular structure (Lumière, 1932). Some surmises were advanced regarding “cyclization” as an underlying chemical cause of colloid condensation, yet the colloids were essentially seen as blobs of matter that “congest” or “dissolve,” with molecular composition and mechanisms unknown. A possible genetic basis of aging and longevity was also proposed in the 1920s and continued to be investigated through the 1940s (Pearl, 1922). Yet it was described mainly in terms of population genetics, without reference to molecular mechanisms. The advent of molecular biology in the late 1940s to early 1950s changed the theoretical perception dramatically, as the precise molecular structure of proteins and genetic material became known. The new theories of aging of the late 1950s were aligned to the new paradigm of molecular biology, attempting to identify causes of aging at the molecular level. Foremost, there appeared the seminal work “Aging: A Theory based on Free Radical and Radiation Chemistry” (1956) by the chemist Denham Harman (1916–2014). This work played a pivotal role both in practical attempts at rejuvenation and in theoretical notions of aging. The theory fully incorporated concepts from molecular biology, such as preventing DNA damage that was said to be caused by oxidative free radicals. Based on the theory, Harman proposed the application of “anti-oxidants” or “easily reduced compounds” that would neutralize the free radicals. Such compounds, he suggested, can be used as “chemical means of prolonging effective life” and to “slow down the aging process” (Harman, 1956). The theory gave rise to the wide use of anti-oxidant supplements, building on the infrastructure of the vitamin industry which was by then firmly established. There also emerged in the 1950s the “Cross-linkage theory of aging” advanced by the Finnish/American researcher Johan Bjorksten (1907–95), in his influential study “A common molecular basis for the aging syndrome” (1958). The theory was a direct descendant of the “colloidal condensation” theory of aging. According to Bjorksten’s theory, “crosslinks” between biomolecules (proteins, nucleic acids, etc.) produce rigid agglomerates that block cellular functions (Bjorksten, 1958). Later on, agglomerates of crosslinked, lipid-containing “lipofuscin” (or “age pigment”) were increasingly seen as a major type of molecular debris leading to

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senescence. Based on the theory, Bjorksten sought to employ proteolytic enzymes or free radical bursts (oxido-reductive depolymerization) that would be able to break molecular crosslinks and thus restore tissue flexibility and molecular turnover to prolong life. He also sought to use chelating agents that would be able to remove heavy metals, a major cause of cross-linkage, and thus prevent the formation of the clogging aggregates in the first place. These lines of research have been continued by life-extensionists to the present (de Grey and Rae, 2007). Another seminal theory of aging that fully incorporated the molecular-biological perspective was the “Somatic mutation theory” proposed in 1958–59 by the Italian/American radiation biologist Gioacchino Failla (1891–1961) and the Hungarian/American nuclear physicist Leó Szilárd (1898–1964, the author of the concept of nuclear chain reaction of 1933). The theory suggested that aging is caused by random DNA damage in somatic cells and that the extent of damage is enhanced by radiation. DNA damage and its exacerbation by radiation were also the underlying concepts in the work of another prominent American researcher of aging, Bernard Louis Strehler (1925–2001, from the NIH Gerontology Research Center, Baltimore, Maryland). The “Somatic mutation theory” is considered to be the first truly stochastic theory of aging. A later stochastic theory was the “error catastrophe theory” proposed in 1963 by the British/American biochemist Leslie Eleazer Orgel (1927–2007), which emphasized the accumulation of errors in the protein-synthesis apparatus (particularly RNA and enzymes necessary for DNA transcription). It was also argued that inaccurate protein synthesis and inaccurate DNA synthesis are coupled phenomena (Kahn, 1985). Several American researchers of the 1960sdRonald Hart, Richard Setlow, George Sacher, Richard Cutler, Bernard Strehler, and othersdactively investigated enzymatic mechanisms of DNA repair, as it was believed that an improved DNA repair system can protect the stability of the human genome against mutations and thus significantly increase the human life span (Kahn, 1985). In the 1960s, Roy Lee Walford (1924–2004, from the University of California at Los Angeles) developed the “auto-immune” or “immunologic” theory of aging, where the increased attack on the organism by its own immune cells was supposed to be due to somatic DNA aberrations (1960, 1969). Among the life extension methods investigated by Walford, there were underfeeding (calorie restriction), cooling (hypothermia) and hibernation (induced by such means as chlorpromazine and marijuana derivatives, and other hibernation inducers), and anti-inflammatory diets and medications (Walford, 2000). In 1961, Leonard Hayflick (b. 1928, at the time working at the Wistar Institute of Anatomy and Biology, Philadelphia) posited a limit to the number of cell divisions, suggesting that cellular aging is genetically predetermined (Hayflick and Moorhead, 1961). The molecular biological view of mechanisms of aging converged with contemporarily emerging mathematical theories of mortality and evolutionary theories of aging that were highly conscious of molecular mutagenesis and sought to identify genetic targets for aging therapies. The development in the late 1940s of Cybernetics (Norbert Wiener, 1948), Information Theory (Claude Shannon, 1949) and the emergence of the first digital electronic computers (John von Neumann’s works on computer architecture, and the Electronic Numerical Integrator And ComputerdENIAC constructed in 1946) were other momentous influences on changing theories of aging. After the advent of cybernetics and information theory, more rigorous quantitative descriptions of homeostasis or deregulation due to aging processes were sought, and analogies between automata and human organisms suggested. Since the 1950s, Information Theory has been widely applied in biomedicine, in diagnosis in particular, especially for the assessment of aging and age-related diseases (Yockey, 1958). Special cybernetic consideration was given to increasing the “reliability” of a living “automaton,” for example, through redundancy of its parts, continuous replacement of parts, or incorporating quality monitors over the working components and replacing those components that show signs of “wearing out” (Eden, 1960). In more futuristic visions, computers figured as harbingers and models of extreme longevity. The concept of “cyborgization” (the term coined by the American electronics engineer Manfred Clynes and psycho-pharmacologist Nathan Kline in 1960), or maintainable man-machine synergy, was advanced. The possibilities of using the rapidly accelerating computer technology for life extension appeared promising. As it was suggested in the 1960s, the computers could be used for massive biological data analysis and thus discovering effective life-extending interventions. They would calculate and prescribe the balance of multitudes of biochemical interactions. They would preserve and expand the human personality. They would enable the unlimited production and communication for future long-lived generations (Stambler, 2014). These possibilities, raised in the early 1960s, have continued to be raised to the present day.

The Present Time: Expansion and Public Involvement The themes raised since the 1950s–1960s have persisted to the present, though their applications, implications and dissemination have continuously expanded. The discussion of the very recent and contemporary period in aging and life extension research is minimized here, both because of its vast expansion that would go far beyond the limited scope of the article, and also because it may overlap with the subject matter of more recent reviews. Yet, it can be noted that not only have the scope and basis of aging and life extension studies expanded, but also the extent of cooperation in such studies, their public support and awareness of them. This has manifested in the wide publicity of aging and longevity studies, as well as in the emergence and development of public associations, both professional and laymen, dedicated to the advancement and support of aging and longevity research. Such associations first emerged in the 1930s–1940s within national frameworks. In the USSR, Alexander Bogomolets (1881–1946) convened the world’s first scientific conference on aging and longevity in 1938 in Kiev, Ukraine. In the United Kingdom, Vladimir Korenchevsky (1880–1959) organized the British Society for Research on Aging in 1939. In the United States, Edmund Vincent Cowdry (1888–1975) established the Gerontological Society of America in 1945. Yet gradually a movement toward international organization took place. Thus, largely thanks to the collaborative efforts of Cowdry and

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Korenchevsky, the International Association of Gerontology (IAG) was formed in 1950, with the inaugural conference in Liege, Belgium, which marked a new period in the internationalization and institutionalization of gerontological research. The active legacy of those organizations has continued to an ever-increasing extent. A list of currently existing life-extensionist professional and grass-roots organizations, clubs, institutes and associations, would be extensive indeed. There is a strong prevalence of such organizations in the United States, yet they have been increasingly emerging across the world. Just a few examples of the larger or more influential ones may be mentioned here. An immense organizational effort to promote the research of aging was made by Robert Neil Butler (1927–2010), the founding director of the NIH National Institute on Aging (1975–82). In 1990, Butler grounded the International Longevity CenterdUnited States, with the expressed mission “to educate individuals on how to live longer and better.” This was one of several research support programs spearheaded by Butler. In 1970, the American Aging Association was founded thanks to the efforts of Denham Harman, the father of the “free-radical theory of aging.” To the present, the association espouses the “drive to conquer aging.” The Gerontology Research Group, founded in 1990 by Leslie Stephen Coles of the University of California, Los Angeles (1941–2014) has been “dedicated to the quest to slow and ultimately reverse human aging.” The Trans-NIH Geroscience Interest Group, founded in 2011 by Felipe Sierra, director of the Division of Aging Biology of the National Institute on Aging, has been devoted to address the biology of agingd“the largest single risk factor for most chronic diseases” (Sierra and Kohanski, 2017). Many other organizations have been dedicated to gerontological research and care, with varying levels of ambition. Though the extent of hopes regarding the ultimately achievable longevity varies among different organizations, from the more “radical” to more “mainstream,” their immediate or short-terms goals are basically identicaldto improve the understanding of degenerative aging processes and use this knowledge to develop effective means to mitigate or postpone aging-related diseases and to extend healthy and productive life for the people. Increasing the social and material support for these goals of life-extensionist organizations has been an ongoing struggle.

Acknowledgment This work was supported by the Shlomo Tyran Foundation, Israel.

References Anon (1743) A treatise of health and long life, with the sure means of attaining it. In 2 books. The first By Leonard Lessius. The Second by Lewis Cornaro. Translated into English by Timothy Smith, C. Hitch, London. Barnes, J. (Ed.), 1984. The complete works of Aristotle: The revised Oxford translation. Princeton University Press, Princeton. Bhishagratna, K.K.L. (Ed.), 1907. An English translation of the Sushruta samhita, based on original Sanskrit text. Calcutta. Bjorksten, J., 1958. A common molecular basis for the aging syndrome. Journal of the American Geriatrics Society 6, 740–748. Breasted JH (1930) (Transl. ed.), The Edwin Smith surgical papyrus, pp. 506–507. The University of Chicago Press, Chicago, XXI9-XXII10. Brown-Séquard CE (1977) Des effets produits chez l’homme par des injections sous-cutanées d’un liquide retiré des testicules frais de cobaye et de chien (Effects in man of subcutaneous injections of freshly prepared liquid from guinea pig and dog testes), Comptes Rendus des Séances de la Société de Biologie, Série 9, 1 (1889) 415–419, reprinted and translatedin: Emerson GM (ed.), Benchmark Papers in Human Physiology, Vol. 11, pp. 68–76. Aging, Dowden, Hutchinson and Ross, Stroudsburg PA. Campbell, C.G., 1929. Eugenics and euthenics. Eugenics: A Journal of Race Betterment 2, 21–25. Cicero MT (1990) Two essays on old age and friendship. Translated from the Latin of Cicero by E. S. Shuckburgh, McMillan and Co., New York. Cohausen, J.H., 1748. Hermippus Redivivus or the Sage’s triumph over old age and the grave, wherein a method is laid down for prolonging the life and vigour of man, including a commentary upon an ancient inscription, in which this great secret is revealed, supported by numerous authorities. The whole is interspersed with a great variety of remarkable and well attested relations. J. Nourse, London (first published in Latin in 1742). Comfort, A., 1963. In: Wolstenholme, G. (Ed.), Man and his future: A CIBA foundation volume. Little Brown and Co., Boston, pp. 217–229. Longevity of man and his tissues. Darmesteter J (Transl.) (1880) The Zend-Avesta, part 1, the Vendidad. In: Müller FM (ed.), Sacred books of the east, vol. 4, pp. 10–20. Clarendon Press, Oxford. Dilman VM (1958) O vozrastnom povyshenii deiatelnosti nekotorikh hypotalamicheskikh centrov, Trudy Instituta Physiologii imeni I.P. Pavlova 7 (1958) 326–336 (on senescent elevation of the activity of some hypothalamic centers, in works of I.P. Pavlov’s Institute of Physiology). Eden, M., 1960. An analogy between probabilistic automata and living organisms. In: Strehler, B. (Ed.), The biology of aging. Waverly Press, Baltimore, pp. 167–169. Ettinger, R., 1964. The prospect of immortality. Doubleday, New York. Finch, C., 1975. Neuroendocrinology of aging: A view of an emerging area. BioScience 25, 645–650. Flourens MJP (1855) On human longevity and the amount of life upon the globe. Translated from the French by Charles Martel, Bailliere, London (first published in French in 1854). Freeman, J.T., 1938. The history of geriatrics. Annals of Medical History 10, 324–335. Galen, 1725. 5th book, De tuenda Sanitate Gerontocomia, quoted in: J. Floyer, Medicina gerocomica, or, the Galenic art of preserving old men’s healths. J. Isted, London, p. 107. Gardner, T.S., 1948. The design of experiments for the cumulative effects of vitamins as anti-aging factors. Journal of the Tennessee Academy of Science 23, 291–306. de Grey, A.D.N.J., Rae, M., 2007. Ending aging. The rejuvenation breakthroughs that could reverse human aging in our lifetime. St. Martin’s Press, New York. Griffith RTH (Transl.) (1896) The Hymns of the Rigveda. E.J. Lazarus, Benares. Grmek MD (1958) On ageing and old age, basic problems and historic aspects of gerontology and geriatrics, Monographiae Biologicae, 5, 2, Den Haag. Gruman, G.J., 1966. A history of ideas about the prolongation of life. The evolution of prolongevity hypotheses to 1800. Transactions of the American Philosophical Society 56, 1–102. Alberto V Haller (1778) Elementa Physiologiae Corporis Humani (physiological elements of the human body), 8, pp. 68–124. III Decrementum, Sumptibus Societatis Typographicae, Lausannae. Hamilton, D., 1986. The monkey gland affair. Chatto and Windus, London. Harman, D., 1956. Aging: A theory based on free radical and radiation chemistry. Journal of Gerontology 11, 298–300. Harrington, A., 1969. The Immortalist. Celestial Arts, Millbrae, CA, p. 1977. Hayflick, L., Moorhead, P.S., 1961. The serial cultivation of human diploid cell strains. Experimental Cell Research 25, 585–621.

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Huxley, J., 1957. Transhumanism. In: New bottles for new wine. Chatto & Windus, London, pp. 13–17. Joachim H (Transl. ed.) (1890) Papyrus Ebers. Das Älteste Buch Über Heilkunde (The Ebers Papyrus, The oldest book on medicine), pp. 105–107, 43–44. Georg Reimer, Berlin. Kahn, C., 1985. Beyond the Helix: DNA and the quest for longevity. Times Books, New York. Lloyd, J.U., 1883. Pharmaceutical preparations. Elixirs, their history, formulae, and methods of preparation. Including practical processes for making the popular elixirs of the present day, and those which have been officinal in the old pharmacopoeias. Together with a résumé of unofficinal elixirs from the days of Paracelsus, 2nd edition. Robert Clarke and Company, Cincinnati. Lumière, A., 1932. Sénilité et Rajeunissement (Aging and Rejuvenation). Librairie J.-B. Baillière et Fils, Paris. McCay, C., 1935. The effect of retarded growth upon the length of life span and upon the ultimate body size. The Journal of Nutrition 10, 63–79. Metchnikoff, I.I., 1961. Etudy o Prirode Cheloveka (etudes on the nature of man). Izdatelstvo Academii Nauk SSSR (The USSR Academy of Sciences Press), Moscow (1915, first published in 1903). Nascher, I.L., 1914. Geriatrics, the diseases of old age and their treatment, including physiological old age, home and institutional care, and medicolegal relations. P. Blakiston’s Son & Co, Philadelphia. Pearl, R., 1922. The biology of death. J.B. Lippincott Company, Philadelphia. Robin, É., 1854. Causes générales de la vieillesse, de la mort sénile et du développement de la taille dans les animaux (General causes of aging, senile death and size development in animals). J.B. Baillière, Paris. Romeis B (1931) Altern und Verjüngung. Eine Kritische Darstellung der Endokrinen “Verjüngungsmethoden”, Ihrer Theoretischen Grundlagen und der Bisher Erzielten Erfolge, Verlag von Curt Kabitzsch, Leipzig, (Aging and Rejuvenation. A Critical Presentation of Endocrine “Rejuvenation Methods,” Their theoretical foundations and up-to-date successes). Rubin, B.L., Dorfman, R.I., Pincus, G., 1955. 17-Ketosteroid excretion in aging subjects. In: Wolstenholme, G.E.W., Cameron, M.P. (Eds.), CIBA foundation colloquia on ageing, vol. 1. General Aspects, J. & A. Churchill Ltd, London, pp. 126–137. Shapin, S., Martyn, C., 2000. How to live forever: Lessons of history. British Medical Journal 321, 1580–1582. Sierra, F., Kohanski, R., 2017. Geroscience and the trans-NIH geroscience Interest Group, GSIG. GeroScience 39, 1–5. Smith WD (ed. Transl.) (1994) Hippocrates, vol. 7, epidemics, Loeb classical library, p. 263. Cambridge, MA: Harvard University Press. Stambler, I., 2014. A history of life-extensionism in the twentieth century, Longevity History, Rishon Lezion. http://www.longevityhistory.com/ accessed 30.09.18. Stambler, I., 2015. Elie MetchnikoffdThe founder of longevity science and a founder of modern medicine: In honor of the 170th anniversary. Advances in Gerontology 28, 207–217. Stambler, I., 2017. Longevity in the ancient Middle East and the Islamic tradition. In: Longevity Promotion: Multidisciplinary Perspectives, Longevity History, Rishon Lezion. http:// www.longevityhistory.com/. (Accessed 30 September 2018). Stearns, P.N., 1976. Old age in European society: The case of France. Holmes & Meier, New York. Steinach, E., Loebel, J., 1940. Sex and life: Forty years of biological and medical experiments. Faber, London. Thane, P., 2001. Geriatrics. In: Bynum, W.F., Porter, R.S. (Eds.), Companion encyclopedia of the history of medicine. Routledge, London, pp. 1092–1115. Thompson, R.C., 1928. (Transl.). The epic of Gilgamesh. Luzac & Co., London. Lao Tzu, Lao-Tse and The Tao Teh King (1891) The Tao and Its Characteristics, J. Legge (Transl.), in: Müller FM (ed.), Sacred Books of the East, vol. 39, pp. 45–126. Clarendon Press, Oxford. Van Loon, G. (Ed.), 2003. Charaka Samhita. Handbook on Ayurveda, Durham NC. Voronoff S (1925) Rejuvenation by Grafting, FF Imianitoff (Transl.). George Allen and Unwin Ltd, London. Waite, A.E. (Ed.), 1894. The Hermetic and Alchemical Writings of Paracelsus, vol. 2. James Elliott and Co., London, 69–76, 108–123. Walford, R.L., 2000. Beyond the 120-year diet: How to double your vital years. Four Walls Eight Windows, New York. Wilson E (ed.), (1867) Hufeland’s Art of Prolonging Life. Lindsay & Blakiston, Philadelphia (originally C.W. Hufeland, Makrobiotik; oder, Die Kunst das menschliche Leben zu verlängern, Jena, 1796). Yockey, H.P. (Ed.), 1958. Symposium on information theory in biology, Gatlinburg, Tennessee, October 29–31, 1956. Pergamon Press, New York.

Further Reading Bailey, W.G., 1987. Human longevity from antiquity to the modern lab: A selected, annotated bibliography. Greenwood Press, Westport, CN. Emerson, G.M. (Ed.), 1977. Benchmark Papers in Human Physiology, Vol. 11, Aging. Dowden, Hutchinson and Ross, Stroudsburg, PA. Freeman, J.T., 1938. The history of geriatrics. Annals of Medical History 10, 324–335. Grmek, M.D., 1958. On aging and old age, basic problems and historic aspects of gerontology and geriatrics, Monographiae Biologicae, 5, 2, Den Haag. Gruman, G.J., 1966. A history of ideas about the prolongation of life. The evolution of Prolongevity hypotheses to 1800. Transactions of the American Philosophical Society 56, 1–102. Kahn, C., 1985. Beyond the Helix: DNA and the quest for longevity. Times Books, New York. Lloyd JU (1883) Pharmaceutical preparations. Elixirs, their history, formulae, and methods of preparation. Including practical processes for making the popular elixirs of the present day, and those which have been officinal in the old pharmacopoeias. Together with a résumé of unofficinal elixirs from the days of Paracelsus, Second Edition. Robert Clarke and Company, Cincinnati. Metchnikoff, I.I., 1961. Etudy o Prirode Cheloveka (etudes on the nature of man). Izdatelstvo Academii Nauk SSSR (The USSR Academy of Sciences Press), Moscow (1915, first published in 1903). Nascher, I.L., 1914. Geriatrics, the diseases of old age and their treatment: Including physiological old age, home and institutional care, and medicolegal relations. P. Blakiston’s Son & Co, Philadelphia. Romeis B (1931) Altern und Verjüngung. Eine Kritische Darstellung der Endokrinen “Verjüngungsmethoden”, Ihrer Theoretischen Grundlagen und der Bisher Erzielten Erfolge, Verlag von Curt Kabitzsch, Leipzig (Aging and Rejuvenation. A Critical Presentation of Endocrine “Rejuvenation Methods,” Their Theoretical Foundations and Up-to-Date Successes). Stambler I (2014) A history of life-extensionism in the 20th century, Longevity History, Rishon Lezion, http://www.longevityhistory.com/ (accessed 30.09.18). Stambler I (2017) Longevity promotion: Multidisciplinary perspectives, Longevity History, Rishon Lezion, http://www.longevityhistory.com/ (accessed 30.09.18). Wilson, E. (Ed.), 1867. Hufeland’s art of prolonging life. Lindsay & Blakiston, Philadelphia (originally C.W. Hufeland, Makrobiotik; oder, Die Kunst das menschliche Leben zu verlängern, Jena, 1796).

Homeostasis, Homeodynamics and Aging Suresh IS Rattan, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark © 2020 Elsevier Inc. All rights reserved.

Introduction Homeodynamic Machinery Homeodynamic Space and Essential Lifespan Aging as the Shrinkage of the Homeodynamic Space Homeodynamics and Aging Intervention References

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Introduction All living systems have the intrinsic ability to respond, to counteract and to adapt to the external and internal sources of disturbance. The traditional conceptual model to describe this property is homeostasis, which has dominated biology, physiology and medicine since 1930s (Cannon, 1929; Modell et al., 2015). However, tremendous advances made in our understanding of the processes of biological growth, development, maturation, reproduction, and finally, of aging, senescence and death have led to the realization that homeostasis model as an explanation is seriously incomplete. The main reason for the incompleteness of the homeostasis model is its defining principle of “stability through constancy,” which does not take into account the new themes, such as cybernetics, control theory, catastrophe theory, chaos theory, information and interaction networks, that comprise and underline the modern biology of complexity (Wolf et al., 2018). Since 1990s, the term homeodynamics is being increasingly useddthough it has not yet fully succeeded in replacing homeostasis (Yates, 1994). The concept of homeodynamics accounts for the fact that the internal milieu of complex biological systems is not permanently fixed, is not at equilibrium, and is a dynamic regulation and interaction among various levels of organization. Almost in parallel with the development of the concept of homeodynamics, another term allostasis, has also been gaining recognition and use (Sterling and Eyer, 1988; Sterling, 2004). According to the allostasis model, “stability through change” is the most realistic situation for living biological systems. Allostasis model also takes into account the characteristics, such as reciprocal tradeoffs between various cells, tissues and organs, accommodative sensing and prediction with respect to the severity of a potential stressor, and the final cost of making a response and readjustment to bring about the necessary change. Every act of allostasis adds to the allostatic load in terms of, for example, unrepaired molecular damage, reduced energy deposits and progressively less efficient or less stable structural and functional components (Sterling, 2004).

Homeodynamic Machinery Of the numerous biochemical and physiological pathways and processes operating in cells, tissues, organs and systems in any organisms, the key pathways and processes which can be considered to be quintessential components of the homeodynamic machinery are the following:

• • • • • • • •

Multiple pathways of nuclear and mitochondrial DNA repair, including those for maintaining the accuracy of the information transfer from DNA to RNA to proteins, and those for the removal of spontaneous lesions in DNA (Hakem, 2008; Vijg, 2008). Processes for sensing and responding to intra- and extra-cellular stressors (Fulda et al., 2010; Bhattacharya and Rattan, 2019). Pathways for protein repair, such as the renaturation of proteins by chaperones, and the enzymic reversal of the oxidization of amino acids (Kaushik and Cuervo, 2015; Mary et al., 2004). Pathways for the removal and turnover of defective proteins by proteasomes and lysosomes (Chondrogianni et al., 2015; Hansen et al., 2018). Antioxidative and enzymic defenses against reactive oxygen species (Davies et al., 2017; Kalyanaraman, 2013). Processes for the detoxification of harmful chemicals in the diet (Zimniak, 2008). Cellular and humoral immune responses against pathogens and parasites, including apoptosis (Pawelec, 2017; Nikolich-Zugich, 2018; Tower, 2015). Processes of wound healing, blood clotting and tissue/organ regeneration.(Calabrese, 2013; Tang, 2013)

In addition to the above main categories of pathways and processes comprising the homeodynamic machinery, other physiological processes include the temperature control, the epigenetic stability of differentiated cells, and fat storage and energy utilization. All these processes give rise to a “homeodynamic space” (Rattan, 2012), which is the ultimate determinant of an individual’s chance and ability to survive and maintain a healthy state.

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Homeodynamic Space and Essential Lifespan The three main characteristics of the homeodynamic space are: (Cannon, 1929) stress response; (Modell et al., 2015) damage control; and (Wolf et al., 2018) constant remodeling (Rattan, 2012; Demirovic and Rattan, 2013). Table 1 gives some examples of the processes that comprise these three characteristics of the homeodynamic space. All these processes involve hundreds of genes and gene products, and collectively these genes are known as the longevity assurance genes (Jazwinski, 1998; Martin, 2007) or vitagenes (Rattan, 1998; Calabrese et al., 2010). Each individual is born with a certain volume of the homeodynamic space without which its survival is impossible. Further growth, development and maturation strengthen the homeodynamic space that enables the individual to reach a reproductive age, in accordance with the evolutionary life history of its species. Such natural lifespan of a species is known as the “essential lifespan” (ELS) (Rattan, 2000), or the “warranty period” of a species (Carnes et al., 2003). ELS is defined as the time required to fulfill the Darwinian purpose of life in terms of a successful reproduction for the continuation of generations. Species undergoing fast maturation and early onset of reproduction with large reproductive potential generally have a short ELS. In contrast, slow maturation, late onset of reproduction, and small reproductive potential of a species is concurrent with its long ELS (Finch and Kirkwood, 2000; Finch, 2009). Furthermore, the three survival characteristics of the homeodynamic space described above generally correlate well with the species lifespan. For example, positive correlations have been reported between species’ lifespan and the ability to repair DNA, to detoxify reactive oxygen species, to counteract stress and to replace worn out cells (Kapahi et al., 1999; Holliday, 2006; Rattan, 2006). In contrast, negative correlation has been demonstrated between species’ lifespan and the rate of molecular damage accumulation, including mutations, epimutations, macromolecular oxidation and aggregation of metabolic by-products (Kapahi et al., 1999; Holliday, 2006; Rattan, 2006). Various ideas, based on the allocation of energy and metabolic resources (EMR), have been developed as the determinants of an organism’s longevity and survival potential (Kirkwood, 2008; Kowald and Kirkwood, 2016). According to these ideas, available EMR must be partitioned between three fundamental features of life: (Cannon, 1929) the basic metabolism, which includes biochemical synthesis, respiration, cell turnover, movement, feeding, digestion and excretion; (Modell et al., 2015) the reproduction; and (Wolf et al., 2018) the maintenance through homeodynamic machinery as described above. Whereas basic metabolism is essential for all animals, the extent of investment in reproduction and somatic maintenance can vary between species. This is the trade-off, known as the disposable soma theory of aging, between investment in maintenance and investment in reproduction, which are related inversely (Kirkwood, 2005). The evolved balance between the two depends on the life history strategy and ecological niche of the species. Although the reasons for the longevity differences among the species can be explained by the disposable soma theory, significant differences among individuals within a species are much harder to explain. Genes, milieu (environment) and chance factors are thought to be the determinants of individual lifespan (Finch and Kirkwood, 2000). Of these factors, some understanding is emerging with respect to the genes and their associations with survival and longevity. In human beings, association studies on gene polymorphism and longevity have identified numerous genes which function in a variety of biochemical pathways, such as cytokines, cholesterol metabolism, DNA repair and heat shock response (Deelen et al., 2014; de Magalhaes, 2014). Such studies will ultimately lead to the elucidation of the nature and number of genes involved in comprising the homeodynamic space of an individual, which may be the basis for its modulation and intervention.

Aging as the Shrinkage of the Homeodynamic Space The evolved nature of the homeodynamic machinery, in accordance with the life history traits of different species, sets an intrinsic genetic limit on the ELS (essential lifespan) as described above. Therefore, aging is considered as an emergent phenomenon seen primarily in protected environments which allow survival beyond the natural lifespan in the wild. No real genes for aging (gerontogenes) are thought to exist, and the nature of genes in aging is understood as being “virtual” gerontogenes owing to their indirect effects on aging and longevity (Rattan, 1995). However, some others view aging as a “developmentally programmed” phenomenon (Vaiserman et al., 2018), or a “quasi-programme” by virtue of continuing hyper-growth, controlled through epigenetic regulators (Blagosklonny, 2013; Mitteldorf, 2016). In any case, aging can be defined as the progressive failure of maintenance (Holliday, 2006) or the progressive shrinkage of the homeodynamic space (Rattan, 2012). A generalized definition of aging as the failure of homeodynamics still requires mechanistic Table 1

Characteristics of the homeodynamic space and the main processes involved.

Characteristic of the homeodynamic space

Main processes involved

Stress response

Autophagy, DNA repair response, oxidative stress response, unfolded protein stress response, nutritional stress response, inflammatory response, energy deficiency stress response DNA repair, protein repair, free radical scavenging, molecular turnover Cellular turnover, wound healing, immune remodeling, bone remodeling, tissue regeneration

Damage control Constant remodeling

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Molecular damage reported to accumulate during aging.

Macromolecule

Examples of damage

DNA (nuclear and mitochondrial) RNA Protein Carbohydrates, lipids, and molecular conjugates

Mutations, epimutations, base modifications, strand breaks, loss of telomeres Base modifications, miscoding, missplicing Amino acid modifications, misincorporation, misfolding, aggregation Advanced glycation end-products (AGE), lipofuscin, aggrosomes

explanation(s) as to why such a failure occurs in the first place, and what controls the rate of failure in different species. Progressive accumulation of molecular damage is the most commonly accepted phenotype of the shrinkage of the homeodynamic space (Rattan, 2008a). Such a shrinkage of the homeodynamic space results in the increased zone of vulnerability that leads to the emergence of one or more age-related diseases, and to eventual frailty and death (Rattan, 2012). The main categories of molecular damage reported to occur and accumulate in a wide range of cells and organisms during aging are listed in Table 2. The mechanisms for the occurrence of molecular damage are pretty well understood, and include oxygen metabolites, nutritional metabolites and biochemical errors (Rattan, 2008a). It is also well realized that the occurrence of molecular damage is mostly stochastic, although certain structural features of a macromolecule, such as its tertiary structure and interactions with other macromolecules, may seem to determine the site and extent of the damage (Finch and Kirkwood, 2000; Basaiawmoit and Rattan, 2010). Furthermore, the accumulation of molecular damage is primarily attributed to the impossibility of having perfect systems owing to the unreliability of the complex systems (Gavrilov and Gavrilova, 2001), and the laws of thermodynamics and entropy (Hayflick, 2007; Boltzmann, 2013). Since the occurrence and accumulation of molecular damage is mainly stochastic, aging is manifested differently in different species, in individuals within a species, organs, tissues, cells and in subcellular-components within an individual (Rattan, 2008a). The main cause of age-related accumulation of molecular damage and its consequences is the inefficiency and failure of maintenance, repair and turnover pathways of the homeodynamic machinery, which constitute the genetically-determined homeodynamic space at a species level (Rattan, 2012).

Homeodynamics and Aging Intervention According to the homeodynamics-based explanations for aging and longevity described above, occurrence of aging in the period beyond ELS, and the onset of one or more diseases before eventual death, appear to be the normal sequence of events. Such an understanding of aging makes modulation of aging different from the treatment of one or more specific diseases (Rattan, 2014a). In the case of a disease, such as a cancer of any specific kind, its therapy will, ideally, mean the removal and elimination of the cancer cells and restoration of the affected organ/tissue to its original disease-free state. What will then be the “treatment” of aging and to what original “age-free” stage one would hope to be restored? Similarly, although piecemeal replacement of nonfunctional or half-functional body parts with natural or synthetic parts made of more durable material may provide a temporary solution to the problems of age-related impairments, it does not modulate the underlying aging process as such. Scientific and rational anti-aging strategies aim to slow down aging, to prevent and/or delay the physiological decline, and to regain lost functional abilities (Vaiserman, 2017). Strengthening, improving or enlarging the homeodynamic space at the level of all genes comprising the homeodynamic machinery of an individual may be the ideal anti-aging solution. However, such a gene-therapy approach for gerontomodulation requires redesigning the blueprint for structural and functional units of the body at the level of genes, gene products, macromolecular interactions, molecular-milieu interactions, and so on. Considering how little information and knowledge we have at present about all those interacting variants of genes, molecules, milieu and chance, it is not clear what this approach really means in practical and achievable terms (Rattan, 2014a,b). In a more realistic and near-future scenario, a promising approach in aging intervention and prevention is based in making use of an organism’s intrinsic homeodynamic space of self-maintenance and repair. Since aging is characterized by a decrease in the adaptive abilities due to progressive failure of homeodynamics, it has been hypothesized that if cells and organisms are exposed to brief periods of stress so that their stress response-induced gene expression is upregulated and the related pathways of maintenance and repair are stimulated, one should observe anti-aging and longevity-promoting effects. Such a phenomenon in which stimulatory responses to low doses of otherwise harmful conditions improve health and enhance lifespan is known as hormesis (Le Bourg and Rattan, 2008; Rattan, 2008b; Rattan and Le Bourg, 2014; Rattan and Kyriazis, 2019).

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Hormesis and Hormetins in Aging Suresh IS Rattan, Aarhus University, Aarhus, Denmark © 2020 Elsevier Inc. All rights reserved.

Introduction Rationale for Applying Hormesis in Aging Molecular Basis of Hormesis Hormetins in Aging Modulation Unresolved Issues References

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Introduction Hormesis is the phenomenon in which low doses of a stressor, that is toxic at high doses, induce stress responses in biological systems, which could eventually be “beneficial” for the system. Specific aspects of this general nonlinearity phenomenon have been described using various terms mainly addressing the shape of the dose–response curve, as biphasic, bimodal, bitonic, Ushaped, inverted-U-shaped, J-shaped, nonmonotonic, functional antagonism and stimulatory inhibitory, among others (Calabrese and Baldwin, 2001a). Furthermore, terms such as adaptive response, preconditioning, autoprotection, heteroprotection, paradoxical and others have also been used to describe the shape of the dose–response patterns (Calabrese and Baldwin, 2001b). Since 2007, the term hormesis has been widely adopted as a result of a collective article written by more than 50 leading researchers from a variety of disciplines, including biomedical gerontology (Calabrese et al., 2007). As stated in that paper: “. we propose a set of recommendations that can achieve some harmony in terminology, fostering better understanding and communication with respect to the dose–response relationship, while being sufficiently flexible to accommodate future scientific developments and refined understanding of the dose–response pattern.” Further refinements of the term were also suggested, such as conditioning hormesis, physiological hormesis, and postexposure conditioning hormesis to deal with the specific aspects of the adaptive stress responses (Calabrese et al., 2007). Independently, two other terms have been proposed to describe: (i) hormetin for any condition that induces hormesis (Ali and Rattan, 2006); and (ii) hormetics for the scientific study of hormesis (Rattan, 2012). The aim of this article is to discuss hormesis and hormetins as applied in aging research and interventions. This is mainly a review of the published literature on various stress conditions which are known to be harmful at high doses, but which at lower doses, have the effects of slowing down aging and/or prolonging the lifespan and health-span of cells and organisms. It should be noted that so far only a few studies have been performed with the specific aim of testing the applicability hormesis in aging research and interventions; and for most studies, interpreted to involve hormesis as the mode of action, those conclusions are generally derived in retrospective analyses (Rattan, 2008a; Le Bourg and SIS, 2008; Rattan and Le Bourg, 2014).

Rationale for Applying Hormesis in Aging Biogerontology, the study of the biological basis of aging, has been remarkably successful in describing the phenomenology of agerelated changes in organisms, organs, tissues, cells and macromolecules, leading to the development of causal theories and elucidation of basic mechanisms of aging According to the fundamental understanding of the aging phenomenon and the process achieved so far, aging is an emergent, epigenetic and a meta-phenomenon, which is not controlled by any specific gerontogenes or by a single common mechanism (Holliday, 2009; Holliday and Rattan, 2010; Rattan, 2000a, b, 2007a; Rattan and Clark, 2005; Carnes, 2011). Aging is an intrinsic, progressive and impairing phenomenon that can be best described as the failure of maintenance (Holliday, 2009; Holliday and Rattan, 2010), or the shrinkage of the homeodynamic space (Rattan, 2000a, b, 2007a; Rattan and Clark, 2005). The concept of homeodynamic space is based on the concept of homeodynamics that means “the same dynamics” of a living system (Yates, 1994), which is in contrast to the classical term homeostasis that means “the same state” (Cannon, 1929), best applicable to the man-made machines. Homeodynamic space may also be considered as the survival ability of a biological system (Rattan, 2007b, 2013). Three main characteristics of the homeodynamic space are: (1) stress response; (2) damage control; and (3) constant remodeling and adaptation in dynamic interactions. A large number of molecular, cellular and physiological pathways and their interconnected networks, including extensive maintenance and repair systems, determine the nature and extent of the homeodynamic space (Rattan, 2007b, 2013). Thus, understanding aging as the shrinkage of the homeodynamic space implies that successful aging interventions should aim for the maintenance and strengthening of the homeodynamic space, rather than specific target-oriented antiaging approaches. Hormesis is one such holistic approach. Hormesis for healthy aging is, therefore, defined as the life-supporting health beneficial

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effects resulting from the cellular responses to single or multiple rounds of mild stress (Rattan, 2008a, 2017; Rattan and Demirovic, 2010).

Molecular Basis of Hormesis The mechanistic and molecular basis of hormesis is the primary event of disruption of homeodynamics leading to the activation of one or more stress responses (SR) to counteract the disruption. Starting from the exposure to a stressor to the potential occurrence of physiological hormesis, the SR process can be elucidated in five conceptual steps: (a) stress-induced disturbance in the homeodynamic equilibrium; (b) activation of signaling pathways to initiate SR pathways; (c) activation of SR pathway-mediated effector responses; (d) restoration of homeodynamics; and (e) enhanced adaptive ability (Bhattacharya and Rattan, 2019). The molecular and physiological processes initiated by SR are not strictly limited to match the level of disruption, and almost always lead to modest overcompensation (Calabrese et al., 2012; Calabrese, 2013). A successful SR not only results in the reestablishment of homeodynamics, but also strengthens the homeodynamic space (Demirovic and Rattan, 2013). Whereas a single exposure to nonlethal severe stress can lead to the hardening or preconditioning of the biological system to a following stress, intermittent exposure to mild stress generally leads the phenomenon of physiological hormesis or enhanced adaptive ability (Calabrese et al., 2007). Preconditioning based on hormetic strengthening of a system has shown positive results during postsurgical recovery in animal models and in humans (Calabrese, 2016). Furthermore, postconditioning hormesis through physical exercise and radiation is being used in medical practice after receiving an acute injury such as stroke and cancer (Safwat, 2000). The common molecular basis of physiological hormesis is the homeodynamic ability of SR. Table 1 gives a list of the intracellular molecular pathways of SR in most eukaryotic systems (Bhattacharya and Rattan, 2019). The molecular biology of these pathways is well understood in terms of its molecular biology, and the Table provides a summary of various SR, examples of a variety of initiating stressors, followed by the immediate or early responses, late responses and the biochemical mediators of the response. For example, heat shock response (HSR), which is a universal and primordial SR, is achieved by the protein denaturation-initiated activation of the HS transcription factor(s), and the preferential synthesis of several heat shock proteins (Hsp) (Verbeke et al., 2001a; Ciocca and Calderwood, 2005; Leak, 2014) Similarly, accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to the so-called ER stress response, also known as the UPR stress response, resulting in the synthesis, activation and translocation of several chaperones. (Lee, 2001; Lin et al., 2007; Ni and Lee, 2007; Yoshida, 2007; Banhegyi et al., 2007) In addition, there are mitochondrial-specific SR in mammalian cells, and involve the induction and activation of various chaperones, including chaperonin-10 (Cpn10/Hsp10), chaperonin-60 (Cpn60/Hsp60), and mortalin (Zhao et al., 2002; Kaul et al., 2007). Other primary SR include oxidative stress response via the activation of Nrf2; hypoxia-induced SR via hypoxia-inducible factor; DNA damage SR; inflammatory SR; energy and nutritional deficiency SR involving AMPK, mTOR and sirtuins and the deacetylation of histones and other proteins in response to reduced levels of metabolic energy (Giblin et al., 2014; Efeyan et al., 2015). Similarly, autophagy is the lysosome-mediated and chaperone-mediated sequestering of damaged membranes and organelles, which is a SR induced during nutritional limitation, starvation, and hypoxia (Ryter and Choi, 2013; Filomeni et al., 2015; Zhang, 2015).

Hormetins in Aging Modulation As defined above, any stress-condition that is potentially able to induce hormesis is termed as a hormetin (Rattan, 2012; Rattan and Le Bourg, 2014). Some examples of hormetins, arranged under different categories, are given in Table 2. What follows is a brief review of the studies performed using the above hormetins as potential modulators of aging and longevity in various biological systems. Exercise: Physical exercise is perhaps the most studied hormetin for its whole body level health beneficial effects (Radak, 2014). These effects include a reduction in the risk of age-related diseases, a reduction in oxidative stress-induced molecular damage, improved immune system, improved cognition, improved neuromuscular coordination, increased life expectancy and improved overall quality of life (Radak, 2014; Weigmann, 2014; Febbraio, 2017; Parker et al., 2017; Bouzid et al., 2018). It is important to note that the effects of exercise-induced hormesis are cumulative and amplified at the whole body level even when the initial targets are focused and specific. For example, physical exercise of the leg muscles provides health benefits much beyond the local muscles, and improves metabolic management, immunity, cognition, mood and so on (Rattan and Demirovic, 2010). However, there can be large interindividual differences in achieving the health benefits of the same type of exercise, which could also involve genetic variations and gene polymorphism (Cherkas et al., 2008). Although the main molecular pathways involved in bringing about the adaptive and hormetic effects of exercise through SR are known, the exact kinetics and dose response at an individual level still need to be worked out. Radiation: Experimental studies performed on insects, including Drosophila and houseflies, have shown various agingmodulatory and lifespan-extending hormetic effects of low dose radiation (LDR) (Zhikrevetskaya et al., 2015). Similarly, several other studies have reported the hormetic effects of gamma rays on longevity in rats, mice and guinea pigs (Caratero et al., 1998; Calabrese and Baldwin, 2000). Some data are also available on the effects of LDR and other stresses on the survival and longevity of the nematode Caenorhabditis elegans (Zhao and Wang, 2012). For example, an increase in the survival of C. elegans was observed

244 Table 1

Hormesis and Hormetins in Aging Stressors and mediators of early and late responses of primary intracellular stress response pathways

Stress response

Stressors

Early response

Late response

Mediators

Heat shock response (HSR)

Heat, denatured proteins, heavy metals, antibiotics

Transcription and translation of HSP

Chaperones (HSP), co-chaperones (HOP), proteases, proteasome

Unfolded protein response (UPR) or ER stress response Oxidative stress response (OSR)

Unfolded/misfolded proteins in ER

Heterotrimerization of HSF1, nuclear translocation and binding to HSE in the promoters of HSP genes Activation of ER stress sensors (IRE1, ATF6, PERK) Nrf2 release from Keap1, stabilization, nuclear translocation, binding to ARE Inhibition of HIFa degradation, nuclear translocation, binding to HIF-b, and later to HRE ATM and ATR recruitment to double-strand and single strand breaks respectively Chemokine release, activation of cell-surface receptors like TNF-a, IL-1 and nuclear translocation of NF-kb AMPK activation, deacetylation of PGC-1a, FOXO

Induction of chaperones, pro/anti-apoptotic genes

Chaperones (GRP78, GRP94), HSP40-type co-chaperones Antioxidant gene products (HO-1, GST, SOD)

Pro-oxidants, freeradicals (ROS, RNS)

Hypoxia-induced stress response (HISR)

Low oxygen levels

DNA damage response (DDR)

Radiation, free-radicals, oxidants

Inflammatory stress response (ISR)

Pathogens, allergens, injuries

Energy stress response (ESR)

Energy deficit (low ATP/ AMP or NADþ/NADH) ratio

Nutritional stress response (NSR)

Nutritional inadequacy

AMPK activation, mTORC1 inhibition, dephosphorylation of ULK1/2, Atg13

Transcription and translation of antioxidative genes Induction of HIF inducible genes

Erythropoietin, HO-1, iNOS, VEGF

Activation of cell cycle checkpoint pathways

p53, mortalin/PBP74, DNA repair enzymes

Induction of genes involved in cell survival, angiogenesis, tumor progression

Cytokines, pro-/antiapoptotic enzymes (IL-2, IL-6, Bax, Bcl-2)

Inhibition of anabolic pathways, activation of catabolic pathways; increased mitochondrial biogenesis Autophagosome formation and lysosomal digestion

AMPK, sirtuins

AMPK, autophagyrelated proteins

Reproduced with permission from Bhattacharya S and Rattan SIS (2019) Primary stress response pathways for pre-conditioning and physiological hormesis. In: Rattan SIS, Kyriazis M (eds.) The Science of Hormesis in Health and Longevity, pp. 35–54. UK: Academic Press.

Table 2

Hormetin categories and some examples

• Physical/environmental hormetins Exercise Radiation High and low temperature Hypergravity Electromagnetism • Chemical/nutritional hormetins Dietary components Dietary restriction Minerals and trace elements Pro-oxidants Nano-particles • Biological hormetins Microbes Psycho-social factors

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after intermediate levels of irradiation (Johnson and Hartman, 1988). However, preexposure to UV or ionizing radiation did not promote subsequent resistance or increased the lifespan of the worms exposed to other hormetic stresses such as heat, hyperbaric oxygen and prooxidants (Cypser and Johnson, 2002). A common explanation given for the life-extending effects of LDR is that irradiation induces stable epigenetic DNA modifications, and enhanced DNA repair capacity. Human embryonic cells exposed to low dose gamma-radiation have increased replicative lifespan in vitro (Watanabe et al., 1992). In the same manner, human embryonic lung diploid fibroblasts sequentially irradiated with 1 Gy gamma rays had their replicative lifespan increased (Holliday, 1991). Hormetic effects of low dose X-irradiation on the proliferative ability, genomic stability and activation of MAP-kinase pathways have also been reported for other human diploid cells (Suzuki et al., 2001). In human beings, exposure to LDR seems to have some health benefits, including cancer prevention and aging-modulation (Wyngaarden and Pauwels, 1995; Parsons, 2003; Kojima et al., 2017). For example, all cause mortality and all cause cancers (leukemia and prostate cancer) were significantly lower for nuclear workers in UK’s Atomic Energy Authority as compared with nonradiation workers (Atkinson et al., 2004). A meta-analysis of a set of 15-country international cohort studies of nuclear workers and of people living near nuclear reactors showed that radiation effects were not linear in terms of survival, and that incidence of cancer and other diseases was reduced significantly (Cardis et al., 2007; Vrijheid et al., 2007). Heat: A rapid exposure to high temperature-induced heat shock (HS) has been extensively used as a hormetin in aging research and interventions. Effects of mild and severe HS have been tested on yeast, nematodes, fruitflies, and on rodent and human cells in culture. For example, wild-type and age-1 long-lived mutants of the nematode C. elegans exposed for 3 to 24 h to 30 C exhibited a significant increase in mean lifespan as compared to the controls (Lithgow et al., 1995; Johnson, 2002; Yokoyama et al., 2002). Furthermore, C. elegans subjected to severe HS at 35 C for different durations showed that HS up to 2 h resulted in an extension of lifespan (Butov et al., 2001; Michalski et al., 2001; Yashin et al., 2001). In a study of multiple stresses in C. elegans an extension of lifespan after 1 and 2 h HS at 35 C was reported (Cypser and Johnson, 2002, 2003). In another study performed on C. elegans it was observed that repeated mild HS throughout life had a larger effect on lifespan compared to a single mild HS early in life, and the effect was related to the levels of heat shock protein (HSP) expression (Olsen et al., 2006). Although most of these longevityextending hormetic effects of HS in C. elegans are reported to be mediated by HSR and HSP, there is evidence that other stress response pathways, such as autophagy, are also involved in achieving these effects (Kumsta et al., 2017). In the case of fruitflies, virgin males of inbred lines of Drosophila melanogaster exhibited an increase in mean lifespan and lower mortality rates during several weeks after a heat treatment of 36 C for 70 min (Khazaeli et al., 1997). It has also been shown that wild-type D. melanogaster exposed to 37 C for 5 min a day for 5 days lived on average 2 days longer than the control flies (Le Bourg et al., 2001). Longer exposures had either no effect or negative effect on lifespan. In another study, exposure of D. melanogaster young flies to 4 rounds of mild HS at 34 C significantly increased the average and maximum lifespan of female flies and increased their resistance to potentially lethal HS (Hercus et al., 2003). Interestingly, the beneficial effects of HS in Drosophila did not entirely depend on a continuous presence of HSP, but were observed long after newly synthesized HSP had disappeared, indicating the involvement of a cascade of poststress events in hormesis (Sørensen et al., 2008). Furthermore, the hormetic effects of HS appear to be to different extents in male and female Drosophila, which may be due to the fact that females have to trade off stress resistance and reproduction (Sørensen et al., 2008). Studies have also been performed on the effect of subjecting transgenic D. melanogaster which over-express the inducible HSP70, to 20 min HS at 36 C (Minois et al., 2001; Minois and Vaynberg, 2002). In the control parental line, such an exposure significantly increased the lifespan of both the virgin flies kept in groups and that of the mated flies. No beneficial effect of such HS has been seen in the transgenic lines, which may be suggestive of upper limits of modulating HS responses (Minois and Vaynberg, 2002). Similarly, long-lived lines do not benefit from hormesis-inducing heat treatment in D. melanogaster, D. buzzatii and the genetic background, sex and duration of a mild heat stress influence the position of the hormetic zone (Sarup and Loeschcke, 2011). The implication of this result could be that, in a genetically diverse population, a treatment that is life-prolonging in one individual could be life-shortening in other individuals. In addition to high temperature induced HSR, there is some evidence that cold stress-induced hardening also increased the survival and longevity of Drosophila at high temperature (Overgaard et al., 2005; Le Bourg, 2008). A study performed with irradiated and nonirradiated mice reported lower mortality in irradiated mice after being given intermittent cold-shocks (Minois, 2000). Similarly, rats kept in water set at 23 C, for 4 h a day for 5 days had a slight increase in average lifespan along with reduced occurrence of age-related diseases (Holloszy and Smith, 1986). Employing a mild stress regimen of exposing serially passaged human skin fibroblasts to 41 C for 1 h twice a week throughout their replicative lifespan, several hormetic effects have been reported. The main aging-modulatory effects of mild repeated HS on human skin fibroblasts include: maintenance of cell morphology and size (Rattan, 1998), reduced accumulation of protein damage (Verbeke et al., 2001b), increased levels of HSP, improved tolerance to other stresses such as ethanol and UV (Fonager et al., 2002), increased proteasomal activity (Beedholm et al., 2004), better maintenance of the basal levels of MAP kinases JNK1, JNK2 and p38 (Nielsen et al., 2006), and improved wound-healing ability (Rattan, 2008b). The choice of the above RMHS regimen was based on several pilot experiments performed for selecting conditions where 30% of the maximal HS response was elicited without affecting cell growth and survival (Rattan, 1998; Kraft et al., 2006). Similar studies have also been performed on normal human epidermal keratinocytes (NHEK), and the results obtained are very much similar to those for dermal fibroblasts. For example, NHEK showed a variety of cellular and biochemical hormetic agingmodulatory effects on repeated exposure to mild HS at 41 C. These effects included maintenance of youthful cellular morphology, enhanced replicative lifespan, enhanced proteasomal activity, and increased levels of HSP (Rattan and Ali, 2007). Additionally, mild

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HS increased the content and activity of Na,K-ATPase in NHEK (Rattan and Ali, 2007), and enhanced the ability of serially passaged keratinocytes to enter into differentiation in the presence of calcium, as measured by the levels of differentiation markers involucrin, p38 and Hsp27 (Berge et al., 2008). Single or multiple exposures to mild HS significantly enhanced the vitamin-D-induced differentiation of human mesenchymal stem cells (hTERT-MSC) into osteoblasts, as measured by determining the levels of osteoblastic markers alkaline phosphatase and mineralized matrix (Nørgaard et al., 2006). It has also been reported that the growth of mesenchymal stem cells from aged mice was stimulated by mild HS (Andreeva et al., 2016). Other hormetic effects of mild HS on human cells that have been reported are improved cell migration and enhanced angiogenesis in vitro (Rattan, 2008b). For example, HS-conditioned medium collected from one set of cultures after 6 h post-HS at 41 C for 1 h enhanced cell migration by 17%–38% in a separate set of cells. This increase by HS-conditioned medium was accompanied by a 68% increase in mobility and migration of cells, and by about 54% enhanced elongation of individual cells. These studies indicate that mild HS induces the synthesis of one or more gene-products, which are secreted by the cells in the culture medium. Improved angiogenesis in vitro is another hormetic effect of mild HS. Preexposure of normal human umbilical vein endothelial cells (HUVEC) to 1 h HS at 41 C or 42.5 C, followed by different periods of recovery at 37 C had hormetic effects with respect to angiogenesis (Rattan et al., 2007). Similarly, mild heat-stress enhances angiogenesis in a coculture system consisting of primary human osteoblasts and endothelial cells (Li et al., 2014). At the mechanistic level, there is some evidence that HSP90 stimulates tube formation by HUVEC via its role in enhancing the expression of nitric oxide synthase (NOS) gene and the production of nitric oxide (Sun and Liao, 2004). Health and aging-associated beneficial hormetic effects of heat have also been reported for mice. For example, mild heat exposure protects against UVB-induced photo-aging in mice (Haarmann-Stemmann et al., 2013). Although there are no long-term and aging-targeted studies on the effects of heated hydrotherapy and sauna, there are some reports on the health beneficial effects of such hormetic treatments in monkeys (Kavanagh et al., 2016) and humans (Scapagnini et al., 2014). As regards the detailed molecular mechanisms through which the hormetic effects of mild HS are achieved, these remain to be elucidated. Although the general mechanisms of severe HS response are well understood, it is not clear whether there are any significant differences between mild HS, which has hormetic effects, and severe HS, which has deleterious effects (Park et al., 2005). Calorie restriction (CR): Hormesis is a major explanation for the lifespan-extending effects of CR observed in yeast, insects, rats, mice, and monkeys, by virtue of CR being a low-intensity stressor (Yu, 1999; Yu and Chung, 2001; Ingram and Roth, 2015). Beneficial effects of various CR regimens, such as 25% and 8.5% chronic CR (Gomez et al., 2007), and intermittent CR (once or twice a week) have also been reported in animal and some human studies (Sogawa and Kubo, 2000; Anson et al., 2003; Martin et al., 2006; Sharma and Kaur, 2005; Singh et al., 2012). The evidence that CR is a low-intensity stressor is its association with the increase in plasma levels of glucocorticoid steroid stress hormones, and the promotion of maintenance and repair pathways, which include: increase in nucleotide excision repair; increase in the level of chaperones; increase in the level of proteosomal activities; enhancement of lysosomal autophagy; reduction in mitochondrial free radical generation and increase in mitochondrial uncoupling; and a shift in the metabolic regulation involving sirtuins and insulin-dependent pathways (Bonelli et al., 2008; Masoro, 2007; Heilbronn et al., 2006; Novelle et al., 2015). Nutritional components: Various dietary components, such as vitamins, antioxidants, trace elements, minerals, and ethanol, have been shown to have typical hormetic dose response in various animals and human systems (Calabrese and Baldwin, 2003; Mocchegiani et al., 2006; Hayes, 2007; Mattson, 2008; Lee et al., 2014, 2015; Khaw et al., 2008). The cardioprotective, neuroprotective, antioxidative and other beneficial effects of wine are considered to be due to flavonoid and nonflavonoid components such as resveratrol (Corder et al., 2006; Putics et al., 2008; Kadlecova et al., 2015; Handing et al., 2015). Other nutritional hormetins are various so-called antioxidants as components of spices and other medicinal plants. Almost all antioxidants show hormetic dose response and become pro-oxidants above certain doses (Halliwell, 2000). In some cases such as alpha lipoic acid and coenzyme Q10, it is their pro-oxidant activity in producing hydrogen peroxide, which induces defensive responses (Linnane and Eastwood, 2006). Certain mimetics of superoxide dimutase claimed to have aging-modulatory effects also appear to work through hormetic pathways by inducing oxidative stress response (Melov et al., 2000; Liu et al., 2003; Keany et al., 2004). Even DNA damage products, for example thymidine dimers, have cytoprotective effects in the skin by inducing DNA repair pathways (Eller et al., 1997; Goukassian et al., 2004). Another secondary DNA damage product, N6-furfuryladenine or kinetin, which is known to slow down aging in human cells, also work as a hormetin through stress-induced hormetic pathways (Berge et al., 2008; Kadlecova et al., 2018). Components of various medicinal plants used frequently in the traditional Chinese medicine (TCM) and in the Indian Ayurvedic system of medicine are claimed to have aging-modulatory effects, which appear to be achieved through hormetic pathways. For example, celasterols and paeoniflorin present in some medicinal herbs used in TCM, have cytoprotective effects and induce HSP in human cells (Westerheide et al., 2004; Yan et al., 2004). Similarly, curcumin, which is the active component in the commonly used yellow food spice from the roots of Curcuma longa, is a coinducer of HSP and has wide ranging biological effects depending on its dosage (Dunsmore et al., 2001; Cronin, 2003; Joe et al., 2004). Hormetic effects of green tea components in the prevention of several features of brain aging have been reported in mice (Unno, 2016). Hormesis may also be an explanation for the health beneficial effects of numerous other foods and food components, such as garlic, Gingko, and other fruits and vegetables (Hayes, 2007, 2005; Lee et al., 2014; Everitt et al., 2006; Ferrari, 2004; Gurib-Fakim, 2006). Understanding the hormetic and interactive mode of action of natural and processed foods is a challenging field of research, and has great potential in developing nutritional and other life style modifications for aging intervention and therapies. For

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example, it may be possible to develop multihormetin formulations as aging-modulatory nutriceuticals and cosmeceuticals whose mode of action is through hormetic pathways by mild stress-induced stimulation of homeodynamic processes (Rattan et al., 2013). Hypergravity and other hormetins: Aging-modulatory and life-prolonging hormetic effects of hypergravity have been studied in Drosophila. Whereas lifelong exposure to hypergravity decreases the lifespan in rodents and fruitflies, a 2-week exposure to 3 or 5 g at earlier stages in life, resulted in an increase of 15% in the lifespan of male, but not of female, D. melanogaster (Minois, 2006). In addition to longevity, other physiological and behavioral parameters, such as fecundity, fertility, locomotor activity, antioxidant enzyme activity, HSP levels and heat resistance, have also been analyzed (Le Bourg, 2008). Further studies have also been performed on combining two or three stresses for their additive or synergistic hormetic effects on Drosophila (Le Bourg, 2017, 2012). Some examples of other potential hormetins that have been investigated with respect to their effects in aging and longevity include injuries, infections, electromagnetic stress, and mechanical stress, but the results obtained are not consistent or well understood. For example, the effects of repeated physical injuries on lifespan have been studied for a marine oligochaete Paranais litoralis, capable of posterior regeneration, and of asexual reproduction (Martínez, 1996). Chronic low-frequency (10 Hz) electric stimulation of young and old male Brown Norwegian rats resulted in more than 2-fold increase in the proportion of type IIa slow muscle fibers and in the content of satellite cells (Putman et al., 2001). Similarly, a long wave-length, low energy and nonthermal electromagnetic frequency (50 MHz/0.5 W) enhanced cellular defenses of human T cells and affected various aging characteristics in human fibroblasts, including wound healing (Perez et al., 2008a, b; Zhao, 2009). Aging-modulatory effects of low doses of nanodiamond and silica nanoparticles on human skin fibroblasts have also been reported (Mytych et al., 2016). Some studies have also been performed on checking the hormetic effects of mental and psychological stress. Although the harmful effects of chronic and acute stress on life functioning, quality of life, and survival are well documented (Padgett and Glaser, 2003; Segerstrom and Miller, 2004), beneficial effects of periodic low-level mental stress in human beings are also reported (Stark, 2012). There are some studies which report that hormesis through mental challenge and through mind-concentrating meditational techniques may be useful in stimulating stress response (Bierhaus et al., 2003). Some psycho-modulatory compounds, such as lithium, have also been shown to extend lifespan of Drosophila through stress-induced hormetic pathways (Castillo-Quan et al., 2016).

Unresolved Issues Since the hormetic effects of mild stress are usually quite moderate, sometimes it is difficult to envisage the biological significance of hormesis in terms of its application in aging intervention. However, although the initial hormetic effects may be relatively small when studied at the level of an individual biochemical step, often the final biological outcome, such as overall stress-tolerance, functional improvement and survival, is much larger, synergistic and pleiotropic (Rattan, 2017). This suggests that hormesis is involved in the biological amplification of adaptive responses leading to the improvement in overall cellular functions and performance (Rattan, 2008a). There are some important issues that remain to be resolved in order for hormesis to be applied as an effective aging-modulatory strategy. These issues include:

• • • • •

establishing stress exposure regimens in terms of the intensity and frequency; adjusting the levels of mild stress to account for age-related changes in the sensitivity to stress; determining the interactive and pleiotropic effects of multiple stresses; establishing the molecular criteria for identifying potential hormetins; and determining the biological trade-off and costs of repeated exposure to stress.

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Hunting, Predation and Senescence in Boars Marle`ne Gamelon, Norwegian University of Science and Technology, Trondheim, Norway © 2020 Elsevier Inc. All rights reserved.

Introduction Estimating Cause-Specific Mortality Hunting Predation Other Sources of Mortality Interaction Between Causes of Mortality Hunting Mortality and Life History Strategy References

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Glossary Adults Individuals older than 2 years of age. Hunting mortality probability The annual probability for an individual to die killed by hunting. Juveniles Individuals between 0 and 1 year of age, also called piglets. Mortality due to predation The annual probability for an individual to die killed by a non-human predator. Main predators for the wild boar are red foxes and wolves. Natural mortality probability The annual probability for an individual to die but not from human and non-human predation. Natural survival probability The probability for an individual to survive from 1 year to the next one, in absence of human and non-human predation. Overall survival probability The probability for an individual to survive from 1 year to the next one and thus not to die from hunting, predation or natural causes. Subadults Individuals between 1 and 2 years of age, also called yearlings.

Introduction Identifying the factors causing mortality over life is of great importance in gerontology. This is indeed the first required step to understand the underlying mechanisms shaping mortality, such as genetic mechanisms and environmental factors. The work from Horiuchi and Wilmoth (1997) is a nice illustrative study showing the major causes of death over life for females in Japan between 1951 and 1990. The same approach used on males and females in France between 1979 and 1994 indicates that malignant neoplasms, hypertensive disease or liver cirrhosis are some of the main causes of mortality between ages 30 and 54. At older ages, death rates increase drastically caused by infection diseases and heart failure (see Fig. 2 in Horiuchi et al., 2003 showing the age pattern of the cause-of-death structure). A better understanding of the sources of mortality affecting individuals from birth to old ages is also crucial in ecology and evolution. For instance, Forrester and Wittmer (2013) reviewed 48 studies to identify the major causes of mortality affecting mule deer and black-tailed deer Odocoileus hemionus at different ages. They found that predation is the main cause of mortality for all ages. Also, malnutrition as well as diseases can severely affect survival and more generally the growth of the populations. In addition of affecting population dynamics, the multiples sources of mortality act as selective pressures shaping life history traits. Studies led on harvested animal populations have provided valuable insight on the key role of age-specific mortality on life history evolution. For instance, there is growing evidence that high hunting mortality on the adult class can induce evolutionary changes such as earlier age at maturity and reduced body size (Proaktor et al., 2007). On the contrary, a removal of non-mature juvenile individuals may mimic natural mortality and predation pattern and thus limit undesirable evolutionary responses due to harvesting (Milner et al., 2011). Ultimately, a better knowledge of the causes of mortality affecting wild vertebrates over life might help elaborating appropriate management actions to control populations in a sustainable way. As most ungulate populations in temperate areas, wild boar (Sus scrofa) abundance and distribution have increased over the last decades across Europe (Apollonio et al., 2010; Massei et al., 2015). Changes in agricultural practices, reduced hunting pressure, global change and land abandonment have favored the expansion of this emblematic game species (Massei and Genov, 2004). When they overturn soil to feed, wild boars lead to important damages to crops and influence plant, animal, fungi and aquatic communities (see Barrios-Garcia and Ballari, 2012 for a review). They are also reservoirs of several diseases with some of them being

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possibly transmitted to humans, such as brucellosis or leptospirosis (Meng et al., 2009). Controlling wild boar populations has thus become an important goal for wildlife managers and hunting has long been proposed as a tool to achieve it. Interestingly, this species exhibits an unusual life history strategy among ungulates rendering its regulation challenging. Firstly, females are particularly fecund, being able to produce up to 14 piglets in a single litter (Servanty et al., 2007), at young ages (from their first year of life, Gamelon et al., 2011) after having reached only 33%–41% of their asymptotic adult body mass (Servanty et al., 2009). Secondly, the generation time, i.e. the mean age of mothers at childbirth, is close to 2 years in some heavily hunted populations whereas it is around 6 years for similar-sized ungulates (Servanty et al., 2011). This short generation time characterizing wild boar life history is typically observed in passerine birds or rodents. This indicates an especially fast turnover, with compensation for reduced survival in heavily hunted environment by reallocation of resources to reproduction (Gamelon et al., 2011; Servanty et al., 2011). The purpose of this chapter is to identify the sources of mortality affecting wild boar over life, discuss how they can interact and shape life history traits. First, I present some general methods to properly estimate age-related causes of mortality. Second, I report some of the studies that have quantified the main causes of mortality affecting wild boars from young to older ages. Based on this literature survey, I discuss the type of mortality an individual is likely to experience according to its age and sex. Third, I argue why it is important to examine how some sources of mortality can interact. Fourth, I discuss how wild boar population growth rates can increase despite a somewhat low survival.

Estimating Cause-Specific Mortality The multiple sources of mortality that affect human and non-human individuals compete and their probability of wining depends on the strength of the different causes of mortality (Ergon et al., 2018). Statisticians have thus long been interested in properly decomposing mortality into its different sources, the so-called “competing risks.” Sometimes, the fate of an individual (i.e. alive or dead) and the cause of death are precisely known. This is the case in medicine, human demography, in plants and captive animal populations. Also, in free-ranging animals, the recent advances in GPS and radiotelemetry technology may allow to identify the cause of death (Tomkiewicz et al., 2010). Estimating age- and cause-specific mortality probability is thus straightforward with classical competing risk statistical models (see Heisey and Patterson, 2006 for a review of methods to estimate cause-specific mortality in presence of competing risks; see also the books from Crowder, 2001; Collett, 2014). However, in non-captive animal populations, knowing the fate of an individual is challenging. For instance, an individual alive is not necessarily detected by the observer. On top of that, when the individual dies, identifying the cause of death is difficult because death is never observed in a wild population. Thanks to the development of multi-state capture-recapture (CR) models, estimating cause-specific mortality probability when detection is imperfect and the cause of death is unobservable is now possible (Pradel, 2005). Briefly, these methods are applicable to the study of marked animals that are recaptured several times during their life and recovered from at least one known cause of mortality (hunting for instance, see Gamelon et al., 2011; Servanty et al., 2010 for case studies on wild boar). For example, Koons et al. (2014) estimated age- and cause-specific mortality probability, namely the mortality probability due to hunting vs. the mortality probability due to human-unrelated causes, on lesser snow geese Chen caerulescens caerulescens and roe deer Capreolus capreolus by fitting multi-state CR models. Noticeably, mortality probability, defined as the probability for an individual to die during a given time interval, is commonly used in the fields of statistical modeling of CR data. On the contrary, mortality hazard rate, corresponding to the latent intensity of deadly events that an individual is exposed to, is classically used in medicine and human demography (see Ergon et al., 2018 for a discussion on the use of mortality hazard rates instead of mortality probabilities).

Hunting From a literature survey, I report some of the studies that have quantified the main causes of mortality affecting wild boars from young to older ages using individual monitoring (Table 1). Hunting is one of the major causes of mortality for the wild boar in Europe (Massei et al., 2015; Keuling et al., 2013). The annual probability for an individual to be killed by hunting ranges from 11% to almost 50% in the reviewed studies (Table 1). It is noteworthy that this probability is often age-dependent. For instance, thanks to a long-term individual monitoring and the use of CR models, it has been shown that this source of mortality increases with increasing ages in males at Châteauvillain in France (Toïgo et al., 2008). In the Nature Reserve of Somiedo in Spain, adults are also those that are preferentially removed by hunting (Nores et al., 2008). This age-specific pattern of human-induced mortality may be explained by the reluctance to shoot juveniles, a general feature observed among hunters (Sæther et al., 2009). Moreover, in wild boar, the probability to be killed by hunting depends on the sex of the individual, subadult and adult males being more likely to die from hunting than females. This sex-specific pattern of human-induced mortality may result from contrasting abilities to escape from hunters. Indeed, wild boar live in matrilineal social groups with one large female leading a group (Kaminski et al., 2005) composed of juveniles with limited movement abilities (Merli et al., 2017). Contrary to solitary subadult and adult males, family groups tend to favor coppice habitats rather than bushlands during the hunting season (Saïd et al., 2012). This can explain why subadult and adult males are

Table 1

Summary of some studies reporting causes of mortality that affect wild boar over life. Location of the studied population, annual mortality probabilities due to hunting, predation or other causes (e.g. disease, starvation) and the reference of the study are provided. Potential age- and sex-related variations in mortality probabilities are also reported with the associated sentences extracted from the papers

Population

Hunting

Predation

Others

Age-related variation

Sex-related variation

Castelporziano, Italy

11%

0%

32%

Hunting : “Harvest rates were highest for juveniles and subadults, albeit for juveniles the proportion harvested alternated between very low (> 2%) to moderately high (10%–15%) in different years”

Focardi et al. (2008) Hunting : “The proportion of males harvested was always larger than the proportion of females, indicating a higher harvest probability for males”

Nature Reserve of Somiedo, Spain

12%

45.6%a

Bialowieza Forest, Poland Châteauvillain, France

a

NA

16%

2 individuals out of 105 during a 9-year period 6%

1 individual out of 105 during a 9-year period NA

49.8%

0%

15%

This value corresponds to the sum of legal hunting (32%) and poaching (13.6%) rates. Natural mortality corresponds to mortality excluding hunting mortality.

Others : “[natural] survival of males and females differed only for yearlings”

NA

Predation : “Wolf exerts a higher pressure on juveniles rather than on adults” Hunting : “Subadult wild boars, no matter their sex, had a slightly significantly higher probability to be killed than adults and piglets” Predation : NA “Wolves hunted young individuals” Hunting : Hunting : “Harvest focused on adult “Probability of being harvested was high and males, [.] with limited hunting pressure increased with age [for males], from 0.41 on adult females and piglets” for piglets to 0.70 for adults”/ “Probability of being harvested did not differ Others : between piglets and adults and averaged “Natural mortality of adults was similar for 0.38 [for females]” males and females” Others : “We estimated natural mortalityb of wild boar males at 0.14 [.] regardless of age-class”/ “piglet females had a higher natural mortality rate (0.18) than adults (0.12)”

Nores et al. (2008)

Merli et al. (2017) Je¸drzejewski et al. (2000) Toïgo et al. (2008)

Hunting, Predation and Senescence in Boars

Tuscan Apennines, Italy

4.5%

Others : “for females, [natural] survival was constant among age classes, [natural] survival of males differed among age classes” Hunting : “The mortality caused by hunting drives tends to affect the adult age groups more”

References

b

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more likely to be hunted than females. Sex-specific patterns of human-induced mortality may also simply result from hunting rules that orientate hunting pressure on individuals with specific phenotypic characteristics. At Châteauvillain in France for instance, hunters have to pay a financial penalty if they shoot females larger than 50 kg (Gamelon et al., 2012). As a consequence, they prefer shooting a solitary male instead of shooting in a group, thus increasing mortality on subadult and adult males and relaxing the hunting pressure on adult females.

Predation In some of the studied areas, human is not the only predator. In one Italian study site where both red foxes (Vulpes vulpes) and wolves (Canis lupus) are present, the monitoring of 164 wild boars tagged with radio-collars or transmitters equipped with a mortality sensor has shown that 2 of them died from predation (Table 1, Merli et al., 2017). In Poland, the analysis of wolf fecal samples has confirmed that wild boar is part of the wolf diet (Je¸drzejewski et al., 2000). In a recent review, Mori et al. (Mori et al., 2017) highlights that wild boar even constitutes the largest frequency of ungulate prey in wolf diet across Italy, before roe deer, red deer (Cervus elaphus) and livestock (Mori et al., 2017). However, for the wild boar, mortality due to predation does not exceed 6% and thus remains small compared with human-induced mortality (Table 1). Remarkably, this cause of mortality mainly affects wild boar at young ages. In Italy, they represent 77% of the wolf diet and this proportion even reaches 94% in Poland. Once again, such an agespecific pattern of predator-induced mortality may be explained by the low abilities of juveniles to escape when facing a predator.

Other Sources of Mortality Wild boar can die from natural causes (i.e. not from human or non-human predation). Natural mortality remains low, especially at adult stages (see table), translating to high natural survival. This is expected among ungulates, where the average natural adult survival probability was estimated to be 88% in males (see Williams, 1957 for an analysis among 18 species) and may exceed 95% in females (Gaillard et al., 2000). The reported studies (Table 1) provide estimates of natural survival at adulthood but age-specific survival patterns are ignored. However, a decline of natural survival with increasing ages (hereafter actuarial senescence) may occur as a result of the decline of the forces of natural selection with age (Medawar, 1952), the selection of genes with a beneficial effect early in life that are deleterious later on (Williams, 1957) as well as high fertility translating to high rate of senescence (Hamilton, 1966). Senescence is pervasive in the wild (see Nussey et al., 2013 for a review) and wild boar is not an exception (Gamelon et al., 2014). Indeed, during an 18-year period at Castelporziano in Italy, 1783 juveniles and subadults were marked with ear-tags, released after handling and recaptured later on. The three oldest monitored individuals were 13 years of age. Thanks to this long-term individual monitoring, we estimated natural survival probabilities for each age and sex (Gamelon et al., 2014). We found a decrease of survival with age from age 3 onwards, with males exhibiting lower natural survival than females. Sex-specific reproductive tactics that increase mortality risks for males (Bonduriansky et al., 2008) can explain this between-sex difference. Also, harsh environmental conditions such as droughts may affect male survival stronger than female survival (Toïgo and Gaillard, 2003). However, it is noteworthy that this between-sex difference in adult survival remains quite weak (about 10%, as in humans). Compared to other ungulates, wild boar females have earlier actuarial senescence for their body size. The high and early fertility of wild boar females may advance the age from which the decline of the forces of natural selection occurs (Gamelon et al., 2014). In the first year of life, natural mortality can be higher than at adulthood (Table 1). At Castelporziano for instance, juvenile survival probability was only 68% [64%; 72%] (Gamelon et al., 2014). The major cause of natural mortality that has been identified at this age is caused by severe winters (see Melis et al., 2006; Vetter et al., 2015 for large-scale studies). Snow cover and low temperatures make food resources in the soil hardly accessible and increase juvenile mortality through disease and/or starvation. For some authors, milder winters and thus enhanced juvenile survival might explain the recent expansion of the species observed in the last decades (Vetter et al., 2015). At Castelporziano, characterized with a typical Mediterranean climate, severe droughts might explain such a low piglet survival (Focardi et al., 2008). In the second year of life, we found that natural survival reaches up to 85% [77%; 91%] for females and drops to 57% [50%; 64%] for males. Such a high natural mortality for subadult males has already been reported in another site, at Châteauvillain in France (Gamelon et al., 2011). At this period of their life, males often disperse from their natal area to become solitary (Truvé and Lemel, 2003) and face with particularly increased mortality risks (e.g. starvation, collision with vehicles).

Interaction Between Causes of Mortality It is clear from the three previous sections that different sources of mortality affect wild boars from birth to older ages (see Fig. 1 for a schematic summary). These causes of mortality are age-specific. For instance, while predators preferentially remove piglets, hunters remove relatively more subadults and adults. They are also sex-specific, with higher mortality risks due to starvation and collision with vehicles for males than for females. Finally, they depend on the location of the studied population. For instance, the probability of dying from starvation because of winter harshness or from predation by wolves obviously depends on the study area.

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Fig. 1 Wild boar life cycle showing the causes of mortality affecting wild boar over life (from left to right) in males (upper plot) and females (lower plot). The font size indicates the relative importance of each cause of mortality (small font size corresponds to low importance and large font size to high importance).

Importantly, these sources of mortality can be additive. Basically, it means that they are independent on each other and the overall mortality probability corresponds to the sum of all causes of mortality. In other words, an individual that dies from hunting would have survived in absence of hunting. But sources of mortality can be dependent on each other and interact. They might be compensatory, i.e. negatively correlated such as the overall mortality probability is lower than the sum of all causes of mortality. For instance, in a harvested duck population, Hepp et al. (1986) showed that the individuals with the lowest body condition and thus with the lowest natural survival were more likely to be killed by hunting. In that case, an increase of hunting mortality leads to a reduction in natural mortality because the “strongest” individuals remain in the population. In that respect, predation by nonhuman predators is directly comparable, because it mainly affects vulnerable individuals in a population such as juveniles and senescents that often exhibit the highest natural mortality probability. Also, an increase of hunting mortality or mortality due to predation might reduce population density and thus disease transmission or competition among individuals. This ultimately leads to a decrease of natural mortality (Boyce et al., 1999). Sources of mortality may be depensatory, i.e. positively correlated such as the overall mortality probability is higher than the sum of all causes of mortality. In that case, hunting can increase the mortality due to other causes. For instance, trophy hunting that aims at removing individuals with the largest horns/antlers potentially removes the individuals that perform the best in the population (Mysterud and Bischof, 2010), leading to an increase of natural survival. Hunting might also influence the way individuals use their habitat. In willow ptarmigan Lagopus lagopus for instance, individuals spend more time in dense forests where foraging opportunities and availability of food resources are limited, thus leading to a decrease of body condition (Brøseth and Pedersen, 2010) and potentially high natural mortality. This change of habitat also increases the risk of predation (Brøseth and Pedersen, 2010). As a consequence, understanding how hunting interacts with other causes of mortality has become a central goal in animal ecology (Péron, 2013, see e.g. Sandercock et al., 2011 for a case study on willow ptarmigan). In wild boar, whether mortalities are additive, compensatory or depensatory is a question that has been addressed in the population of Châteauvillain, in France. In that area, hunting constitutes the main source of mortality, followed by natural mortality (see Table 1). Servanty et al. (2010) found that these two sources of mortality are depensatory, natural mortality increasing with hunting mortality. Several factors can explain this result. First, selective hunting with the removal of the “best” individuals in the population may lead to increased natural mortality probability. However, hunters are posted around a given area and wait for animals startled by beaters and dogs. It is thus unlikely that they actually assess the phenotypic quality of the individuals when they are flushed out of the vegetation. Second, increased emigration in response to hunting can wrongly be interpreted as higher natural mortality. However, wild boar is sedentary (Truvé and Lemel, 2003) and it is unlikely that increasing hunting pressure is associated with increasing emigration rates. The only plausible explanation for an increased natural mortality with high hunting mortality is crippling loss. Individuals wounded or killed by hunting but never retrieved and recovered by hunters are considered as dead from natural causes. This can explain higher mortality probabilities when the probability to be killed by hunting is high (Servanty et al., 2010). Whether depensatory mortalities are a common feature among wild boar populations or are specific to the studied population remains to be investigated.

Hunting Mortality and Life History Strategy Wild boar survival is strongly affected by hunting at all ages. In addition, predation, starvation, disease, collision with vehicles and finally senescence at older ages are additional sources of mortality for the species. All these causes of mortality may result in a particularly low overall survival probability. At Châteauvillain in France, overall survival probability is close to 45% for females and drops

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to 23% for adult males (Toïgo et al., 2008) leading to a somewhat short lifespan for such a long-lived species. In that context, one can wonder how wild boar numbers can still increase throughout Europe despite such a low overall survival. This is because fecundity has become the focus of all selective pressures and particularly of hunting pressure. At Châteauvillain in France, birth dates have advanced by up to 12 days in a 22-year period, selected by a high hunting pressure. This allows juveniles born early in the season, to grow for longer and thus reach the threshold body mass to reproduce early in life, in their first year of life (Gamelon et al., 2011). These findings of earlier age at first breeding are in line with a demographic analysis (see Servanty et al., 2011) that has compared two wild boar populations in contrasting environments: the French population suffering from a high hunting pressure and the lightly hunted Italian population at Castelporziano in Italy (see Table 1). This analysis shows that the lightly hunted population has a typical demography of long-lived species with a high contribution of adult survival to the population growth rate and a generation time of 3.6 years. However, the heavily hunted population has a typical demography of shortlived species such as passerines, with the highest contribution for juvenile survival and exhibits an accelerated life history with a shorter generation time close to 2 years (Servanty et al., 2011). Therefore, in environments characterized with a hunting mortality probability, wild boar females compensate by reallocating resources to reproduction early in life. This explains why an increase of hunting mortality probability does not translate to reduced population growth rates in wild boar, contrary to other ungulate species such as roe deer. In that respect, wild boar exhibits an unusual life history strategy among ungulates.

References Apollonio, M., Andersen, R., Putman, R., 2010. European ungulates and their management 21st century. Cambridge University Press, Cambridge. Barrios-Garcia, M.N., Ballari, S.A., 2012. Impact of wild boar (Sus scrofa) in its introduced and native range: A review. Biological Invasions 14 (11), 2283–2300. Bonduriansky, R., Maklakov, A., Zajitschek, F., Brooks, R., 2008. Sexual selection, sexual conflict and the evolution of ageing and life span. Functional Ecology 22 (3), 443–453. Boyce, M.S., Sinclair, A.R.E., White, G.C., 1999. Seasonal compensation of predation and harvesting. Oikos 87 (3), 419–426. Brøseth, H., Pedersen, H.C., 2010. Disturbance effects of hunting activity in a willow ptarmigan Lagopus lagopus population. Wildlife Biology 16 (3), 241–248. Collett, D., 2014. Modelling survival data in medical research, 3rd edn. CRC Press, London. Crowder, M.J., 2001. Classical competing risks. CRC Press, London. Ergon, T., Borgan, Ø., Nater, C.R., Vindenes, Y., 2018. The utility of mortality hazard rates in population analyses. Methods in Ecology and Evolution 9, 2046–2056. Focardi, S., Gaillard, J.-M., Ronchi, F., Rossi, S., 2008. Survival of wild boars in a variable environment: Unexpected life-history variation in an unusual ungulate. Journal of Mammalogy 89 (5), 1113–1123. Forrester, T.D., Wittmer, H.U., 2013. A review of the population dynamics of mule deer and black-tailed deer Odocoileus hemionus in North America. Mammal Review 43 (4), 292–308. Gaillard, J.-M., Festa-Bianchet, M., Yoccoz, N.G., Loison, A., Toïgo, C., 2000. Temporal variation in fitness components and population dynamics of large herbivores. Annual Review of Ecology and Systematics 31 (1), 367–393. Gamelon, M., Besnard, A., Gaillard, J.-M., Servanty, S., Baubet, E., Brandt, S., et al., 2011. High hunting pressure selects for earlier birth date: Wild boar as a case study. Evolution 65 (11), 3100–3112. Gamelon, M., Gaillard, J.-M., Servanty, S., Gimenez, O., Toïgo, C., Baubet, E., et al., 2012. Making use of harvest information to examine alternative management scenarios: A body weight-structured model for wild boar. Journal of Applied Ecology 49 (4), 833–841. Gamelon, M., Focardi, S., Gaillard, J.-M., Gimenez, O., Bonenfant, C., Franzetti, B., et al., 2014. Do age-specific survival patterns of wild boar fit current evolutionary theories of senescence? Evolution 68 (12), 3636–3643. Hamilton, W.D., 1966. The moulding of senescence by natural selection. Journal of Theoretical Biology 12 (1), 12–45. Heisey, D.M., Patterson, B.R., 2006. A review of methods to estimate cause-specific mortality in presence of competing risks. Journal of Wildlife Management 70 (6), 12. Hepp, G.R., Blohm, R.J., Reynolds, R.E., Hines, J.E., Nichols, J.D., 1986. Physiological condition of autumn-banded mallards and its relationship to hunting vulnerability. Journal of Wildlife Management 50 (2), 177–183. Horiuchi, S., Wilmoth, J.R., 1997. Age patterns of the life table aging rate for major causes of death in Japan, 1951-1990. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 52 (1), B67–B77. Horiuchi, S., Finch, C.E., Meslé, F., Vallin, J., 2003. Differential patterns of age-related mortality increase in middle age and old age. The Journals of Gerontology, Series A 58 (6), B495–B507. Kaminski, G., Brandt, S., Baubet, E., Baudoin, C., 2005. Life-history patterns in female wild boars (Sus scrofa): Mother–daughter postweaning associations. Canadian Journal of Zoology 83 (3), 474–480. Keuling, O., Baubet, E., Duscher, A., Ebert, C., Fischer, C., Monaco, A., et al., 2013. Mortality rates of wild boar Sus scrofa L. in Central Europe. European Journal of Wildlife Research 59 (6), 805–814. Koons, D.N., Gamelon, M., Gaillard, J.-M., Aubry, L.M., Rockwell, R.F., Klein, F., et al., 2014. Methods for studying cause-specific senescence in the wild. Methods in Ecology and Evolution 5 (9), 924–933. Massei, G., Genov, P.V., 2004. The environmental impact of wild boar. Galemys Boletín informativo de la Sociedad Española para la conservación y estudio de los mamíferos 16 (1), 135–145. Massei, G., Kindberg, J., Licoppe, A., Ga
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Sprem, N., Kamler, J., et al., 2015. Wild boar populations up, numbers of hunters down? A review of trends and implications for Europe. Pest Management Science 71 (4), 492–500. Medawar, P.B., 1952. An unsolved problem of biology. Lewis, London. Melis, C., Szafranska, P.A., Je˛ drzejewska, B., Barton, K., 2006. Biogeographical variation in the population density of wild boar (Sus scrofa) in western Eurasia. Journal of Biogeography 33 (5), 803–811. Meng, X.J., Lindsay, D.S., Sriranganathan, N., 2009. Wild boars as sources for infectious diseases in livestock and humans. Philosophical Transactions of the Royal Society B: Biological Sciences 364 (1530), 2697–2707. Merli, E., Grignolio, S., Marcon, A., Apollonio, M., 2017. Wild boar under fire: The effect of spatial behaviour, habitat use and social class on hunting mortality. Journal of Zoology 303 (2), 155–164. Milner, J.M., Bonenfant, C., Mysterud, A., 2011. Hunting Bambi - evaluating the basis for selective harvesting of juveniles. European Journal of Wildlife Research 57 (3), 565–574. Mori, E., Benatti, L., Lovari, S., Ferretti, F., 2017. What does the wild boar mean to the wolf? European Journal of Wildlife Research 63 (1), 9. Mysterud, A., Bischof, R., 2010. Can compensatory culling offset undesirable evolutionary consequences of trophy hunting? The Journal of Animal Ecology 79 (1), 148–160. Nores, C., Llaneza, L., Álvarez, Á., 2008. Wild boar Sus scrofa mortality by hunting and wolf Canis lupus predation: An example in northern Spain. Wildlife Biology 14 (1), 44–51.

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Nussey, D.H., Froy, H., Lemaître, J.-F., Gaillard, J.-M., Austad, S.N., 2013. Senescence in natural populations of animals: Widespread evidence and its implications for biogerontology. Ageing Research Reviews 12 (1), 214–225. Péron, G., 2013. Compensation and additivity of anthropogenic mortality: Life-history effects and review of methods. The Journal of Animal Ecology 82 (2), 408–417. Pradel, R., 2005. Multievent: An extension of multistate capture-recapture models to uncertain states. Biometrics 61 (2), 442–447. Proaktor, G., Coulson, T., Milner-Gulland, E.J., 2007. Evolutionary responses to harvesting in ungulates. The Journal of Animal Ecology 76 (4), 669–678. Sæther, B.-E., Engen, S., Solberg, E.J., 2009. Effective size of harvested ungulate populations. Animal Conservation 12 (5), 488–495. Saïd, S., Tolon, V., Brandt, S., Baubet, E., 2012. Sex effect on habitat selection in response to hunting disturbance: The study of wild boar. European Journal of Wildlife Research 58 (1), 107–115. Sandercock, B.K., Nilsen, E.B., Brøseth, H., Pedersen, H.C., 2011. Is hunting mortality additive or compensatory to natural mortality? Effects of experimental harvest on the survival and cause-specific mortality of willow ptarmigan. The Journal of Animal Ecology 80 (1), 244–258. Servanty, S., Gaillard, J.-M., Allainé, D., Brandt, S., Baubet, E., 2007. Litter size and fetal sex ratio adjustment in a highly polytocous species: The wild boar. Behavioral Ecology 18 (2), 427–432. Servanty, S., Gaillard, J.-M., Toïgo, C., Brandt, S., Baubet, E., 2009. Pulsed resources and climate-induced variation in the reproductive traits of wild boar under high hunting pressure. The Journal of Animal Ecology 78 (6), 1278–1290. Servanty, S., Choquet, R., Baubet, E., Brandt, S., Gaillard, J.-M., Schaub, M., et al., 2010. Assessing whether mortality is additive using marked animals: A Bayesian state-space modeling approach. Ecology 91 (7), 1916–1923. Servanty, S., Gaillard, J.-M., Ronchi, F., Focardi, S., Baubet, E., Gimenez, O., 2011. Influence of harvesting pressure on demographic tactics: Implications for wildlife management. Journal of Applied Ecology 48 (4), 835–843. Toïgo, C., Gaillard, J.-M., 2003. Causes of sex-biased adult survival in ungulates: Sexual size dimorphism, mating tactic or environment harshness? Oikos 101 (2), 376–384. Toïgo, C., Servanty, S., Gaillard, J.-M., Brandt, S., Baubet, E., 2008. Disentangling natural from hunting mortality in an intensively hunted wild boar population. Journal of Wildlife Management 72 (7), 1532–1539. Tomkiewicz, S.M., Fuller, M.R., Kie, J.G., Bates, K.K., 2010. Global positioning system and associated technologies in animal behaviour and ecological research. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 365 (1550), 2163–2176. Truvé, J., Lemel, J., 2003. Timing and distance of natal dispersal for wild boar Sus scrofa in Sweden. Wildlife Biology 9 (1), 51–57. Vetter, S.G., Ruf, T., Bieber, C., Arnold, W., 2015. What is a mild winter? Regional differences in within-species responses to climate change. PLoS One 10 (7), e0132178. Williams, G.C., 1957. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11 (4), 398–411. _ primeval Forest, Poland. Journal of Je¸drzejewski, W.I., Je¸drzejewska, B., Okarma, H., Schmidt, K., Zub, K., Musiani, M., 2000. Prey selection and predation by wolves in BiaŁowieZa Mammalogy 81 (1), 197–212.

Hypertension in the Elderly Jose´ Alfie and Paula Edit Cuffaro, Italian Hospital, Buenos Aires, Argentine © 2020 Elsevier Inc. All rights reserved.

Epidemiology Hemodynamic Determinants of the Age-Related Change in Blood Pressure Aging and Salt Sensitivity Predictive Value of Blood Pressure in the Elderly Predictive Value of Blood Pressure in the Very Elderly Hypertension and Risk of Dementia Out of Office Blood Pressure Patterns in Old Age White Coat Hypertension Aging and Night-Time Blood Pressure Blood Pressure Variability Morning Hypertension Masked Hypotension Antihypertensive Treatment in the Elderly Benefits of BP Lowering in the Elderly Treatment of Isolated Systolic Hypertension How Intensively the Elderly Should Be Treated? Treatment of Hypertension in the Very Elderly Antihypertensive Treatment in the “Real World” Current International Guidelines References

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Epidemiology Hypertension is one of the most common diseases in modern society and its prevalence is expected to increase in parallel with the rapidly aging population. Data from the Framingham Heart Study, indicated that normotensive persons reaching age 65 years had a 90% lifetime risk of developing hypertension (predominantly of the systolic subtype) if they lived a further 20–25 years (Levy et al., 1996). Hypertension, defined as 140/90 mmHg or higher, affects z60% of adults older than 60 years and z 75% over the age of 75 years (Yoon et al., 2015). The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines redefined stage 1 hypertension at a blood pressure (BP) threshold of 130/80 mmHg, and the classic threshold of 140/90 mmHg as stage 2 hypertension (Whelton et al., 2018). The impact of the new classification on the prevalence of hypertension is greater in younger than in older individuals. Among those under age 45, the prevalence would be more than doubled (from 10% to 24%), whereas it would increase < 10% (from 75% to 82%) above 75 years (Muntner et al., 2018). The age related increase in BP is strongly influenced by modern lifestyles over the life span of individuals since it is not observed in populations not exposed to high sodium, high-calorie diets, low physical activity levels or social stress (Gurven et al., 2012). A 32year prospective study comparing changes in BP between 144 nuns in a secluded order in Italy and 138 healthy lay women living nearby, showed that BP remained virtually unchanged among the nuns while the women of control group showed increase in BP over time (Timio et al., 1999). The influence of lifestyle on the age related change in BP is also apparent in indigenous communities such as Kuna from islands in the Panamanian Caribbean, who exhibit little age-related rise in BP or hypertension, unless they migrate to Panama City (Hollenberg et al., 1997). In addition, the increase in BP with age differs according to environmental factors such as altitude in the sense that people who inhabit high altitude regions show a steeper age related increase in BP than people living at low altitude (Otsuka et al., 2005). The typical pattern of age related change in BP in urban populations shows that systolic blood pressure (SBP) increases linearly with age, whereas diastolic blood pressure (DBP) increases up to 50 years and declines after 60 years, conditioning a steep widening of pulse pressure (PP) (Joffres et al., 2013). Prevalence of diastolic hypertension plateaus as patients reach middle-age and subsequently declines, whereas the prevalence of systolic hypertension consistently rises after 60 years becoming the most common form of hypertension in the aging societies (Franklin et al., 2001). However, at very old age, SBP also decreases preannouncing the end of life (Delgado et al., 2018; Ravindrarajah et al., 2017). Population studies using 24 h ambulatory blood pressure monitoring (ABPM) show an attenuated age related increase in ambulatory SBP compared to office values (Wiinberg et al., 1995). The Pamela study showed a steeper increase in clinic and home compared to 24 h SBP (Sega et al., 1997). Similarly, in a meta-analysis of 9550 untreated individuals from 13 population-based cohorts (IDACO) daytime BP was significantly higher than clinic BP before age 50, whereas the inverse was found in those

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aged
60 years. In consequence, the prevalence of white coat hypertension (WCH) increased with age, from 2% in participants aged < 30 years to almost 20% in those aged
70 years, whereas the prevalence of masked hypertension was greatest (almost 20%) among those aged 30–50 years (Conen et al., 2014). These data suggest that the increase of the SBP with aging described in different populations at least partly might reflect the greater impact of a greater alerting reaction to BP measurement in older people. Arterial stiffness could amplify the alerting reaction to BP measurement in older subjects (de Simone et al., 2007) and could contribute to the increasing clinic-ambulatory SBP difference associated with age. However, the parallel increase in clinic and home SBP with age described in an international population (Niiranen et al., 2012), makes a greater alerting reaction an unlike mechanism to explain the increasing difference between clinic and daytime SBP. Furthermore, subjects in the very advanced age decades display a reduced pressor response to a variety of stressful stimuli, such as the alerting reaction to BP measurement or laboratory maneuvers, with 24-h ambulatory SBP values being even greater than the corresponding clinic values in nonagenarians and centenarians (Carugo et al., 2012b). Therefore, factors beyond white coat effect (i.e., decrease in physical activity, more prolonged daytime rest, or larger orthostatic fall in BP) could contribute to the flatter age trajectory of ambulatory BP.

Hemodynamic Determinants of the Age-Related Change in Blood Pressure Pulse pressure is determined by stroke volume and arterial compliance. Large distensible arteries buffer PP by storing part of the stroke volume during systole and draining it during diastole ensuring a constant flow in the microcirculation. Arterial aging includes thinning and fracturing of elastin, increased vascular smooth muscle cells (VSMC) contractility, VSMC dedifferentiation, increased collagen deposition and medial calcifications, resulting in wall thickening and stiffening (Lacolley et al., 2018). Arterial stiffness reduces arterial compliance, impairing the ability to dampen arterial pulsatility. The pulsatile injury damages the arterial wall, which activates a reparatory response that results in fibrosis that in turn worsens arterial stiffness and increase pulsatility, establishing a feed-forward loop (AlGhatrif et al., 2017). A simultaneous increase in vascular resistance and decrease in arterial compliance associated with aging exert opposite effects on DBP but additive effects on SBP. In patients with isolated systolic hypertension (ISH), a relatively lower arterial compliance overcomes the effect of peripheral resistance on DBP (Galarza et al., 1997). Arterial compliance maintains a nonlinear relationship with distending pressure (Hallock and Benson, 1937). A greater severity of hypertension in elderly patients is associated with a much higher increase in SBP compared to DBP, whereas the opposite pattern is observed before age 40 years (Alfie et al., 2005). Conversely, a lower distending pressure secondary to antihypertensive treatment determines a much larger decrease in SBP compared to DBP in elderly patients compared to the younger counterparts (Wang et al., 2005). The pressure wave represents the superposition of the incident wave, generated by the ventricular ejection, and the reflected waves traveling backwards from the periphery. In young subjects, the reflected waves return to the left ventricle in diastole, enhancing coronary perfusion. Arterial stiffness, which increases pulse wave velocity, anticipates the return of reflected waves, augmenting central systolic pressure. In consequence, central SBP exhibits a steeper age related increase than brachial SBP. The augmented central SBP translates in greater left ventricular wall tension, while a lower DBP impairs coronary perfusion. The concomitant increase in oxygen demand and decrease in coronary blood flow, predispose to myocardial ischemia (O’Rourke and Nichols, 2005). Blood pressure lowering improves arterial distensibility and consequently reduces pulse wave velocity and central systolic pressure augmentation. However, beta blockers are less effective in reducing central aortic than brachial pressure because bradycardia exacerbates central systolic pressure augmentation (i.e., pseudo-antihypertensive effect) (Messerli et al., 2016). This effect could account for the lack of reduction in cardiovascular end points compared with placebo despite the effective (brachial) blood pressure lowering in the Medical Research Council trial of treatment of hypertension in older adults.

Aging and Salt Sensitivity Salt sensitivity of BP increases significantly with increasing age, but the relation is more striking in hypertensive subjects (Weinberger and Fineberg, 1991). In older subjects, the increase in SBP in response to salt supplementation is most pronounced in those with ISH and could be modulated by the angiotensinogen genotype (Johnson et al., 2001). Plasma renin activity decreases with age, particularly in hypertensives subjects without a parallel change in aldosterone concentration (Luft et al., 1992), indicating a transition to a renin-independent aldosterone secretion with aging. Recent histopathologic studies demonstrated that older age is associated with a progressively replacement of the continuous expression pattern of aldosterone producing cells in the zona glomerulosa observed in young adrenal glands by clusters of nonneoplastic foci of cell producing inappropriate aldosterone secretion. These abnormal cells carry mutation in the CACNA1D gene which encodes the voltage-dependent L-type calcium channel subunit a-1D. The result is an autonomous increase in intracellular calcium levels that activates aldosterone synthase transcription, susceptible to be inhibited by L-type calcium channel blockers (Nanba et al., 2018). High sodium consumption accelerates the age-related increase in arterial stiffness. Arterial stiffness, a hallmark of vascular aging, was markedly attenuated in Chinese populations not exposed to a lifestyle of high sodium than those with high sodium

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consumption (Avolio et al., 1985). On the other hand, restriction of dietary sodium intake reduces arterial stiffness at least in part independent of the change in BP (D’Elia et al., 2018). Excess salt intake normally promotes production of transforming growth factor beta (TGF-b) and simultaneously nitric oxide, which serves as a factor that mitigates the effects of TGF-b (Kanbay et al., 2011). An insufficient nitric oxide production during high salt might accelerate the profibrotic effect of TGF-b in the vasculature of salt sensitivity individuals. Beyond its role as regulator of renal sodium reabsorption, an inappropriate aldosterone concentration in relation to salt consumption promotes arterial stiffness acting through mineralocorticoid receptors (MR) expressed in VSMC (Galmiche et al., 2014). Furthermore, MR expression is increased in aged VSMCs, promoting proinflammatory gene expression in a ligand independent manner (Krug et al., 2010). The abundance of epithelial sodium channel, which are also expressed in vascular endothelium, increases with age in mice leading to endothelial dysfunction when exposed to high ambient sodium indicating a pathophysiological link between systemic and endothelial salt sensitivity with age (Paar et al., 2014). The natriuretic hormone marinobufagenin, an endogenous a1 Naþ, Kþ-ATPase inhibitor, provides another link between increased salt-sensitivity and arterial stiffness in aging. In middle-aged and older adults, marinobufagenin is positively associated with SBP, aortic stiffness (aortic pulse-wave velocity), and dietary sodium restriction reduces urinary marinobufagenin excretion. Interestingly, marinobufagenin stimulates vascular synthesis of collagen, an effect that is blocked by spironolactone (Jablonski et al., 2013).

Predictive Value of Blood Pressure in the Elderly The Framingham study (Kannel et al., 1971) and the Multiple Risk Factor Intervention Trial (MRFIT) (Rutan et al., 1988) described the increasing predictive value of SBP compared with that of DBP with older age. The MRFIT a cohort of 317,871 white men 35– 57 years old, showed that at any level of DBP, the level of SBP appeared to be the major determinant of all-cause and coronary heart disease (CHD) mortality. Those with ISH (defined at that time as SBP > 160 and DBP < 90 mmHg) had the highest 12-year CHD and mortality. The significance of SBP, DBP and PP as predictors of cardiovascular disease changes with age. In those aged 50–59 years, a transition occurred, during which the three BP indices were similarly accurate predictors, but in those aged
60 years, DBP was negatively associated with the risk of CHD, so that PP became a superior predictor than SBP (Franklin et al., 1999). In a 10-year follow-up study of a cohort of 688 hypertensive patients, pretreatment 24-h intraarterial DBP but not SBP was related to outcome in younger subjects, whereas in the elderly group (> 60 years), SBP was positively and DBP was negatively related to outcome. In contrast, clinic BP measurements failed to provide any independent prognostic value in either age group (Khattar et al., 2001). Similarly, the IDACO database (8341 untreated people randomly recruited from 12 populations) showed that the risks conferred by 24 h DBP and SBP were age dependent. Specifically, the 24 h DBP and isolated diastolic hypertension drove coronary complications below age 50, whereas above age 50, 24 h SBP and isolated systolic and mixed hypertension were the predominant risk factors (Li et al., 2014). Office and ambulatory SBP and PP were significant predictors of cardiovascular (CV) morbidity in 70-year-old men (n ¼ 872) participating in a longitudinal population-based study. Ambulatory PP predicted CV morbidity independently of office PP and other established CV risk factors (Björklund et al., 2004). Similarly, both ambulatory PP and SBP rather than DBP predicted mortality in older treated hypertensives (Balietti et al., 2018). Population data from IDACO and IDHOCO cohorts indicated that an ambulatory PP of
64 and a home PP of
76 mmHg predicted CV outcomes in the elderly, whereas PP did not refine risk stratification before 60 years of age (Gu et al., 2014). On the other hand, high 24-PP at the expense of low DBP (Jonas et al., 2018) was associated with an increased risk of fall injury in a retrospective study of community-based elderly patients (age
70 years) who were referred to 24-h ABPM. Contrary to expectations, intensification of antihypertensive treatment following 24-h ABPM was not associated with an increased risk of fall injury.

Predictive Value of Blood Pressure in the Very Elderly The Prospective Studies Collaboration, that included one million adults with no previous vascular disease at baseline, showed that usual BP was strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mmHg. Proportional differences in vascular mortality were about half at ages 80–89 years as at ages 40–49 years, but the absolute differences in risk were greater in old age (Lewington et al., 2002). On the other hand, several longitudinal studies of community-living octogenarians observed an inverse J-curve association between SBP with all-cause mortality (paradoxical survival of elderly with high BP), suggesting that lower BP is not necessarily better among octogenarians (Langer et al., 1993; Mattila et al., 1988; Hakala et al., 1997; Boshuizen et al., 1998; Satish et al., 2001a; Rastas et al., 2006; Molander et al., 2008). Other studies showed a U-shaped relationship between BP and mortality in old (Gutiérrez-Misis et al., 2013; Okumiya et al., 1999) and in very old people (Lv et al., 2018). The mechanisms underlying the U-shaped association between BP and mortality differed at the lower and higher ends of SBP distribution. While noncardiovascular deaths were increased in the lowest SBP group, cardiovascular deaths were higher in the highest SBP group (Lv et al., 2018).

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A BP fall in the years preceding death (Glynn et al., 1995; Satish et al., 2001b; Ravindrarajah et al., 2017; Delgado et al., 2018) indicates that low BP in elderly people could be a sign of terminal decline rather than the cause of death, frailty or cognitive decline (reverse causality) as also described with other traditional risk factors (Abdelhafiz et al., 2012). Consistent with the reverse causality hypothesis, the association between BP and mortality in old and in very old subjects varies with health and functional status. In a cohort of 2340 noninstitutionalized persons 65 years and older (mean age 74 years), the expected association between elevated SBP and DBP and mortality was not observed among slower-walkers (cutoff value of 0.8 m/s), and elevated SBP and DBP was even associated with a lower mortality risk in those who did not complete the walk test (Odden et al., 2012). Similarly, the analysis of 806 very elderly participants (mean age 90 years) in the population-based prospective Umeå 85þ/ GERDA study confirmed that the association of BP with mortality differed among gait speed subcohorts. In the total sample and slower-walking subcohort (cutoff value of 0.5 m/s), SBP was inversely associated with mortality, whereas mortality risk was more than twice higher in the faster-walking participants with SBP
165 mmHg and 140–149 mmHg than in those with SBP of 126–139 mmHg (Weidung et al., 2015).

Hypertension and Risk of Dementia A SBP
130 mmHg at age 50 is associated with increased risk of dementia. In contrast, hypertension appears to no longer be a risk factor at very advanced ages (Abell et al., 2018). Indeed, individuals who developed dementia exhibited a greater BP decline, which could be an effect rather than a cause of dementia (Molander et al., 2010). Furthermore, it was recently reported that at very old ages, dementia risk was lowest in people with the highest BP. Specifically, onset of hypertension after age 90 had the lowest risk of dementia compared with those without hypertension and participants whose hypertension onset age was 80–89 years (Corrada et al., 2017). In contrast to the effectiveness to prevent strokes, antihypertensive treatment in elderly patients did not reduce incidence of dementia in the Hypertension in Very Elderly Trial (HYVET) (Peters et al., 2008). Against the concern that old patients would need an appropriate level of BP to maintain an adequate cerebral perfusion, a study demonstrated that intensive BP lowering (< 130/80 vs. < 140/85 mmHg) increases cerebral blood flow in older subjects (> 70 years) with systolic hypertension, suggesting a reshift of the cerebral autoregulatory curve (Tryambake et al., 2013). Accordingly, preliminary results from the SPRINT Memory and Cognition IN Decreased Hypertension (SPRINT-MIND) showed a significantly lower rate of incident mild cognitive impairment (MCI) and the combined risk of MCI and dementia in the intensive vs. standard treatment group. Treating to a SBP target < 120 mmHg also reduced the increase in cerebral white matter lesion (American College of Cardiology, 2018).

Out of Office Blood Pressure Patterns in Old Age White Coat Hypertension The 2012 IDACO study showed that in untreated older patients, the risk related to white-coat ISH hypertension (clinic BP
140/ 20%) in the elderly may be partially explained by its association with a steeper morning surge in BP, which frequently accompanies an excessive nocturnal fall in BP (Parati et al., 2014).

Blood Pressure Variability Blood pressure variability significantly increases with age, predominantly due to increased arterial stiffness and baroreflex failure and may promote target organ damage and trigger CV events in the elderly patients (Kario and Pickering, 2000). Old age is characterized by high ambulatory BP variability (BPV) (Morano et al., 2018). Increased 24 h SBP variability was inversely related to glomerular filtration rate in hospitalized elderly male hypertensive patients with controlled BP (Wang et al., 2018). In elderly patients with well ambulatory BP control, higher BPV but not average ambulatory BP level was associated with cognitive impairment (Cho et al., 2018). Increased ambulatory BPV was associated with poorer cognitive function over 5-year follow-up in an unselected older community-dwelling cohort (McDonald et al., 2017). Higher SBP levels and Systolic BPV were independent risk factors for cerebral small-vessel disease (Yang et al., 2018).

Morning Hypertension In older Japanese hypertensives (mean age 72 years), a higher morning BP surge was associated with stroke risk independently of f 24-h BP and nocturnal BP dipping status. For each 10 mmHg increase in baseline early morning systolic BP, the relative risk of stroke increase 22% (Kario et al., 2003a). Morning hypertension by means of ABPM was the strongest independent predictor for future clinical stroke events in Japanese elderly hypertensive patients (Kario et al., 2006). Home Blood Pressure Monitoring (HBPM) is a suitable method for screening early morning hypertension during repeated days. In the Ohasama study, home BP measured every morning predicted CV death more accurately than randomly obtained BP measurements (Ohkubo et al., 1998). This is particularly important because uncontrolled hypertension in early morning was present in more than half of treated elderly patients with controlled office BP (Wang et al., 2017). Furthermore, isolated morning hypertension usually coexists with subclinical postprandial hypotension as detected by HBPM (Barochiner et al. 2015).

Masked Hypotension The coexistence of uncontrolled hypertension and subclinical (masked) hypotension, represents a frequent therapeutic dilemma in older patients. Postural and postprandial hypotension are frequent phenomena in the elderly that can be exaggerated by antihypertensive drugs, such as diuretics or alpha-blockers, and also by noncardiovascular drugs such as neuroleptics and antidepressants (Stergiou et al., 2018). Out of office BP monitoring is useful for the screening of masked hypotension, particularly in elderly patients with diabetes, Parkinson’s disease, vascular disease or on antihypertensive polytherapy. In very elderly patients a lower cognitive function was associated with lower nighttime SBP and DBP levels and lower 24-h SBP compared to subjects with higher cognitive function (Axelsson et al., 2008). In addition, low nocturnal BP, whether occurring spontaneously or as a result of medications, may lead to worsening of visual field defects in patients whit normotensive glaucoma

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(Charlson et al., 2014). Extreme-dippers (nocturnal hypotension) are at risk for nonfatal ischemic stroke and silent myocardial ischemia (Kario and Shimada, 2004). On the other hand, an inverted circadian rhythm could be associated with sustained orthostatic hypotension determining low daytime BP (Fagard and De Cort, 2010; Lanthier et al., 2011; Ejaz et al., 2007; Ejaz et al., 2006). In 588 elderly patients (mean age 78.7 years) who underwent a 24 h ABPM, z55% presented at least one episode of SBP < 100 mmHg, about 20% presented
10% of the SBP below 100 mmHg, and > 30% of participants with 24-h SBP, daytime, and nighttime BP above the reference threshold had hypotension (Scuteri et al., 2012). In 5066 patients aged 80 years and older with treated hypertension from the Spanish ABPM Registry Participants, 22.8% had office hypotension (< 110 and/or 70 mmHg), 33.7% daytime hypotension (< 105 and/or 65 mmHg), 9.2% nighttime hypotension (< 90 and/or 50 mmHg), and 20.5% 24-h hypotension (< 100 and/or 60 mmHg). Low DBP was responsible for 90% of cases of hypotension. The variables independently associated with office and ABPM hypotension were diabetes, CHD, and a higher number of antihypertensive medications (Divisón-Garrote et al., 2017). A similar study conducted with HBPM in 302 patients, the prevalence of hypotension was 29.8% at the office and 23.9% at home, whereas the prevalence of masked hypotension was 10.4%, mostly at the expense of low DBP. Older age, diabetes and ischemic heart disease were predictors for home hypotension (Barochiner et al., 2018). Postprandial hypotension can be detected by means of ABPM, however care should be taken to not misinterpret the siesta dipping as lunch-induced hypotension. The diagnosis of postprandial hypotension should be considered in patients with syncope, falls and dizziness occurring within 2 h after a meal (Naschitz, 2018). The inclusion of preprandial and postprandial measurements in the protocol of HBPM allows the detection of postprandial hypotension in older hypertensive patients (Alfie, 2015). Postprandial hypotension detected by means of HBPM was more common in very old patients with uncontrolled hypertension and particularly with isolated morning hypertension (Barochiner et al., 2014b).

Antihypertensive Treatment in the Elderly Benefits of BP Lowering in the Elderly Randomized trials demonstrated that treating older persons with hypertension is highly efficacious. Elderly patients have a higher baseline cardiac risk profile and benefit more than their younger counterparts from even modest reductions in BP. Similar proportional reductions in risk across the age range translate into much higher absolute benefit in older patients than in younger ones: two to four times as many of the younger subjects as the older subjects needed to be treated for 5 years to prevent morbid and mortal events (Mulrow et al., 1994). The meta-analysis by the Blood Pressure Lowering Treatment Trialists’ Collaboration across 31 trials of > 190,000 randomized patients, showed that the relative risk reduction of a CV event with tighter BP control occurs irrespective of the patient’s age. Because of the higher absolute risk of CV events, for a similar relative risk reduction in BP, far fewer patient-years of treatment are needed to prevent one major CV event in an elderly person (Blood Pressure Lowering Treatment Trialists’ Collaboration et al., 2008).

Treatment of Isolated Systolic Hypertension Early clinical trial of antihypertensive treatment in the elderly focused on patients with combined systodiastolic hypertension, since treatment of ISH raised the dilemma of treating systolic hypertension and lowering an already normal DBP (Thijs et al., 1994). The controversy remained until the publication of the Systolic Hypertension in the Elderly Program (SHEP), Systolic Hypertension in Europe (Syst-Eur) Trial, and Systolic Hypertension in China (Syst-China) Trial, demonstrating the CV benefit and safety of antihypertensive drug treatment in elderly patients with ISH. Inclusion criteria were age 60 years or older and SBP ranged from 160 to 219 mmHg. Mean BP at randomization was 170/77 mmHg in SHEP (Anon, 1991), 174/85 mmHg in Syst-Eur (Staessen et al., 1997b) and 171/86 mmHg in Syst-China trial (Wang et al., 2000). Active treatment in SHEP was initiated with chlorthalidone (12.5–25 mg/day), whereas in the Syst-Eur and Syst-China trials was initiated with nitrendipine (10–40 mg/d). Achieved SBP in active and placebo arms was 143 versus 155 mmHg in SHEP, 151 versus 161 mmHg in Syst-Eur, and 151 versus 160 mmHg in Syst-China. Staessen’s meta-analysis confirmed that in older patients the target level of BP to be reached by antihypertensive drug treatment should be based on systolic rather than on diastolic pressure (Staessen et al., 2000). Blood pressure of 15,693 patients at enrollment averaged 174/83 mmHg. The mean (baseline-corrected) differences in systolic and diastolic pressures between patients assigned to control or active treatment were 10.4 and 4.1 mmHg, respectively. Active treatment reduced total mortality by 13%, CV mortality by 18%, all CV complications by 26%, stroke by 30% and coronary events by 23%. The absolute benefit was larger in men, in patients aged 70 years or more, and in those with previous CV complications or wider PP. The number of patients needed to treat for 5 years to prevent one major CV complication was as low as 18 in men (38 in women), 19 at 70 years or more (39 at 60–69 years), and 16 in patients with previous cardiovascular complications (37 in patients without such a history). The number of patients to treat to prevent one cardiovascular death was 63, if PP at baseline was 90 mmHg or greater compared with 119 for patients with smaller PP. The risk of death in control patients was positively correlated with SBP at entry, whereas the association with DBP was negative. Indeed, at any given level of SBP, a lower DBP was associated with a higher death rate. However, further lowering of DBP to < 70 mmHg in treated patients did not produce harm (Staessen et al., 2000). A lower DBP at baseline and the coexistence of coronary heart disease might influence the limit below which an additional decrease in DBP could increase the risk. A subanalysis of SHEP showed that a low treated DBP in subjects who received active

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treatment, but not in those receiving placebo, was associated with increased CV disease, with significant effects observed first at 70 mmHg and then more strongly at 60 mmHg or below. Despite this, patients receiving treatment for ISH never perform worse than patients receiving placebo in terms of CV events (Somes et al., 1999). Post hoc analyses of Syst-Eur indicated that when SBP is not under control, antihypertensive treatment can be intensified at least until DBP reaches 55 mmHg, and probably 70 mmHg in patients with concomitant CHD (Fagard et al., 2007). Accordingly, a secondary analysis of the International Verapamil SR-Trandolapril Study (INVEST) in hypertensive subjects with CHD showed a J-shaped relationship among each age group with on-treatment SBP and DBP and the corresponding nadir for the very old was 140 and 70 mmHg, respectively (Denardo et al., 2010).

How Intensively the Elderly Should Be Treated? Incremental benefit of BP lowering decreases as target BP is lowered. On the other hand, lower on-treatment BP values are associated with higher incidence of serious adverse events and treatment discontinuation (Thomopoulos et al., 2016b). Four trials have randomized antihypertensive treatment to intensive versus standard BP targets specifically in older individuals. The VALISH (Valsartan in Elderly Isolated Systolic Hypertension) study (Ogihara et al., 2010) and JATOS (Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients) (JATOS Study Group, 2008) suggest no additional benefit of a systolic BP target below 140 mmHg compared with SBP targets below 150 and 160 mmHg, respectively. The absence of improvements associated with achieving SBP 130 to < 140 mmHg could be partially explained by the lower CV risk profile of the participants included in these trials, and the consequent low number of events, impairing the power to detect a possible benefit. In contrast, intensive antihypertensive treatment was beneficial in a smaller study of Chinese hypertensive patients older than 70 years (Wei et al., 2013). A substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) in hypertensive persons aged 75 years or older demonstrated that intensifying SBP control from 142/71 to < 120 mmHg, compared with a standard SBP target of < 140 mmHg, reduced CV disease by 33% and total mortality by 32% (Williamson et al., 2016). The benefit of intensive BP control was consistent among persons who were frail or had reduced gait speed. The overall serious adverse events rate was comparable by treatment group. Furthermore, improved BP control reduced risk for orthostatic hypotension and had no effect on risk for injurious falls. In SPRINT, the achieved SBP in the intensive treatment arm (123 mmHg) was lower than the achieved SBP in the intensive treatment arms of the other three trials (136–137 mmHg). The discrepancy lies in the method of measuring BP. In SPRINT, BP measurements were taken without a nurse or physician present with patients sitting in a quiet room. Accordingly, the intensive BP arm in SPRINT may translate into a SBP < 140 mmHg in other trials. A meta-analysis of the four trials (Bavishi et al., 2017) indicated that intensive BP-lowering treatment (< 140 mmHg) was associated with lower CV outcomes, including 29% reduction in major adverse CV events, 33% reduction in CV mortality, and 37% reduction in heart failure compared with a standard strategy (140–159 mmHg). The meta-regression analysis showed that the difference in the magnitude of CV protection among trials was proportional to the difference in achieved SBP reduction between the two strategies, suggesting that a higher magnitude of reduction in SBP may translate into better outcomes. Consistent with this hypothesis, incident chronic kidney disease in the setting of intensive SBP lowering was accompanied by decreases, rather than elevations, in levels of kidney damage biomarkers (Malhotra et al., 2018; Zhang et al., 2018).

Treatment of Hypertension in the Very Elderly Most elderly patients enrolled in earlier trials were younger than 80 years of age. The meta-analysis of data from participants > 80 years in randomized controlled trials of antihypertensive drugs previous to the HYVET showed that while reduction of BP reduces the risk of CV events such as stroke, the decrease in BP could increase mortality, raising the dilemma of preventing strokes at the cost of increasing mortality (Gueyffier et al., 1999). The fear of treating hypertension in very elderly patients might come at the cost of higher mortality remained until the anticipated termination of HYVET (Beckett et al., 2008). The HYVET proved the benefit and safety of lowering BP in untreated very old patients (
80 years) with systolic hypertension (
160 mmHg) or diastolic hypertension (90–109 mmHg) to below 150/80 mmHg. Active treatment in HYVET was initiated with indapamide sustained release 1.5 mg or matching placebo. If BP remained above 150/80 mmHg, perindopril 2 or 4 mg or matching placebo could be added. Achieved BP of 143.5/77.9 mmHg was associated with a 30% reduction in the rate of fatal or nonfatal stroke, a 39% reduction in the rate of death from stroke, a 21% reduction in the rate of death from any cause, a 23% reduction in the rate of death from CV causes, and a 64% reduction in the rate of heart failure, compared with the placebo group with the achieved BP of 158.5/84.0 mmHg. Meta-analyses of randomized controlled trials in very old patients including HYVET showed that BP lowering reduces stroke (35%) and heart failure (50%) without significant reduction in CHD mortality and morbidity. Reduction in mortality was achieved in trials with the least BP reductions and the lowest intensity of therapy (Bejan-Angoulvant et al., 2010). The HYVET reduced total mortality by 21% and CV mortality by 23% with low doses of two antihypertensive drugs. The use of a low dose diuretic in combination with an angiotensin converting enzyme inhibitor ensured a neutral impact on potassium. In contrast, subgroups of very elderly participants from earlier trials used higher doses of more antihypertensive drugs and showed a trend towards increased total mortality. These observations suggest that less aggressive treatment is probably a good approach in the very elderly.

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The meta-analyses by Thomopoulos et al. including the SPRINT study indicated that: (1) all CV outcomes were significantly reduced by antihypertensive treatment independent of age; (2) BP lowering induced comparable relative risk reduction in young and older patients but absolute risk reductions were significantly higher in older individuals; (3) the recommendation to initiate treatment at SBP values 140–159 mmHg is supported at age > 60 years; (4) SBP and DBP values lower than 140 and 80 mmHg can be aimed at with incremental benefits without disproportionate burdens until age 80 years, above which available evidence is for benefits at on treatment SBP 140–149 mmHg; (5) there was no evidence that treatment discontinuations for adverse events or hypotension/syncope were more frequent at age > 65 (Thomopoulos et al., 2016a). The meta-analysis (Thomopoulos et al., 2016b) also showed that most BP-lowering drug classes were equally effective in preventing risk of fatal and nonfatal CV events both in older and younger patients; with the exception of beta-blockers, which showed less effectiveness at an older age. As mentioned above, the relative inefficacy of beta-blockers may be partially attributable the pseudo-antihypertensive effect (bradycardia mediated increase in central systolic pressure augmentation) (Messerli et al., 2016).

Antihypertensive Treatment in the “Real World” Patients enrolled in clinical trials tend to be fitter and have less severe comorbidities than “real world” patients receiving treatment in a usual care setting under more relaxed follow up. Patients enrolled in HYVET were healthier than the average very elderly population, largely a primary prevention group, DBP was unusually high (z 90 mmHg) and upright SBP was higher than 140 mmHg. The majority of the HYVET patients had an age only slightly above 80 years (22% aged > 85 years), leaving patients close to 90 years old and older poorly represented. Those with dementia were excluded as were those requiring residential nursing care and participants. In SPRINT patients were excluded if they had type 2 diabetes, prior stroke, heart failure, dementia, unintentional weight loss, upright SBP of < 110 mmHg, or residency in a nursing home. However, the benefits of antihypertensive treatment, or intensive control of the hypertension respectively, was extensible to frail octogenarian included in HYVET and SPRINT, respectively (Warwick et al., 2015; Williams et al., 2018). There are fewer data evaluating the benefit and risk of antihypertensive treatment among institutionalized elderly patients or those with advanced comorbidities. Hypertension in very elderly people is commonly associated with low DBP, orthostatic hypotension or comorbidities such as CHD, diabetes, chronic kidney disease. Although treatment of ISH have demonstrated considerable benefits, the question arises of whether a very low DBP (< 60 mmHg) could counteract the benefit of lowering SBP, particularly in those with documented CHD (Langer et al., 1993). Patients with Parkinson or diabetes are more susceptible to orthostatic and postprandial hypotension. In these patients the intensity of the antihypertensive treatment should be individualized to identify the best achievable BP according to tolerability and adverse effects. Measurements of BP in the upright position, and self-measurements after eating, are indicated in these persons (Alfie, 2015). In variance with the HYVET study, population-based cohorts of oldest old individuals with treated hypertension showed greater mortality in those with “unplanned” low SBP. In the Jerusalem Longitudinal Study, a prospective observational study of 1159 representative community-dwelling subjects aged 85, the lowest survival rate occurred in treated subjects with controlled SBP. However, hypertensive subjects receiving treatment had greater cardiovascular comorbidity at baseline than untreated hypertensives (Jacobs et al., 2012). Similarly, the PARTAGE study in elderly subjects living in nursing homes (mean, 87.6 years), showed that mortality from all causes was highest in those with SBP < 130 mmHg receiving
2 antihypertensive drugs (Benetos et al., 2015). In the Leiden 85-Plus cohort, patients 85-year-old with low SBP under antihypertensive treatment experienced accelerated cognitive decline and higher all-cause mortality (29% higher per 10 mmHg lower blood pressure under therapy), whereas such associations were not observed in participants without therapy (Streit et al., 2018). A retrospective cohort of 398,419 treated hypertensive subjects from the Kaiser Permanente Southern California health system described a U-shaped curve for the composite outcome of mortality/end stage renal disease with a higher nadir SBP in patients older than 70 years (140 versus 133 mmHg in older and younger patients, respectively) (Sim et al., 2014). In treated octogenarian from the IDHACO cohort, home SBP levels and cardiovascular events described a U-shaped relationship with a nadir at 149 mmHg, without modifying effects of DBP (Aparicio et al., 2015). In the English Longitudinal Study of Ageing (ELSA), the lowest CV disease and all-cause mortality risk among treated octogenarians was observed for an SBP range of 140–149 mmHg (1.04, 0.60–1.78) and 160–169 mmHg (0.78, 0.51–1.21) (Dregan et al., 2016). In the large nationally representative cohort of English individuals aged 80 and older without major comorbidities at baseline, taking antihypertensive medication to achieve a SBP < 150 mmHg according to national guidance, the risk of all-cause mortality showed a U-shaped pattern with lowest mortality in individuals with SBP of 135–154 mmHg, without modifying effects of DBP. Risk of heart failure increased below 125 mmHg, whereas risk of stroke and myocardial infarction rose above 145– 154 mmHg (Delgado et al., 2017). A different approach to evaluate the effect of the decrease in BP in the community is to analyze the relationship between adherence to antihypertensive drugs and the risk of CV events. Among 155,597 Medicare beneficiaries aged 66–79 years newly diagnosed with hypertension and initiated on antihypertensive medication, those classified as being highly adherent had less than half the risk of having a cardiovascular event compared with those classified as having moderate or low adherence (Yang et al., 2017). Similarly, unselected patients aged 85 years or older (average 88 years) who were newly treated with antihypertensive drugs showed a markedly reduced risk of fatal and nonfatal CV outcomes, including heart failure, stroke and all-cause

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death associated with increasing adherence with antihypertensive drug therapy. Similar findings were obtained in a cohort of patients aged 70–84 years (Corrao et al., 2017).

Current International Guidelines Both the ACC/AHA 2017 (Whelton et al., 2018) and the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) 2018 guidelines (Williams et al., 2018) recommend lower BP thresholds for treatment, combination drug therapy and lower BP treatment targets, and encourage out-of-office BP measurements to identify white coat and masked hypertension and to guide treatment. Current US guideline defined Stage 1 hypertension as 130–139 or 80–89 mmHg, and Stage 2 hypertension as to the previous definition of “hypertension” (> 140 or > 90 mmHg). The 2017 guideline recommends > 130/80 mmHg as the threshold for drug treatment for persons at high CV disease risk based on known clinical CV disease or an estimated 10-year atherosclerotic CV disease risk of 10% or greater (using the ACC/AHA Pooled Cohort Equations). Virtually all individuals aged 70 and older and most aged 65 and older will be above this level of CV disease risk. The European guideline recommends a different BP threshold for treatment according to age: > 140/90 mmHg between 18 and 79 years, and > 160/90 mmHg in those aged 80 years and over. The goal suggested in previous guidelines (140–150 mmHg) currently seems too conservative for many elderly and very elderly patients who are active and independent. Consequently, European guideline recommend that BP be reduced in elderly hypertensive patients to 130–139/80 mmHg, but not below 130 mmHg, whereas the US guideline recommend a BP goal of < 130/80 mmHg for all patients including the elderly. These recommendations apply only to older adults who can walk and are living in the community. The European 2018 guidelines on arterial hypertension recommends a low-dose combination of two-drugs (preferentially angiotensin converting enzyme inhibitor or angiotensin receptor blocker with a calcium channel blocker and/or a thiazide/ thiazide-like diuretic) as initial therapy to achieve BP control for most patients except in those with high–normal BP and a high CV risk or in frail older patients, in whom treatment initiation with monotherapy may be more appropriate. Beta-blockers in combination should be preferentially used when there is a specific indication for their use. A Canadian consensus guideline for frail older adults recommended a less intense antihypertensive treatment in frail elderly patients, a systolic threshold of 160 mmHg or higher for initiating drug treatment, and to reduce it to the range 140 and 160 mmHg (unless it drops to < 140 mmHg upon standing or treatment adversely affect quality of life), avoiding the use of more than two antihypertensive medications. The consensus suggested that a systolic target of 160–190 mmHg may be reasonable when the patient is severely frail and has a short life expectancy (Mallery et al., 2014).

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Thomopoulos, C., Parati, G., Zanchetti, A., 2016b. Effects of blood pressure lowering treatment in hypertension: 8. Outcome reductions vs. discontinuations because of adverse drug eventsdMeta-analyses of randomized trials. Journal of Hypertension 34 (8), 1451–1463. https://doi.org/10.1097/HJH.0000000000000972. Timio, M., Saronio, P., Venanzi, S., Gentili, S., Verdura, C., Timio, F., 1999. Blood pressure in nuns in a secluded order: A 30-year follow-up. Mineral and Electrolyte Metabolism 25 (1–2), 73–79. https://doi.org/10.1159/000057424. Tryambake, D., He, J., Firbank, M.J., O’Brien, J.T., Blamire, A.M., Ford, G.A., 2013. Intensive blood pressure lowering increases cerebral blood flow in older subjects with hypertension. Hypertension 61 (6), 1309–1315. https://doi.org/10.1161/HYPERTENSIONAHA.112.200972. Uzu, T., Kimura, G., 1999. Diuretics shift circadian rhythm of blood pressure from nondipper to dipper in essential hypertension. Circulation 100 (15), 1635–1638. Uzu, T., Kazembe, F.S., Ishikawa, K., Nakamura, S., Inenaga, T., Kimura, G., 1996. High sodium sensitivity implicates nocturnal hypertension in essential hypertension. Hypertension 28 (1), 139–142. Wang, J.G., Staessen, J.A., Gong, L., Liu, L., 2000. Chinese trial on isolated systolic hypertension in the elderly. Systolic hypertension in China (Syst-China) collaborative group. Archives of Internal Medicine 160 (2), 211–220. Wang, J.-G., Staessen, J.A., Franklin, S.S., Fagard, R., Gueyffier, F., 2005. Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 45 (5), 907–913. https://doi.org/10.1161/01.HYP.0000165020.14745.79. Wang, Y., Chen, L., Wang, Y., Qain, Y., Zhang, J., Tang, X., Li, Y., Zhu, D., 2017. Morning hypertension is more common in elderly hypertensive patients with controlled documented office blood pressure in primary care clinics. Journal of Hypertension 35 (11), 2192–2198. https://doi.org/10.1097/HJH.0000000000001449. Wang, X., Wang, F., Chen, M., Wang, X., Zheng, J., Qin, A., 2018. Twenty-four-hour systolic blood pressure variability and renal function decline in elderly male hypertensive patients with well-controlled blood pressure. Clinical Interventions in Aging 13, 533–540. https://doi.org/10.2147/CIA.S161752. Warwick, J., Falaschetti, E., Rockwood, K., Mitnitski, A., Thijs, L., Beckett, N., Bulpitt, C., Peters, R., 2015. No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: An investigation of the impact of frailty upon treatment effect in the hypertension in the very elderly trial (HYVET) study, a double-blind, placebocontrolled study of antihypertensives in people with hypertension aged 80 and over. BMC Medicine 13 (1), 78. https://doi.org/10.1186/s12916-015-0328-1. Wei, Y., Jin, Z., Shen, G., Zhao, X., Yang, W., Zhong, Y., Wang, J., 2013. Effects of intensive antihypertensive treatment on Chinese hypertensive patients older than 70 years. Journal of Clinical Hypertension 15 (6), 420–427. https://doi.org/10.1111/jch.12094. Weidung, B., Boström, G., Toots, A., Nordström, P., Carlberg, B., Gustafson, Y., Littbrand, H., 2015. Blood pressure, gait speed, and mortality in very old individuals: A populationbased cohort study. Journal of the American Medical Directors Association 16 (3), 208–214. https://doi.org/10.1016/j.jamda.2014.09.004. Weinberger, M.H., Fineberg, N.S., 1991. Sodium and volume sensitivity of blood pressure: Age and pressure change over time. Hypertension 18 (1), 67–71. Whelton, P.K., Carey, R.M., Aronow, W.S., Casey, D.E., Collins, K.J., Himmelfarb, C.D., DePalma, S.M., et al., 2018. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/ PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: Executive summary: A report of the American College of Cardiology/ American Heart Association task Force on Clinical Practice Guidelines. Circulation 138 (17), e426–e483. https://doi.org/10.1161/CIR.0000000000000597. Wiinberg, N., Høegholm, A., Christensen, H.R., Bang, L.E., Mikkelsen, K.L., Nielsen, P.E., Svendsen, T.L., Kampmann, J.P., Madsen, N.H., Bentzon, M.W., 1995. 24-h ambulatory blood pressure in 352 Normal Danish subjects, related to age and gender. American Journal of Hypertension 8 (10), 978–986. https://doi.org/10.1016/0895-7061(95) 00216-2. Williams, B., Mancia, G., Spiering, W., Rosei, E.A., Azizi, M., Burnier, M., Clement, D.L., et al., 2018. 2018 ESC/ESH guidelines for the management of arterial hypertension: The task force for the Management of Arterial Hypertension of the European Society of Cardiology and the European Society of Hypertension. Journal of Hypertension 36 (10), 1953– 2041. https://doi.org/10.1097/HJH.0000000000001940. Williamson, J.D., Supiano, M.A., Applegate, W.B., Berlowitz, D.R., Campbell, R.C., Chertow, G.M., Fine, L.J., et al., 2016. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged
75 years. JAMA 315 (24), 2673. https://doi.org/10.1001/jama.2016.7050. Yang, Q., Chang, A., Ritchey, M.D., Loustalot, F., 2017. Antihypertensive medication adherence and risk of cardiovascular disease among older adults: A population-based cohort study. Journal of the American Heart Association 6 (6). https://doi.org/10.1161/JAHA.117.006056. Yang, S., Yuan, J., Qin, W., Yang, L., Fan, H., Li, Y., Wenli, H., 2018. Twenty-four-hour ambulatory blood-pressure variability is associated with Total magnetic resonance-imaging burden in cerebral small-vessel disease. Clinical Interventions in Aging 13, 1419–1427. https://doi.org/10.2147/CIA.S171261. Yano, Y., Inokuchi, T., Hoshide, S., Kanemaru, Y., Shimada, K., Kario, K., 2011. Association of poor physical function and cognitive dysfunction with high nocturnal blood pressure level in treated elderly hypertensive patients. American Journal of Hypertension 24 (3), 285–291. https://doi.org/10.1038/ajh.2010.224. Yoon, Sung Sug Sarah, Margaret D Carroll, and Cheryl D Fryar (2015) Hypertension prevalence and control among adults: United States, 2011–2014. NCHS Data Brief, no. 220, 1–8. Zhang, W.R., Craven, T.E., Malhotra, R., Cheung, A.K., Chonchol, M., Drawz, P., Sarnak, M.J., et al., 2018. Kidney damage biomarkers and incident chronic kidney disease during blood pressure reduction: A case-control study. Annals of Internal Medicine 169 (9), 610–618. https://doi.org/10.7326/M18-1037.

Inflammaging Targets Miriam Capri, Claudio Franceschi, and Stefano Salvioli, Alma Mater Studiorum University of Bologna, Bologna, Italy © 2020 Elsevier Inc. All rights reserved.

Introduction Molecular Targets of Inflammaging Cellular Targets of Inflammaging Organ and Tissue Targets of Inflammaging Systemic Targets of Inflammaging Immune System Central Nervous System Intestine/Gut Microbiota System Potential Therapeutic Interventions Conclusions References Further Reading

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Introduction Since 2000, our team has proposed and used the term “inflammaging” referred to the chronic, low-grade inflammation that develops with age and may favor the onset of age-related diseases (ARDs), such as type 2 diabetes (T2D), inflammatoryautoimmune diseases, cardiovascular diseases (CVDs), neurodegeneration (Alzheimer’s disease, dementia) and geriatric syndromes (GS) among others (Franceschi et al., 2000). Undeniably, inflammation is essential for survival, therefore the development of inflammaging can be explained within the framework of the antagonistic pleiotropy theory of aging. In other words, inflammation has beneficial effects toward the neutralization of dangerous or harmful agents early in life and in adulthood, while these effects become detrimental in old age, a phase of life that, contrary to childhood, has not undergone selection during evolution. Moreover, as it will be discussed, inflammaging is likely a phenomenon of body adaptation and remodeling (Fulop et al., 2018) and thus may also favor an extension of life-span and promote longevity, since this process is also present in centenarians (Franceschi et al., 2007). These apparent conflicting data will be discussed in the context of inflammaging targets. Interestingly, the molecular circuits able to sustain inflammaging affect different biological layers or targets, such as molecules (including DNA and RNA), cells, organ/tissues and systems as depicted in Fig. 1. In turn, these targets become mediators of the process. Here, we would like to outline the double role of molecules involved in inflammaging as both targets and mediators/regulators contributing not only to age-related pathologies (Franceschi et al., 2018a), but also to successful aging or longevity.

Fig. 1 The different layers (molecules/cells/tissues/organs and systems) contributing to inflammaging both as targets and mediators likely as an adaptation to stress events all along the life period.

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Molecular Targets of Inflammaging Overall, the inflammatory phenotype originates inside the cells as a response to different types of stress including DNA damage, mitochondrial dysfunction, proteasome/lysosomes alteration, endoplasmic reticulum (ER) stress and autophagy impairment. It therefore entails the involvement of different organelles, including the nucleus, and mechanisms, such as DNA damage response (DDR), post-transduction protein modification (e.g., N-glycosylation), and activation of oxidative stress responsive elements including inflammasomes. Many of these mechanisms may converge on the activation of NF-kB pathway. Moreover, an increased availability of misplaced/misfolded/damaged “self” components that are not properly disposed can activate DAMPs receptors triggering a feed-forward propagation–amplification cycle of inflammation and inflammaging, an idea that has been recently summarized under the name of “garbaging” (Franceschi et al., 2017). According to this idea, molecular garbage (including not only misfolded/misplaced proteins but also nucleic acids released outside their native cellular compartments) can be considered as the major fuel of inflammaging together with the related chronic activation of the innate immune system. A further stunning feature of inflammaging is the apparent capability to spread from cells and tissues to distal districts through different shuttles actively secreted by cells, such as exosomes and ectosomes (or extracellular vesicles, EVs) (Franceschi et al., 2017). Among the main actors of propagation, increasing importance has been attributed to short nucleic acids, such as microRNAs (miRNAs). miRNAs are wellknown 17–25 nt-long epigenetic regulators that circulate in the blood and other body fluids at different levels, transported by various shuttles. Some miRNAs appear to be modulated with age and ARDs-GSs. In particular, circulating miRNAs influence not only nearby cells, but also distant acceptor cells by traveling via the circulatory and lymphatic systems (Olivieri et al., 2017), thus potentially exert their epigenetic effects at distant organ/tissue and systems. Additionally, changes at chromatin level including increased genomic instability through loss of heterochromatin and increased DNA damage, telomere attrition, and epigenetic alterations appear to be at the core of immune dysfunction in aging, thus making the inflammaging process much more complex than previously thought (Keenan and Allan, 2018). Changes with age also include nucleic acid burden circulating in the peripheral blood (cell free-and nucleosome DNA fragments, mitochondrial DNA, different types of RNAs) able to elicit chronic inflammation when interacting with DAMP receptors which amplify the effect on the “tone” of inflammation by activating cGAS-STING pathway (Franceschi et al., 2018b). Furthermore, gene-specific agemodifications of DNA methylation level (Garagnani et al., 2012) are definitively recognized and many of them can favor proinflammatory micro-environment indicated as “senescent cell epigenome” (Yang and Sen, 2018). Inflammaging has been assessed by measuring a limited number of inflammatory molecules, namely cytokines, chemokines, and acute-phase proteins, in the blood of older subjects (Franceschi et al., 2007). Recently, in the “InCHIANTI” study, 19 inflammatory biomarkers were measured and an unexpected relation among these markers was statistically revealed (Morrisette-Thomas et al., 2014). In particular, soluble tumor necrosis factor receptors (STNF-RI and STNF-RII), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-a), high-sensitive C reactive protein (hsCRP), IL-18, and IL-1 receptor antagonist (IL-1RA) were strongly correlated with age as principal component of variance. The second component of variance was largely explained by monocyte chemoattractant protein (MCP), IL-12, and IL-8. All these molecules are involved in inflammation and are strongly predictive of mortality and multiple chronic diseases even if in opposite directions (Morrisette-Thomas et al., 2014). It is interesting to note that the first component “is driven by higher levels of both pro- and antiinflammatory markers, indicating a more activated (but not necessarily more inflamed) inflammatory system”. Together, these components explained only 29% of the total variance among the inflammatory markers considered, enough to indicate their importance but suggesting that additional markers and pathways await discovery and likely contribute to the “tone” of inflammaging within a biological structure characterized by complex and still largely unknown molecular interactions and pathways. These data also suggest, as expected, that “inflammaging players” are more numerous and not restricted to classical cytokines.

Cellular Targets of Inflammaging Inflammaging tone may also be regulated by two crucial phenomena that control cell homeostasis, that is, cell senescence and apoptosis. Cell senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a proinflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. SASP can contribute to senescencerelated inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes and eventually ARD-GSs onset (Franceschi et al., 2018a; Kirkland and Tchkonia, 2017). Noteworthy, several data suggest that cell senescence propagates from cell to cell via a bystander effect (“senescence-induced senescence”) (Nelson et al., 2012) and is transmitted in a paracrine fashion by activation of inflammasomes and IL-1 signaling (Acosta et al., 2013). Local propagation can be particularly important in pathologies such as cancer in older subjects, where systemic inflammaging occurs (Franceschi and Campisi, 2014; Bonafè et al., 2012). In in vivo animal models, cell senescence has been found to modulate steatohepatitis (Ogrodnik et al., 2017) promoting hepatic fat accumulation, thus suggesting an acceleration of liver aging in nonalcoholic steatohepatitis. Conversely, some recent papers have demonstrated that in mice model the selected elimination of senescent cells may restore a “young” phenotype. Baar et al. (Baar et al., 2017) reported that the disruption of the complex formed by forkhead box protein O4 (FOXO4) and the protein p53 by a pharmacological peptide called FOXO4-DRI, leads to the selective elimination of senescent cells. In fact, FOXO4-DRI competes with FOXO4 for p53 binding, pushing senescent cells to undergo apoptotic cell death. Administration of this drug ameliorated the effects of aging and

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chemotherapy, paving the way for new antiaging drugs based on the selective elimination of senescent cells. For this reason, the compounds able to target such cells are indicated as “senolytic” drugs. Apoptosis and other different types of programmed cell death, such as pyroptosis and necroptosis among others, can be triggered by inflammatory events, including the activation of different inflammasomes or specific molecules such as RIP kinases (Silke et al., 2015), respectively. They may modulate the susceptibility to a proinflammatory microenvironment thus favoring ARDs onset (Gudipaty et al., 2018). Recent advancements suggest that necroptosis and theoretically pyroptosis could be reversible processes, highlighting the role of antiapoptotic treatment to counteract stress-and pathological-related molecular mechanisms (Gong et al., 2018), even if more studies are needed to verify the cancer-related effect of antiapoptotic treatment. Interestingly, in a mice model necroptosis increases with age and is reduced by dietary restriction (Deepa et al., 2018). Overall, cell senescence and apoptosis appear to be two faces of the same coin, as they affect not only the general body homeostasis but also the inflammatory “tone”, that increases during the aging process (Franceschi et al., 2018b) and they can be both considered as mediators and targets of inflammaging.

Organ and Tissue Targets of Inflammaging Inflammaging can be considered the result of a continuous adaptation of the cells to stress events all along life span and its contribution to organ/tissue-age-related diseases has been recently proposed (Franceschi et al., 2018a). In particular, adipose tissue, skeletal-muscle system and brain appear to be the most relevant tissues/organ, being sensitive to the inflammatory tone and inducing systemic effects. In particular, adipose tissue is highly interconnected with “metaflammation” (Hotamisligil and Erbay, 2008). The concept of metaflammation was developed from studies on the effect of overfeeding in animal models. The increase in low-grade physiological inflammation under conditions of high nutrient intake is a critical contributor to the onset of insulin resistance. The result is an increased activation of inflammatory responses that affects a variety of organs (such as adipose tissue, liver, pancreas, muscle and brain). The basis of metaflammation is the physiological inflammatory activation elicited by the ingestion of any meal (in which lipids have a central role). Postprandial lipoproteins are involved in the inflammatory process that precedes the development of cardiometabolic diseases (such as atherosclerotic cardiovascular disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and T2DM) (Higgins and Rutledge, 2009). Importantly, metaflammation is a mediator of metabolic syndrome, obesity, skeletal-muscle weakeness and sarcopenia-osteoporosis (Franceschi et al., 2018a; Conte et al., 2016). Skeletal muscle and bones are important targets of inflammaging. During aging, a physiological decrease of skeletal muscle mass and force occurs. When exacerbated, this loss becomes massive and ensues in sarcopenia, loss of independency and increased risk of comorbidity and mortality. It has been shown that augmented low-grade inflammation may favor muscle protein breakdown and inhibit protein synthesis (Balage et al., 2010) and studies on patients with sarcopenia indicate that IL-6 and TNF-a as well as activation of proinflammatory pathways, are found in muscle biopsies (Beyer et al., 2012). It is however to mention that IL-6 is also an important factor for muscle repair triggering. As far as bone, systemic inflammation has been implicated as an underlying mechanism of primary osteoporosis, while secondary osteopenia/osteoporosis is a common complication of chronic inflammatory disease (McLean, 2009). Furthermore, circumstantial evidence is accumulating suggesting that macrophages may also contribute to the pathogenesis of osteoporosis, thus indicating that bone is a target of inflammaging (Batoon et al., 2017). As far as brain, the reader is referred to the following paragraph. However, many data suggest that inflammaging can stimulate the development of neuroinflammation and neurodegeneration (Perry, 2004).

Systemic Targets of Inflammaging A further layer of Inflammaging targets is represented by complex or multiorgan systems such as the Immune System (IS), the Central Nervous System (CNS) and the intestine-gut microbiota system. In fact, many components of these systems are able to sense antigenic, metabolic and environmental stresses and to respond to these stresses by inducing inflammation, and can be in turn affected by inflammation. In the following paragraphs we will briefly discuss the available data on the effects of inflammaging in these systems.

Immune System Inflammaging was originally postulated on the basis of data obtained on immune cells (macrophages and lymphocytes), so that the IS has been since then considered not only a target but also the primary cause of inflammaging. Subsequent studies have highlighted that the causes of inflammaging go far beyond immune cells and include senescent cells and possibly all the cells/tissues capable to synthetize proinflammatory mediators (adipose tissue, skeletal muscle, fibroblasts, endothelial cells, etc.) (Franceschi et al., 2018a). We will not discuss here the contribution to inflammaging of single IS components, but rather briefly expose the effects that inflammaging (or actors involved in it) has on IS cells, including macrophages, dendritic cells, lymphocytes. Macrophages are phagocytic cells that express MHC-II, CD11b, CD45, CD14 and CD16. These cells were at the center of the original theory of Inflammaging (Franceschi et al., 2000) as they are a major source of proinflammatory mediators. However, to

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some extent they can also considered as target of inflammaging. In fact, a recent study suggested that senescent cells (or some unidentified factors produced by such cells) are able to induce the expression of markers of cell senescence such as b-gal and p16Ink4a in macrophages from old mice (Hall et al., 2016). This indicates that in old animals senescent cells (and likely their proinflammatory secretory phenotype, SASP) can hit the macrophages devoted to their rapid clearance making these latter senescent as well, and accounting, at least in part, for the accumulation of senescent cells during aging. Dendritic cells (DCs) appear functionally impaired during aging in particular with regard to the capacity of antigen uptake, phagocytosis, migration, priming of CD4þ and CD8 þ T cells, and production of IFN-I and IFN-III. Moreover, DCs from old persons secrete increased levels of proinflammatory cytokines and decreased levels of antiinflammatory and immune-regulatory cytokines) (Agrawal et al., 2017). This impairment is likely to play an important role in the age-associated progressive decline of adaptive immune responses, loss of tolerance, and development of inflammaging. Interestingly, it has been shown that proinflammatory C Reactive Protein (CRP) can reduce the yield of CD11c þ bone marrow-derived DCs, prevents their full expression of MHC class II and the costimulatory molecules CD86 and CD40, and decreases their ability to stimulate antigen-driven proliferation of T cells in vitro (Jimenez et al., 2018). Therefore, it is possible that the age-related impairment of DCs’ function could be due, at least in part, to chronic inflammation. Lymphocyte subpopulations undergo dramatic changes during aging, as part of the phenomenon of immunosenescence. These changes have been widely described elsewhere and fall apart from the scopes of this article, however, it must be reminded that in seminal studies, PBMC from old persons were observed to produce high amounts of proinflammatory mediators. Why they do so is at present not totally clear. Some of these PBMC are monocytes, some others can be senescent (“exhausted”) lymphocytes provided with a SASP. There are many possible reasons for such an accumulation of senescent lymphocytes within the pool of peripheral blood mononuclear cells (PBMC), in particular it has been recently observed that in the bone marrow there is an increased production of IL-15 and IL-6 with age that correlates with increased oxidative stress. These two cytokines are classical inflammaging markers and are able to strongly modulate the survival of bone marrow mononuclear cells, including senescent CD8þ CD28 T cells, plasma cells and CD4þ T cells (these cytokines support the survival of the former while contrasting that of the two latter) (Pangrazzi et al., 2017). Chronic inflammation is also able to modify the differentiation of hemopoietic stem cells toward the myeloid lineage at the expenses of the lymphoid one, accounting for some of the main changes in white blood cells proportions observed during aging (Pietras, 2017). Other data on animal models suggest that IL-6 can impinge upon not only stem cells, but also mature T cells with a plethora of different effects. Just to mention few examples, IL-6 can modulate the expression of ICOS on Treg from old animals (Raynor et al., 2015), and induces the differentiation of a subset of naïve CD8þ T cells into IL-21 producing cells able to help B cell isotype switching (Yang et al., 2016). As a whole, these data support the idea that immune cells are not only a cause of inflammaging, but also a target for it. As mentioned, it is very likely that inflammaging is an adaptive response to sensu lato environmental conditions (persistent antigenic exposure, oxidative stress, accumulation of damaged/misplaced self molecules, etc.) occurring as we age. As such, its biological significance is not necessarily negative. While it has been largely observed that inflammaging is associated with increased incidence of comorbidity, as well as with occurrence and progression of many chronic diseases, such as obesity, cardiovascular diseases and neurodegenerative diseases, many types of cancer, type 2 diabetes, etc. (Franceschi and Campisi, 2014), it is also emerging that preserved immune parameters and the capacity to mount immune response toward persistent antigens such as CMV are needed for survival at old age (Derhovanessian et al., 2013; Bucci et al., 2014). Since T cells from old people have a blunted response to costimulatory molecules such as IL-6, it is reasonable to think that higher levels of IL-6 in old persons may be useful in order to maintain effective immune responses needed for survival (Brahmakshatriya et al., 2017).

Central Nervous System The CNS has long been considered as a site of immunological privilege where immune and inflammatory reactions were only observed during pathological conditions. This vision is now overcome by the finding that immune activities are found within the CNS and that the CNS is not completely isolated by anatomical barriers from the rest of the organism. Moreover, a number of studies have revealed the presence of a certain level of proinflammatory mediators in brains of old persons free of symptoms of neurodegenerative diseases, indicating that a low degree of neuroinflammation is likely a normal find. More, this suggests that there could be a continuum between the physiological tone of inflammation in the CNS and the clinically evident neurodegenerative diseases such as Alzheimer’ Disease (AD) and Parkinson’ Disease (PD) (Calabrese et al., 2018; Di Benedetto et al., 2017). In particular, AD and PD have a strong inflammatory component due to soluble mediators that can enter the blood–brain barrier, essentially cytokines, whose network can be deranged in AD (Goncharova and Tarakanov, 2007). A meta-analysis demonstrated that increased serum levels of IL-6, TNF-a, IL-1b, TGFb, IL-12, IL-18, and IFNg characterize AD (Swardfager et al., 2010). Interestingly, IL-6 is capable of entering the blood–brain barrier and has a role in memory consolidation) (Benedict et al., 2009). It was also shown that IL-1b and TNF-a in combination with IFNg can exacerbate the pathology in AD due to alterations of the b-amyloid precursor protein (bAPP) metabolism resulting in triggering the production of b-amyloid peptides (Blasko et al., 2000). Similarly, recent data indicate that aging and PD share basic characteristics such as accumulation of senescent cells, inflammation, and propagation phenomena. It has been reported that senescent and inflammatory cells (astrocytes) are present in the brain of PD patients (Chinta et al., 2013) and a “transmission hypothesis” has been proposed regarding the pathogenesis of “PD as a prion disease” (Olanow, 2014), where intercellular transmission of pathological protein aggregates (a-synuclein) occurs, causing a prionlike spreading of neuronal damage and neuroinflammation (Guo and Lee, 2014). Aggregated a-synuclein, released by neuronal

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degeneration acts as an endogenous trigger inducing a strong inflammatory response in PD (Codolo et al., 2013). Similar propagation phenomena have been described for beta-amyloid and Alzheimer’s disease (Domert et al., 2014) and all these data converge on the basic hypothesis that inflammaging per se may propagate with deep effects at systemic layers, as described above. A number of findings support the idea that CNS is actually a target of inflammaging. In fact, within the CNS, many cell types can sustain immune/inflammatory reactions, including microglia, macrophages and dendritic cells. At variance, other immune cells such as resident CD4þ or CD8þ T cells present in different regions of the CNS are believed to have protective actions toward the neural cells, being some of them characterized by a Treg phenotype (Derecki et al., 2010; Kipnis et al., 2012; Ritzel et al., 2016). Microglia are the primary immune cell type in the brain, and play a role similar to those of resident macrophages, however they are not derived from bone marrow, but rather from myeloid progenitor originated in the yolk sac (Ransohoff and Cardona, 2010). Once activated, these cells can produce proinflammatory mediators such as TNF-a, b, IL-6, IL-1b and iNOS, that can be detected in both brain regions, cerebrospinal fluid (CSF) and plasma and are particularly elevated in patients with PD and AD (Knott et al., 2000; Chong, 1997). While the acute activation of microglia is likely protective, prolonged (chronic) activation, due, as an example, to persistent presence of beta amyloid (Ab) may result in an excess inflammation, reactive microgliosis and exacerbation of AD pathology (Hickman et al., 2008). As discussed above, macrophages are phagocytic cells considered central for Inflammaging (Franceschi et al., 2000) (Franceschi et al., 2000). Cells with macrophage activity and phenotype can be found in almost every tissue, including CNS, where their main function seems to be immune surveillance, and antigen capture and presentation at the level of regional lymph nodes. Upon activation, they can secrete many proinflammatory cytokines (e.g., TNF-a, IFN-g, IL-12, IL-1b, IL-18) and chemokines (e.g., CCL2, CCL3), to enhance chemotaxis and induce inflammation (Ousman and Kubes, 2012). Dendritic cells (DCs) are fundamental actors for antigen presentation to T cells. In CNS, DCs have been found in regions lacking the blood brain barrier, such as the circumventricular regions, the perivascular space, and zones of the glia limitans (Prodinger et al., 2011), where they act in immune surveillance, antigen capture, and antigenic delivery and presentation to the cervical lymph nodes (Colton, 2013). DCs play a role in inflammation by stimulating cytokine production (e.g., IL-1b, IL-23, IL-12, TNF-a, IFN-g, IL-10) (McMahon et al., 2006). When DCs recognize inflammatory molecules, damaged tissue, and/or auto-antigens, they move to sites of inflammation and to lymph nodes to stimulate T-cells and contribute to neuroinflammation) (McMahon et al., 2006; D’Agostino et al., 2012). Finally, it is to note that, as mentioned above, CNS is not completely separated from other organs and tissues of the body that can generate proinflammatory mediators. These mediators can in turn reach the brain either passively through the nontotally impenetrable barriers of the CNS, or actively through specific transporters (Di Benedetto et al., 2017). Alternatively, cytokine production at CNS level can be induced by peripheral stimulation via the vagal sensory nerve activity or via the sympathetic nervous system (Hansen et al., 1998). The biological significance of a neuronal inflammation is not always negative, as a certain level of proinflammatory mediators seems important for the correct adult neurogenesis (Baron et al., 2008; Jakubs et al., 2008). On the other hand, while a plethora of works indicate a detrimental role for inflammation in CNS, some studies did not find alterations in cytokine levels in neurodegenerative diseases like PD (Calabrese et al., 2018). As a whole, inflammaging seems a normal find in CNS, where it can also have a positive role for adult neurogenesis and cognitive functions, but it turns detrimental on the long run and likely represents a strong risk factor for neuroinflammation and neurodegenerative disorders.

Intestine/Gut Microbiota System Gut Microbiota (GM) is the most complex ecosystem of human body being composed by approximately 100 trillions of bacteria belonging to > 1000 different species. After weaning, the composition of GM remains quite stable all over adult life but it undergoes changes at old and very old age (Biagi et al., 2017). Briefly, most studies reported an age-related reduction of diversity in the gut ecosystem, as well as an increased colonization by opportunistic species and pathobionts, such as streptococci, staphylococci, enterobacteria and enterococci, accompanied by rearrangements in the saccharolytic and proteolytic population, that is, Firmicutes and Bacteroidetes, with a reduction in species known for producing short-chain fatty acids, in particular butyrate. Due to the tight interconnections between GM and the intestinal IS, it is not unexpected that inflammatory responses can be modulated by these changes. In fact, it has been demonstrated that gut dysbiosis and alteration of bacterial metabolites (e.g., increased production of p-cresyl sulfate, or trimethylamine-N-oxide) dictate SASP and inflammaging (Fernandes et al., 2018) and that a GM from old animals induces the appearance of inflammaging once transplanted in young animals (Fransen et al., 2017). It is at present unclear whether other than modulating inflammaging, GM can be also a target of it. However, it is likely that this may be the case (Guigoz et al., 2008; Biagi et al., 2010). In this regard, it is to note that a debate is still on-going on whether the age-associated changes in GM composition are to be considered a dysbiosis or an adaptation to environmental changes. It is not yet clear what are the actual effects of inflammaging on GM considering: (i) the great heterogeneity of human cohorts in terms of GM composition; (ii) the deep interconnections between GM and intestinal IS and between GM and body metabolism; (iii) the extremely dynamic changes of GM in response to stimuli that can occur independently from, but simultaneously to inflammaging. Interestingly, very long-lived people like semi-supercentenarians (> 105 years of age) have been studied as a model of successful adaptation of GM (Biagi et al., 2016). A core microbiota of highly occurring bacterial groups (mostly belonging to Ruminococcaceae, Lachnospiraceae and Bacteroidaceae families) was confirmed to decrease in abundance with aging. At variance, an age-related enrichment of subdominant taxa was observed in the GM of these persons, accommodating, along with proinflammatory species,

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also health-associated taxa such as Akkermansia, Bifidobacterium and Christensenellaceae, known to promote immunomodulation, protect against inflammation, and promote a healthy metabolic homeostasis. These latter changes might support healthy aging and longevity (Biagi et al., 2016).

Potential Therapeutic Interventions The potential therapeutic interventions to slow down inflammaging include systemic nonpharmaceutical treatments such as physical activity, caloric restriction and Mediterranean diet (Martucci et al., 2017), or drug-based interventions. For sake of brevity only a couple of examples of drug-based interventions will be mentioned here. Promising treatments based on the selective elimination of senescent cell using the so-called senolytic drugs are still under investigation, as previously mentioned (Baar et al., 2017). At variance, two widely used therapies are already available since many years, that is, Metformin and nonsteroidal antiinflammatory drugs (NSAIDs). Calorie restriction mimetics, such as metformin (metf) and its analogs, rank at the top of antiaging and antiinflammatory field researches. Metf is a N,N-dimethylbiguanide currently used for the treatment of type 2 diabetes patients as it is able to lower glycaemia. This effect is per se an antiinflammatory mechanism since high plasmatic levels of glucose are known to induce oxidative reactions and proinflammatory status. In fact, several studies demonstrated antiinflammatory pleiotropic effects of metf in diabetic patients. Various mechanisms of action have been proposed for metf, most of them impinging upon mTOR pathway. Due to the ability of metf to induce autophagy by activation of AMPK, metf is regarded as a potential hormesis-inducing agent with healthspanpromoting and pro-longevity properties (Piskovatska et al., 2019). Furthermore, experimental data obtained from human cells showed that metf inhibits IL-1b-induced release of the IL-6 and IL-8 in human vascular smooth muscle cells (SMCs), macrophages, and endothelial cells in a dose-dependent manner (Isoda et al., 2006). This study also showed a reduction in the activation and nuclear translocation of NF-kB in SMCs upon metf treatment, as well as the suppression of the proinflammatory phosphokinases Akt, p38 and Erk (Isoda et al., 2006). Nonsteroidal antiinflammatory drugs (NSAIDs) such as acetylsalicylic acid/aspirin, are among the most used drugs worldwide and have been investigated since many years in animal models and humans for possible off-label uses. They have a well-known antiinflammatory action, due to the inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, and consequent block of the synthesis of prostaglandins and thromboxanes. Recent studies suggest that aspirin seems to recapitulate molecular changes of caloric restriction affecting autophagic flux in animal models with potential beneficial effects on lifespan (Pietrocola et al., 2018).

Conclusions As briefly discussed in these paragraphs, inflammaging is a pervasive phenomenon impinging upon molecular, cellular, tissue/ organ and systems levels and is able to shape many body responses that can lead (together with other mechanisms) to normative aging and disease but, maybe, also (in a limited number of cases) to successful aging and longevity. This suggest that a clear boundary does not exist between healthy aging and ARDs-GS, but rather these phenomena are part of a continuum characterized by a different slope (or rate) of the aging process, of which inflammaging can be one of the main drivers. Healthy aging should be characterized by low (or well counter-balanced) levels of inflammaging, while ARDs-GS are characterized by elevated (or unbalanced) levels of inflammaging. If so, the control of this phenomenon should be considered a crucial target of future therapeutic approaches aimed at counter-acting aging as a whole and, at the same time, many if not all of the ARDs-GS, according to the conceptualization of Geroscience (Kennedy et al., 2014).

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Further Reading Franceschi, C., Capri, M., Garagnani, P., Ostan, R., Santoro, A., Monti, D., Salvioli, S., 2017. Inflammaging. In: Handbook of Immunosenescence. Springer, Cham. https://doi.org/ 10.1007/978-3-319-64597-1.

Intermittent Fasting Oleh Lushchak and Olha Strilbyska, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine Veronika Piskovatska, University Clinic of Martin Luther University, Halle, Germany Alexander Koliada, D.F. Chebotarev Institute of Gerontology, NAMS, Kyiv, Ukraine Kenneth B Storey, Carleton University, Ottawa, ON, Canada © 2020 Elsevier Inc. All rights reserved.

Introduction Types of IF Whole Day Fasting Alternate-Day Fasting (ADF) Time-Restricted Feeding (TRF) Daily IF (or 16/8) 12/12 Type 20/4 Type 5:2 Diet Fasting-Mimicking Diet (FMD) Religious Fasting Ramadan Fasting Positive Effect of IF Cellular Level Insulin level: Decreased, fat burning Growth hormone: Increased, fat burning Cellular repair: Induction Organismal Level Weight loss and abdominal fat reduction Decreased risk of type 2 diabetes mellitus Decreased oxidative stress and inflammation Improved heart health Cancer prevention Brain function Alzheimer’s disease Lifespan extension Negative Effects of IF Hunger and Overeating Headaches Low Energy Adrenal Stress Cold Sex Hormones and Fertility Experimental Models for Investigating the Molecular Mechanisms of IF Evidence From Clinical Studies in Humans Conclusions Acknowledgments References

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Introduction Intermittent fasting (IF) is not a diet, but rather a specific modification of generally-accepted daily eating patterns, that is now being hailed as a promising nonpharmacological strategy for disease prevention and longevity. In this scenario, the amount of food and nutrient composition do not matter; instead, switching between eating and fasting intervals is of great importance. IF appears to be one of the simplest ways to achieve weight loss through caloric restriction. The key point of IF is that calorie intake during the feeding period is not limited, unlike under calorie restriction regimens, whereas the rate of meal consumption is reduced to create prolonged episodes of fasting. IF might be a plausible strategy for weight loss, as long as it can be accompanied by muscle mass maintenance. A growing body of evidence supports the lifespan-extending effects of IF in model organisms. IF might also play

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a role in restoring circadian rhythms by modulating the levels of multiple compounds involved in finely-tuned regulation of appetite, satiety, sleep, and vigilance. A whole IF cycle consists of feeding and fasting intervals. During a feeding interval, there are usually no restrictions on the amount or content of food eaten, so insulin levels are high and the body does not need to use fat depots as energy sources. The fasting interval is associated with 8–12 h of post absorptive state. During this time insulin levels are low, promoting fat burning. Hence, it is proposed that when using IF, a person will lose fat without changing either the amount or composition of consumed foods or physical activity levels. Animal studies of IF have demonstrated lower total cholesterol and triacylglycerol concentrations, lower heart rate, increased resistance of myocardium against hypoxia, and lower blood pressure (Varady and Hellerstein, 2007). In general, IF is involved in adaptive cellular responses that reduce oxidative damage and inflammation, optimize energy metabolism, and bolster cellular protection. Moreover, IF activates many of lifespan-extending mechanisms that are similar in calorie restriction (CR). However, IF may be a more beneficial strategy compared to CR, since CR can lead to nutrient deficiencies, whereas IF restricts only the frequency of eating. It is worth noting that the effects of IF are, at least in part, attributable to ketone production during the fasting phases. Interestingly, IF ameliorates side effects caused by chemotherapies during cancer treatment in humans (Safdie et al., 2009). The beneficial effects of fasting appear to be mediated by the nervous system. The main advantage of IF is high compliance, particularly in obese subjects. International Society of Sports Nutrition provides clarity on the beneficial effects of IF on body composition. However, all body composition assessment methods have strengths and limitations (Aragon et al., 2017). IF as the potential method to delay aging and assist in treatment of age-related diseases, has minimal side effects. Humans are evolutionarily adapted to IF regimens. Indeed, our ancestors were frequently subjected to extended fasting, when food was not available or scarce. However, IF cannot be applied to children, elderly, underweight individuals, pregnant and breastfeeding women, since it is accompanied by substantial risks in these specific populations. Clinical studies in humans, examining long-term effects of IF in health/disease and longevity are limited and the mechanisms that mediate the metabolic effects of different IF regimes in humans still remain unclear. Further analysis of the mechanisms responsible for the beneficial effects of IF may provide novel therapeutic strategies to promote favorable metabolic changes, prevent age-related diseases and conditions, and reach healthy longevity.

Types of IF Intermittent fasting is an umbrella term, including variable dietary regimens characterized by periodic cycles of caloric and/or nutrient restriction, followed by period of regular nutrition. There are three basic types of intermittent fasting: whole-day fasting, alternateday fasting, and time-restricted feeding. However, multiple modifications of these regimens exist, allowing individuals to tailor restrictions to their needs and preferences. Multiple perturbations of IF are listed below.

Whole Day Fasting Also known as “Eat-Stop-Eat” regimen, this form of IF involves periodic (from 2 nonconsequent days per week to once a month) abstinence from food for 24 h.

Alternate-Day Fasting (ADF) Often referred as day-to-day fasting, ADF uses alternation between fasting days, when consumption of nutrient-containing food and drinks is excluded, with feeding days, when meals are consumed ad libitum.

Time-Restricted Feeding (TRF) In this form of IF, ad libitum intake of foods is allowed only during specified hours during the day, creating prolonged intervals without food.

Daily IF (or 16/8) This type of TRF is characterized by 16 h of fasting, followed by 8 h of feeding each day.

12/12 Type This is often more feasible than the 16/8 type of TRF, and consists of a 12-h period of fasting followed by a 12-h eating period.

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20/4 Type This extreme form of TRF is characterized by a 20 h fasting period followed by a 4 h eating time each day. Food consumption in this case is limited to 1–2 meals per day.

5:2 Diet This is one type of alternate-day fasting. Subjects are allowed to eat ad libitum for 5 days per week but during the remaining 2 days the calorie intake of is severely restricted to only about one-quarter of normal levels in order to maintain energy balance (i.e., 500 kcal d
1 for men, 600 kcal d
1 for women).

Fasting-Mimicking Diet (FMD) This diet is low in calories, sugars, and protein, but high in unsaturated fats, and has been shown to reduce biomarkers of agingrelated diseases.

Religious Fasting Fasting is an important part of many religious and spiritual practices. Fasting periods are variable in length and typically include limitations on the foods eaten, such as a mostly vegetarian diet (Greek Orthodox Christians, Catholics, Buddhism) or abstinence from food for certain periods of time (Members of the Church of Jesus Christ of Latter-Day Saints, Seventh-day Adventists).

Ramadan Fasting This is a 28–30 day fast in which food and drink are prohibited during the daylight hours. Usually a large meal is consumed after sunset and a lighter one before sunrise, creating a fasting window that is around 12 h long, depending on the latitude at which Muslims are living. For example, in 2018 in Canada, fasting was about 16 h in Toronto and 19 h in Edmonton.

Positive Effect of IF Intermittent fasting affects both lifespan and healthspan by triggering multiple targets (Fig. 1). Its systemic effects evolve decrease of inflammation and oxidative stress with activated autophagy. IF decreases circulating insulin and fasting glucose levels in parallel

Fig. 1 Physiological effects of intermittent fasting. IF was shown to beneficially modify vast range of cardiometabolic factors, improving glycemic control, insulin sensitivity, and lipid profile, providing significant weight loss and reduction of abdominal adiposity. IF reduces levels of proinflammatory cytokines and markers of chronic inflammation. Concomitant autophagy promotion could mediate anti-cancer properties of IF, together with certain beneficial effects demonstrated in cancer patients, undergoing chemotherapy. Supposedly, it can induce neurogenesis due to enhanced secretion of brain neurotrophic factor, affecting cognition and preventing brain damage.

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with increased concentration of growth hormone and insulin sensitivity of responsible tissues. Fasting protects brain from damages and prevent cognitive declines. Moreover, decreased blood pressure, concentration of cholesterol, LDL and triglycerides are among benefits to cardiovascular system. They are tightly linked to weight loss and abdominal fat reduction with significant improvement of other metabolic markers.

Cellular Level Insulin level: Decreased, fat burning Reductions in circulating levels of insulin and glucose were observed in mice and rats under ADF (Anson et al., 2003). In healthy subjects, serum IGF-I levels decreased significantly after 5 days of ADF fasting. Interestingly, when ADF was characterized by the same calorie intake but a decrease in meal frequency, this did not lead to substantial weight loss but reduced glucose and insulin concentrations and increased resistance to endotoxic stress in mice (Anson et al., 2003). TRF reduced insulin levels, improving insulin sensitivity and b-cell responsiveness and these changes occurred independent of weight loss (Sutton et al., 2018). Decreased insulin levels under IF were associated with fat burning processes.

Growth hormone: Increased, fat burning Nutrient deprivation in healthy humans leads to increased serum growth hormone (GH) and reduced insulin-like growth factor I (IGF-I) concentrations. Hence, a fasting-associated decrease in IGF-I concentrations may mediate increased GH secretion. Two days of fasting induced a fivefold increase in endogenous GH production rate in nine tested men (Hartman et al., 1992). Animal models, including pigs, dogs, rabbits, and chickens, displayed higher GH levels under fasting conditions but, in rats, GH release decreased. It was suggested that increased GH levels are mediated by an increased frequency release, and longer periods of somatostatin withdrawal. Enhanced GH release during starvation may promote lipolysis and nitrogen conservation. Moreover, high levels of GH facilitate fat burning and muscle gain.

Cellular repair: Induction A decrease in meal frequency induces cellular repair processes and changes hormone levels to make stored body fat more accessible. IF triggers cellular repair processes, such as removing waste material from cells (Alirezaei et al., 2010). Autophagy is a key homeostatic mechanism that involves the degradation of damaged cytosolic components and recycling them through lysosomes. Autophagy activation has a beneficial impact on defense mechanisms against malignancy, infection, and neurodegenerative diseases. Fasting can potentially promote autophagy in neurons. Starvation intervals increase autophagosome abundance and characteristics, and diminish neuronal mTOR activity. Hence, IF might be a plausible method to induce cellular repair and reach therapeutic effects in chronic diseases that are associated with the accumulation of cellular waste (e.g., atherosclerosis, AD, amyloidosis). A fasting regime is also known to increase the production of ketone bodies, such as b-hydroxybutyrate, and activation of ketogenesis might play a key role in the cytoprotective effects of IF (Anson et al., 2003).

Organismal Level Weight loss and abdominal fat reduction Therapeutic fasting was adopted as an effective approach to treat obesity in 1950s and 1960s. IF is one of the most promising methods, allowing to achieve weight loss and maintain muscle mass. Moreover, it is a viable strategy for weight maintenance in persons with normal BMI and weight management in overweight subjects. IF allows moderate weight loss, approximately 5– 6 kg (3%–8% of body mass), during a short period (3–24 weeks). The mechanism of fat loss involves increased lipolysis, with subsequent reduction of adipocyte size. Within the first day of fasting the body uses up most of its stored glycogen and, once depleted, the body looks to other sources of metabolic fuel. This process involves mobilizing lipid reserves for oxidation as well as producing ketones in the liver, which results in ketosis. Ketones are important replacement fuels for brain when glucose is low and can also be used by muscles and heart. Ketosis can also have some side effects such as boosted metabolic rate, inhibition of the hunger sensation, and stabilization of hormone levels. Fasting-induced hormonal changes (increases in noradrenaline, growth hormone, reduction of insulin levels) also promote weight loss. Fasting results in effective weight loss due to both severe restriction of consumed calories and boosted metabolic rate. Under fasting conditions, the body begins to burn its stored fuels for energy. One result is a decrease in the size of lipid droplets in cells. The reduced size of lipid droplets in muscle and liver cells causes these cells to be more responsive to insulin. IF is an effective way to lose belly fat. Getting rid of belly fat is very important for health, because this fat releases substances that cause inflammation in the body. High belly fat is strongly linked to diseases like type 2 diabetes and heart disease. IF regimens promote the oxidation of this type of fat.

Decreased risk of type 2 diabetes mellitus Animal model such as BioBreeding (BB) rat (model of human insulin-dependent diabetes mellitus (IDDM)) subjected to IF demonstrated fasting glucose and insulin concentrations, fat oxidation, a degree of insulitis, and occurrence of type 2 diabetes. Indeed, rodent models showing a diabetes phenotype that were subjected to IF developed ameliorated hyperglycemia (Pedersen et al., 1999). IF also helped to preserve b-cells in mice that had been manipulated to have obesity-induced diabetes. IF may help to restore

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autophagic flux in islets and improve glucose tolerance by enhancing glucose-stimulated insulin secretion, b-cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration (Liu et al., 2017). Human trials suggest that IF has no impact on fasting concentrations of glucose but has a beneficial effect on insulin sensitivity (Halberg et al., 2005). IF may help improve fasting glucose, body weight, and postprandial blood sugar levels in people with type 2 diabetes (Arnason et al., 2017). Diabetic patients, subjected to an intermittent low calorie diet, tend to have better glycemic control and improved weight loss (Mattson, 2005). Interestingly, short-term alternate-day fasting may be more beneficial in reducing type 2 diabetes risk in men than in women. This suggests a sex-specific effect of IF in the glucose tolerance effect. The decrease in lipolysis and circulating concentrations of free fatty acids under alternate-day fasting also suggests an indirect protective effect on diabetes risk. It is worth noting that fasting may also protect against kidney damage, which is one complication of diabetes. The potential mechanism of diabetes prevention is the increase in insulin sensitivity of cells/tissues that is induced by IF.

Decreased oxidative stress and inflammation IF has beneficial effects for immune function in adults. Indeed, a decrease in the frequency of food intake causes reduced production of tumor necrosis factor by macrophages, which indicates a decline in inflammatory responses. A study by Longo and colleagues also suggested that prolonged fasting may be effective for regenerating immune cells. “When you starve, the (body) tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged,” says Longo. Moreover, IF causes reduced IGF-1, which is associated with aging, cancer risk, and tumor growth (Longo and Fabrizio, 2002). Overweight women at risk for breast cancer subjected to 2 days per week of fasting exhibited reduced oxidative stress and inflammation. Inflammatory cytokines may also be implicated in IF-mediated processes. Accumulation of adipose tissue that often accompanies the aging process is also significantly reduced under an IF regimen. Inflammation may be the cause of many chronic diseases including Alzheimer’s, dementia, obesity, diabetes, and others. There are several possible ways how IF can help to reduce inflammation. Firstly, IF activates autophagy, helping the body to destroy old or damaged cells, thereby reducing inflammation. Secondly, shifting metabolism from utilizing sugar to fat as a fuel leads to ketogenesis and the ketone, b-hydroxybutyrate, is known to block a part of the immune system that is responsible for regulating inflammatory disorders like arthritis and even Alzheimer’s disease (Youm et al., 2015). It is also known that overeating leads to lipid peroxidation and the accumulation of oxidatively damaged proteins and DNA. These events are the major indicators of oxidative stress intensification. A decrease in meal frequency suppresses oxidative stress via reducing the production of superoxide anion radicals while also activating expression of genes that encode antioxidant enzymes (Johnson et al., 2007). IF also leads to increased levels of circulating corticosterone (Wan et al., 2003), an important indicator of organismal stress response. IF regimens trigger antioxidant defense mechanisms, neurotrophic factors (BDNF and FGF2), protein chaperones (HSP-70 and GRP-78) and reduce levels of proinflammatory cytokines (TNF-a, IL-1b, and IL-6) (Arumugam et al., 2010).

Improved heart health Factors including heart rate, blood pressure, circulating lipids, and ischemic injury all contribute to an individual’s risk of cardiovascular disease (CVD). Long-term IF can protect heart cells against ischemic damage. One potential mechanism of this protection is via increased levels of adiponectin, a hormone that reduces blood pressure and insulin resistance. Animal studies on mice demonstrated decreased circulating lipid concentrations under alternate-day fasting (8 weeks) (Gotthardt et al., 2016). Short term alternate-day fasting in humans caused increases in circulating concentrations of HDL cholesterol in women, whereas a decrease in triacylglycerol concentration occurred in men (Heilbronn et al., 2005). IF decreases resting heart rate and blood pressure, and improves cardiovascular stress adaptation (Wan et al., 2003). It also improves survival from myocardial ischemia through proangiogenic and antiapoptotic effects. Hence, IF is a novel nonpharmacological, nongenetic therapeutic intervention for treatment and prevention of certain types of heart diseases.

Cancer prevention A beneficial effect of IF was also demonstrated in cancer prevention. Rodents subjected to IF exhibited a lower risk of spontaneous tumors. Moreover, fasted animals were protected against development and growth of induced cancers (Mattson, 2005). Indeed, it was shown that fasting for 1 day per week significantly decreased the onset of spontaneous tumors in mice (Berrigan et al., 2002). Rats subjected to IF were also more resistant to hepatocarcinogenesis induced by diethylnitrosamine. A protective effect was also detected under an ADF regime, which impacted age-associated lymphoma and hepatocarcinogenesis in mice. This study also found increased mitochondrial superoxide dismutase (SOD) activity that was associated with reduced mitochondrial generation of reactive oxygen species (ROS) (Descamps et al., 2005). The potential mechanism of cancer prevention by IF involves enhancement of apoptosis and inhibition of angiogenesis. An additional mechanism behind the anticancerogenic effect of IF may be metabolic regulation by the sirtuin family proteins. Sirtuins are also involved in longevity, stress response, and metabolism. SIRT1 and SIRT3 were activated when meal frequency decreased, and, in turn, this had a positive impact on insulin response, antioxidant defense, and glycolysis. In this way sirtuins decreased the incidence of carcinogenesis via modulation of metabolism resulting in reduced proliferative capacity of cells (Zhu et al., 2013). Fasting could retard cancerogenesis by protecting cells from DNA damage, suppressing cell growth and enhancing apoptosis of damaged cells.

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Brain function IF is beneficial for the brain by reducing the level of oxidative stress and by enhancing cellular stress resistance. Studies on model organisms demonstrated, that IF is a highly neuroprotective dietary regimen, which improves functional outcome in animal models of stroke, Parkinson’s and Huntington’s diseases (Mattson, 2005). Fasted mice exhibit increased levels of brain-derived neurotrophic factor (BDNF) that is known to play important signaling roles in multiple areas of the brain, including the hippocampus, facilitating learning and memory, and protecting neurons against oxidative damage (Duan et al., 2001). Moreover, BDNF is involved in synaptic plasticity, neurogenesis, and neuronal resistance to injury and disease. Interestingly, BDNF also plays key roles in the regulation of appetite, peripheral glucose metabolism, and functioning of the gastrointestinal tract. IF also enhances excitability in the CNS. Indeed, a 16/8 IF regimen enhanced basal neurogenesis and improved defense after an ischemic stroke in mice, possibly by maintaining leptin levels, which could be an emerging biomarker of brain damage after stroke (Manzanero et al., 2014).

Alzheimer’s disease Alzheimer’s disease (AD) is an irreversible, progressive brain disorder that slowly causes degeneration of memory and cognition, and eventually the ability to carry out the simplest tasks. Numerous studies have suggested that diabetes and metabolic disorders, associated with a Western lifestyle, promote AD development. Limitation of food consumption in the form of CR or IF might be a beneficial strategy to reduce AD risk. IF was shown to have protective effects against cognitive disturbances and dyslipidemia, ameliorating synaptic plasticity and energy metabolism in an AD rat model. Indeed, IF-rats with AD were protected against short-term and special memory loss in comparison to animals fed ad libitum. Furthermore, cortisol levels, that were increased in AD rats, were reduced by IF and IF also offered protection against multiple metabolic disturbances of glucose, lipid, and bone metabolism (Shin et al., 2018).

Lifespan extension Modern scientists have taken a major interest of IF as a plausible tool to retard the aging process. Caloric restriction has been shown to delay the onset of many age-related diseases. A significant body of evidence confirms that every other day fasting caused longevity phenotypes in rats and mice. It was demonstrated, that alternate-day fasting increased median and maximal life span in C57Bl/6 mice associated with decreased body weight (Goodrick et al., 1990). However, the same ADF protocol in A/J mice extended lifespan, but did not result in increased loss of body weight (Goodrick et al., 1990). Fasting for 24 h twice a week throughout adult life resulted in a significant increase in lifespan of black-hooded rats (Kendrick, 1973). The lifespan extension effect caused by IF is associated with improved glucose metabolism, cardiovascular function, and enhanced brain function (Carlson and Hoezel, 1946). IF improved survival of diabetic mice without affecting glycated hemoglobin levels (Beli et al., 2018). Hence, a decrease in meal frequency can lead to many beneficial effects, including improved insulin sensitivity, increased sirtuin levels, and improved DNA repair. All of these complex changes enhance stem cell function, mitochondrial function, and activate autophagy and tissue repair, all of these being crucial elements of longevity. Hence, studies in rats can link intermittent fasting with increased longevity, but this is not yet proven in humans. However, IF might amends the factors, contributing to cardiovascular risk: accumulation of lipids in endothelial cells, lipid oxidation, blood hypercoagulation, increased blood pressure, vessel wall rigidity. Indeed, a decrease in meal frequency resulted in reduced LDL cholesterol (the bad cholesterol), increased HDL (the good cholesterol), reduced blood pressure, and improved glucose tolerance and insulin sensitivity.

Negative Effects of IF As a quite extreme type of dietary restriction, IF has also been found to have a range of potential side-effects.

Hunger and Overeating Hunger is the primary side effect of intermittent fasting. Hunger is an adaptive response to food deprivation that is regulated through multiple sensory, cognitive, and neuroendocrine changes. The hormones ghrelin, NPY and orexins stimulate appetite and promote fat deposition. Ghrelin is produced in the stomach and plays an important role in the circadian rhythm of food intake and activity. Under fasting conditions, ghrelin levels increase, leading to hunger, and food-seeking behavior. By contrast, insulin and leptin decrease hunger. A potential side effect of fasting is an imbalance between satiety and hunger hormones that can lead to development of eating disordersdovereating or binge eating. The small feeding window allowed by IF can also cause simultaneous consumption of excessive foods, resulting in abdominal discomfort and reducing quality of sleep, if consumed in the second half of the day.

Headaches Headaches are common side-effects during fasting or severe dietary restrictions. Dehydration, very low glucose levels, and increased levels of stress hormones could be contributing factors for this concerning symptom. Careful evaluation of symptoms and

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individual tailoring of fasting intervals with adequate amount of drinking liquids and careful balance between exercise and rest can prevent headaches.

Low Energy Fasting might result in weakness, muscular fatigue and dizziness. These symptoms are direct consequences of severe nutrient restriction and usually subside after renewal of feeding.

Adrenal Stress Low plasma protein or carbohydrates during a period of fasting signals the liver to produce glucose via gluconeogenesis, and this involves cortisol and catecholamines. Long-term fasting can lead to a depletion of adrenal function and subsequent symptoms of “adrenal fatigue.” Moreover, fasting increases cortisol levels and can activate the fight-or-flight response. These hormonal alterations might be beneficial for weight loss, however long-term outcomes of sympathetic hyperactivation are underinvestigated to date.

Cold Severe restriction of calories and nutrients might reduce thermogenesis and thereby decrease tolerance against cold environmental temperatures. This side-effect might be an obstacle for those who practice fasting during cold times of the year in unfavorable fasting conditions. On the other hand, if you increase lipid catabolism to support shivering thermogenesis, this could accelerate weight loss in people who are using IF as a mechanism of weight management.

Sex Hormones and Fertility Women’s reproductive hormones are highly sensitive to energy intake. Indeed, under IF women can experience irregularities with their menstrual period, metabolic disturbances and early-onset menopause. Studies with animal models have confirmed that IF leads to masculinization and infertility in female rats (Martin et al., 2007). This masculinization might be explained by a favored development of more beneficial traits, such as those that assist in food-seeking behavior. Changes in the menstrual cycle in women are likely due to depletion of fat depots, releasing estrogen and thus, altering the menstruation cycle. The influence of regular or long-term fasting on human fertility is still underinvestigated.

Experimental Models for Investigating the Molecular Mechanisms of IF Laboratory animals are widely used to study the fundamental aspects of nutrition control of the health and longevity. Whereas most studies of the frequency of food intake on human health were conducted over short time periods and with low numbers of subjects, animal models might lead us to a better determination of novel approaches that can be used for increasing both the quality and quantity of life. The size and frequency of meals strongly impacts the development of various diseases and organismal lifespan by mechanisms that include effects on oxidative damage and stress resistance. IF-induced longevity features reduced oxidative damage and increased stress resistance but the molecular mechanisms underlying this process still remain largely unknown. In bacteria, Escherichia coli, switching cells from nutrient rich broth to a medium without calories lead to four times longer survival (Gonidakis et al., 2010). The potential trigger of longevity phenotype may be the production of ketone body carbon sources such as acetate, which triggers an “alternative metabolic program.” Moreover, ketone body catabolism allows animals from microorganisms to mammals to extend their survival time during periods of food deprivation. Chronological lifespan extension by twofold was observed in yeast, Saccharomyces cerevisiae, when cells were switched from a standard growth medium to water alone (Longo et al., 2012). Lifespan extension was associated with increased resistance to multiple stresses (Longo et al., 1997). The mechanisms of lifespan extension under fasting involve the downregulation of the nutrient sensing TOR pathway and the glucose-responsive Rasdadenylate cyclasedPKA pathway, which triggers the activation of the serine/threonine kinase Rim15 (a key enzyme involved in the protective responses). However, fasting extends yeast lifespan independently of established pro-longevity genes. Under fasting conditions yeast enter a hypometabolic mode and minimize using carbon sources of energy. Herewith, yeast accumulate high levels of the ketone body-like acetic acid as an alternative source of energy (Hu et al., 2014). The nematode worm, Caenorhabditis elegans, was shown to be an excellent model system for aging research. Fasting was found to extend lifespan with alternate-day fasting and every 2 days fasting increasing C. elegans lifespan by 41% and 57%, respectively. Moreover, every 2 days fasting increased resistance to heat and oxidative stress. IF also suppressed age-dependent loss of locomotor activity and decrease in muscle integrity. This study also showed the involvement of RHEB-1 (a direct TOR activator) in mediating IF effects in both TOR-dependent and independent manners. Extended lifespan was also seen in daf-16 (mu86) mutants, suggesting that daf-16 partially mediates IF-induced longevity (Honjoh et al., 2009). DAF-16, the forkhead transcription factor, is involved in mediating effects of the insulin-signaling pathway on longevity. Hence, both TOR and insulin signaling play key roles in lifespan extension under an IF regimen.

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The evolutionary conservation of metabolic pathways and regulatory processes between Drosophila and mammals (including humans) made this fly an outstanding model to study longevity and physiological processes that are associated with aging. It was shown that IF has beneficial effects on Drosophila longevity. Previously most studies indicated that decreased meal frequency did not affect lifespan. However, the IF protocol of fasting three times per week may enhance pathways necessary for endurance of acute starvation, while having no beneficial effect on the oxidative damage response. Moreover, fasted flies were able to maintain normal, homeostatic triglyceride levels. IF may also benefit Drosophila by increasing levels of autophagy. Fasted Drosophila also displayed a more youthful acute stress response and improved activity levels (Kotzebue, 2012). The first demonstration that IF could increase lifespan was a study using rats as the model organism. Rats were divided into four groups: control ad libitum fed and rats that were fasted 1 day in 4, 3 or 2 days. Fasting started at the age of 42 days. The optimal amount of fasting appeared to be fasting for 1 day in 3. The longevity phenotype in rats was associated with decrease in development of mammary tumors (Carlson and Hoezel, 1946). Every other day feeding also prolonged lifespan and resulted in profound beneficial physiological changes in mice. Alternate day calorie restriction in mice had a beneficial effect on organismal physiology after 2 weeks of the experiment. In this regimen, mice were allowed ad libitum feeding on 1 day and a restricted diet of 20%–50% of daily calorie restriction on the second day (Johnson et al., 2006). Multiple interactive pathways and molecular mechanisms are involved in mediating beneficial effects of IF on organismal physiology. Insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, which in turn enhance stress resistance and protect against diseases. Enhanced stress resistance has been proposed as a major mechanism whereby IF increase organismal lifespan. Together these studies demonstrate beneficial effects of fasting in a wide variety of organisms, and show the general mechanisms of the adaptive responses to fasting. Fasting results in an approximately 20% decrease in serum glucose and depletion of the hepatic glycogen. Under these conditions, metabolism shifts to utilization of fat-derived ketone bodies and free fatty acids as energy sources. These ketone bodies, free fatty acids and gluconeogenesis allow survival under conditions of food deprivation or restriction. Depending on body composition, humans can survive 30 or more days of complete starvation. Interestingly, some dietary supplements and drugs activate the same cellular and molecular pathways that occur in various tissues in response to IF. Dietary supplementation with 2-deoxy-D-glucose causes similar beneficial physiological effects as seen in IF. Moreover, similar to IF, resveratrol activates sirtuins, which induce antiaging effects at the cellular level. Today IF is receiving increasing attention for its potential therapeutic role in human health and longevity. Many studies of animal models have indicated that IF may be a safe, tolerable dietary intervention for disease prevention and treatment. However, the mechanisms underlying the impact of meal frequency on human health and longevity are still unclear. More research is required to establish the molecular mechanisms of IF dietary regimens in human aging.

Evidence From Clinical Studies in Humans Existing evidence demonstrates modest, but consistent and reproducible metabolic effects of IF in humans (Patterson and Sears, 2017). Most of these studies indicated that IF reduced traditional metabolic and cardiovascular risk factors. IF exerted different effects on glycemic control and markers of insulin resistance in different populations of patients. IF reduced fasting glucose and insulin levels in prediabetic patients and patients with T2DM, whereas in healthy adults IF had no effect on glycaemia or glycated hemoglobin (Antoni et al., 2017). IF promoted reduction of total cholesterol and LDL, modestly decreased systolic and diastolic blood pressure, but showed inconsistent results for HDL and TG (Patterson and Sears, 2017). Some studies showed a reduction of inflammatory markers: C-reactive protein, IL-6 and TNF-a (Stockman et al., 2018; Dixit et al., 2011). Intermittent food restriction was shown to modulate hormones involved in hunger and satiety including leptin, ghrelin, and peptide YY (Hoddy et al., 2016; Coutinho et al., 2018). In addition, fasting periods were accompanied by reduced formation of advanced glycation endproducts (AGEs) and levels of oxidative stress (Golbidi et al., 2017; Iwashige et al., 2004). In some studies, changes in metabolic parameters were not statistically significant (Patterson and Sears, 2017; Anton et al., 2018). Overall, these results provided valuable insights on the potential benefits and possible mechanisms of IF in different human populations but it remains unclear whether the positive metabolic effects of IF are exclusively attributable to body weight reduction. These studies indicated beneficial metabolic effects of IF but, unfortunately, these cannot be directly translated into clinical medicine for various reasons including (a) the research was conducted on small groups of subjects, (b) the research enrolled only specific populations (overweight, obese, diabetics), (c) some studies did not include a control group, or (d) most studies employed fasting interventions for only a limited period of time. To date, long-term outcomes for the use of dietary restriction in the prevention/limitation of chronic or agerelated diseases in humans are unknown. Many traditional religious practices involve abstinence from food on certain days or at a certain time of the day. For example, Ramadan fasting, as one of the varieties of TRF (12/12), showed multiple effects on body weight and metabolism. A period of 29– 30 days of consecutive fasting were shown to decrease blood glucose and LDL in healthy subjects (Kul et al., 2014). A systematic review and meta-analysis showed that Ramadan fasting leads to a small weight loss that was quickly reversed after returning to regular eating pattern (Sadeghirad et al., 2014). Another systematic review concentrated on immunomodulatory effects of Ramadan. In patients with CVD, fasting improved the lipid profile and alleviated oxidative stress. Such fasting also showed safety and high tolerability in other vulnerable groupsdpatients with asthma, immune deficiency, autoimmune disorders, as well as pregnant women and athletes (Adawi et al., 2017). However, most of the metabolic changes described were not sustainable and were

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reported to rebound to prefasting levels after the return to a regular diet. Additionally, multiple concerns regarding the safety of this intervention and long-term outcomes need to be properly validated and adopted as guidelines for diabetic patients due to increased risk of hypoglycemia episodes (Lee et al., 2016), or patients with kidney disease or at risk of kidney stone formation, since the hydration during the fasting window is also limited (Hassan et al., 2018; Miladipour et al., 2012). IF involving total abstinence from food also raises concerns about tolerability in certain patient populations. Diabetics on oral glucose-lowering agents, people with low BMI and gastrointestinal disorders are at risk of unwanted adverse events (Horne et al., 2015). Severe dietary restrictions in the elderly, especially in protein consumption are associated with increased frailty and additional health risks (Baum et al., 2016). Some of the studies suggest that protein amounts in meals should be evenly distributed throughout the day to provide benefit to seniors with decreased protein digestion, uptake and prevent conditions like sarcopenia (Deer and Volpi, 2015; Beasley et al., 2013). Total fasting is often associated with difficulties in maintaining nitrogen balance and muscle mass (Harvie and Howell, 2016). However, several studies have shown that IF in the form of 16/8 TRF does not affect physical performance or body mass (Gasmi et al., 2018), along with fat-free mass, muscle area of the arm and thigh, and maximal strength (Moro et al., 2016). A randomized controlled trial in young males, performing resistance training did not show adverse effects of 20/4 TRF on lean body mass maintenance. In addition, subjects in the TRF group showed a greater increase in upper and lower body strength and lower body muscular endurance (Tinsley et al., 2017). These results indicate the safety and feasibility of this type of dietary intervention in healthy adults although this evidence does not provide any perspective on whether the use of IF in older adults, or patients with diseases and multiple morbidities is appropriate. Another counter-argument is that even if an IF regimen does not demonstrate clear benefits, neither in adherence nor in metabolic improvements, it could still be considered superior compared to benefits derived from other regimens such as those obtained from caloric restriction (Trepanowski et al., 2017; Catenacci et al., 2016). In addition, prolonged time periods of food abstinence are potentially dangerous for patients with eating disorders, provoking ravenous hunger and overconsumption of calories and macronutrients during the next meal or on ad libitum feeding day. Total food abstinence might be difficult to follow compared to other forms of energy restriction. Apart from significant effects on metabolic health, FMD fasting increased efficacy of cancer chemotherapy in a range of in vitro and in vivo models (D’Aronzo et al., 2015), offering some protective effects to tissues of a host organism. Short-term fasting prior to platinum-based chemotherapy was safe and highly tolerable for cancer patients, alleviating chemotherapy-related toxicity. An ongoing randomized clinical trial is supposed to elucidate potential effects of 72 h of fasting in cancer patients undergoing chemotherapy (Dorff et al., 2016). A pilot study of short-term fasting (STF) in cancer patients, undergoing chemotherapy for breast or ovarian cancer showed STF to be a feasible intervention, improving life quality (Bauersfeld et al., 2018). In another clinical study STF in breast cancer patients reduced the hematological toxicity of docetaxel/doxorubicin/cyclophosphamide and was welltolerated (De Groot et al., 2015). Emerging modified dietary interventions allow avoidance of total food abstinence during fasting, amending possible compliance issues. Fasting-mimicking diet (FMD) is a nutritional intervention that includes periodical cycles of lowprotein, high-fat plant-based diet, mimicking the effects of fasting. This program was designed to create a hypocaloric meal plan without micronutrient depletion. FMD when combined with chemotherapy showed promising results in animal studies, delaying the progression of breast cancer and melanoma in a mouse model and improving immune response (Di Biase et al., 2016). Recent animal studies have demonstrated beneficial effects or regeneration and/or rejuvenation for endocrine, immune, and nervous systems. In mouse models FMD improved cognitive performance, reduced cancer incidence (Brandhorst et al., 2015) promoted regeneration of brain tissues in model of multiple sclerosis (Choi et al., 2016), regeneration of pancreatic tissues in T1D and T2D models (Cheng et al., 2017). In a pilot randomized controlled clinical trial healthy subjects followed FMD for 5 consecutive days every month for 3 months and returned to normal diet in-between FMDs. Results suggest that FMD significantly decreased fasting blood glucose, body weight and promoted lowering of serum CRP without major adverse effects. Some biomarkers, like fasting glucose remained lower than at the baseline levels even after returning to normal food intake (Brandhorst et al., 2015). The influence of FMD on metabolism in cancer patients, as well as the safety and feasibility of this dietary intervention is being researched in an ongoing clinical trial (https://clinicaltrials.gov/ct2/show/study/ NCT03340935?show_desc¼Y). Emerging studies suggest that dietary interventions employing intermittent nutrient restriction might serve as an adjuvant cancer treatment, affecting metabolic pathways of cancer cells, promoting their chemo-/radiovulnerability, and at the same time protecting noncancer tissues from adverse effects of anticancer agents (Lettieri-Barbato and Aquilano, 2018; Vernieri et al., 2016). Emerging studies are addressing problems of disrupted circadian rhythms, influencing health of populations and increasing risks of chronic diseases and cancer (Longo and Panda, 2016; Longo and Mattson, 2014). Thus, mismatched eating and sleeping patterns are suggested to be associated with breast and prostate cancer (Kogevinas et al., 2018; Li et al., 2017). IF strategies, including a prolonged nighttime fasting window, might potentially contribute to prevention of these diseases in the population. Existing evidence does not determine the optimal duration of fasting intervals, periodicity of fasting, or severity of energy restriction. It remains unclear whether eating behavior on nonfasting days should be limited, or ad libitum intake could be encouraged (so called “fasting-feasting”). The question of IF applicability in cases of altered eating behaviors remains under discussion and requires large-scale studies to be conducted (Hoddy et al., 2015). Large-scale randomized clinical trials with a long duration of intervention are warranted to answer numerous questions regarding sustainability of effects of IF and long-term outcomes, including aging and age-related diseases.

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Conclusions Fasting is an important and feasible lifestyle modification that naturally facilitates a variety of beneficial biochemical processes within the human body. Results from experimental studies and clinical trials demonstrate the great potential of IF for treatment of certain diseases, either as a stand-alone therapy, or in combination with other interventions. Multiple metabolic effects, including weight loss and improvement of metabolic markers, reduction of oxidative stress and inflammation are great assets in prevention of chronic age-related diseases. Different modifications of IF allow applying fasting intervals of different duration, individualizing restrictions towards lifestyle, tolerance and overall health condition. It is hard to say which IF modifications may be the most beneficial in the long run; for example, will restriction of the feeding window to several hours in the day with a prolonged overnight fasted state, versus severe caloric restriction two times a week combined with a usual diet on the other days. Future studies on free-living adults, employing dietary restrictions for longer time periods, are necessary to elucidate how often and how long we need to starve to prolong healthy lifespan. Unfortunately, it is too early to speak about the routine application of fasting regimens into standard methods of disease treatment and prevention. There are multiple vulnerable categories of patients that have a high risk of side-effects when experiencing severe food restrictions.

Acknowledgments Work of the authors is partially supported via a grant from the Ministry of Education and Science of Ukraine to OL (#0117U006426) and discovery grant from the Natural Sciences and Engineering Research Council of Canada (#6793) to KBS.

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iPSCs-Induced Cellular Reprogramming Khachik K Muradian, State Institute of Gerontology of National Academy of Medical Sciences of Ukraine, Kiev, Ukraine Vadim E Fraifeld, State Institute of Gerontology of National Academy of Medical Sciences of Ukraine, Kiev, Ukraine; and Ben-Gurion University of the Negev, Beer-Sheva, Israel © 2020 Elsevier Inc. All rights reserved.

Introduction Inducers and Enhancers of Pluripotency Pluripotency Induced by Small Molecules Bridging Pluripotency, Aging, Longevity, and Cellular Rejuvenation Pluripotency Hub as a Lighthouse for Reversibility of Cellular Aging Concluding Remarks Acknowledgments References

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Abbreviations ciPSC(s) Chemically induced pluripotent stem cell(s) ESC(s) Embryonic stem cell(s) iPSC(s) Induced pluripotent stem cell(s) mtDNA Mitochondrial DNA nDNA Nuclear DNA SMs Small molecules

Introduction Depletion of stem cell pool and gradual loss of parenchymal cells is one of the most prominent patterns of aging, manifesting in a reduced tissue repair, declined functionality, and eventually elevated mortality. Therefore, replacement of damaged or worn out cells has long been recognized as a pivotal anti-aging strategy. For decades, it has mistakenly been assumed that cellular differentiation, senescence and aging are unidirectional and irreversible processes. Recent findings in nuclear reprogramming and induced pluripotency have, however, undermined this long-lasting dogma and opened new exciting opportunities in the field. The rapid progress in stem cell biology and particularly in induced pluripotency leaves little doubt that cellular differentiation and aging are associated with epigenetic rather than genetic modifications. The most important point is that such epigenetic changes are reversible and could be eliminated, as it occurs in embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) (López-León and Goya, 2017; Taguchi and Yamada, 2017). ESCs and iPSCs can be differentiated into all other cell types, germ cells included. For example, iPSCs generated from tail tip fibroblasts of mice could be converted into fully potent sperm and oocytes and give rise to practically unlimited number of gametes and fertile offspring. In fact, conversion of a somatic cell into gametes breaks the “Weismann barrier” in transferring genetic information from soma to germline and paves the way to immortality (Surani, 2012). However, the first successful attempts of cellular rejuvenation did not receive proper attention at that time. Nuclear reprogramming by transplantation of intestinal epithelium or fibroblasts’ nuclei into enucleated recipient eggs of frog Xenopus laevis, performed by Sir John Gurdon over half a century ago, resulted in birth of normal tadpoles (Gurdon, 1962). This pioneering study revealed that the genome of fully differentiated cells preserves plasticity which is high enough for converting back to the totipotency. Decades later, principally the same kind of cloning experiments proved reality of receiving “one parent offspring” in various mammalian speciesdsheep, pig, goat, horse, cat, monkey, etc. However, only breakthrough findings of induced pluripotency, first discovered by Takahashi and Yamanaka in 2006 by ectopic overexpression of four stemness-related transcription factors in mouse fibroblasts, proved the plasticity potential of differentiated cells to rejuvenate back to the ESC-like state (Takahashi and Yamanaka, 2006). The very possibility of induced pluripotency has soon been confirmed worldwide in other cell types and species. The 2012 Noble Prize in Physiology and Medicine awarded to Sir John Gurdon and Prof. Shinya Yamanaka crowned the important role of nuclear reprogramming and induced pluripotency in biology and medicine. As noted by George Daley, “these two scientists achieved the seemingly impossible in cellular alchemy, transforming the leaden state of somatic tissues into the golden opportunity of pluripotent stem cells” (Daley, 2012).

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Inducers and Enhancers of Pluripotency iPSCs can produce unlimited number of rejuvenated cells by using actually inexhaustible pool of somatic cells taken from patients of any age. Surprisingly, iPSCs can be derived by relatively simple methods of activation of few transcription factors, which are usually highly expressed in ESCs. For example, this can be achieved by viral delivery of POU class 5 homeobox 1 (Oct4), sex determining region Y-box 2 (Sox2), Kruppel-like factor 4 (Klf4) and myelocytomatosis oncogene (c-Myc), collectively known as OSKM cocktail, or “Yamanaka factors” (Takahashi and Yamanaka, 2006). Another cocktail (OSNL) for iPSC generation was discovered soon in Thompson’s laboratory; it consisted of two Yamanaka factors (Oct4 and Sox2), Nanog and Lin28 (Yu et al., 2007). Both cocktails generated iPSCs with almost the same efficiency (100–200 iPSCs per 106 initial human fibroblasts). The features of iPSCs, including transcriptome profile, expression of cell surface markers, high activity of telomerase, and potential to differentiate into the all three germ layers were indistinguishable from ESCs (Takahashi and Yamanaka, 2006; Yu et al., 2007). Combination of the two cocktails into a six-factor cocktail OSKMNL increased reprogramming efficiency by almost 10-fold (Liao et al., 2008). Currently, there are numerous combinations of transcription factors, which however differ in their efficacy to produce iPSCs and iPSC quality. Selection of optimal combination of transcription factors showed that ectopic expression of Sall4, Nanog, Esrrb, and Lin28 (SNEL) ensured higher quality of iPSCs than OSKM and other studied combinations of transcription factors (Buganim et al., 2014). Timing analysis of the OSKM transcription factors, expressed together or each factor separately, showed that reprogramming was accompanied by gradual silencing of lineage-specific genes and activation of embryonic markers. Alkaline phosphatase and stage-specific embryonic antigen 1 are activated first, followed by expression of Nanog and the endogenous Oct4 genes (Brambrink et al., 2008). Differentiation status is an important predictor of induced pluripotency. Stem and progenitor cells usually exhibit substantially higher efficiency in reprogramming than fully differentiated cells. Of note, forced expression of certain lineage-specific transcription factors can induce direct reprogramming (transdifferentiation), that is, converting a differentiated cell into other types of differentiated cells by encompassing complete dedifferentiation and pluripotency (Mikkelsen et al., 2008). Direct reprogramming is apparently a more efficient and safer way of stem cells replenishment, especially preferable in in vivo interventions, because it diminishes probability of hazards associated with complete recovery of pluripotency, such as cancer and teratoma formation. However, in contrast to iPSCs, directly reprogrammed cells preserve “load of aging” from the donor cells (Tang et al., 2017). In 2009, 3 years after discovery of iPSCs, Yamanaka proposed a well-accepted stochastic model of pluripotency induction, which predicted that all somatic cells can be converted into iPSCs by epigenetic modifications (Yamanaka, 2009). Epigenetic modifications primarily induce alterations in methylation status of DNA and post-translational modifications of histones causing chromatin remodeling. DNA demethylation and histone acetylation are key stages in acquisition of pluripotency. In contrast, silencing of the stemness transcription factors in differentiated cells is achieved by hypermethylation of DNA and hypoacetylation of histones in their promoter loci (Polo et al., 2012; Chen et al., 2013). Yet, traditional methods of delivery and forced expression of exogenous transcription factors by randomly integrating plasmids or viral vectors seriously hamper the implementation of iPSCs in regenerative and anti-aging medicine. This is additionally augmented by oncogenicity of Klf4 and c-Myc. Concerns of genome stability and safety stimulated the search of alternative nonintegrative reprogramming approaches (Heng and Fussenegger, 2014). Among the tested approaches are those based on cell membrane permeable proteins of the transcription factors, mRNAs, miRNAs, activation of transcription factors by CRISPR (Weltner et al., 2018), and small molecules (Hou et al., 2013; Qin et al., 2017). Cells generated by these methods usually exhibited the majority of pluripotency markers and were able to differentiate into the three germ layers. Along with direct inducers of pluripotency, a great number of compounds, especially small molecules (see the next section), can enhance reprogramming efficiency and quality of iPSCs. Genome-wide analyses of the promoter binding and expression showed that target genes of transcription factors in iPSCs and ESCs significantly overlap (Sridharan et al., 2009). Yet, expression profile, epigenetics and differentiation potential of iPSCs depended on the method of reprogramming, cell passage number, culturing conditions, genetic background, laboratory, etc. Churko et al. (2017) compared various lines of human iPSCs, generated from the same primary line of fibroblasts under standardized cell culturing conditions and passage number, by six reprogramming methods (mRNA, miRNA, minicircle vectors, episomal vectors, lentivirus and Sendai virus). Though all iPSC lines could terminally differentiate, reprogramming method impacted transcriptome profile and similarity between the iPSCs and ESCs (Churko et al., 2017). Currently, iPSCs have been generated from somatic cells of several dozens of mammalian species (Temkin and Spyropoulos, 2014; Lee et al., 2018) as well as several non-mammalian and even invertebrate species (Rosselló et al., 2013). Comparative analysis of iPSCs characteristics and their correlation with species-specific maximum life span could be an intriguing issue. In particular, it could be important for assessing the role of this powerful rejuvenating machinery in species longevity and in search of tools for life span extension. In addition, such an analysis will surely widen our knowledge and areas of iPSC application, including veterinary and farming animal industry.

Pluripotency Induced by Small Molecules Among the non-viral and non-integrative protocols, induction of pluripotency by small molecules (SMs, molecular weight < 900 Da) seems the most attractive, especially in terms of putative in vivo application. First, the low molecular-weight of SMs usually ensures rapid diffusion across cell membranes and oral bioavailability. Second, many SMs are natural metabolites or have a structure close to

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them, thus ensuring minimum adverse or side effects. Third, induction of pluripotency is a complex multistage process and should be not only properly activated but also timely inactivated to avoid malignancy and teratoma. That is, the reliability of the dose- and timedependency control is a critical issue. From this point of view, SMs have obvious advantages. Their proliferation-activating effects could be fine-tuned by varying the concentrations of SMs, while application of lineage-specific SMs could induce differentiation and inhibit cell proliferation. Moreover, SMs are distinguished by non-immunogenicity, cost-efficiency, minimal residual effects on the genome, and feasibility of in vivo application (Xie et al., 2017; Huang et al., 2018). SMs with pluripotency potential represent a growing family of substances some of which are well-known drugs (Xie et al., 2017; Baranek et al., 2017). For example, valproic acid, a drug included in the World Health Organization’s List of Essential Medicines and recommended for treatment of epilepsy (Leeman and Cole, 2008), is recognized as the most efficient low-molecular inducer of pluripotency. In human cell cultures, valproic acid and its derivatives rapidly inhibit histone deacetylase allosterically, without affecting the histone deacetylase protein levels (Eikel et al., 2006). SMs can replace exogenous transcription factors or significantly enhance reprogramming efficiency and quality of generated iPSCs, acting alone or in combination with transcription factors delivered by integrative or non-integrative technics. For example, Oct4 was once presumed to be an indispensable upper gene and “master switch” of pluripotency. However, screening of over 10,000 SMs revealed that Oct4 could be substituted by forskolin, 2-methyl-5hydroxytryptamine (Hou et al., 2013) or bromodeoxyuridine (Long et al., 2015). iPSCs generated completely by SMs, without exogenous transcription factors, known as chemically-induced pluripotent stem cells (ciPSCs), were first obtained in 2013 from mouse fibroblasts at a high frequency of up to 0.2%, using a combination of seven SMs (valproic acid, CHIR99021, RepSox, forskolin, parnate, TTNPB and DZnep) (Hou et al., 2013). Such ciPSCs highly resembled ESCs in gene expression profiles, epigenetic status, potential for differentiation, and germline transmission. Moreover, newborn and adult chimeric mice generated by injection of ciPSCs into blastocysts showed considerably better survival than analogous mice generated by delivery of OSKM transcription factors (Hou et al., 2013). ciPSCs could also be generated by cocktails consisting of fewer SMs, e.g., bromodeoxyuridine, CHIR99021, RepSox and forskolin (Long et al., 2015). It is important that SMs are efficient not only in generation of iPSCs but also in transdifferentiation, partial dedifferentiation (Qin et al., 2017; Xie et al., 2017) or redifferentiation of pluripotent cells into various types of somatic cells (Anwar et al., 2016). Moreover, SMs can be useful for apoptotic elimination of unwanted cells, which remain after cell transplantation and could become a source of tumors or teratomas. Practically limitless number of small molecular cocktails represents unique advantages in diversity of specific effects on cellular differentiation, dedifferentiation and aging. SMs determine cell fate primarily by modification of signaling pathways, metabolic processes and epigenetics (Long et al., 2015; Anwar et al., 2016). Epigenetic modifiers are commonly included in cocktails for generation of iPSCs, because histone acetylation and DNA demethylation of the pluripotency transcription factor genes are key events in their reactivation. No surprise that SMs often are inhibitors of histone deacetylases or DNA methyltranspherases. Remarkably, some cocktails of SMs induced pluripotency without activation of the key transcription factors. For example, valproic acid, CHIR99021, 616,452, tranylcypromine and forskolin generated iPSCs without signs of expression of endogenous Oct4 and Nanog which promoters remained overmethylated (Hou et al., 2013). All in all, SMs with pluripotency potential are highly promising biomedical agents because of numerous advantages as inducers or enhancers of pluripotency, and as such, represent valuable means for manipulation of cell fate by differentiation, transdifferentiation, dedifferentiation, apoptosis, etc. The impressive scope of SM effects on cell fate determination could have deep evolutionary roots. We hypothesize that SMs might be representatives of the elite group of metabolites once selected in prokaryotes to perform regulatory functions. Prototypes of SMs could emerge at the very beginning of cellularity origin. In early prokaryotes with limited genome size, periodical switching from cell growth to replication and rejuvenation was apparently regulated by metabolites resembling SMs (valproic acid, butyrate, derivatives of nucleotides, etc.), whereas the network of transcription factors emerged apparently later in eukaryotes with genome size large enough for such genetic constructions. In support of suggested coevolution and biological value of two systems, chemical and genetic, is that combination of SMs and transcription factors often substantially increases efficiency of iPSCs generation. Whatever the origin of these two systems would be, they might coexist and cooperate with each other. Even moderate achievements in realization of the powerful rejuvenating potential of induced pluripotency or direct reprogramming in vitro and especially in vivo could have tremendous and far-lasting consequences (Sogabe et al., 2018). As an example, automatically beating cardiomyocyte-like cells were generated by direct reprogramming of mouse fibroblasts by a cocktail of small molecules (valproic acid, CHIR99021, RepSox, forskolin, parnate, TTNPB and DZnep). The generated cells expressed sarcomeric organization, cardiomyocyte-specific markers and electrophysiological features. Genetic analysis showed that they passed cardiac progenitor stage instead of pluripotency, thus supporting possibility of in vivo cardiac transdifferentiation by small molecules (Huang et al., 2018). Another example includes oral administration of sodium valproate (150 mg/kg, twice daily for 7 days), which significantly increased markers of pluripotency (expression of endogenous Oct4, Nanog, Klf4) and markers of neuronal stem cells (Sox1 and Pax6) in the brain of C57BL/6 mice (Asadi et al., 2015). Thorough study of SMs is important for (but not limited to) generation of iPSCs for cell transplantation, disease modeling or drug discovery. Most importantly, SMs have good chances to be developed into clinical-grade drugs suitable for in vivo recovery and rejuvenation.

Bridging Pluripotency, Aging, Longevity, and Cellular Rejuvenation In contrast to somatic cells, ESCs and iPSCs can divide infinitely without signs of replicative senescence (Takahashi and Yamanaka, 2006). However, differentiated progeny of ESCs and iPSCs recovered the features of limited replication, thus indicating that pluripotent cells are not immortalized per se (Lapasset et al., 2011). Nevertheless, changes occurring during reprogramming are typical for

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cellular rejuvenation. Indeed, pluripotency-provoked modifications resulted in a number of characteristic events including (i) enhanced DNA repair, elevated genetic integrity and resistance to mutagenesis (Suhr et al., 2010; Cooper et al., 2017); (ii) telomere elongation due to higher telomerase activity and alternative lengthening of telomeres (Huang et al., 2014; Liu, 2017); (iii) rearrangements of mitochondrial network accompanied by reduced free radical production (Folmes et al., 2011; Mathieu and Ruohola-Baker, 2017), etc. For example, iPSC-derived motoneurons lose aging hallmarks and “memory” of the old donor cells, thus succeeding to reset cellular senescence and aging. In contrast, the motoneurons directly reprogrammed from fibroblasts of old donors preserved a higher activity of the cellular senescence marker SA-b-galactosidase, DNA damage, telomere attrition, loss of heterochromatin, and defects of nuclear organization (Tang et al., 2017). The iPSCs-derived differentiated cells often appear too “young” to be used for cell replacement therapy (Ronaldson-Bouchard et al., 2018). In fact, the fetal-like nature of iPSCs progeny is not always a real advantage, and iPSCs-derived cells need preliminary functional maturity (e.g., by long-term culturing) before transplantation. Thus, stem cell-based therapy faces new challenges in controlling cellular maturity and age (Cornacchia and Studer, 2017). Anyway, it proves that biological time could be reversibledan old cell could be rejuvenated and aged again to a preset degree, if necessary. Aging and cellular senescence are considered unfavorable factors for quantity and quality of iPSCs (Banito et al., 2009; Phanthong et al., 2013). Nevertheless, their negative effects have often been neutralized by relatively simple modifications of the pluripotency protocols. For example, combination of transcription factors from the Yamanaka and Thompson cocktails (OSKMNL) was sufficient to produce completely rejuvenated iPSCs from fibroblasts of centenarians or senescent cells of elderly patients. Such iPSCs were indistinguishable from ESCs and could redifferentiate into fully rejuvenated cells (Lapasset et al., 2011). Trokovic et al. (2015) reported that reprogramming efficacy of fibroblasts derived from 0 to 83-year-old subjects correlated negatively with donors’ age or duration of in vitro culturing of iPSCs. This was apparently associated with upregulation of p21 because its knockdown restored iPSCs generation even in the long-term cultures derived from old donors (Trokovic et al., 2015). Remarkably, iPSCs were generated even from postmortem fibroblasts of exceptionally old patients (up to 109 years old) by the conventional OSKM cocktail and were further successfully differentiated into neuronal cells (Yagi et al., 2012). In mice, iPSCs derived from bone marrow myeloid cells of 2-month-old and 18-month-old animals and redifferentiated into cardiac tissue revealed comparable reprogramming characteristics (Cheng et al., 2017). Although iPSCs generated from musclederived fibroblasts of 14 months old mice showed declined Nanog expression, lower proliferative activity and reprogramming compared with 6 weeks or 6 months old counterparts, the age-related decline of Nanog expression and iPSCs self-renewal were restored by inhibition of the tumor growth factor (TGF-b) and bone morphogenetic protein signaling pathways. Cellular reprogramming induced by short-term cyclic expression of OSKM transcription factors has shown promising results not only in cell cultures, but also in in vivo models. In particular, it improved markers of cellular and physiological aging and extended life span of short-lived mice (Ocampo et al., 2016). Thus, although aging in vivo and in vitro decreases efficacy of iPSCs generation, most effects of aging could be reverted by relatively simple interventions. Pluripotent cells generated from somatic cells of old patients do not exhibit declined differentiation potential, neither does donor’s age limit iPSCs generation; also, iPSCs progeny does not accelerate cellular senescence in culture (Strassler et al., 2018). Further complicating the relationships between induced pluripotency and cellular senescence is the observation that OSKM-driven reprogramming in vivo was accompanied by accumulation of senescent cells. Moreover, senescent cells promoted generation of iPSCs by releasing IL-6 (Mosteiro et al., 2016, 2018), an age-related increase of which in the blood is one of the markers of human aging (Justice et al., 2018). It is well-known that stability of biological systems is supported by constant fluctuation of virtually all biological variables around certain optimal values. However, consequences of such deviations from a quasi-stable state could often be unpredictable. Many efficient small molecular inducers/enhancers of pluripotency (e.g., the short-chain fatty acidsdvalproic acid and butyrate, derivatives of nucleotides, vitamins, antioxidants, etc.) are natural metabolites. Then, occasional fluctuations of SMs’ concentrations might reach critical levels that could be enough to induce pluripotency. In other words, there is a probability (though small but not infinitesimal) that induction of pluripotency could occur in vivo due to spontaneous or directional metabolic alterations. Considering possible evolutionary roots of SMs origin (see previous section), such situations could be orchestrated by specific genetic programs to replenish exhausted pool of stem cells in later periods of ontogenesis. Even if our hypothesis is not correct and such systems of induced pluripotency do not exist in nature, it is worth to do our utmost for accomplishing the task artificially. Indeed, it is attractive to speculate that anti-aging effects of SMs are primarily realized through pluripotency induction. This notion is further supported by the facts that many SMs are efficient in life span extension (Chen et al., 2011; our unpublished data). Yet, such pleiotropic effects of SMs could also be realized through other regulatory and metabolic pathways. For example, valproic acid and butyrate could downregulate the p16/p21 pathway and thereby suppress cellular senescence (Chen et al., 2016), which is one of the causal factors of aging and age-related diseases (López-Otín et al., 2013; Yanai and Fraifeld, 2018). Of note, several SMs (e.g., quercetin and fisetin) are known senolytics, that is, they not only suppress cellular senescence but are also able to eliminate senescent cells from tissues. The role of SMs in cell renewal/rejuvenation and the control of life span may underpin the existence of cause-and-effect relations between pluripotency, senescence and longevity. This could especially be relevant in species with extreme longevity. Periodical rejuvenation of stem cell pools by SMs might be a key explanation why some species live much longer than other kin species. Unfortunately, we know too little about possible role of SMs in extreme longevity. Mitochondria and energy metabolism could be another important point linking pluripotency and longevity. As we have previously shown, metabolic rate and stability of mitochondrial DNA (mtDNA) are among major determinants of mammalian longevity (Lehmann et al., 2008; Lehmann et al., 2013). Maximum life span correlates negatively with resting metabolic rate and positively

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with mtDNA stability (Lehmann et al., 2008; Toren et al., 2016). Cellular metabolism controls gene expression and chromatin reorganization during reprogramming, thus underpinning key role of energy supply in modulation of regenerative capacity of stem cells. Therefore, interventions that modify metabolism of pluripotent cells are often fateful for their epigenetic configuration and differentiation (Zhang et al., 2017). Eukaryotic cells generate energy by dynamic contribution of oxidative phosphorylation and glycolysis. Switching between the two pathways depends on the environment, type of cellular differentiation, functional loading, etc. (Mathieu and RuoholaBaker, 2017). Pluripotent stem cells support their unlimited replicative capacity and genome integrity by combining enhanced repair with low levels of damaging factors. One of the efficient ways to reduce a potential damage is activation of glycolysis and suppression of mitogenesis, with a subsequent decrease in generation of reactive oxygen species. ESCs and iPSCs show similar mitochondrial biogenesis and oxidative stress defense (Frolkic and Muradian, 1991; Armstrong et al., 2010). They rely heavily on anaerobic glycolysis rather than on oxidative phosphorylation, presumably because glycolysis is evolutionarily earlier, faster and safer channel of energy supply (Suhr et al., 2010; Liu, 2017; Vazquez-Martin et al., 2012; Xu et al., 2013). Mitochondria in iPSCs and ESCs have preferentially perinuclear localization, swollen cristae and lower fusion into filamentous structures than in differentiated cells (Suhr et al., 2010; Folmes et al., 2011; Hsu et al., 2016). Compared with their parental somatic cells, iPSCs and ESCs are characterized by depolarized mitochondria with higher levels of uncoupling protein 2, lower rates of oxygen consumption, decreased levels of ATP and reactive oxygen species, and a decreased copy number of mtDNA. Opposite changes in mitochondrial biogenesis and oxidative phosphorylation are observed during cellular differentiation and in terminally differentiated cells (Chen et al., 2011; Zhang et al., 2017; Xu et al., 2013; Varum et al., 2011; Prieto et al., 2016). Reprogramming is accompanied by down-regulation of complex I subunit of the electron transport chain and upregulation of glycolytic enzyme expression and activity, thus promoting elevated glucose utilization and accumulation of lactate and other glycolytic end-products. Proteome analysis of reprogramming revealed protein modifications indicative of upregulated glycolysis (Folmes et al., 2011; Varum et al., 2011). ESCs showed almost 90% metabolite similarly with fully reprogrammed iPSCs and only 74% similarity with partially reprogrammed iPSCs, meaning that a continuous replacement of mitochondrial respiration by glycolysis is a critical issue for full reprogramming (Park et al., 2017). As it could be expected, inhibition of glycolytic enzymes decreases reprogramming efficiency whereas their activation has an opposite effect. Hypoxia (Yoshida et al., 2009), antioxidants (e.g., ascorbic acid (Esteban et al., 2010)), lactate or overexpression of lactic acid transporters (Liu et al., 2013)dall enhanced iPSCs generation. Switching from oxidative phosphorylation to glycolysis was typical not only for the mouse or human fibroblasts reprogrammed by using viral vectors and transcription factors but also for iPSCs reprogrammed from fibroblasts in fully chemically defined conditions by application of SMs (Li et al., 2018). Cyclic fission and fusion of mitochondria are important for their proper function and quality control. Induced pluripotency was associated with activation of mitochondrial fission and degradation, while inhibition of these processes hampered reprogramming (Vazquez-Martin et al., 2012; Prieto et al., 2016). Overall, the fibroblasts redifferentiated from the fibroblast-derived iPSCs showed dramatic improvements of mitochondria compared with mitochondria of the input cells (Suhr et al., 2010). This suggests that induced pluripotency could rejuvenate not only cellular replicative capacity but also mitochondria. Remarkably, reprogramming increased the number of mtDNA copies or its fragments in the nucleus. It could be important in view of suggested recovering of persistent mtDNA mutations through its hybridization with the better-preserved nuclear copies of mtDNA, known as NUMTs. In line with this notion, we found a highly significant positive correlation between the number or abundance of NUMTs and maximum life span in mammals (Muradian et al., 2010). It seems that the increased number of mtDNA sequences in the nucleus of reprogramming cells, along with pre-existing NUMTs, could be essential for rejuvenation of mtDNA in pluripotent cells.

Pluripotency Hub as a Lighthouse for Reversibility of Cellular Aging ESCs and iPSCs share unique similarity. ESCs are immortal pluripotent cells derived from the inner cells mass of blastocysts whereas iPSCs are practically the same kind immortal pluripotent cells generated directly from somatic cells. Similarity of ESCs and iPSCs could hardly be coincidental. Pluripotency is apparently a singular cellular hub. Suffice it to mention that all highways of differentiation emanate from this hub while dedifferentiation routes converge to it. Immortal and undifferentiated cell lines, resembling pluripotent-like state, should evolutionarily exist prior to appearance of complicated metabolic and epigenetic landscapes of differentiation. Therefore, pluripotency had higher chances of capturing thermodynamically advantageous landscapes compared with differentiated cells. Thermodynamically advantageous configuration means that a system can enter into such state spontaneously, without energy expenditure. Consequently, spontaneous transitions of differentiated cells would direct a cell towards the state of pluripotency. The idea is supported by the fact that spontaneous transformation of terminally differentiated cells into immortal cancer cell lines occurs with much higher probability than conversion of cancerous cells back to the differentiated state. Indeed, it is well known that transformation of various types of differentiated cells into immortal cancer cells is the death cause of significant part of human and animal populations whereas sporadic cases in the opposite direction are usually perceived as “miraculous healing.” The preferential thermodynamics of pluripotency also supports the idea of how cells, irrespective to their source and methods of pluripotency induction, get the way back to the point of their origin. It is noteworthy that all cells of a multicellular organism originate from partially differentiated somatic (adult) stem cells (i.e., multipotent or progenitor cells) with no direct experience of pluripotency. Yet, iPSCs generated from them find faultlessly a way back to the formerly unknown destination. Benefits of the pluripotency hub might explain how and why a terminally differentiated cell endeavors to reach it, thus “striving” to be young and immortal rather than be infected by the time-associated damages and sentenced to death. Whatever it may be, the

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important point is that iPSCs are individually specific and ethically acceptable source of pluripotent cells derived from differentiated cells of various type and donor age, centenarians included (Lapasset et al., 2011; Trokovic et al., 2015; Lo Sardo et al., 2017). Despite the host of difficulties and still unsolved problems, the amazing capacity of induced pluripotency to convert a terminally differentiated cell of elderly into practically unlimited number of rejuvenated autologous cells or fertile gametes opens unprecedented perspectives in regenerative, reproductive, and anti-aging medicine (López-León and Goya, 2017; Rando, 2006; Rando and Chang, 2012; Abramovich et al., 2008; Pareja-Galeano et al., 2016; Mendelsohn et al., 2017). This also confers definite priority of iPSCs in cell-based therapy, disease modeling, and drug screening.

Concluding Remarks Aging is commonly assumed as an irreversible process of gradual accumulation of destructive changes at all levels of biological organization. Consequently, it seems impossible to confront such ubiquitous, diverse and massive changes. Therefore, it is generally believed that aging could be slowed-down or retarded but not stopped or reversed. The discovery of cellular reprogramming and generation of iPSCs from differentiated cells of any type and age, including senescent and centenarians’ cells, was a revolutionary breakthrough allowing to reconsider the conventional tools and strategies of anti-aging. Rejuvenation of somatic cells back to the ESC-like state assumes that aging-associated cellular changes, unless they have not transgressed the point of “nonreturning,” are reversible. In other words, unlike the unidirectionally flowing physical time, biological time could be reversible by its essence. Quite unexpectedly, cell rejuvenation can be achieved by relatively simple epigenetic interventions, implying that cells of multicellular organisms are obviously capable of neutralizing nearly all age-associated damages by themselves. It seems that a somatic cell just needs an appropriate signaling (e.g., overexpression of the defined transcription factors or a cocktail of small molecules) to initiate reprogramming back to ESC-like rejuvenated state. Unfortunately, this powerful anti-aging machinery is not properly addressed yet. The impressive number of small molecules and other drugs with specific differentiation and dedifferentiation effects make the purposeful epigenetic modifications highly promising research direction. Indeed, advances in reprogramming technology shed a light on how epigenetic aberrations in aging and age-associated pathology, cancer included, could be neutralized (Skamagki et al., 2017), thus blurring the connotation whether induced pluripotency is a treatment or threat for cancer development. An efficient anti-aging strategy should preferentially be focused on usage of the actually limitless rejuvenation potential of a cell. However, combination of this approach with conventional preventive interventions seems the most rational solution. It is remarkable that in all studied types of somatic cells or rejuvenation protocols, the genome reprogramming has led to the same end-pointdpluripotency. We suggest that this end-point corresponds to the basic (primordial) and thermodynamically more stable epigenetic configuration, the pathway to which, at least partly, has been found spontaneously. It is worth stressing again that cell rejuvenation by induced pluripotency is not associated with creation of extraordinarily complex artificial constructions but could often be achieved by application of small molecules. This apparent simplicity is, however, coupled to potentially dangerous consequences as induction of pluripotency, as such, makes the cells prone to unpredictable genetic and epigenetic aberrations (Grafi, 2013). That is why pluripotent stem cells should be frequently monitored. Although tremendous scales of further research are necessary to develop the safe and efficient in vivo protocols for controlled dedifferentiation-redifferentiation, overcoming such obstacles seems a more feasible way to rejuvenation than it has long been thought. Existence of the inner machinery and striving of a cell to rejuvenate at appropriate conditions is a powerful anti-aging factor, proving huge potentials in the field. Thus, despite numerous unanswered questions and huge technical and legal roadblocks, we are on the verge of new exciting discoveries in understanding why nature created obligatory mortal multicellulars from immortal elements (cells), and if it is possible to bypass the existing hurdles and limitations.

Acknowledgments This work was supported by the Fund in Memory of Dr. Amir Abramovich. We appreciate the assistance of Mrs. Anna Knyazer (Ben-Gurion University of the Negev) in preparation of the manuscript. We would like to apologize to those whose work we did not cite because of huge number of publications in the field.

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Ischemic Heart Disease in Older Adults FM Trotta, Geriatria, Accettazione geriatrica e Centro di ricerca per l’invecchiamento. IRCCS INRCA, Ancona, Italy D Caraceni and R Antonicelli, Cardiologia, IRCCS INRCA, Ancona, Italy A Cherubini, Geriatria, Accettazione geriatrica e Centro di ricerca per l’invecchiamento. IRCCS INRCA, Ancona, Italy © 2020 Elsevier Inc. All rights reserved.

Introduction Epidemiology Pathophysiology Clinical Presentation, Diagnosis, Assessment SCAD Step 1 Step 2 MI Treatment SCAD Lifestyle modification and risk factor control Pharmacological management of SCAD patients NSTE-ACS (NSTEMI/UA) Pharmacological treatment of ischemia Invasive coronary angiography and revascularization STEMI Pharmacological treatment of ischemia Reperfusion therapy Medical therapy for secondary prevention (ACS and UA) Cardiac rehabilitation Geriatric Conditions in Older Patients With Acute Coronary Syndromes References Further Reading

300 301 301 302 303 303 303 304 305 305 305 306 307 307 308 308 308 309 309 309 309 310 311

Nomenclature ACS Acute coronary syndrome CMR Cardiac magnetic resonance CTA Computer tomography angiography CR Cardiac rehabilitation DAPT Dual antiplatelet therapy DES Drug-eluting stent ECG Electrocardiogram ICA Invasive coronary angiography IHD Ischemic heart disease INOCA Ischemia and no obstructive coronary artery disease LBBB Left bundle branch block LVEF Left ventricular ejection fraction MI Myocardial infarction MINOCA Myocardial infarction with no obstructive coronary artery disease MPI Myocardial perfusion imaging NSTE-ACS Non-ST-segment elevation acute coronary syndrome PCI Percutaneous coronary intervention PTP Pre-test probabilities PUFA Polyunsaturated fatty acids PVD Peripheral vascular disease SCAD Stable coronary heart disease SPECT Single photon emission computed tomography

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STEMI ST-segment elevation myocardial infarction UA Unstable angina

Introduction Ischemic heart disease (IHD) is a condition related to coronary artery disease (obstructive atherosclerosis, inflammation, endothelial dysfunction, microvascular dysfunction, platelet dysfunction, thrombosis, and vasomotor dysfunction). This term includes a group of heart diseases characterized by the reduction of oxygen supply to the heart muscle following the narrowing or obstruction of the coronary arteries. The main clinical forms of ischemic heart disease are: acute, that is, myocardial infarction and unstable angina, and chronic, that is, stable coronary heart disease. Myocardial infarction (MI) defines cardiomyocyte necrosis in a clinical setting consistent with acute myocardial ischemia. The following criteria are required to meet the diagnosis of acute MI: an increase and/or decrease of a cardiac biomarker, preferably highsensitivity cardiac troponin, with at least one value above the 99th percentile of the upper reference limit and at least one of the following: – – – – –

symptoms of ischemia, new or presumably new significant ST-segment–T wave (ST–T), changes or new left bundle branch block (LBBB), development of pathological Q waves in the ECG, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, identification of an intracoronary thrombus by angiography or autopsy. (Ibanez et al., 2017; Thygesen et al., 2012; Roffi et al., 2016).

The ESC/ACCF/AHA/WHF joint task force classifies the acute MI according to the cause (Roffi et al., 2016) (Table 1). Moreover, based on the electrocardiogram (ECG), two groups of patients should be differentiated: patients with acute chest pain and persistent (> 20 min) ST-segment elevation in at least two contiguous leads (STEMI); patients with acute chest pain but no persistent ST-segment elevation (transient ST-segment elevation, persistent or transient ST-segment depression, T-wave inversion, flat T waves or pseudo-normalization of T waves) or the ECG may be normal (NSTEMI) (Ibanez et al., 2017; Roffi et al., 2016). Unstable angina (UA) is defined as myocardial ischemia at rest or after minimal exertion in the absence of cardiomyocyte necrosis (Roffi et al., 2016). UA is characterized by angina pectoris (or an equivalent type of ischemic discomfort) with at least one of three features: – occurring at rest (or minimal exertion) and usually lasting > 20 min (if not interrupted by the administration of a nitrate or an analgesic); – being severe and usually described as frank pain; – occurring with a crescendo pattern. Unstable angina is also considered an acute coronary syndrome (ACS), because it is an imminent precursor to myocardial infarction. Unstable angina has a similar pathophysiology to NSTEMI, and they are together referred to as non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Stable Coronary Heart Disease (SCAD) is generally characterized by episodes of reversible myocardial demand/supply mismatch, related to ischemia or hypoxia, which are usually inducible by exercise, emotion or other stress and reproducible but, which may also be occurring spontaneously (Montalescot et al., 2013) and refers to patients who have no recent acute changes in their symptomatic status. These are patients with recent-onset or stable angina or ischemic equivalent symptoms, such as dyspnea or arm pain with exertion; post-ACS stabilized after revascularization or medical therapy; and asymptomatic stable ischemic heart disease diagnosed by abnormal stress tests or imaging studies (DAI et al., 2016).

Table 1 Type 1 Type 2 Type 3 Type 4a Type 4b Type 5

Myocardial infarction classification according to the cause (Roffi et al., 2016) MI consequent to coronary arterial pathologic conditions (e.g., plaque erosion/rupture, fissuring, or dissection), resulting in intraluminal thrombus MI consequent to increased oxygen demand or decreased supply (e.g., coronary endothelial dysfunction, coronary artery spasm, coronary artery embolus, anemia, tachyarrhythmias/bradyarrhythmias, anemia, respiratory failure, hypertension, or hypotension) Sudden unexpected cardiac death before blood samples for biomarkers could be drawn or before their appearance in the blood MI related to PCI MI related to stent thrombosis MI related to CABG

MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; CABG ¼ coronary artery bypass graft.

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Epidemiology Age is a strong independent risk factor for the development of coronary artery disease. IHD is a leading cause of morbidity and mortality in older adults: it is the most common cause of death in Europe, even if there has been an overall trend for a reduction in ischemic heart disease mortality over the past three decades. It accounts for 20% of all deaths, of which > 80% occurs in the older persons (over 65 years of age) and > 60% in people over 75 years, without significant differences between male and female (Townsend et al., 2016). The average annual rate of first cardiovascular event rises from 3 per 1000 men at 35–44 years of age to 74 per 1000 men at 85–94 years of age. For women, comparable rates occur 10 years later in life (Mozaffarian et al., 2015). As SCAD is multifaceted, its prevalence and incidence have been difficult to assess and numbers vary between studies, depending on the definition that has been used (Montalescot et al., 2013). The prevalence of angina in population-based studies increases with age in both sexes, from 5% to 7% in women aged 45– 64 years to 10%–12% in women aged 65–84 and from 4% to 7% in men aged 45–64 years to 12%–14% in men aged 65–84 (in the older adults, SCAD has equal prevalence in men and women). In the coming decades, increase of the prevalence of SCAD in the older adults is projected because the world’s population is aging, with those aged 80 and older expanding most rapidly. Furthermore, the acute myocardial infarction survival rate has improved dramatically under current ACS care, so large numbers of MI patients become SCAD patients; the increased use of diagnostic modalities adds significantly to the number diagnosed with SCAD (DAI et al., 2016). Acute myocardial infarction is the most severe manifestation of coronary artery disease, which causes > 2.4 million deaths in the United States and > 4 million deaths in Europe. Although ischemic heart disease develops on average 7–10 years later in women compared with men, MI remains a leading cause of death in women. ACS occurs three to four times more often in men than in women below the age of 60 years, but after the age of 75, women represent the majority of patients (The EUGenMed and Cardiovascular Clinical Study Group, 2016). Since the mid-1990s there has been a steady decline in the proportion of patients with STsegment elevation myocardial infarction (STEMI), and a smaller increase in non-STEMI (NSTEMI), leading to an overall decline in myocardial infarction. NSTEMI comprises 60%–75% of all myocardial infarction. In the European countries, the incidence rate of ACS STEMI ranged from 43 to 144 per 100,000 per year. There is a consistent pattern for STEMI to be relatively more common in younger than in older people, and more common in men than in women. The mortality in STEMI patients is influenced by many factors, for example, advanced age, Killip class, time delay to treatment. Nevertheless, mortality remains substantial; the in-hospital mortality of unselected patients with STEMI in the national registries of the ESC countries varies between 4% and 12%, while reported 1-year mortality among STEMI patients in angiography registries is approximately 10% (Ibanez et al., 2017). NSTEMI patients appear to have lower short-term mortality compared with STEMI individuals, while at 1- or 2-years follow-up the mortality rates become comparable, likely due to differences in baseline characteristics, including older age and a greater prevalence of co-morbidities in the NSTEMI population (Roffi et al., 2016).

Pathophysiology Myocardial ischemia may result from pathophysiological processes affecting the epicardial conduit artery, the microvasculature or both. Necropsy studies demonstrated a high prevalence ( 60%) of obstructive IHD in patients  80 years of age, often with features of advanced disease (e.g., calcification [80%–90%], multivessel disease [ 40%], and tortuosity) (Roffi et al., 2016). Epidemiological studies have underscored the contribution of lifestyle factors in the development of atherosclerosis and myocardial infarction. Hypertension (specifically, elevate systolic pressure and fall in diastolic pressure due to aorta stiffens is typical of aging (Paneni et al., 2017)), dyslipidemia, diabetes, renal dysfunction, and history of cigarette smoking are all established risk factors for CAD and they are frequent in patients of advanced age. Whether obesity is a risk factor for IHD in younger subjects, in older patients its role is uncertain and some studies suggesting lower risk in more obese patients (“obesity paradox”) (Madhavan et al., 2018). Independent of the presence of co-morbidities and risk factors, aging is directly associated to changes that contribute to the higher cardiovascular risk respect younger people. Signaling factors can contribute to both age-related macrovascular and microvascular remodeling, resulting in myocardial dysfunction and ischemia in older patients. Studies assessed alterations in the following areas: extracellular matrix (increased collagen and decreased elastin which involves a reduction in vascular wall); pro-inflammatory state (senescent immune cells release a disproportional amounts pro-inflammatory cytokines leading to an exaggerated immune response that can contribute to alter the hemostatic equilibrium affecting fibrinolysis); coagulation and hemostatic system (increase in procoagulation factors); endothelial dysfunction (reduction of vasodilatory and antithrombotic properties, with increase in oxidative stress and inflammatory cytokines favoring atherogenesis and thrombosis); impaired cardiac metabolism and regenerative capacity (mitochondrial dysfunction due to a decrease in ATP production and reduced turnover rate of cardiomyocytes compared to younger heart); lipid metabolism (decrease in the atheroprotective properties of high-density lipoprotein, HDL) (Badimon et al., 2016). These changes promote impaired vasodilatory mechanics, diminished ability of vessels to respond appropriately to injury, and intimal thickening, all of which predispose to CAD (Madhavan et al., 2018). Furthermore, the presence of such age-related changes in other organ systems may influence prognosis and cardiovascular treatments. Less frequently, myocardial ischemia may occur in the absence of coronary obstruction: in this case the following terns are used ischemia and no obstructive coronary artery disease (INOCA) and myocardial infarction with no obstructive coronary artery disease

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(MINOCA). There are different etiologies causing MINOCA: epicardial coronary artery disorders (e.g., atherosclerotic plaque rupture, ulceration, fissuring, erosion, or coronary dissection with non-obstructive or no CAD); imbalance between oxygen supply and demand (e.g., coronary artery spasm and coronary embolism); myocardial injury conditions (coronary endothelial dysfunction, myocardial disorders without involvement of the coronary arteries, i.e., myocarditis and Takotsubo cardiomyopathy) (Agewall et al., 2017). The main initiating mechanism of ACS is a plaque rupture or erosion with overlying thrombosis and platelet activation and aggregation onto the exposed thrombogenic surface supported by an acute inflammatory process (the initial stimulus to inflammation is unknown); activated platelets release inflammatory and mitogenic substances into the microenvironment, primarily altering the chemotactic, adhesive and proteolytic properties of the endothelium. The regulatory mechanisms of endothelial thromboresistance limit the extent and duration of platelet activation in response to vascular injury. Coronary atherothrombosis is a dynamic process, in which repeated episodes of thrombus formation and fragmentation occur over a disrupted plaque. Finally, focal or diffuse spasm of coronary arteries may cause ACS. In the STEMI the underlying lesions cause transmural infarcts in which myocardial necrosis involves the full thickness of the ventricular wall. Older patients are more likely to have myocardial ischemia and infarction due to increased myocardial oxygen demand or reduced blood flow (type 2 MI) compared with younger persons. Myocardial ischemia and hypoxia in SCAD are caused by a transient imbalance between blood supply and metabolic demand. Angina is ultimately caused by the release of ischemic metabolites that stimulate sensitive nerve endings, although angina may be absent even with severe ischemia owing, for instance, to impaired transmission of painful stimuli to the cortex. The various clinical presentations of SCAD are associated with different underlying mechanisms that mainly include: plaquerelated obstruction of epicardial arteries; focal or diffuse spasm of normal or plaque-diseased arteries; microvascular dysfunction and left ventricular dysfunction caused by prior acute myocardial necrosis and/or hibernation (ischemic cardiomyopathy) (Montalescot et al., 2013). At histology, the epicardial atherosclerotic lesions of SCAD patients, as compared with those of ACS patients, less commonly show an erosion or rupture of the endothelial lining; the lesions are typically fibrotic, poorly cellular, with small necrotic cores, thick fibrous caps and little or no overlying thrombus.

Clinical Presentation, Diagnosis, Assessment Angina is the typical symptom of ischemic heart disease. It is characterized by chest pain, near the sternum, often described as pressure, tightness or heaviness. However, it may be felt anywhere from the epigastrium to the lower jaw or teeth, between the shoulder blades or in either arm to the wrist and fingers. Less-specific symptoms (such as dyspnea, fatigue or faintness, nausea, burning, restlessness or a sense of impending doom) may accompanied it (Montalescot et al., 2013). An important characteristic is the relationship to exercise, specific activities or emotional stress: symptoms classically appear or become more severe with increased levels of exertion. The appearance or worsening of symptomatology after a heavy meal or after waking up in the morning is also a classical features of discomfort related to myocardial ischemia. Buccal or sublingual nitrates rapidly relieve angina (Montalescot et al., 2013). In patients with suspected angina, medical history and physical examination are important to assess the presence of anemia, hypertension, valvular heart disease, hypertrophic obstructive cardiomyopathy or arrhythmias and search for evidence of noncoronary vascular disease (Montalescot et al., 2013). More often, in older patients, clinical classification can be difficult because ischemic heart disease presents with nonspecific and vague symptoms (e.g., fatigue, dyspnea, nausea, vomiting, mid-epigastric/postprandial pain, or syncope) rather than classic angina pectoris. Moreover, in these subjects it may be difficult to collect the medical history due to hearing loss or cognitive impairment and the presence of ECG abnormalities at baseline limits the utility of ECG screening. Furthermore, in older people, a severe coronary artery disease, as well as other important pathological conditions such as peripheral obliterative arteriopathy or respiratory failure, may remain clinically silent for a long time if the functional performances are significantly reduced (e.g., in the presence of reduced mobility from disabling osteoarthritis or from advanced Parkinson’s disease) and the presence of multimorbidity which reduces the possibility of performing stress may mask awareness of SCAD (Madhavan et al., 2018; Fihn et al., 2012). In older patients, the diagnosis of type 2 myocardial infarction (due to evidence of a condition other than the underlying coronary disease that leads to an imbalance between myocardial oxygen supply and/or demand) or myocardial injury (increase in troponin with no argument for an ischemic phenomenon) are more common. Compared with subjects with type 1 myocardial infarction, people with type 2 myocardial infarction have more hypertension and cardiovascular comorbidities (coronary artery disease, chronic heart failure, chronic renal failure, stroke, peripheral arterial disease, anemia). Frequent causes of type 2 myocardial infarction in older patients are infection, anemia, respiratory failure, and arrhythmias. Older patients are highly heterogeneous. While some subjects are active and fully independent, many others suffer from multimorbidity, frailty with or without significant disability. Therefore, the diagnostic approach has first of all to consider the health status of the subject and the estimated life expectancy. In particular, the level of autonomy is the main indicator of health in older subjects. Therefore, while in independent or mildly disabled older subjects the diagnostic approach should not differ from that

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used in adults, in older patients with severe disability the approach should be carefully tailored and invasive testing should be minimized or avoided.

SCAD The Canadian Cardiovascular Society classification is widely used as a grading system for stable angina (Table 2). ESC guidelines (valid for all subjects) recommend a stepwise approach for decision making in patients with suspected SCAD. Step 1: Clinical assessment of the probability that SCAD is present. Step 2: Non-invasive testing to establish the diagnosis of SCAD or non-obstructive atherosclerosis (typically by performing carotid ultrasound) in patients with an intermediate probability of disease. Step 3: Starting optimal medical therapy and stratification for risk of subsequent events in order to select patients who may benefit from invasive investigation and revascularization. Depending on the severity of symptoms, early invasive coronary angiography may be performed bypassing non-invasive testing in Steps 2 and 3 (Montalescot et al., 2013).

Step 1 Before any testing, it is considered one must assess general health, comorbidities and quality of life (QoL) of the patient. If this assessment suggests that revascularization is unlikely to be an acceptable option, further testing may be reduced to a clinically indicated minimum and appropriate therapy should be instituted even if a diagnosis of SCAD has not been fully demonstrated (Montalescot et al., 2013). This patient specific approach, evaluating potential risks and benefits of invasive evaluation, is even more necessary in older patient (Montalescot et al., 2013). In all patient are recommended the following biochemical test: – full blood count including hemoglobin and white cell count; – creatinine measurement and estimation of renal function (creatinine clearance); – a fasting lipid profile. Other biochemical tests can be performed in specific cases: repeated measurements of troponin (preferably high sensitivity or ultrasensitive assays) to rule out myocardial necrosis if evaluation suggests clinical instability or acute coronary syndrome; screening for potential type 2 diabetes mellitus; BNP/NT-proBNP; assessment of thyroid function; liver function tests; creatine kinase measurement (in patients taking statins and complaining of symptoms suggestive of myopathy). In older people it would also be appropriate to evaluate the nutritional status for a better evaluation of the basal clinical conditions and to better inform the diagnostic and therapeutic decisions. Annual control of lipids, glucose metabolism and creatinine is recommended in all patients with known SCAD. The recommended instrumental tests are: a resting 12-lead ECG; ambulatory ECG monitoring if suspected arrhythmia or vasospastic angina; a resting transthoracic echocardiogram; chest X-ray. In older people, ECG abnormalities (Q waves, bundle branch or intraventricular block, left ventricular hypertrophy, ST-T-wave changes, and atrial fibrillation) are frequent and they limit the utility of ECG screening (Madhavan et al., 2018). It is therefore necessary, if possible, to compare the ECG with previous ECGs. The clinical pre-test probabilities (PTP) in patients with stable chest pain symptoms is calculated based on sex (men, women), age (divided by decades of age from 30 to over 80), and type of angina (typical, atypical, non-anginal pain) (Montalescot et al., 2013).

Step 2 – PTP < 15%: can be managed without further testing. People over 65 have PTP > 15% regardless of the type of angina and sex; therefore, according to these guidelines, all older people should perform a diagnostic investigation. However, in patients of advanced age, also based on lack of studies that provide specific Table 2 Class I Class II Class III Class IV

The Canadian Cardiovascular Society classification (Montalescot et al., 2013) Ordinary activity does not cause angina such as walking and climbing stairs. Angina with strenuous or rapid or prolonged exertion at work or recreation Slight limitation of ordinary activity. Angina on walking or climbing stairs rapidly, walking or stair climbing after meals, or in cold, wind or under emotional stress, or only during the first few hours after awakening. Walking more than two blocks on the level and climbing more than one flight of ordinary stairs at a normal pace and in normal conditions Marked limitation of ordinary physical activity. Angina on walking one to two blocks on the level of one flight of stairs in normal conditions and at a normal pace Inability to carry on any physical activity without discomfortdangina syndrome may be present at rest

One box ¼ equivalent to 100 m.

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recommendations (Fihn et al., 2012, 2014), a patient-specific approach, weighing the potential risks and benefits of invasive evaluation, is essential before recommending cardiac catheterization (Madhavan et al., 2018). – PTP 15%–65%: non-invasive testing for diagnostic purposes are recommended. (exercise ECG free of anti-ischemic drugs, if feasible as the initial test). However, if local expertise and availability permit a non-invasive imaging based test for ischemia this would be preferable given the superior diagnostic capabilities of such tests; – PTP 66%–85%, or if left ventricular ejection fraction (LVEF) is < 50% in patients without typical angina, or patients with resting ECG abnormalities which prevent accurate interpretation of ECG changes during stress: a non-invasive imaging functional test is indicated. Exercise stress testing (treadmill or bicycle ergometer) is recommended rather than pharmacologic testing whenever possible; pharmacological test is preferred when there is already a significant resting wall motion and/or, as in many older people, if the patient is unable to exercise adequately (the pharmacological agent of choice to produce supply-demand mismatch is dobutamine). Pharmacological stress echocardiography, single photon emission computed tomography (SPECT), and myocardial perfusion imaging (MPI) have been demonstrated to effectively risk stratify patients (Madhavan et al., 2018). Cardiac magnetic resonance (CMR) stress testing, in conjunction with a dobutamine infusion, can be used to detect wall motion abnormalities induced by ischemia coronary computer tomography angiography (CTA) should be considered as an alternative to stress imaging techniques for ruling out SCAD or after a no conclusive exercise ECG or stress imaging test or who have contraindications to stress testing in order to avoid otherwise necessary invasive coronary angiography if fully diagnostic image quality of coronary CTA can be expected. However, in the older patients, who often have difficulty holding their breath for the test and more often suffering from atrial fibrillation, renal failure, and dense coronary calcification, CTA is less suitable (Madhavan et al., 2018). – PTP > 85%: patients need risk stratification only, because it can be assumed that SCAD is present (Montalescot et al., 2013). Invasive coronary angiography (ICA) is indicated for establishing or excluding the diagnosis in special case (patients who cannot undergo stress imaging techniques, patients with a reduced LVEF < 50% and typical angina because they are at high risk for cardiovascular events, patients with special professions such as pilots, due to regulatory issues) and, following non-invasive risk stratification, for determination of options for revascularization. ICA should not be performed in patients with angina who refuse invasive procedures, prefer to avoid revascularization, who are not candidates for percutaneous coronary intervention or coronary artery bypass graft, or in whom revascularization is not expected to improve functional status or quality of life (Montalescot et al., 2013).

MI It is recommended to base diagnosis and initial short-term ischemic and bleeding risk stratification on a combination of clinical history, symptoms, vital signs, other physical findings, resting 12-lead ECG and laboratory results (Roffi et al., 2016). Clinical evaluation include vital sign, respiratory status, volume status, end-organ perfusion, and mental status (Madhavan et al., 2018). Anginal pain may have the following presentations: – prolonged (> 20 min) anginal pain at rest; – new onset (de novo) angina (class II or III of the Canadian Cardiovascular Society classification); – recent destabilization of previously stable angina with at least Canadian Cardiovascular Society Class III angina characteristics (crescendo angina); – post-MI angina (Roffi et al., 2016). Atypical symptoms (such as epigastric pain, indigestion-like symptoms, isolated dyspnea, palpitations, syncope) are more often observed in older subjects, in women and in patients with diabetes, chronic renal disease or dementia. It is recommended to obtain a resting 12-lead ECG within 10 min of the patient’s arrival in the emergency room or, ideally, at first contact with emergency medical services in the prehospital setting and to have it immediately interpreted by a qualified physician (Roffi et al., 2016). If the standard leads are inconclusive and the patient has signs or symptoms suggestive of ongoing myocardial ischemia, additional leads should be recorded (V7–V9 for suspected posterior MI; V3R and V4R in patients with inferior MI) (Ibanez et al., 2017). Comparison with previous tracings is valuable, particularly in patients with pre-existing ECG abnormalities. The finding of persistent ST elevation indicates STEMI, which mandates immediate reperfusion (Ibanez et al., 2017) and ECG monitoring with defibrillator capacity is indicated as soon as possible in all patients with suspected STEMI (Ibanez et al., 2017). Characteristic abnormalities in the NSTEMI include ST depression, transient ST elevation and T-wave changes, however, the ECG may be normal. Continuous rhythm monitoring is recommended until the diagnosis of NSTEMI is established or ruled out and, in patients with MI NSTEMI up to 24 h percutaneous coronary intervention (Roffi et al., 2016). ECG is of no help for the diagnosis of MI in patients with bundle branch block or paced rhythm. In the MI STEMI routine blood sampling for serum markers is indicated as soon as possible in the acute phase but should not delay reperfusion treatment (Ibanez et al., 2017). Measurement of a biomarker of cardiomyocyte injury, preferably high-sensitivity cardiac troponin, is mandatory in all patients with suspected MI. If the clinical presentation is compatible with myocardial ischemia, dynamic elevation of cardiac troponin above the 99th percentile of healthy individuals indicates MI (Roffi et al., 2016).

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Different conditions can affect the levels of troponin: aortic dissection, pulmonary embolism, renal dysfunction, or in the type 2 MI (such as infection, anemia, respiratory failure, and arrhythmias). Furthermore, studies show an age related increase of hs-cTnT levels in old and very old persons without clinical evidence of cardiac ischemic damage and suggest that the cut off of this marker should be tailored to specific age groups to improve the diagnostic accuracy (Olivieri et al., 2012; Normann et al., 2012). It is recommended to measure cardiac troponins with sensitive or high-sensitivity assays and obtain the results within 60 min and a further high-sensitivity cardiac troponin assessment at 3 h from baseline. Additional testing after 3–6 h is indicated if the first two troponin measurements are not conclusive and the clinical condition is still suggestive of acute coronary syndrome (Roffi et al., 2016). Transthoracic echocardiography is useful to identify abnormalities suggestive of myocardial ischemia or necrosis and in detecting alternative pathologies associated with chest pain (e.g., acute aortic dissection, pericardial effusion, aortic valve stenosis, hypertrophic cardiomyopathy or right ventricular dilatation suggestive of acute pulmonary embolism). Furthermore, echocardiography is the diagnostic tool of choice for patients with hemodynamic instability of suspected cardiac origin and the evaluation of left ventricular systolic function, is important to estimate prognosis. It is recommended to use established risk scores for prognosis estimation (GRACE risk score): this assessment guides initial evaluation, selection of the site of care and therapy. The use of the CRUSADE score may be considered in patients undergoing coronary angiography to quantify bleeding risk. Multidetector computed tomography coronary angiography should be considered as an alternative to invasive angiography to exclude ACS when there is a low to intermediate likelihood of coronary artery disease and when cardiac troponin and/or ECG are inconclusive (Roffi et al., 2016). The presence of frailty should be considered in risk stratification in older subjects in the initial evaluation and in the risk stratification of subjects with ACS (Alonso Salinas et al., 2016; Sanchis et al., 2014).

Treatment The treatment of ischemic heart disease in the older people is based on very limited evidence, because older adults are often excluded from cardiovascular clinical trials or they are underrepresented and evidence based on younger populations may have limited applicability to older adults (as described above, coronary artery disease in these subjects has characteristics that are clearly different from those of young people). Moreover, in the clinical trial, subjects are often defined “elderly” as aged 65 and older, although many geriatricians and investigators now define elderly as aged 75 and older and it is important to consider the distinctiveness and heterogeneity of older adults. Therefore, it is not enough to recruit an adequate number of elderly people in clinical trials, but studies focused specifically on this population and that incorporate outcomes such as symptom relief or function preservation, which many older adults prioritize over life prolongation, should be undertaken.

SCAD The aim of management of SCAD is to reduce symptoms and improve prognosis. To this purpose, in addition to evidence-based drug therapy, a lifestyle modification and risk factor control is necessary, also in older patient.

Lifestyle modification and risk factor control The following recommendations about lifestyle modification and risk factor control refer both for SCAD and for acute coronary syndromes/unstable angina. Smoking prevalence is certainly greater in 65–74 years old adults (13.4%) than in  75 years old subjects (8.2%) (Lugo et al., 2013), anyway smoking is a strong and independent risk factor for cardiovascular diseases. We have no specific prognostic data regarding older subjects, but quitting smoking is potentially the most effective of all preventive measures. Strong evidence suggests that consumption of at least 250 mg/day of n 3 long-chain PUFA reduces the risk of cardiovascular death in high-risk subjects (Mozaffarian and Wu, 2011). The Mediterranean diet seems also to play an important role in primary prevention, its efficacy seems to be superimposable to the use of drugs such as ace-inhibitors and aspirin (Widmer et al., 2015). Also in this case there are no specific evidences referable to older patients. A balanced and regular physical activity can significantly reduce the incidence of cardiovascular events. Some studies show a beneficial effect also in patients over 65 years old (Yamamoto et al., 2014), although for some subjects it is difficult to perform regular physical activity because of general clinical conditions and associated co-morbidities. Overweight and obesity are associated with an increased risk of death in CAD patients and their prevalence increases with age. Weight reduction in overweight and obese people is recommended in order to achieve favorable effects on blood pressure, dyslipidemia and glucose metabolism, even if the relationship between overweight or obesity and mortality is not yet clear in the older people; in subjects over 85 years old overweight is not a risk factor for mortality, and a slight overweight would even be “protective.” In the older subjects underweight and loss of lean mass could be a more relevant problem than overweight. Therefore, in the older people, an “aggressive” loss of weight must be avoid, and in some subjects the goal could only be weight maintenance or a slow and very gradual decline only until the reduction and/or disappearance of the symptoms related to obesity.

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Patients with documented ischemic cardiopathy should be treated as very high risk. Therefore, the target LDL cholesterol level to be attained should be < 70 mg/dL (or 1.8 mmol/L). If the target can not be reached, cholesterol must be reduced by > 50%. Therapy may include the use of highly effective statins (Atorvastatin, Rosuvastatin), Ezetimibe and CPSK9 inhibitors (Evolocumab and Alirocumab). There is evidence showing an important reduction of cardiovascular events and mortality with the use of statins also in older patients with high cardiovascular risk (Wilmot et al., 2015). However, statins in the older people are associated with greater risk of adverse effects and current evidence supporting statins for primary prevention in these subjects remains limited. Clinical trial results support the use of statin therapy for the primary prevention of non-fatal cardiovascular disease in individuals 66–75 years of age. The European Society of Cardiology recommends treatment to age 65 and the American Heart Association up to age 75 (Aidan et al., 2018); the NICE guidelines indirectly provide a universal statin indication over the range of 76–84 years of age and also provides a specific treatment recommendation for atorvastatin 20 mg in individuals < 85 years of age. However, extrapolation of efficacy and safety data from those < 75 years of age to those > 75 years of age should be done cautiously, considering, in addition to cardiovascular risk, multimorbidity, polypharmacy, potential side effects, and limited life expectancy (Mortensen and Falk, 2018). Efficacy of statin therapy in the very older people is well documented in secondary prevention trials. It is therefore recommended to use moderate dose of statins, with close monitoring of possible adverse effects. Elevated blood pressure is a major risk factor for CAD as well as heart failure, cerebrovascular disease and renal failure. Clinical trials provided controversial data on the blood pressure target to achieve in older patients (Beckett et al., 2008), however, frail patients, dependent patients, and patients with postural hypotension have been excluded from RCTs. The ESC guidelines recommend that, in older patients (> 65 years), systolic blood pressure should be targeted to between 130 and 140 mmHg, and a diastolic value < 80 mmHg, if tolerated, but not < 70 mmHg, monitoring for any adverse effects or tolerability problems associated with blood pressure-lowering treatment (Benetos et al., 2015, 2016; Williams et al., 2018). Diabetes mellitus is a strong risk factor for cardiovascular complications and increases the risk of progression of coronary disease. The therapeutic goal in diabetic patients is glycated hemoglobin < 7% (or 53 mmol/mol) avoiding symptomatic hypoglycemia and excessive hyperglycemia. When possible, use of medications with low risk for hypoglycemia (first choice metformin; if contraindicated or not tolerated DPP-4 inhibitors, or acarbose, GLP-1 receptor agonists, SGLT-2 inhibitor and pioglitazone) is advisable. In patients with a previous cardiovascular event, if not contraindicated and tolerated, hypoglycemic therapy should include medications with documented cardiovascular benefits (empagliflozin, liraglutide or pioglitazone). This is true also for robust older patients. The older subjects, compared to the younger, are more vulnerable to the hypoglycemia: they are more likely to develop neuroglycopenic manifestations (irritation, mental confusion, delirium, asthenia) with consequent difficulty in recognizing symptoms of hypoglycemia. In addition, hypoglycemia increases the cardiovascular risk (heart attack, stroke, ventricular arrhythmias), the risk of falls and therefore fracture. If the use of drugs at risk of hypoglycemia (sulphonylureas, repaglinide, insulin) is essential, in older patients should be pursued a less at risk of hypoglycemia (HbA1c 7.0%–7.5%, 53–58 mmol/mol). The target is different in the presence of frailty, relevant comorbidities, cognitive decline and complex pharmacological treatments, being acceptable to reach values of HbA1c up to 8%, that is, 58–64 mmol/mol. For these reasons it is indicated starting with low doses and insulin must be used with caution (Bansal et al., 2015). An annual influenza vaccination is recommended for patients with CAD, especially the older subject.

Pharmacological management of SCAD patients The objectives of drug therapy are symptom control and prevention of cardiovascular events. Symptom relief therapy Nitrates reduce anginal symptoms by venous and arteriolar dilatation and reduced preload. Short-acting nitrates are drugs to be used immediately in case of angina attack (sublingual nitroglycerin or isosorbide dinitrate sublingual). Isosorbide dinitrate is effective 3–4 min after intake, but the duration of action is more prolonged (about 1 h). Long acting nitrates (oral formulation or as skin patches) are very effective on anginal symptoms but are second-line drugs because without a nitrate-free period (8–10 h) tolerance may arise. They can also cause worsening of endothelial dysfunction. The action of beta-blockers in ischemic heart disease is achieved by reducing heart rate, contractility, A-V conduction and ectopic activity. In post-MI and heart failure patients (but not in SCAD patients), the beta-blockers improve the prognosis. For these reasons they are first-line drugs for the relief from anginal symptoms. Older patients are often affected by COPD and peripheral arterial disease. Then, b1 highly selective and low dose beta blockers should be used (i.e., metoprolol, atenolol, bisoprolol, and nebivolol). Calcium channel blockers (dihydropyridine and not dihydropyridine) are vasodilators by inhibiting the L-channel situated in vascular smooth muscle. Non-dihydropyridines (Verapamil and Diltiazem) also reduce heart rate by nodal inhibition, however, both drugs, but particularly verapamil, should be carefully used in older adults because of a high risk of constipation and fecal impaction. The dihydropyridine approved for stress angina are nifedipine long acting and amlodipine. Ivabradine causes a reduction in the heart rate by selectively blocking the If current in the sinoatrial node, not modifying the blood pressure and without inotropic effects; it can be used alone or in combination with beta-blockers. Ivabradine is a secondline drug in patients with sinus rhythm and heart rate  70 bpm. A sub-analysis of the ADDITIONS study showed that addition of ivabradine to beta-blockers was effective in reducing HR, angina attacks and nitrate consumption in older patients ( 75 years) with stable angina pectoris (Müller-Werdan et al., 2014). In older patients it should be started with a low dose (2.5 mg twice daily).

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Ranolazine is a selective inhibitor of late sodium current with anti-ischemic and metabolic properties; it is effective in reducing angina and increasing exercise capacity without changing heart rate and blood pressure. In diabetic patients, ranolazine, in addition to reducing anginal symptoms and improving exercise capacity, has shown a significant reduction of glycated hemoglobin. Therefore, it is considered a first-line drug in these patients. Event prevention therapy Inhibition of platelet aggregation can prevent the formation of coronary thrombosis and consequently the risk of myocardial infarction. While increasing the risk of bleeding, antiplatelet agents have a favorable risk/benefit ratio in SCAD patients. Aspirin (75– 150 mg daily) remains the cornerstone therapy, but the CAPRIE study shows benefit with the use of Clopidogrel 75 mg daily in patients with previous myocardial infarction, previous stroke or peripheral vascular disease (PVD). Patients undergoing stent implantation should be treated for a period of 1–6 months (depending on the type of stent) with Aspirin and Clopidogrel. There are no clinical data for the use of Prasugrel or Ticagrelor in SCAD patients. Other drugs indicated in the prevention of patients with SCAD are lipid-lowering agents (see lipid management, above) and renin-angiotensin-aldosterone system blockers. ACE inhibitors are indicated in SCAD patients especially in presence of arterial hypertension, heart failure with LVEF < 40%, diabetes or chronic kidney damage, because in these subgroups of patients, they showed positive prognostic effects. Angiotensin II receptor antagonist may be an alternative therapy for patients with SCAD when ACE inhibition is indicated but not tolerated. Aldosterone blockade with spironolactone or eplerenone is recommended for use in post-MI patients without significant renal dysfunction or hyperkalemia, who are already receiving therapeutic doses of an ACE inhibitor and a b-blocker, have an LVEF  40% and have either diabetes or heart failure. Revascularization therapy Not all patients with stable angina should be revascularized: revascularization can have the goal of improving symptoms (if they persist despite optimal medical therapy) or prognosis (evaluation based on the site, the extent and severity of the coronary stenoses). In the older patients the decision must also be made on the basis of many factors, such as life expectancy, renal function, frailty, cognitive impairment. In the TIME study, the use of revascularization in older patients allowed a reduction in anginal symptoms and cardiovascular events, but not in mortality (Pfisterer, 2004). Furthermore, older patients might benefit from a drug-eluting stent (DES) to reduce the need of repeated revascularization related to re-stenosis and to allow shorter duration of dual antiplatelet therapy (they frequently have an indication for anticoagulation, a higher probability of invasive procedure within months following stent implantation, and a higher risk of poor compliance to treatment).

NSTE-ACS (NSTEMI/UA) Pharmacological treatment of ischemia The goal of pharmacological anti-ischaemic therapy is to decrease myocardial oxygen demand (secondary to a decrease in heart rate, blood pressure, preload or myocardial contractility) or to increase myocardial oxygen supply (by administration of oxygen or through coronary vasodilation). Oxygen should be administered when blood oxygen saturation is < 90% or if the patient is in respiratory distress. If the patient has strong agitation and respiratory distress despite oxygen therapy, it is possible to use morphine (3–10 mg iv). Nitrates reduce anginal symptoms and intravenous nitrates are more effective than sublingual nitrates. They are contraindicated if the patient has taken phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil). Beta-blockers competitively inhibit the myocardial effects of circulating catecholamines and reduce myocardial oxygen consumption by lowering heart rate, blood pressure and myocardial contractility. Oral beta-blockers reduce infarct progression and improve both long-term and short-term outcomes. Except in hemodynamically unstable patients, the magnitude of benefit from early beta-blocker use appears to be greater in the older patients, compared to younger ACS patients (Alexander et al., 2007). Patients with NSTE-ACS should be treated with Dual Antiplatelet Therapy (DAPT), Aspirin þ P2Y12 inhibitor (Clopidogrel, Prasugrel or Ticagrelor), for 1 year, regardless of whether or not percutaneous coronary intervention (PCI) is performed. The CURE study demonstrated the superiority of DAPT (Aspirin þ Clopidogrel) versus Aspirin alone with a reduction of the primary endpoint: death from cardiovascular causes, nonfatal myocardial infarction, or stroke, even with an increase in major bleeding (Yusuf et al., 2001). An oral loading dose (150–300 mg) of Aspirin (non-enteric-coated formulation) or intravenous (i.v.) dose (150 mg) is recommended; the maintenance dose is 75–100 mg/day. Clopidogrel (300–600 mg loading and 75 mg/day maintenance dose) is an inactive prodrug that requires oxidation by the hepatic cytochrome P450 (CYP) system to generate an active metabolite. Prasugrel (60 mg loading and 10 mg/day maintenance dose) is a prodrug that irreversibly blocks platelet P2Y12 receptors with a faster onset and a more profound inhibitory effect than clopidogrel. In the TRITON-TIMI 38 study (Prasugrel vs. Clopidogrel), Prasugrel significantly reduced the primary efficacy end-point, but increased major, fatal and non-fatal bleeding in patients undergoing PCI. Prasugrel is contraindicated in patients with a previous stroke and does not bring benefits in patients over 75 years and in patients weighing < 60 kg (Wiviott et al., 2007). In TRILOGY ACS trial (not revascularized patients) and ELDERLY ACS 2 trial (patients undergoing PCI), in patients  75 years, low dose of Prasugrel showed no benefits versus Clopidogrel either in terms

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of efficacy or safety (Savonitto et al., 2018). Ticagrelor (180 mg loading dose followed by 90 mg twice a day) is an oral, reversibly binding P2Y12 inhibitor with a plasma half-life of 6–12 h and inhibits adenosine reuptake via equilabrative nucleoside transporter 1 (ENT1). A subanalysis assessed clinical outcomes in older ( 75 years of age) versus younger (< 75 years of age) patients in the PLATO trial and showed that Ticagrelor compared with Clopidogrel reduced ischemic outcomes and mortality without increasing overall major bleeding rates; these advantages were not found to depend on age category (Husted et al., 2012). There is evidence that anticoagulation is effective in reducing ischemic events in NSTE-ACS and that the combination with platelet inhibitors is more effective than either treatment alone; in patients who had no indication of anticoagulation prior to ACS, anticoagulant therapy should continue until PCI or for a week and, if not contraindicated, Fondaparinux (2.5 mg/day) is the drug with the best efficacy/safety ratio (Yusuf et al., 2006). Alternatively, the use of Enoxaparin can be considered (1 mg/kg twice daily, while the dose is reduced to 1 mg/kg once a day if eGFR < 30 mL/min/1.73 m2). Unfractionated heparin (UFH) can be used in patients with severe chronic kidney disease and also in patients receiving vitamin K antagonist or new oral anticoagulant before ACS.

Invasive coronary angiography and revascularization The decision whether to undergo the patient with NSTE ACS, especially if older, to coronary angiography must be taken on the basis of numerous criteria: clinical presentation, comorbidities, risk stratification, presence of high-risk features specific for a revascularization modality, frailty, cognitive status, estimated life expectancy. Numerous studies have shown a reduction in cardiovascular events and mortality with systematically invasive approach that is greater in the older patients than the younger one (Damman et al., 2012; Savonitto et al., 2012). The timing of revascularization must be evaluated based on the patient’s risk on hospital admission (Navarese et al., 2013) (Table 3). In very-high-risk patients an immediate (< 2 h from hospital admission, analogous to STEMI management) invasive strategy with intent to perform revascularization is recommended, irrespective of ECG or biomarker findings. High-risk patients must undergo coronarography within 24 h, intermediate-risk one within 72 h (Navarese et al., 2013). Low-risk patients must undergo a provocative stress test before discharge (and possible elective coronarography in presence of inducible myocardial ischemia).

STEMI Pharmacological treatment of ischemia The same recommendations apply as for NSTE ACS about general supportive measures (oxygen and morphine) and nitrates. Based on the current available evidence, early administration of i.v. beta-blockers at the time of presentation followed by oral beta-blockers should be considered in haemodynamically stable patients undergoing primary PCI (Halkin et al., 2004). In the presence of left ventricular dysfunction and in the absence of contraindications (acute heart failure, haemodynamic instability, or higher degree AV block), oral beta-blockers should be started within 24 h of admission. Routine use of calcium antagonists in the acute phase is not indicated. In the chronic phase, in patients with contraindications to beta-blockers, calcium antagonists are a reasonable option for patients without heart failure or impaired LV function. As with NSTE ACS, patients with STEMI should be treated with DAPT (Aspirin þ P2Y12 inhibitor). The loading dose of Clopidogrel is 600 mg and it should be used if the patient is being treated with fibrinolysis. Duration of DAPT is up to 12 months (in the absence of complications).

Table 3

Risk criteria at admission in SCA NSTEMI subjects (Navarese et al., 2013)

Very high-risk criteria

High-risk criteria Intermediate-risk criteria

Low-risk criteria

• • • • • • • • • • • • • • • •

haemodynamic instability or cardiogenic shock; recurrent or ongoing chest pain refractory to medical treatment; life-threatening arrhythmias or cardiac arrest; mechanical complications of MI; acute heart failure; recurrent dynamic ST-T wave changes particularly with intermittent ST elevation rise or fall in cardiac troponin compatible with MI; dynamic ST or T-wave changes (symptomatic or silent); GRACE score >140 diabetes mellitus; renal insufficiency (eGFR 5 years) (Ekerstad et al., 2018), prolonged hospital care (Ekerstad et al., 2011), major bleeding within 30 days after o type 1 myocardial infarction (Alonso Salinas et al., 2016). Delirium is one other geriatric condition that frequently complicates the hospitalization of older patients. Delirium is an independent predictor of prolonged length of stay, high rates of morbidity and short and long-term mortality, readmission, increased risk of institutionalization and dementia. Furthermore, hyperactive delirium can cause difficulties in the optimal management (i.e., echocardiogram, non-invasive imaging functional test, ICA), while hypoactive delirium may results in complications related to immobility (i.e., infections and pressure sores). Long term cognitive impairment after acute delirium can hinder the cardiac rehabilitation. Delirium has been well evaluated in cardiac surgical subjects, in mechanically ventilated patients, in medical patients and in subjects hospitalized with acute heart failure. In an observational study of patient hospitalized for acute heart disease, 17% developed delirium during hospitalization. Delirium is associated with preventable hospital procedures (i.e., urinary catheter, prolonged fluid therapy, administration of therapy during night hours, physical restraint measures, and immobility) and hence is amenable by preventive interventions. A systematic review evaluated the associations of cardiovascular disorders and falls, that are a leading cause of injury in older people (about 1 in 3 people older than 65 will suffer a fall each year) (Jansen et al., 2016). The most consistent associations were observed for low blood pressure, heart failure and cardiac arrhythmia and, even if the coronary artery disease showed inconsistent association with falls in this review, the aforementioned conditions can complicate the myocardial ischemic event or manifest itself as a result of the anti-ischemic therapy undertaken (aggressive lowering of blood pressure, i.e., also associated with stroke and cognitive impairment, use of diuretic and beta blocker drugs, cardiac catheterization). Moreover, syncope secondary to underlying cardiovascular disease is more common in older subjects and may lead to injurious falls. Therefore, for improving cardiovascular disease care in the older patients considering and managing also non cardiac factors (such as general health, multimorbidity, cognitive status and frailty) is important. Routine clinical evaluation in cardiology does not include the assessment of specific geriatric conditions. However, given their impact on the prognosis and their importance in the management of the older patient, it would be desirable to provide a comprehensive multidimensional geriatric evaluation on admission in order to identify a tailored path for each older patient and to try to prevent complications such as delirium, functional decline during the hospitalization, and institutionalization.

References Afilalo, J., Alexander, K.P., Mack, M.J., 2014. Frailty assessment in the cardiovascular care of older adults. Journal of the American College of Cardiology 63, 747–762. Agewall, S., Beltrame, J.F., Reynolds, H.R., et al., 2017. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. European Heart Journal 38, 143–153. Aidan, R., Heath, S., Cook, P., 2018. Primary prevention with statins for older adults. BMJ 362, k3695. Alexander, K.P., Newby, L.K., Cannon, C.P., et al., 2007. Acute coronary care in the elderly, part I: Non-ST-segment-elevation acute coronary syndromes: A scientific statement for healthcare professionals from the American Heart Association Council on clinical cardiology: In collaboration with the Society of Geriatric Cardiology. Circulation 115, 2549. Alonso Salinas, G.L., Sanmartín Fernández, M., Pascual Izco, M., et al., 2016. Frailty predicts major bleeding within 30 days in elderly patients with acute coronary syndrome. International Journal of Cardiology 222, 590–593. Alonso Salinas, G.L., Sanmartin, M., Pascual Izco, M., 2017. Frailty is an independent prognostic marker in elderly patients with myocardial infarction. Clinical Cardiology 40, 925–931. Badimon, L., Bugiardini, R., Cubedo, J., 2016. Pathophysiology of acute coronary syndromes in the elderly. International Journal of Cardiology 222, 1105–1109. Bansal, N., Dhaliwal, R., Weinstock, R.S., 2015. Management of diabetes in the elderly. The Medical Clinics of North America 99, 351–377. Beckett, N.S., Peters, R., Fletcher, A.E., et al., 2008. Treatment of hypertension in patients 80 years of age or older. The New England Journal of Medicine 358, 1887–1898. Benetos, A., Rossignol, P., Cherubini, A., et al., 2015. Polypharmacy in the aging patient: Management of hypertension in octogenarians. JAMA 314, 170–180. Benetos, A., Bulpitt, C.J., Petrovic, M., et al., 2016. An expert opinion from the European Society of Hypertension-European Union Geriatric Medicine Society Working Group on the Management of Hypertension in very old, frail subjects. Hypertension 67, 820–825. Borghi, C., Omboni, S., Novo, S., et al., 2017. Early treatment with Zofenopril and Ramipril in combination with acetyl salicylic acid in patients with left ventricular systolic dysfunction after acute myocardial infarction: Results of a 5-year follow-up of patients of the SMILE-4 study. Journal of Cardiovascular Pharmacology 69, 298–304. Bueno, H., Betriu, A., Heras, M., et al., 2011. Primary angioplasty vs fibrinolysis in very old patients with acute myocardial infarction: TRIANA (TRatamiento del Infarto Agudo de miocardio eN Ancianos) randomized trial and pooled analysis with previous studies. European Heart Journal 32, 51–60. DAI, X., Busby-Whitehead, J., Forman, D.E., Alexander, K.P., 2016. Stable ischemic heart disease in the older adults. Journal of Geriatric Cardiology 13, 109–114. Damman, P., Clayton, T., Wallentin, L., et al., 2012. Effects of age on long-term outcomes after a routine invasive or selective invasive strategy in patients presenting with non-ST segment elevation acute coronary syndromes: A collaborative analysis of individual data from the FRISC IIdICTUSdRITA-3 (FIR) trials. Heart 98, 207–213. Ekerstad, N., Swahn, E., Janzon, M., et al., 2011. Frailty is independently associated with short-term outcomes for elderly patients with non-ST-segment elevation myocardial infarction. Circulation 124, 2397–2404. Ekerstad, N., Pettersson, S., Alexander, K., et al., 2018. Frailty as an instrument for evaluation of elderly patients with non-ST-segment elevation myocardial infarction: A follow-up after more than 5 years. European Journal of Preventive Cardiology 25 (17), 1813–1821. Epub ahead of print. Fihn, S.D., Gardin, J.M., Abrams, J., et al., 2012. ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, preventive cardiovascular nurses association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Journal of the American College of Cardiology 60 (2012), e44–164. Fihn, S.D., Blankenship, J.C., Alexander, K.P., 2014. ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: A report of the American College of Cardiology/American Heart Association task force on practice guidelines, and the American Association for Thoracic Surgery, preventive cardiovascular nurses association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Journal of the American College of Cardiology 64 (2014), 1929–1949.

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Halkin, A., Grines, C.L., Cox, D.A., et al., 2004. Impact of intravenous beta-blockade before primary angioplasty on survival in patients undergoing mechanical reperfusion therapy for acute myocardial infarction. Journal of the American College of Cardiology 43, 1780–1787. Husted, S., James, S., Becker, R.C., et al., 2012. Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes: A substudy from the prospective randomized PLATelet inhibition and patient outcomes (PLATO) trial. Circulation. Cardiovascular Quality and Outcomes 5, 680–688. Ibanez, B., James, S., Agewall, S., Antunes, M.J., et al., 2017. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal 39 (2018), 119–177. Jansen, S., Bhangu, J., de Rooij, S., et al., 2016. The Association of Cardiovascular disorders and falls: A systematic review. Journal of the American Medical Directors Association 17, 193–199. Lugo, A., La Vecchia, C., Boccia, S., Murisic, B., Gallus, S., 2013. Patterns of smoking prevalence among the elderly in Europe. International Journal of Environmental Research and Public Health 10, 4418–4431. Madhavan, M.V., Gersh, B.J., Alexander, K.P., Granger, C.B., Stone, G.W., 2018. Coronary artery disease in patients  80 years of age. Journal of the American College of Cardiology 71, 2015–2040. Montalescot, G., Sechtem, U., Achenbach, S., et al., 2013. ESC guidelines on the management of stable coronary artery disease: The task force on the management of stable coronary artery disease of the European Society of Cardiology. European Heart Journal 34 (2013), 2949–3003. Mortensen, M.B., Falk, E., 2018. Primary prevention with statins in the elderly. Journal of the American College of Cardiology 71, 85–94. Mozaffarian, D., Wu, J.H., 2011. Omega-3 fatty acids and cardiovascular disease: Effects on risk factors, molecular pathways, and clinical events. Journal of the American College of Cardiology 58, 2047–2067. Mozaffarian, D., Benjamin, E.J., Go, A.S., et al., 2015. Heart disease and stroke statisticsd2015 update a report from the American Heart Association. Circulation 131, e29–322. Müller-Werdan, U., Stöckl, G., Ebelt, H., et al., 2014. Ivabradine in combination with beta-blocker reduces symptoms and improves quality of life in elderly patients with stable angina pectoris: Age-related results from the ADDITIONS study. Experimental Gerontology 59, 34–41. Navarese, E.P., Gurbel, P.A., Andreotti, F., et al., 2013. Optimal timing of coronary invasive strategy in non-ST-segment elevation acute coronary syndromes: A systematic review and meta-analysis. Annals of Internal Medicine 158, 261–270. Normann, J., Mueller, M., Biener, M., et al., 2012. Effect of older age on diagnostic and prognostic performance of high-sensitivity troponin T in patients presenting to an emergency department. American Heart Journal 164, 698–705. Olivieri, F., Galeazzi, R., Giavarina, D., et al., 2012. Aged-related increase of high sensitive troponin T and its implication in acute myocardial infarction diagnosis of elderly patients. Mechanisms of Ageing and Development 133, 300–305. Paneni, F., Diaz Cañestro, C., Libby, P., Lüscher, T.F., Camici, G.G., 2017. The aging cardiovascular system understanding it at the cellular and clinical levels. Journal of the American College of Cardiology 69, 1952–1967. Pfisterer, M., 2004. Trial of invasive versus medical therapy in elderly patients investigators, long-term outcome in elderly patients with chronic angina managed invasively versus by optimized medical therapy: Four-year follow-up of the randomized trial of invasive versus medical therapy in elderly patients (TIME). Circulation 110, 1213–1218. Roffi, M., Patrono, C., Collet, J.P., et al., 2016. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task force for the Management of Acute Coronary Syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal 37, 267–315. Sanchis, J., Bonanad, C., Ruiz, V., 2014. Frailty and other geriatric conditions for risk stratification of older patients with acute coronary syndrome. American Heart Journal 168, 784–791. Savonitto, S., Cavallini, C., Petronio, A.S., et al., 2012. Early aggressive versus initially conservative treatment in elderly patients with non-ST-segment elevation acute coronary syndrome: A randomized controlled trial. JACC. Cardiovascular Interventions 5, 906–916. Savonitto, S., Ferri, L.A., Piatti, L., et al., 2018. Comparison of reduced-dose prasugrel and standard-dose clopidogrel in elderly patients with acute coronary syndromes undergoing early percutaneous revascularization. Circulation 137, 2435–2445. Schopfer, D.W., Forman, D.E., 2016. Cardiac rehabilitation in older adults. The Canadian Journal of Cardiology 32, 1088–1096. The EUGenMed Cardiovascular Clinical Study Group, Regitz-Zagrosek, V., Oertelt-Prigione, S., Prescott, E., et al., 2016. Gender in cardiovascular diseases: Impact on clinical manifestations, management, and outcomes. European Heart Journal 37, 24–34. Thygesen, K., Alpert, J.S., Jaffe, A.S., et al., 2012. Third universal definition of myocardial infarction. European Heart Journal 33, 2551–2567. Townsend, N., Wilson, L., Bhatnagar, P., et al., 2016. Cardiovascular disease in Europe: Epidemiological update 2016. European Heart Journal 37, 3232–3245. Widmer, R.J., Flammer, A.J., Lerman, L.O., Lerman, A., 2015. The Mediterranean diet, its components, and cardiovascular disease. The American Journal of Medicine 128, 229–238. Williams, B., Mancia, G., Spiering, W., et al., 2018. ESC/ESH guidelines for the management of arterial hypertension. European Heart Journal 39, 3021–3104. Wilmot, K.A., Khan, A., Krishnan, S., Eapen, D.J., Sperling, L., 2015. Statins in the elderly: A patient-focused approach. Clinical Cardiology 38, 56–61. Wiviott, S.D., Braunwald, E., McCabe, C.H., et al., 2007. Prasugrel versus clopidogrel in patients with acute coronary syndromes. The New England Journal of Medicine 357, 2001–2015. Yamamoto, S., Matsunaga, A., Wang, G., et al., 2014. Effect of balance training on walking speed and cardiac events in elderly patients with ischemic heart disease. International Heart Journal 55, 397–403. Yusuf, S., Zhao, F., Mehta, S.R., et al., 2001. Clopidogrel in unstable angina to prevent recurrent events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. The New England Journal of Medicine 345, 494–502. Yusuf, S., Mehta, S.R., Chrolavicius, S., et al., 2006. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. The New England Journal of Medicine 354, 1464–1476.

Further Reading Bourgeois, F.T., Orenstein, L., Ballakur, S., Mandl, K.D., Ioannidis, J.P.A., 2017. Exclusion of elderly people from randomized clinical trials of drugs for ischemic heart disease. Journal of the American Geriatrics Society 65, 2354–2361. Dodson, J.A., Chaudhry, S.I., Krumholz, H.M., 2017. Time for a new approach to studying older people with ischemic heart disease. Journal of the American Geriatrics Society 65, 2349–2351. Rafanelli, M., Orso, F., Marchionni, N., 2017. Ischaemic heart disease. In: Michel, J.P., Beattie, B.L., Martin, F.C., Walston, J.D. (Eds.), Oxford textbook of geriatric medicine, 3rd edn. Oxford University Press, Oxford Medicine Online, pp. 1–20. Menezes, A.R., Lavie, C.J., Forman, D.E., et al., 2014. Cardiac rehabilitation in the elderly. Progress in Cardiovascular Diseases 57, 152–159. Kang, L., Zhang, S.Y., Zhu, W.L., et al., 2015. Is frailty associated with short-term outcomes for elderly patients with acute coronary syndrome? Journal of Geriatric Cardiology 12, 662–667. Montilla Padilla, I., Martín-Asenjo, R., Bueno, H., 2017. Management of acute coronary syndromes in geriatric patients. Heart, Lung & Circulation 26, 107–113.

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Sato, K., Kubota, K., Oda, H., Taniguchi, T., 2017. The impact of delirium on outcomes in acute, non-intubated cardiac patients. European Heart Journal Acute Cardiovascular Care 6, 553–559. Peeters, G., Tett, S.E., Hollingworth, S.A., et al., 2017. Associations of guideline recommended medications for acute coronary syndromes with fall-related hospitalizations and cardiovascular events in older women with ischemic heart disease. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 72, 259–265. White, H.D., Westerhout, C.M., Alexander, K.P., et al., 2016. Frailty is associated with worse outcomes in non-ST-segment elevation acute coronary syndromes: Insights from the TaRgeted platelet inhibition to cLarify the optimal strateGy to medicallY manage acute coronary syndromes (TRILOGY ACS) trial. European Heart Journal Acute Cardiovascular Care 5, 231–242. von Haehling, S., Anker, S.D., Doehner, W., Morley, J.E., Vellas, B., 2013. Frailty and heart disease. International Journal of Cardiology 168, 1745–1747. Parnell, S.T., Smith, A.T., 2018. Acute coronary syndrome in octogenarians: Expect the unexpected. The Journal of Emergency Medicine 54, e27–e30. Palta, P., Huang, E.S., Kalyani, R.R., Golden, S.H., Yeh, H.C., 2017. Hemoglobin A1c and mortality in older adults with and without diabetes: Results from the National Health and nutrition examination surveys (1988-2011). Diabetes Care 40, 453–460. Pilotto, A., Gallina, P., Panza, F., et al., 2016. Relation of statin use and mortality in community-dwelling frail older patients with coronary artery disease. The American Journal of Cardiology 118, 1624–1630. Aguiar Rosa, S.A., Timoteo, A.T., Nogueira, M.A., Belo, A., Ferreira, R.C., 2017. Acute coronary syndrome in elderlydWhat is the place for invasive strategy? European Geriatric Medicine 8, 90–95.

Life Expectancy and Health Expectancy Yuan S Zhang, Hyunju Shim, and Eileen M Crimmins, The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States © 2020 Elsevier Inc. All rights reserved.

Life Expectancy Calculation of Life Expectancy in a Life Table Period Life Tables and Cohort Life Tables Trends in Life Expectancy Life Expectancy for Men and Women Regional Life Expectancy European region Western Pacific region Region of the Americas Africa region South-East Asia and Eastern Mediterranean region Health Expectancies Research Using Health Expectancy Measures of Health Expectancy Disability Diseases and conditions Perceived health Calculation of Health Expectancy Sullivan method Multistate life table method Other methods Available Software to Compute Health Expectancy The Future of Life Expectancy and Health Expectancy References Further Reading Relevant Websites

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Life Expectancy Life expectancy is an estimate of the average remaining length of life expected to be lived after birth or after a specified age for a population experiencing each level of age-specific mortality used in the estimation. It is represented by the symbol ex0 with x indicating the exact age at which life expectancy is estimated. The most frequently used measure for life expectancy is life expectancy at birth, which is the average number of years that a newborn infant could expect to live if the age-specific mortality rates at the time of birth were experienced at every age of life. Life expectancy can be calculated at any age, for instance life expectancy at age 65 provides an estimate of the remaining length of life expected at older ages; partial life expectancy can be calculated for an age range, for instance life expectancy from ages 20–64 can provide an estimate of expected length of life in the working years.

Calculation of Life Expectancy in a Life Table The life table is the basis for the calculation of life expectancy. Age-specific mortality rates are the only input required to compute life expectancy. There are a number of functions within the life table identified with conventional notation and interpreted as indicated below. The columns of the life table, from left to right, are: x: exact age. q(x): Probability of dying between age x and x þ 1, which is computed from the age-specific mortality rates m(x) which are usually available from the vital statistics. q(x) forms the basis of the life table and is the only input needed to make a life table. q(x) multiplied by the number of persons alive at the beginning of the interval provides an estimate of the number of persons dying in the interval, d(x). l(x): the number of persons alive at an exact age x. The radix of the life table, or the initial l(x) value, is usually set at 100,000 at the beginning age of the life table. The value then decreases with age from 100,000 to 0 when the life table is completed everyone has

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died. The number of persons alive at one age minus the number of deaths in the interval provides the number of persons alive at the next age. d(x): the number of persons dying between ages x and x þ 1. Across all ages, 100,000 people will die if 100,000 is the radix of the life table. L(x): Person-years lived between age x and x þ 1. Because it is assumed that people die at the midpoint of the interval, L(x) is the average number of people alive in the age range during the year. T(x): Total number of person-years lived from age x to the end of life which is estimated by summing the L(x) column. e(x): the remaining years of life expectancy at age x which is computed by dividing T(x) by l(x). Looking at the life table for France in 2015 provides an example of these functions (Table 1). We can see that the probability of dying (qx) between age 0 and 1 is 0.00359. The number of births (lx) begins with 100,000 entrants to the life table, and under mortality conditions in France in 2015, 99,641 of them would reach age 1. The number of deaths between age 0 and 1 (dx) is 359, qx  lx (¼ 0.00359  100,000). The total number of person-years lived (Lx) between age 0 and 1 is 99,692, and the cohort would live a total of 8,215,084 person-years (Tx) over their lifetime. The life expectancy at birth or age 0 is 82.15, which is calculated by dividing Tx by lx (¼ 8.215,084/100,000). Life expectancy at birth in France in 2015 can be interpreted as the average length of life expected for a baby born in France in 2015 if the baby was exposed to the mortality conditions existing at each age of the life table in 2015. Out of 100,000 babies born, more than 88,000 should live to age 65 and almost 3000 to age 100.

Table 1

Life table for France, 2015

Age x

qx

lx

dx

Lx

Tx

ex

mx

0 1 2 3 4 5 . 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 . 100 101 102 103 104 105 106 107 108 109 110

0.00359 0.00026 0.00016 0.00015 0.00010 0.00008 . 0.0097 0.01017 0.01065 0.01163 0.01235 0.01367 0.01474 0.01591 0.01717 0.01895 0.02058 0.02312 0.02509 0.02801 0.03152 0.03576 0.04103 0.04575 0.05209 0.05955 0.0678 . 0.34146 0.36679 0.39184 0.41633 0.43999 0.46259 0.48393 0.50388 0.52235 0.53929 1

100,000 99,641 99,615 99,600 99,585 99,575 . 88,369 87,512 86,622 85,700 84,703 83,657 82,513 81,297 80,004 78,630 77,140 75,553 73,806 71,955 69,939 67,734 65,312 62,632 59,767 56,654 53,280 . 2817 1855 1175 714 417 234 125 65 32 15 7

359 26 16 15 10 8 . 857 890 922 997 1046 1144 1216 1293 1374 1490 1587 1746 1852 2015 2205 2422 2680 2866 3113 3374 3613 . 962 680 460 297 183 108 61 33 17 8 7

99,692 99,628 99,607 99,592 99,580 99,571 . 87,941 87,067 86,161 85,201 84,180 83,085 81,905 80,651 79,317 77,885 76,346 74,680 72,881 70,947 68,837 66,523 63,972 61,200 58,210 54,967 51,474 . 2336 1515 945 566 325 179 95 48 24 11 9

8,215,084 8,115,392 8,015,763 7,916,156 7,816,563 7,716,983 . 1,876,381 1,788,440 1,701,373 1,615,212 1,530,011 1,445,831 1,362,746 1,280,840 1,200,190 1,120,872 1,042,987 966,641 891,961 819,080 748,134 679,297 612,774 548,801 487,602 429,391 374,425 . 6054 3718 2203 1258 692 367 188 93 44 20 9

82.15 81.45 80.47 79.48 78.49 77.50 . 21.23 20.44 19.64 18.85 18.06 17.28 16.52 15.76 15 14.25 13.52 12.79 12.09 11.38 10.7 10.03 9.38 8.76 8.16 7.58 7.03 . 2.15 2.00 1.88 1.76 1.66 1.57 1.50 1.43 1.37 1.33 1.30

0.00360 0.00026 0.00016 0.00015 0.00010 0.00008 . 0.00975 0.01022 0.01071 0.0117 0.01243 0.01377 0.01485 0.01603 0.01732 0.01914 0.02079 0.02339 0.02541 0.02841 0.03203 0.03641 0.04189 0.04682 0.05348 0.06138 0.07018 . 0.41175 0.44916 0.48732 0.52578 0.56409 0.60177 0.63840 0.67359 0.70700 0.73839 0.76758

Source: The Human Mortality Database. Life Tables by Country: France (2015). Available from https://www.mortality.org/.

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Period Life Tables and Cohort Life Tables The life table in Table 1 is a period life table which is the most frequently available life table. A period life table is based on cross-sectional mortality data for a particular year and thus represents the mortality experience of a hypothetical cohort at a specific moment in time (Crimmins, 2011). It is based on mortality data that are readily available in vital statistics systems. In Table 2, we present a period life table for France in 1910 (Human Mortality Database, 2018). The period life expectancy at a given age in this table represents the average number of years of life expected for a person at that exact age, born in 1910. In 1910, life expectancy in France was 51.35; this is the life expectancy at birth of those who were 105 years of age in 2015. For them, life expectancy at birth was about half of the time they eventually lived. The very high mortality of infants and children is reflected in this life table with more than 11,000 deaths before the first birthday. The low likelihood of making it to the oldest years is shown in that only 15 people out of the initial 100,000 make it to 100; whereas in the 2015 life table that number is almost 3000. A cohort life table is constructed from the experience of an actual cohort as it lives through the lifecycle and depicts mortality experience over the entire lifetime as actually lived by a cohort of people. Complete cohort life tables require 100 years of mortality data collected over the lifecycle. These are not used frequently for monitoring health in populations for this reason. Cohort life tables are not as readily available as period life tables because of a lack of reliable data. Table 3 shows the cohort life table for the 1910 birth cohort in France. We can see that the life expectancy of the actual cohort born in 1910 in France was 57.16 or about 6 years longer than the period life table for 1910. The similarity of the cohort actual life expectancy and Table 2

Period life table, France, 1910

Age

qx

lx

dx

Lx

Tx

ex

mx

0 1 2 3 4 5 . 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 . 100 101 102 103 104 105 106 107 108 109 110

0.11482 0.0275 0.01203 0.00751 0.00534 0.00417 . 0.03916 0.04207 0.04615 0.04937 0.05341 0.05901 0.06512 0.07073 0.07875 0.08579 0.0945 0.10448 0.11367 0.12542 0.12573 0.14572 0.15164 0.16775 0.1788 0.19833 0.20997 . 0.44939 0.46375 0.47756 0.4908 0.50343 0.51544 0.52682 0.53757 0.54769 0.55719 1

100,000 88,518 86,084 85,048 84,409 83,959 . 44,315 42,580 40,788 38,906 36,985 35,010 32,944 30,798 28,620 26,366 24,104 21,827 19,546 17,324 15,152 13,247 11,316 9600 7990 6561 5260 . 15 8 4 2 1 1 0 0 0 0 0

11,482 2435 1035 639 451 350 . 1735 1791 1882 1921 1975 2066 2145 2178 2254 2262 2278 2280 2222 2173 1905 1930 1716 1610 1429 1301 1104 . 7 4 2 1 1 0 0 0 0 0 0

92,029 87,301 85,566 84,729 84,184 83,784 . 43,447 41,684 39,847 37,945 35,997 33,977 31,871 29,709 27,493 25,235 22,965 20,686 18,435 16,238 14,199 12,281 10,458 8795 7276 5911 4708 . 11 6 3 2 1 0 0 0 0 0 0

5,134,912 5,042,883 4,955,582 4,870,016 4,785,288 4,701,104 . 502,884 459,437 417,753 377,906 339,961 303,964 269,987 238,116 208,407 180,914 155,678 132,713 112,027 93,592 77,354 63,155 50,873 40,415 31,620 24,344 18,434 . 24 13 7 3 2 1 0 0 0 0 0

51.35 56.97 57.57 57.26 56.69 55.99 . 11.35 10.79 10.24 9.71 9.19 8.68 8.2 7.73 7.28 6.86 6.46 6.08 5.73 5.4 5.11 4.77 4.5 4.21 3.96 3.71 3.5 . 1.65 1.59 1.54 1.49 1.45 1.41 1.37 1.34 1.31 1.28 1.27

0.12476 0.02789 0.0121 0.00754 0.00535 0.00418 . 0.03994 0.04298 0.04724 0.05062 0.05487 0.0608 0.06731 0.07333 0.08198 0.08963 0.09918 0.11024 0.12052 0.13381 0.13416 0.15718 0.16408 0.1831 0.19635 0.22016 0.23459 . 0.57964 0.60375 0.62737 0.6504 0.67277 0.69439 0.71521 0.73517 0.75423 0.77237 0.78956

Source: The Human Mortality Database. Period data: France (1910). Available from https://www.mortality.org/.

316 Table 3

Life Expectancy and Health Expectancy Cohort life Table, France, Birth Cohort of 1910

Age

qx

lx

dx

Lx

Tx

ex

mx

0 1 2 3 4 5 . 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 . 100 101 102 103 104 105 106 107 108 109 110

0.12373 0.03305 0.01154 0.00674 0.00587 0.0051 . 0.02081 0.02081 0.02182 0.02379 0.0254 0.02765 0.02941 0.03172 0.03425 0.03731 0.04049 0.04259 0.04555 0.04981 0.05531 0.05847 0.06419 0.07031 0.07764 0.0839 0.09513 . 0.32249 0.35509 0.38268 0.35869 0.42289 0.39744 0.41317 0.4268 0.44134 0.46197 1

100,000 87,627 84,731 83,754 83,189 82,701 . 55,876 54,713 53,575 52,406 51,159 49,860 48,481 47,055 45,563 44,002 42,360 40,645 38,914 37,141 35,291 33,339 31,390 29,375 27,310 25,189 23,076 . 972 659 425 262 168 97 58 34 20 11 6

12,373 2896 978 564 488 422 . 1163 1138 1169 1247 1300 1379 1426 1493 1560 1642 1715 1731 1773 1850 1952 1949 2015 2065 2120 2113 2195 . 314 234 163 94 71 39 24 15 9 5 6

91,410 86,035 84,241 83,468 82,956 82,489 . 55,293 54,138 52,993 51,785 50,512 49,175 47,769 46,316 44,782 43,190 41,513 39,782 38,029 36,215 34,316 32,370 30,385 28,351 26,247 24,143 21,988 . 813 543 343 215 133 77 46 27 15 8 8

5,716,410 5,625,000 5,538,965 5,454,724 5,371,256 5,288,299 . 970,619 915,327 861,189 808,196 756,411 705,898 656,723 608,955 562,639 517,857 474,668 433,154 393,372 355,344 319,129 284,813 252,443 222,058 193,707 167,460 143,316 . 2228 1415 872 529 315 182 104 58 31 16 8

57.16 64.19 65.37 65.13 64.57 63.94 . 17.37 16.73 16.07 15.42 14.79 14.16 13.55 12.94 12.35 11.77 11.21 10.66 10.11 9.57 9.04 8.54 8.04 7.56 7.09 6.65 6.21 . 2.29 2.15 2.05 2.02 1.87 1.87 1.78 1.70 1.60 1.48 1.34

0.13536 0.03366 0.0116 0.00676 0.00589 0.00511 . 0.02103 0.02103 0.02206 0.02407 0.02573 0.02803 0.02985 0.03223 0.03485 0.03801 0.04132 0.04351 0.04661 0.05109 0.05688 0.06022 0.06631 0.07285 0.08078 0.08754 0.09984 . 0.38569 0.43077 0.47391 0.43838 0.53508 0.49894 0.52431 0.54667 0.57084 0.60581 0.74864

Source: The Human Mortality Database. Cohort data: France (1910). Available from https://www.mortality.org/.

life expectancy for the period when they were born results from the high levels of early life mortality. We can also see that the number of people in the cohort who actually lived to be 100 was somewhat less than 1000 out of 100,000, not the almost 3000 expected by today’s levels of mortality.

Trends in Life Expectancy The 20th century was a time of historically unprecedented increase in life expectancy, as many countries changed from a life expectancy of about 40 years to a life expectancy about 80 years (Crimmins, 2015). This remarkable increase is due in large part to declines in infectious diseases resulting from improved conditions of public health and medical knowledge as well to increases in economic circumstances. By 1950, infant mortality in most Western developed countries had decreased from its historical rate of 20%–30% to a mere 2%–3%, and it has continued to decline to 0.5%–1.0% in most of these countries (Wilmoth, 2000). This was because infants and young children were particularly vulnerable to infectious disease. For instance, infectious disease mortality declined by 95% in England from 1841 to 1971, while life expectancy at birth increased by 30 years around roughly the same time (Cutler et al., 2006). Mortality declined across the age range during this period, but mortality decline at older ages was less influenced by the improvements in control of infectious disease because deaths at older ages are primarily caused by chronic diseases, specifically cardiovascular disease and cancer (Vaupel, 2010). Mortality in countries of Asia, Latin and South America, and Africa declined much later than in Europe and North America, most beginning mortality transitions in the middle of the

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20th century with the availability of antibiotics and spread of child immunizations. Globally, world life expectancy at birth went from less than 30 years to above 66 years during the period from 1800 to 2001 (Riley, 2005); the pace of increase has slowed as life expectancy has gotten higher, world life expectancy was 72 years in 2016, an increase of approximately 5.5 years from 2001 to 2016 (World Health Organization, 2018). The increase in life expectancy is a major part of the “epidemiologic transition” which all countries have now at least begun and most have accomplished (Omran, 1971). Differing levels of life expectancy are characteristic of three stages of the demographic transition: the age of pestilence and famine, the age of receding pandemics, and the age of degenerative and man-made diseases. During the first stage, the life expectancy remains low, in the 20 to 40-year range; in the second stage, life expectancy at birth increases from 30 to 50 years; and during the final stage, the life expectancy at birth exceeds 50 years and mortality declines begin to decelerate. The models are further classified into the classical/Western model, the accelerated transition model, and the contemporary/delayed model depending on the pace of progress in moving from one stage to the next. The theory has been widely used to characterize epidemiological stages of a country in terms of life expectancy; however, since the 1960s, some scholars have proposed adding a “fourth stage” where life expectancy increases as mortality from cardiovascular diseases declines (Olshansky and Ault, 1986). While the transition in Western developed countries fit the model well, the transition in some Asian countries was not as clearly described by this model as it happened in a short period of time and with different causes. Life expectancy is differentially responsive to change in mortality at younger and older ages. Life expectancy changed dramatically with initial declines from high mortality when the decline was concentrated at younger ages. Life expectancy changes much less with changes in mortality concentrated at older ages which occur where mortality is low and life expectancy is high. This reduced response of life expectancy to change with mortality improvement at older ages is one factor leading to the emergence of the concept of healthy life expectancy, which will be discussed later in this article.

Life Expectancy for Men and Women The world life expectancy for men in 2016 was 69.8 years, while the world life expectancy for women was 74.2 years (World Health Organization, 2018). In all countries of the world, life expectancy for men now exceeds that for women (World Health Organization, 2018). The largest gender gap in life expectancy in 2016 was in Russia with 10.8 years difference (Wang et al., 2017). An increase in the gap between men and women’s life expectancy emerged in the 20th century at approximately the same time the dramatic increase in life expectancy occurred (Beltrán-Sánchez et al., 2015). Explanations of the gender difference in life expectancy include biological, genetic, and health behavioral factors (Austad, 2006). A biological perspective implicates men and women’s differential inflammatory response and men’s greater vulnerability to cardiovascular diseases and the hormonal differences between men and women (Beltrán-Sánchez et al., 2015). A genetic perspective posits that sex differences are situated in the X and Y chromosomes (Finch, 2010). A health behavioral perspective links differences to health behaviors and social roles. One of the most frequently cited reasons is the differential uptake of smoking as a significant contributor to the gender difference in life expectancy (National Research Council, 2011). What is clear is that the difference in maledfemale life expectancy varies markedly across countries and over time periods (Crimmins et al., 2019a).

Regional Life Expectancy Life expectancy around the world has increased dramatically in the past century, yet different parts of the world have had different trends. In this section, we discuss life expectancy in each World Health Organization (WHO) region based on the 2016 data. Regional variations in life expectancy are substantial. In 2016, all countries with life expectancy greater than 80 years are in the European Region, Region of Americas, and the Western Pacific Region, whereas all countries with life expectancy less than 60 are located in the Africa Region, with one exception - Somalia in the Eastern Mediterranean Region (World Health Organization, 2018).

European region Life expectancy in the European Region was 77.5 years in 2016, which is the highest among all WHO regions (World Health Organization, 2018). Most countries with life expectancy higher than 80 years are in this region. Europe represents the classical model of the epidemiologic transition with a gradual pace of change in life expectancy occurring over centuries (Omran, 1971). The average gap between the highest and lowest life expectancy within Europe since the 1990s has been 16 years on average with the Eastern European countries having lower life expectancy than the Northern and Western (WHO Regional Office for Europe, 2015). Divergence in European life expectancy began when mortality from infectious diseases began to decline in Western Europe and countries in Southern and Eastern Europe fell behind the Northern and Western countries (Mackenbach, 2013). Recently, this divergence became acute in Eastern Europe following the collapse of the Soviet Union when mortality declines from cardiovascular diseases did not progress as much as in other regions in Europe (Mackenbach, 2013). The gap in national incomes across countries within Europe has been identified as an important determinant of regional variation in life expectancy. It is also true that smoking patterns in Europe, with less smoking among women in the Mediterranean region, has caused differentials within Europe to shift in recent decades. The lack of smoking among women in the Southern countries has raised their life expectancy relative to the higher smoking Northern countries.

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Western Pacific region This region includes the countries with the highest life expectancies, such as Japan (84.2 years), Singapore (82.9 years), Australia (82.9 years), Republic of Korea (82.7 years), and New Zealand (82.2 years) (World Health Organization, 2018). Compared to Europe and North America, the epidemiological transition occurred much later but at a more accelerated pace in the Western Pacific Region (Omran, 1971). For instance, Sweden took 80 years to move from Stage 1 (the age of pestilence and famine) to Stage 3 (the age of degenerative and man-made diseases) from 1874 to 1954, while Japan took only 35 years from 1935 to 1970 (Santosa et al., 2014).

Region of the Americas There is great variability in life expectancy in this region. In 2016, the lowest life expectancy was observed in Haiti (63.5 years), whereas Canada had the highest life expectancy of 82.8 years. The United States ranked 5th (78.5 years), following Canada, Costa Rica, Chile, and Cuba (World Health Organization, 2018). Life expectancy in the United States is relatively low when compared to other high-income countries (National Research Council, 2011). Smoking and obesity have been identified as major contributing factors to the poor performance of the United States (National Research Council, 2011). The US life expectancy dropped during 2014–15 and 2015–16 because of the recent increases in mortality from unintentional injuries, suicide, and substance abuse (Ho and Hendi, 2018). In fact, there appear to be systematic root causes, rather than a single factor, that are responsible for the low level and slow improvement of life expectancy in the United States (Woolf et al., 2018). Many Latin American and the Caribbean countries are facing the dual burden of relatively high infectious diseases and chronic diseases because they experienced a relatively recent demographic transition (Palloni and Pinto-Aguirre, 2011).

Africa region Life expectancy in the region was 61.2 years in 2016, the lowest life expectancy in the world (World Health Organization, 2018), but this region reported the highest rate of increase in life expectancy in recent years, 5.1% from 2010 to 2015 (World Health Organization, 2017). This was mostly due to the reduction in infant mortality and improvement in addressing HIV/AIDS mortality which has had a significant effect in this region. The causes of adult mortality remain dominated by infectious diseasesdlower respiratory infections (10.9%), HIV/AIDS (8.3%), and diarrheal diseases (7.0%) (World Health Organization, 2017).

South-East Asia and Eastern Mediterranean region In 2016, no country in these two regions had life expectancy of more than 80 years. In the South-East Asia Region, life expectancy ranged from 66.8 (Myanmar) to 78.4 (Maldives) years in 2016. In the Eastern Mediterranean Region, the countries with the highest life expectancy in 2016 are Bahrain (79.1 years), Qatar (78.1 years) and the United Arab Emirates (77.2 years), whereas Somalia has a life expectancy among the lowest in the world, 55.4 years in 2016 (World Health Organization, 2018).

Health Expectancies Health expectancy is a natural extension of life expectancy. In this era of much longer life expectancy, an important question has arisen: Are we living longer healthy lives (Crimmins, 2015)? Have we achieved a compression of morbidity into a shorted period of life, or rather seen longer lives with disabilities and diseases? These questions led to the development and implementation of the concept of healthy life expectancy. As mortality declines and life expectancy increases, the link between mortality and morbidity changes. Before the epidemiological transition where mortality was heavily determined by infectious conditions, people got an infectious disease and either lived or dies in a relatively short period of time. Now that most mortality is due to chronic conditions, people get diseases and typically are treated and live for an extensive period of time with the disease even if they die from it. A focus on only mortality for monitoring population health can then underestimate the burden of ill-health or disability caused by chronic disabling diseases. Therefore, indicators of population health that can capture both mortality and morbidity are desirable because they include indicators of the quantity of years lived in various states of health.

Research Using Health Expectancy Since the concept of combining schedules of mortality and morbidity was introduced in the 1960s (Mathers, 2002; Sanders, 1964), health expectancy has joined life expectancy for monitoring population health, evaluating health policy, and forecasting the needs of care. In the last 30 years, the International Network on Health Expectancy and the Disability Process (REVES, Réseau Espérance de Vie en Santé) has promoted the use of health expectancy as a population health indicator and research to clarify definitions, measurement, calculation, and comparison of health expectancy globally. Health expectancies have been calculated for more than 60 countries (Jagger and Robine, 2011). In 2005, the European Union started to use disability-free life expectancy, or healthy life years, to monitor progress toward objectives such as the 2000 Lisbon Strategy (Bogaert et al., 2018). In 2015, the World Health Organization set “optimizing functional ability” as the goal of healthy aging (World Health Organization, 2015). Significant research has used the healthy life years approach to clarify the effect of risk factors for disease and disability on the length of healthy life. At the individual level, low education (Mäki et al., 2013; Crimmins and Saito, 2001), low occupational status

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(Cambois et al., 2001), less income (Wilkins and Adams, 1983), unemployment (Jagger et al., 2016) smoking and alcoholic drink (Mehta and Myrskyla, 2017), obesity (Reynolds et al., 2005), and physical inactivity (Ferrucci et al., 1999) are associated with fewer healthy life years, suggesting that these shared-determinants of multiple health outcomes are critical for reducing the burden of disease and disability in the future (Guzman-Castillo et al., 2017). At the macro-level, Gross Domestic Product and expenditure on elderly care are positively associated with the length of healthy life expectancy (Jagger et al., 2016). Much of the research has been oriented to understanding time trends in healthy life and their relationship to time trends in life expectancy. How they relate depends on the years of observation, the measure of health examined, and the composition of the study population (Crimmins et al., 2016). Some studies representing a number of high-income countries report that the length of life with moderate and severe disability has been reduced since the 1980s (Perenboom et al., 2004). Although the length of both life with disability and disabled life tends to be extended as life expectancy increases, in some studies the increase in disability-free life was somewhat greater than the increase in disabled life at older ages resulting in some compression of morbidity as measured by disability (Cambois et al., 2001; Crimmins et al., 2016). However, this improvement does not apply to all population subgroups. In the United States, increase in total life expectancy and years free of disability has been larger for men than women (Freedman et al., 2016). Individuals with higher socioeconomic status are more likely to experience a compression of morbidity than those of lower status (Crimmins and Saito, 2001). Where there is improvement in disabled life expectancy in the United States, reductions are due to declines in disability associated with cardiovascular disease and vision problems (Chernew et al., 2016). If the length of life with chronic diseases is used as an indicator of healthy life, there is no hint of decline in the length and proportion of life spent with most major diseases (Crimmins and Beltrán-Sánchez, 2011). Declines in mortality have resulted in the increase in survival of people with diseases at older ages through delaying the progression of disease (Beltrán-Sánchez et al., 2008). Consequently, the prevalence of chronic diseases is rising but diseases have fewer consequences, such as disability and early mortality (Crimmins and Beltrán-Sánchez, 2011). Older adults in more recent years actually have more diseases before death compared to those in earlier years, suggesting that older persons now experience a greater burden from diseases which impart lower mortality risk (Beltrán-Sánchez et al., 2016). Improving morbidity and decreasing the length of unhealthy life require prevention or delay of the onset of disease, functioning problems, and disability (Crimmins et al., 1994). Recent studies show that the incidence of a number of disabling diseases including heart disease, myocardial infarction, stroke, and dementia has declined in the older population (Jagger et al., 2016; Crimmins et al., 2019b), indicating some improvement of population health that will lead to reductions in the length of life with disease.

Measures of Health Expectancy Unlike life expectancy which is based only on mortality, health expectancy includes information on life expectancy in different health states; so it requires information on health states. There are as many health expectancy measures as there are measures of health. Research on health expectancy has used information on diseases, conditions, impairments, and functional loss or disability together with mortality rates to define health states and compute health expectancy. We discuss some of the measures of health below.

Disability The most commonly used health expectancy is disability-free life expectancy. Much work on disability-free life expectancy has concentrated on estimates of the length of life able to perform activities of daily living (ADLs), a measure of an individual’s ability to carry out essential activities for an independent life at older ages. ADLs include activities such as bathing, dressing, eating, toileting, transferring from/to bed/chair, and walking inside the home. Ability to perform instrumental activities of daily living (IADLs) is another widely used disability measure on which estimates of disability-free life expectancy are based. IADL disability is based on activities such as preparing meals, shopping for personal items, using a telephone, taking medication, and managing money. Some studies include both ADLs and IADLs to construct a composite measure indicating different levels of disability, for instance, able to perform all ADLs and IADLs, unable to perform one or more of the ADLs, able to perform all ADLs but unable to perform one or more IADLs (Crimmins et al., 2009). Unlike measures based on ADLs and IADLs which are based on multiple activities, the Global Active Limitation Indicator (GALI) is a global instrument for measuring disability based on the question “For at least the past six months, to what extent have you been limited because of a health problem in activities people usually do? Would you say you have been severely limited, limited but not severely, not limited at all?” GALI has been used to make health expectancy comparisons across Europe (Van Oyen et al., 2006), and is now included in major European health surveys such as the Survey of Health, Aging and Retirement in Europe (SHARE) and European Health Interview Survey (EHIS). Since 2004, GALI became the underlying measure of the European indicator “Healthy Life Years (HLY)” (Bogaert et al., 2018).

Diseases and conditions Life with and without disease can also be used to reflect health. Stenholm et al. combined a set of chronic diseases including cardiovascular disease, cancer, respiratory disease, and diabetes and estimated life expectancy free of chronic disease for older persons (Stenholm et al., 2017). Life expectancy with and without hypertension (Tareque and Saito, 2017), diabetes (Cunningham

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et al., 2011), cardiovascular disease (Franco et al., 2005), heart disease (Crimmins et al., 2008), and stroke (Van Den Hout and Matthews, 2010) have also been calculated. The length of life with cognitive impairment or dementia has been calculated in many countries to reflect the growing burden of these conditions in aging populations. Initial studies on dementia-free life expectancy used diagnostic criteria for senile dementia (Ritchie and Polge, 2002). Recent research on this topic has been based on the assessment of cognitive functioning using a range of tests of cognitive abilities in population health surveys. For instance, Jagger and colleagues use the score of the Mini-Mental State Examination (MMSE) to define three cognitive impairment groups: severe impairment, mild impairment, or no impairment (Jagger et al., 2016). Crimmins and colleagues use a summary cognitive scores based on tests of immediate and delayed recall of 10 words, 5 trials of Serial 7s, and backward counting along with proxy responses for those who could not do the tests to classify individuals as having good cognition, dementia, or cognitive impairment without dementia (Crimmins et al., 2018). They then computed cognitively healthy life expectancy, life expectancy with cognitive impairment without dementia, and life expectancy with dementia.

Perceived health Self-rated health provides another indicator that can be used to estimate the length of perceived healthy life. It is based on a single question asking individuals to evaluate their general health status on a five-point scale. “Would you say your health is excellent, very good, good, fair, or poor.” Numerous studies have shown that self-perceived health is related to a variety of health outcomes including physiological dysregulations (Jylha et al., 2006), morbidity onset (Latham and Peek, 2013), and mortality (Jylha, 2009). When self-rated health is the measure of health in health expectancy research, life expectancy “with good or better perceived health” is typically the measure of “healthy life expectancy.”

Calculation of Health Expectancy The choice of the method largely depends on the type of data to be used. When cross-sectional data for a population are available, a prevalence-based method, exemplified by the Sullivan method, is generally applied. When longitudinal data are available, other methods can be applied. In this section, we introduce the two commonly used methods, the Sullivan method and multistate life table method, and then briefly discuss two alternative approaches: the microsimulation approach and the Bayesian approach.

Sullivan method The Sullivan method is the most commonly used method for calculating health expectancy. It is based on the age-specific prevalence of ill-health from a cross-sectional survey of the target population. This is usually combined with a period life table for the same population for the same time period as the survey. The Sullivan method provides a distribution of the years of life lived in the life table into healthy and non-healthy years based on the current prevalence of health in the surveyed population. Below is a brief discussion of the computational steps involved in estimating healthy life expectancy (Saito et al., 2014) Using standard notations of for the life table parameters indicated above, nPREVx denotes the prevalence rates of the unhealthy population between age x and x þ n, we can calculate health expectancies as follows: First, the age-specific prevalence rates of the unhealthy population are used to calculate the person-years lived in the unhealthy status: U n Lx

¼ n Lx  n PREV x

where U denotes unhealthy status. Then, the total person-years lived in an unhealthy status after age x are calculated by summing the person-years lived in the unhealthy status for each age interval from exact age x X TxU ¼ LU x The number of expected years lived in the unhealthy status is computed by dividing the total person-years lived in unhealthy status after age x by lx (from life table). U eU x ¼ Tx =lx

Since total life expectancy at exact age x (exT) is given by the life table, the number of expected years lived in a healthy state at exact age x (exH) can be obtained by subtracting unhealthy life expectancy at exact age x (exU) from total life expectancy at exact age x T U eH x ¼ ex  ex

A detailed calculation guide of the Sullivan Method is available at the REVES website including variance estimation (https:// reves.site.ined.fr/fichier/s_rubrique/20182/sullivan.guide.pre.final.oct2014.en.pdf). Because a period life table for the target population is the source of mortality data, the Sullivan method generally assumes that mortality rates are the same for all individuals, regardless of health status. Because the Sullivan method is straightforward to apply with data that are regularly available, it has been used to calculate health expectancies for many countries around the world (Jagger and Robine, 2011). Another advantage of the Sullivan method is that it as a prevalence-based method that is based on large

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population samples, it may be less influenced by survey design and analytic strategies than some of the methods discussed below (Saito et al., 1991).

Multistate life table method The multistate life table method provides an approach to modeling the dynamic processes of health change that underlie the prevalence numbers used in Sullivan-based life tables. The modeling of the current change in health state reflects current processes. In addition, the modeling of mortality from each health state allows mortality to vary with health. This approach characterizes population movement overtime in a finite, discrete, and mutually exclusive state spaces as Markov processes (Rogers and Rogers, 1989). The multistate method requires longitudinal data for the calculation of transition rates between health states. As an example, assuming there are two states healthy and unhealthy and movement can be between these states and into death which is called an absorbing state the model of transitions is displayed in Fig. 1. In this simplest situation, there are six possible transitions in total becoming unhealthy, returning to healthy, staying in the same state, and dying. The first step is to estimate an age-specific set of observed transition rates or probabilities. If transition rates are estimated, the matrix of transition rates M(x, n) should then be converted to a matrix of transition probabilities P(x, n) (Rogers and Ledent, 1976). The computed transition probability matrix then allows the calculation of the survivorship matrix and the matrix of person-years lived in health states between age x and x þ n, denoted as L(x, n). Then, the expected transfers between health states for each age x can be estimated (Crimmins et al., 1994): Dðx; nÞ ¼ Lðx; nÞ∙Mðx; nÞ Then, life expectancy in state i at exact age x can be calculated as follows: eix ¼

Txi lx

where Txi is the number of person-years lived in state i after exact age x by individuals in the cohort who survived to age x. Total life expectancy is the sum of life expectancies in each health state. Multistate life tables can be population-based or status-based. The assumption for the population-based method is that the population enters the life table with the distribution by health states observed at the radix age, allowing the population-based life table to represent potential lifecycle events for the whole population. The status-based method assumes that every individual enters the life table in a given health state; thus, the status-based health expectancy is a conditional health expectancy, depending on the health status at the reference age (Beltrán-Sánchez et al., 2008). The multi-state measure of healthy life expectancy has many desirable features but it also has some limitations. Data for estimating transitions can quickly become sparse with multiple health states. In addition, parameterized models often affect results more than is desirable.

Other methods Several recent innovations for calculating health expectancy have been introduced including the microsimulation approach and the Bayesian approach. The basic approach of microsimulation can be thought of as a random experiment for each individual in a population. The microsimulation approach starts with estimating transition probabilities using a discrete-time Markov chain model, and then uses microsimulation to simulate individuals’ life histories based on the estimated transition probabilities. The results of the simulation are then used to construct life tables (Beltrán-Sánchez et al., 2016). Because health expectancies calculated by the microsimulation method are based on individual-level analyses of events and relationships they allow assessment of variability in the process within the population (Crimmins et al., 1994). While the microsimulation method permits flexibility in terms of the inclusion of covariates and the handling of time intervals between transitions, widths of intervals for health expectancies are highly dependent on the assumptions regarding the frequency of transitions between states (Crimmins et al., 2019b). Lynch and Brown (2005) introduced a Bayesian Markov chain Monte Carlo method that allows for the relatively simple construction of interval estimates and more flexibility in conducting formal hypothesis tests (Crimmins et al., 2019b).

Healthy (H)

Unhealthy (U)

Dead (D) Fig. 1 Description of possible transitions among health states. Reprinted from Saito Y, Robine J, Crimmins EM. (2014). The methods and materials of health expectancy. Statistical Journal of the IAOS 30(3): 209–223. Page 215, with permission from IOS Press. The publication is available at IOS Press through https://doi.org/ https://doi.org/10.3233/SJI-140840

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Variants of healthy life expectancy depend not only on the methods but on other aspects of the measures. The World Health Organization and the Global Burden of Disease uses a variant of healthy life expectancy (HALE) and disability-adjusted life expectancy (DALE) to provide indicators of population health for its member countries. HALE and DALE are calculated based on the Sullivan method but weights are assigned to the health states based on the severity of ill health. This means that years in less than perfect health are not counted as full years of life but are “adjusted” for ill health and disability. In these estimates years of life do not add to the total years lived. The idea of incorporating weights is to adjust total life expectancy by the amount of time spent in imperfect health. Specifically, HALE is calculated by estimating years lived with disability multiplied by weights representing the effect of the disability in reducing the value of a year of life and then subtracting disabled years from total life expectancy (World Health Organization, 2018); DALEs are determined by estimating years lived with a disability of specified severity and duration for each condition, and then summing over all conditions (Mathers et al., 2000).

Available Software to Compute Health Expectancy A number of computer software and programs have been developed to calculate health expectancies using panel data. We briefly introduce some currently available programs. IMaCh (for Interpolated Markov Chain) was designed to estimate transition probabilities from longitudinal surveys and calculate health expectancy and corresponding variance estimators. IMaCh estimates transition probabilities using a discrete-time embedded Markov chain approach pioneered by Laditka and Wolf (1998). This approach recognizes that changes in health status may not be observed between waves. Details of the method are described by Lièvre et al. (2003). The required input data for IMaCh which must be prepared in a specified format include month and year of birth, month and year of each interview, and the health state including death, at each wave. IMaCh does not require a fixed interval length and can incorporate information from cases with missed interviews using an interpolation method. A sampling weight can be applied but it does not allow for adjusting bias in variance estimation arising from a clustered survey design. Missing values are allowed for the month of birth and date of interview. It can incorporate both time-invariant and time-variant covariates, but covariates should be dichotomous. The IMaCh package and the detailed manual for this program are available at http://euroreves.ined.fr/imach/. IMaCh is a standalone package and can be run on Windows, MacOS/X, and Linux. The SPACE (Stochastic Population Analysis for Complex Events) program is a package of SAS programs which can be used to compute health expectancies. It was originally developed by Liming Cai when he was at the National Center for Health Statistics, US Centers for Disease Control and Prevention, and now is maintained and updated by Chi-Tsun Chiu at Academia Sinica, Taiwan. The SPACE program permits users to choose a method for estimating health expectancies; it uses multinomial logistic regressions to estimate transition probabilities and uses hazard regression models to estimate transition rates. Health expectancy can be calculated using the deterministic approach or microsimulation. It can incorporate complex survey design factors such as weighting, stratification, and clustering. Details about this method and its application can be found in Cai et al. (2010). The SPACE program and its manual are available at http://sites.utexas.edu/space/. ELECT (Estimation of Life Expectancies using Continuous-Time multi-state survival models) is a set of functions written in R to construct multistate life tables developed by Van den Hout and is available from the CRAN website. ELECT estimates transition rates by using the msm package in R and then estimates total life expectancy and life expectancies in different health states. A website for ELECT including a manual and example R code and data is available at http://www.ucl.ac.uk/ucakadl/ELECT/ indexELECT.html GSMLT (Gibbs Sampler for Multistate Life Tables Software) was introduced by Lynch and Brown using the Bayesian approach. GSMLT estimates a multivariate hazard model for generating smoothed transition probabilities, and then generating multistate life tables (Lynch and Brown, 2005). The programs are available from the developer. A detailed manual of the GSMLT software can be found at https://reves.site.ined.fr/fichier/s_rubrique/20183/lynch_brown_gsmltmanual.en.pdf

The Future of Life Expectancy and Health Expectancy World life expectancy increased by more than twofold in the past two centuries (Oeppen and Vaupel, 2002), although the pace of growth has slowed since 1950 in most countries (Cardona and Bishai, 2018). Predictions of future life expectancy depend on what happens to mortality at the oldest ages. In the past, researchers suggested that the limit to human life expectancy might be 85 years (Olshansky et al., 2001), a value which has now been exceeded in some populations in the 21st century (Christensen et al., 2009). Other researchers have suggested that life expectancy will continue to increase as it has in the past eventually reaching 100 years (Christensen et al., 2009). On the other hand, Bongaarts (2009), who bases his projection on recent patterns of decline in senescent mortality, expects more modest but regular gains in life expectancy (Bongaarts, 2009). An analysis of mortality data from eight European countries for cohorts born between 1800 and 1920 showed that the age-specific increase in the mortality rate indicated by the Gompertz model parameter would need to be 50% lower for life expectancy to increase to 100 which would be a fundamental change in the rate of aging (Finch et al., 2013). Potential improvement in life expectancy from even the elimination of cancer or heart disease are not sufficient to raise life expectancy over 100, only gains from delaying the rate of aging substantially could increase life expectancy markedly (Goldman et al., 2013).

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We are generally optimistic that future cohorts of older adults will be healthier at a given age than those who precede them; this will be necessary to maintain a balance between healthy life and unhealthy life expectancy. Reductions in age specific rates of onset of health conditions will be required in order to really reduce the proportion of time with unhealthy life expectancy (Crimmins et al., 1994). Research on health trends in recent decades has documented the decreases in the incidence of some disabling diseases including dementia, and severe disability in high-income countries (Crimmins et al., 2018, 2019b; Freedman, 2018). It is suggested that increases in levels of educational attainment and the use of assistive technology in older populations are likely to have been responsible in part for these improvements (Freedman, 2018). New medical technologies for early diagnosis and prevention can also aid in delaying disease progression. However, the escalating global epidemic of obesity may prevent older persons from reaping the benefits of other factors working to improve health.

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Human population growth and the demographic transition. Philosophical Transactions of the Royal Society, B: Biological Sciences 364 (1532), 2985–2990. Cai, L., Hayward, M.D., Saito, Y., Lubitz, J., Hagedorn, A., Crimmins, E., 2010. Estimation of multi-state life table functions and their variability from complex survey data using the SPACE program. Demographic Research 22 (6), 129–158. Cambois, E., Robine, J., Hayward, M.D., 2001. Social inequalities in disability-free life expectancy in the French male population, 1980–1991. Demography 38 (4), 513–524. Cardona, C., Bishai, D., 2018. The slowing pace of life expectancy gains since 1950. BMC Public Health 18 (1), 151. Chernew, M., Cutler, D.M., Ghosh, K., Landrum, M.B., 2016. Understanding the improvement in disability free life expectancy in the US elderly population. In: National Bureau of Economic Research. Christensen, K., Doblhammer, G., Rau, R., Vaupel, J.W., 2009. Ageing populations: The challenges ahead. 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Life with and without heart disease among women and men over 50. Journal of Women & Aging 20 (1–2), 5–19. Crimmins, E.M., Hayward, M.D., Hagedorn, A., Saito, Y., Brouard, N., 2009. Change in disability-free life expectancy for Americans 70 years old and older. Demography 46 (3), 627–646. Crimmins, E.M., Zhang, Y., Saito, Y., 2016. Trends over 4 decades in disability-free life expectancy in the United States. American Journal of Public Health 106 (7), 1287–1293. Crimmins, E.M., Saito, Y., Kim, J.K., Zhang, Y.S., Sasson, I., Hayward, M.D., 2018. Educational differences in the prevalence of dementia and life expectancy with dementia: Changes from 2000 to 2010. The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences 73 (Suppl_1), S28. Crimmins, E.M., Shim, H., Zhang, Y.S., Kim, J.K., 2019a. Differences between men and women in mortality and the health dimensions of the morbidity process. Clin Chem 65 (1), 135–145. Crimmins, E.M., Zhang, Y.S., Kim, J.K., Levine, M.E., 2019b. Changing disease prevalence, incidence, and mortality among older cohorts: The Health and Retirement study. Journal of Gerontology: Medical Sciences. Forthcoming. Cunningham, S.A., Riosmena, F., Wang, J., Boyle, J.P., Rolka, D.B., Geiss, L.S., 2011. Decreases in diabetes-free life expectancy in the U.S. and the role of obesity. Diabetes Care 34 (10), 2225–2230. Cutler, D., Deaton, A., Lleras-Muney, A., 2006. The determinants of mortality. Journal of Economic Perspectives 20 (3), 97–120. Ferrucci, L., Izmirlian, G., Leveille, S., Phillips, C.L., Corti, M.C., Brock, D.B., et al., 1999. Smoking, physical activity, and active life expectancy. American Journal of Epidemiology 149 (7), 645–653. Finch, C.E., 2010. The biology of human longevity: Inflammation, nutrition, and aging in the evolution of lifespans. Elsevier. Finch, C.E., Beltrán-Sánchez, H., Crimmins, E.M., 2013. Uneven futures of human lifespans: Reckonings from Gompertz mortality rates, climate change, and air pollution. Gerontology 60 (2), 183–188. Franco, O.H., de Laet, C., Peeters, A., Jonker, J., Mackenbach, J., Nusselder, W., 2005. Effects of physical activity on life expectancy with cardiovascular disease. Archives of Internal Medicine 165 (20), 2355–2360. Freedman, V., 2018. The Demography of late-life disability. In: Hayward, M.D., Majmundar, M.K. (Eds.), Future directions for the Demography of aging: Proceedings of a workshop. National Academies Press, Washington DC. Freedman, V.A., Wolf, D.A., Spillman, B.C., 2016. Disability-free life expectancy over 30 years: A growing female disadvantage in the US population. American Journal of Public Health 106 (6), 1079–1085. Goldman, D.P., Cutler, D., Rowe, J.W., Michaud, P.C., Sullivan, J., Peneva, D., et al., 2013. Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Affairs 32 (10), 1698–1705. Guzman-Castillo, M., Ahmadi-Abhari, S., Bandosz, P., Capewell, S., Steptoe, A., Singh-Manoux, A., et al., 2017. Forecasted trends in disability and life expectancy in England and Wales up to 2025: A modelling study. The Lancet Public Health 2 (7), e313. Ho, J.Y., Hendi, A.S., 2018. Recent trends in life expectancy across high income countries: Retrospective observational study. BMJ 362, k2562. Human Mortality Database (2018) Available at: https://www.mortality.org. Accessed Sept 11, 2018.

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Jagger, C., Robine, J., 2011. Healthy life expectancy. International handbook of adult mortality. Springer, pp. 551–568. Jagger, C., Matthews, F.E., Wohland, P., Fouweather, T., Stephan, B.C., Robinson, L., et al., 2016. A comparison of health expectancies over two decades in England: Results of the cognitive function and ageing study I and II. The Lancet 387 (10020), 779–786. Jylha, M., 2009. What is self-rated health and why does it predict mortality? Towards a unified conceptual model. Social Science & Medicine 69 (3), 307–316. Jylha, M., Volpato, S., Guralnik, J.M., 2006. Self-rated health showed a graded association with frequently used biomarkers in a large population sample. Journal of Clinical Epidemiology 59 (5), 465–471. Laditka, S.B., Wolf, D.A., 1998. New methods for analyzing active life expectancy. Journal of Aging and Health 10 (2), 214–241. Latham, K., Peek, C.W., 2013. Self-rated health and morbidity onset among late midlife U.S. adults. The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences 68 (1), 107–116. Lièvre, A., Brouard, N., Heathcote, C., 2003. The estimation of health expectancies from cross-longitudinal surveys. Mathematical Population Studies 10 (4), 211–248. Lynch, S.M., Brown, J.S., 2005. Gibbs sampler for multistate life tables software (GSMLT v.90). Mackenbach, J.P., 2013. Convergence and divergence of life expectancy in Europe: A centennial view. European Journal of Epidemiology 28 (3), 229–240. Mäki, N., Martikainen, P., Eikemo, T., Menvielle, G., Lundberg, O., Östergren, O., et al., 2013. Educational differences in disability-free life expectancy: A comparative study of longstanding activity limitation in eight European countries. Social Science & Medicine 94, 1–8. Mathers, C.D., 2002. Health expectancies: An overview and critical appraisal. In: Summary measures of population health: Concepts, ethics, measurement and applications. World Health Organization, Geneva, pp. 177–204. Mathers, C.D., Sadana, R., Salomon, J.A., Murray, C.J., Lopez, A.D., 2000. Estimates of DALE for 191 countries: Methods and results. In: Global programme on evidence for health policy working paper no. 16. Mehta, N., Myrskyla, M., 2017. The population health benefits of a healthy lifestyle: Life expectancy increased and onset of disability delayed. Health Affairs 36 (8), 1495–1502. National Research Council, 2011. Committee on population. Explaining divergent levels of longevity in high-income countries. National Academies Press. Oeppen, J., Vaupel, J.W., 2002. Broken limits to life expectancy. Science 296 (5570), 1029–1031. Olshansky, S.J., Ault, A.B., 1986. The fourth stage of the epidemiologic transition: The age of delayed degenerative diseases. The Milbank Quarterly 355–391. Olshansky, S.J., Carnes, B.A., Desesquelles, A., 2001. Demography. Prospects for human longevity. Science 291 (5508), 1491–1492. Omran, A.R., 1971. The epidemiologic transition: A theory of the epidemiology of population change. The Milbank Memorial Fund Quarterly 49 (4), 509–538. Palloni, A., Pinto-Aguirre, G., 2011. Adult mortality in Latin America and the Caribbean. In: Rogers, R.G., Crimmins, E.M. (Eds.), International handbook of adult mortality. Springer Netherlands, Dordrecht, pp. 101–132. Perenboom, R.J., Van Herten, L.M., Boshuizen, H.C., Van Den Bos, G.A., 2004. Trends in disability-free life expectancy. Disability and Rehabilitation 26 (7), 377–386. Reynolds, S.L., Saito, Y., Crimmins, E.M., 2005. The impact of obesity on active life expectancy in older American men and women. Gerontologist 45 (4), 438–444. Riley, J.C., 2005. Estimates of regional and global life expectancy, 1800–2001. Population and Development Review 31 (3), 537–543. Ritchie, K., Polge, C., 2002. Mental health expectancy. In: Determining health expectancies, pp. 175–182. Rogers, A., Ledent, J., 1976. Increment-decrement life tables: A comment. Demography 13 (2), 287–290. Rogers, A., Rogers, R.G., 1989. Branch LG. A multistate analysis of active life expectancy. Public Health Reports 104 (3), 222–226. Saito, Y., Crimmins, E.M., Hayward, M.D., 1991. Stability of estimates of active life expectancy using two methods of life table construction. Cahiers québécois de démographie 20 (2), 291–327 autommme. Saito, Y., Robine, J., Crimmins, E.M., 2014. The methods and materials of health expectancy. Statistical Journal of the IAOS 30 (3), 209–223. Sanders, B.S., 1964. Measuring community health levels. American Journal of Public Health and the Nations Health 54 (7), 1063–1070. Santosa, A., Wall, S., Fottrell, E., Högberg, U., Byass, P., 2014. The development and experience of epidemiological transition theory over four decades: A systematic review. Global Health Action 7 (1), 23574. Stenholm, S., Head, J., Aalto, V., Kivimaki, M., Kawachi, I., Zins, M., et al., 2017. Body mass index as a predictor of healthy and disease-free life expectancy between ages 50 and 75: A multicohort study. International Journal of Obesity 41 (5), 769–775. Tareque, M.I., Saito, Y., 2017. Gender differences in hypertension-free life expectancy in Bangladesh. International Journal of Population Studies 3 (1), 110–120. Van Den Hout, A., Matthews, F.E., 2010. Estimating stroke-free and total life expectancy in the presence of non-ignorable missing values. Journal of the Royal Statistical Society: Series A (Statistics in Society) 173 (2), 331–349. Van Oyen, H., Van der Heyden, J., Perenboom, R., Jagger, C., 2006. Monitoring population disability: Evaluation of a new global activity limitation Indicator (GALI). Sozial- und Präventivmedizin 51 (3), 153–161. Vaupel, J.W., 2010. Biodemography of human ageing. Nature 464 (7288), 536. Wang, H., Abajobir, A.A., Abate, K.H., Abbafati, C., Abbas, K.M., Abd-Allah, F., et al., 2017. Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: A systematic analysis for the global burden of disease study 2016. The Lancet 390 (10100), 1084–1150. WHO Regional Office for Europe, 2015. The European health report 2015: Targets and beyond-reaching new frontiers in evidence. WHO Regional Office for Europe. Wilkins, R., Adams, O.B., 1983. Health expectancy in Canada, late 1970s: Demographic, regional, and social dimensions. American Journal of Public Health 73 (9), 1073–1080. Wilmoth, J.R., 2000. Demography of longevity: Past, present, and future trends. Experimental Gerontology 35 (9–10), 1111–1129. Woolf, S.H., Chapman, D.A., Buchanich, J.M., Bobby, K.J., Zimmerman, E.B., Blackburn, S.M., 2018. Changes in midlife death rates across racial and ethnic groups in the United States: Systematic analysis of vital statistics. BMJ 362, k3096. World Health Organization, 2015. World report on ageing and health. 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Further Reading Preston, S., Heuveline, P., Guillot, M., 2000. Demography: Measuring and modeling population processes, 1st edn. Wiley-Blackwell. Rogers, R.G., Crimmins, E.M. (Eds.), 2011. International handbook of adult mortality, vol. 2. Springer, Dordrecht. Saito, Y., Robine, J.M., Crimmins, E.M., 2014. The methods and materials of health expectancy. Statistical Journal of the IAOS 30 (3), 209–223. Swanson, D.A., Siegel, J.S., 2004. The methods and materials of Demography, 2nd edn. US Academic Press. Robine, J.M., Jagger, C., Mathers, C.D., Crimmins, E.M., Suzman, R.M. (Eds.), 2003. Determining health expectancies. John Wiley & Sons. Robine, J.M. (Ed.), 1993. Calculation of life expectancies in health, vol. 226. John Libbey Eurotext (in French).

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Relevant Websites Gapminderdhttps://www.gapminder.org/tools/#$chart-type ¼ bubbles Human mortality databasedhttps://www.mortality.org/. Réseau Espérance de Vie en Santé (REVES)dhttps://reves.site.ined.fr/en/ Institute for Health Metrics and Evaluation (IHME) at University of Washingtondhttps://vizhub.healthdata.org/mortality/ Global Burden of Diseasedhttp://www.healthdata.org/gbd U.S. Census Bureau International Data Basedhttps://www.census.gov/data-tools/demo/idb/informationGateway.php. WHO Global Health Observatory Datadhttp://www.who.int/gho/en/

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Defining Loneliness Loneliness in Data Consequences of Loneliness Intervening in Loneliness General Analysis “Always Accompanied” Programme Conclusions References

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Defining Loneliness Loneliness had been the sole concern of the arts and philosophy until about half a century ago and had little repercussion in the sciences (Sønderby, 2013). Extremely different authors have tried to define and understand the concept of loneliness over the past few decades and some have mercilessly reduced it to superficial questions. For example, those who compare loneliness with isolationdRubenstein and Shaver (1980, 1982) were already warning us of this danger when, in referring to loneliness, they stated that social psychology is “unfortunately remarkable for its ability to reduce profound and fascinating human issues to rather superficial and uninteresting generalizations”dand others who seek a more profound, multifaceted view. In short, loneliness can be approached in many nonmutually exclusive ways and these must be understood and conceptualized by integrating diverse complementary perspectives. Loneliness is therefore: i. A feeling of isolation that can be objective or subjective, metaphysical or communicative, existential, social, etc., and it is always present and a core part of the personal, nontransferable experience of what is known as “loneliness” (Stein and Tuval-Mashiach, 2015). ii. Loneliness can also be deprivation or hardship when referring to the feelings of emptiness or abandonment associated with the absence of intimate relations (de Jong Gierveld, 1987). In other words, loneliness has a strong relational component at its root. iii. Loneliness is the result of a cognitive discrepancy between the relationships that a person has and those one is expected to have, the appearance and/or maintenance of which depend on the person’s own subjective evaluation of the quality and quantity of one’s own social relationships (Peplau and Perlman, 1982; Yanguas et al., 2018a). iv. Loneliness is always accompanied by a series of emotional aspects, such as sadness, melancholy, frustration, shame or despair (de Jong Gierveld, 1987; de Jong Gierveld et al., 2015; Yanguas et al., 2018a), and these are usually linked to the presence of a deficiency that always entails bitterness and pain (although through it a person candhypotheticallydlearn, improve, develop personally, etc.). v. Loneliness can stem from objective causes (e.g., a lack of relationships) or be independent of such objective causes (a person may not be alone, but may feel alone) and it is not necessarily linked to the social abilities of the person suffering from it (Vitkus and Horowitz, 1987): as opposed to the belief that people who are alone have bad social relationships, empirical evidence tells us that many people in situations of loneliness possess good social skills. vi. In addition to being caused by a lack of relationship with other people, loneliness can also include an element of a lack of community bonding. The community in which an individual lives provides one (Dalton et al., 2001) with feelings of belonging, identification with others, emotional security, reciprocal influence, perception of sharing values and resources, emotional connection and satisfaction of needs, etc., and a lack of these can provoke feelings of loneliness. In this sense, important authors such as Cacioppo and Patrick (2008) define loneliness as a “social pain” comparable to physical pain, endowing it with a specific function: if physical pain occurs to protect us from physical dangers, loneliness, in the form of “social pain,” would be manifested as a way of protecting us from the danger of remaining isolated (this is obviously related to the importance of social connections). vii. Loneliness needs time to begin to take shape (a person does not feel “loneliness” from 1 day to the next, although one can feel alone). It therefore requires a time horizon in which an individual builds and perceives one’s own loneliness (de Jong Gierveld, 1998). viii. Loneliness is an experience that takes the form of multiple realities (Victor et al., 2009; Victor and Sullivan, 2015) that are unique, distinct and shifting personal experiences constructed and reconstructed by an individual within the context of one’s own life and life history, the nuances of which change over time. Loneliness is something dynamic and requires interventions capable of assuming this. ix. There are also as many forms of loneliness as there are the reasons that generate different feelings of isolation, emptiness, exclusion, etc. that people experience in situations of loneliness (Yanguas et al., 2018b).

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x. Loneliness (Victor et al., 2009; Victor and Sullivan, 2015) depends on the mutual interaction of many variables, some of which belong to an individual and others outside this individual in terms of mutual interaction (some that one can influence and others that do not depend at all on one’s will): a. Intrapersonal factors: personality and cognitive “styles” (expectations, evaluation of the situation by an individual, etc.). b. Extrapersonal factors: such as interpersonal engagement (i.e. the social functioning of a person throughout one’s life cycle); life events that happen to people both in terms of their health (illnesses, etc.) and socially (retirement, widowhood, losses, children leaving for other countries, etc.); socioeconomic factors (income, existence or not of care services); “social environment” in which people live (housing, architectural barriers, facilities, more individualistic or collective type of community, rural versus urban, etc.; lifestyles (use of free time, hobbies, etc.); cultural factors, social stereotypes (ageism), etc. Therefore, the phenomenon of loneliness, far from being something simple, spans everything from emotions to cognitive processes, includes the individual and the community, encompasses “intrapersonal” and cultural variables, is influenced by behavior and mediated by external factors like housing, is related to fragility and vulnerability and a long etcetera of issues in which both its complexity and the challenge to our societies can be found.

Loneliness in Data Studies dealing with loneliness from the point of view of social network (social isolation) and feelings of loneliness present a complex image of it, with disparate and even contradictory data, with samples whose intercultural comparison is complex and whose methodological issues (sample, evaluation tests, etc.) make it difficult to compare. Assuming all of the above, a snapshot of the challenge that loneliness poses for Western societies would be the following: i. According to Eurostat data (2017), 6% of the EU population have no one to turn to if they require help (sample of adults aged 16 and over), with data ranging from 2% in countries like the Czech Republic, Finland, Slovakia and Sweden to 13% in Italy and Luxembourg. A similar percentage of the EU population, 6%, have no one to speak about or discuss their personal affairs. The highest figures were in France and Italy (12%) and the lowest in Cyprus, Spain, Slovakia, Czech Republic and Hungary (2%). Another issue (Eurostat, 2017): socioeconomic inequalities seem to be fundamental in addressing social isolation, given that the difference in the rate of social isolation was more than double among Europeans with higher and lower incomes. ii. In a work entitled “Quality of Life in Europe” (European Foundation for the Improvement of Living and Working Conditions, 2014), the percentage of people who answered that they have “never” felt lonely varied between 35% and 45% in countries like Italy, Poland or Greece; 48–56% in countries like Spain, Belgium, Portugal, France; and 59–75% in countries like Germany, Finland, Austria, Holland or Denmark. A proven pattern seems to appear in other works (Dykstra, 2009; de Jong Gierveld and Tesch-Römer, 2012; Hansen and Slagsvold, 2015; Yanguas et al., 2018a) that shows that loneliness is more pronounced in Southern Europe than in the North and greater in Eastern than in Western Europe. In other words, more “family-based” societies seem to have a higher prevalence of loneliness than more “individualistic” societies (less loneliness). A recent study to be published in the Social Observatory of ”la Caixa” that used a representative sample of nine Spanish cities found the following: the prevalence of the risk of social isolation in the family network is 9.7% (65–79 years) and 13.3% (over 80 years), while 27.7% are at risk of isolation (65–79 years) and 45.5% (aged 80 and over) in the network of friends. In addition, the rate of social loneliness reaches 29.14% of those aged 65–79 and 34.83% of those aged 80 and over and emotional loneliness affects 39.81% of those aged 65–79 and 48.1% of those aged 80 and over. iii. Loneliness appears to be greater in late adolescence and in old age than at other times in the life cycle (Luhmann and Hawkley, 2016) and has been linked to indicators of social integration, such as partner relationships, perceived social support and acceptance. Research assumes that single people feel lonelier than married people (Luhmann and Hawkley, 2016), but it seems that not having children has no direct effect on loneliness in older people, although living alone is related to a smaller social network, which is an indicator of loneliness in both men and women. As regards gender, the empirical evidence is contradictory: some research studies found no differences (Zebhauser et al., 2014), while others (Tesch-Römer et al., 2013) found higher rates of loneliness in men than in women and others (Zebhauser et al., 2014) found that the average level of loneliness only differed in those aged 85 and over, when loneliness was greater in women than in men. iv. Differences have also been found at a socioeconomic level. The personal health and social networks of people living in different countries could facilitate or hinder their opportunities to participate in social activities and have satisfactory social relations (Hansen and Slagsvold, 2015). The influence of cultural values in different countries on the personality of their inhabitants has also been confirmed, which would affect the expectations they have on their social relationships and consequently contribute to a greater or lesser prevalence of loneliness (Yang and Victor, 2011).

Consequences of Loneliness The empirical evidence describing the influence of loneliness on both physical and psychological health is overwhelming (Yanguas et al., 2018a; Yanguas, 2018) and this has been the focus of much research: understanding the consequences of loneliness in the various areas in which an individual operates.

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Therefore, loneliness has an influence on: i. Physical health because: a. It worsens the vascular system (Cacioppo et al., 2002). b. It increases systolic pressure (Hawkley et al., 2010). c. It increases the possibility of recurrent vascular accidents (Cacioppo et al., 2014). d. It decreases the expression of genes linked to the anti-inflammatory response and increases the overexpression of genes associated with proinflammation (Cole et al., 2007). e. It amplifies the activity of the hypothalamic-pituitary-adrenal HPA axis (Steptoe et al., 2004), which is essential in stress processes. f. It elevates immune system disturbances (Pressman et al., 2005) and worsens nutrition (Ramic et al., 2011). g. It accentuates obesity (Lauder et al., 2006). h. It amplifies a decline in motor function (Buchman et al., 2010). i. It enhances a reduction in physical activity and functional capacity (Shiovitz-Ezra and Ayalon, 2010). j. It influences the relationship between genes and the environment (Goossens et al., 2015). ii. And psychological health because: a. It predicts depressive symptoms (Holwerda et al., 2012). b. It increases sleeping problems (Cacioppo et al., 2002). c. It worsens cognitive functioning and increases the risk of Alzheimer’s disease (Wilson et al., 2007), as well as worsening neuropsychological test scores in various cognitive functions that include immediate memory, visual memory, episodic memory, semantic memory, processing speed and executive function (Zhong et al., 2017). d. It increases mental health problems (Tylova et al., 2013). e. It increases the rate of institutionalization (Longman et al., 2013). f. It increases mortality (Steptoe et al., 2013). g. Some authors believe that loneliness functions as a health risk that is similar to those established as “classic” risk factors, such as obesity, cholesterol, etc. (Holt-Lunstad et al., 2010), in addition to generating suffering and decreasing the quality of life. To recapitulate, the suffering and pain generated by loneliness correlates widely with both physical and psychological health and it can undoubtedly be said that loneliness, in addition to being something that is very unfair when a person reaches old age (and obviously also at any age), is a serious and prevalent health problem (Cacioppo and Patrick, 2008; Hawkley et al., 2010) with countless negative consequences and an (as yet unquantified) economic cost that is presumed to be very high.

Intervening in Loneliness General Analysis Publications on intervening in loneliness (Yanguas, 2018; Yanguas et al., 2018a) and/or social isolation in the elderly presenting data that evaluates and measures the effect of programs on participants are scarce, with small samples and usually incomplete methodology (usually without control groups, etc.). It could be stressed that: i. According to various review articles, group interventions accompanied by supporting educational activities aimed at specific groups and relying on existing community resources, and also including specific training and support for the generally voluntary facilitators of these actions (Yanguas et al., 2018b), seem to be the most effective interventions. ii. Four intervention strategies have received most scientific endorsement (Mais et al., 2011): those increasing social skills, those aimed at strengthening social support, those increasing opportunities for social interaction and those aimed at sociocognitive training. iii. Major methodological differences exist that make it very difficult to compare the various intervention programs and strategies both in terms of design (Yanguas et al., 2018a) and measuring instrument tests (those used include the University California Los Angeles Loneliness Scale, de Jong Gierveld Scale, Lubben Social Network Scale and mood scales such as Positive and Negative Affect Schedule, PANAS) that do not measure the same constitutive or operational construct and thus their results are hardly comparable (Yanguas, 2018). iv. There are many systematic reviews as regards effectiveness (Yanguas, 2018), with a particularly high level of group interventions and a lower level of individual interventions, in which comparability is also more complex. Interventions based on technology and physical activity programs appear to be a promising alternative, although several authors have sounded the alarm about the need to conduct “good” and not just “technologically innovative” interventions (Poscia et al., 2016; Yanguas et al., 2018b). Most of these technology-based interventions focus on strengthening social bonds and friendship. They have been fuelled by their ease and low cost, in addition to their great potential for expanding social networks and hypothetically reducing “loneliness,” as well as Europe’s commitment to social and welfare uses. Nonetheless, existing empirical evidence seems to question some of the benefits of these types of systems: Pitkala et al. (2009) found encouraging results as regards effectiveness, but they recently (Chipps et al., 2017) identified that some programs were moderately effective and the studies that supported them

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showed a lack of rigor after they had conducted a systematic review of “e-interventions,” concluding that the evidence for these types of interventions is currently inconsistent and weak. As several authors have indicated (Cohen-Mansfield and Perach, 2015; Ong et al., 2016), there are more intervention programs than evidence of their benefits and this is due to: a lack of methodological rigor and deficiencies in evaluation, highly varied approaches (cognitive, fostering relationships, companionship, increasing opportunities for relationships, technologies, etc.) that make it very complicated to compare them and a lack of multidimensionality in the way of understanding interventions on loneliness that, for example, do not include the necessary empowerment of lonely people so that they can learn to manage and live their own loneliness.

“Always Accompanied” Programme The “Always Accompanied” Programmedthe most extensive in Spaindwas created (Yanguas et al., 2018a; Yanguas, 2019) in November 2013 as part of the Elderly Programme of the ”la Caixa” Banking Foundation and in collaboration with the Red Cross of Catalonia in order to address situations of unwanted loneliness based on the following fundamental premises: i. Understand and intervene in loneliness based on all its complexity: The intervention proposed by the “Always Accompanied” Programme brings together various approaches aimed at both emotional and cognitive management (ideas, beliefs and attributions) and deals with negative stereotypes about loneliness, learning solitary activities, promoting community bonding, etc., both in individual and group formats. ii. Addressing the complexity of the phenomenon requires intervention at many levels and this implies: a. Working with people in situations of loneliness. Social functioning and loneliness depend on (although not exclusively) what a person “does,” and what occurs in other spheres of one’s own life (physical health, for example). An individual responsibility exists to take care of your social relationships and individually manage (if required) one’s own loneliness and this is impossible to avoid. The program aims to offer opportunities for empowering people so that they can manage their relationships and own loneliness based on trusting themselves and their abilities. Individual intervention is based on one’s own knowledge and personal project, through individual empowerment (improving personal resources to manage one’s own loneliness) and involvement, coordinating and integrating actions. b. Working with communities: create community architectures and support networks as much as possible, welfare and care among citizens, promoting processes of social engagement and enabling people and entities to face shared challenges. Loneliness/social relationships are (as discussed above) linked to a feeling of belonging, the possibility of mutual influence, satisfying one’s own and common needs, a shared emotional connection. c. Raising public awareness by generating interdependence and mutual care, both in matters relating to loneliness in particular and to aging and situations of vulnerability in general. d. Seek specific differentiated solutions at a local and territorial level, based on their own idiosyncrasies and culture and also from personal and community stories. The interventions of the “Always Accompanied” Programme do not represent a “catalogue” of fixed resources (“whatever you may have, whatever you may feel, whether your personal resources are different from those of another person, and your community is different,” etc., what is in the catalogue is applied to you), but a project that seeks to intermediate, “negotiate” and implement innovative solutions in each case, in agreement with the participants (individual, community, citizens and professionals), a project committed to a people-focused intervention (people in situations of loneliness, volunteers, associations, etc.). iii. Loneliness requires a common, territory-based approach among public administrations, entities, associations and people, interacting and working together (with methodologies elaborated to that effect) by respecting their particularities in the consensual search for an objective. Therefore, promoting volunteering, neighborhood advocacy and the involvement of professionals in community work structures are other key issues in this program. iv. Various methodological elements have been created, developed and validated in order to undertake such an approach: a. Understanding and evaluating individuals and communities. b. Undertaking joint intervention plans among people, professionals and volunteers. c. Creating spaces for community work (Social Action Groups) in which response actions are articulated based on the resources of one’s own community for the needs of people in a situation of loneliness, as well as organizing the community. v. The lessons learned to date can be summarized as follows: a. Importance of creating and articulating what have come to be known as “Social Action Groups” in loneliness intervention (at a community level). These are working groups involving the participation of a variety of agentsdboth professionals and citizensdin order to facilitate the creation of new spaces of knowledge, reflection and joint work that provide a more comprehensive view of the elderly and the elderly in situations of loneliness, as well as more diverse, complex actions. These groups include the participation of town councils (departments of social services, public safety, etc.), regional governments, hospitals and healthcare centers, social entities, centers for the elderly, civic centers, associations of the elderly, associations of neighbors and traders, professional associations (pharmacists, etc.), parish churches, real estate agents and many more. b. Increasing and improving (in terms of quality) the presence and involvement of the public in work spaces continues to be one of the most important challenges of a program of this type, by facilitating the positive relationship between technical and nontechnical resources, increasing the capacity to contribute both in planning actions and raising awareness.

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c. Data extracted from this pilot study (as well as from others previously commented on in the third point of this article) confirm the existence of stereotypes prevalent in the population both as regards old age in general and elderly people in situations of loneliness. These stereotypes are an obstacle and create resistance in people participating and this must be overcome. d. Loneliness often feeds on other situations of fragility and vulnerability. The “Always Accompanied” Programme helps to visualize other problems associated with loneliness in the elderly and promotes joint work on them (various agents working together) by adapting resources and activities to their needs and empowering people in environments of trust for them. e. Importance of properly diagnosing elderly people in situations of loneliness, thereby helping people (who suffer loneliness) to become aware of, reflect upon and obtain a greater understanding of their situation, viewing this step as fundamental before beginning any action that implies their empowerment. f. There is a need to further examine the work with families, if there are any family members, as particularly relevant agents. Working with the families of people in situations of loneliness is especially sensitive and delicate and requires a distinctive approach. g. Individual intervention (adapting to each situation) has been redesigned and is now focused on three different phases: i. A first phase of assessment and implementation based on the trust between the professional and the individual to begin an evaluation/diagnosis and conclude with the joint development (professionals, individual, volunteers) and implementation of the intervention plan. ii. A second phase of monitoring both the individual and the community network supporting this individual that includes reevaluating the situation and re-elaborating the previously agreed joint intervention plans. iii. A third phase that aims (although this is not always feasible) to integrate the individual into the community and abandon the program. vi. The experience of recent years has underlined the need to extend the training of professionals, volunteers and the public on social relationships and loneliness at different yet complementary levels.

Conclusions The approach to unwanted loneliness calls for the implementation (and evaluation) of complex programs with different intervention formats (emotional, motivational, cognitive, etc.) and a variety of intervention levels (individual, community, increasing public awareness, etc.), involving various institutional agents (public and private, a variety) working together. It is the inaction and/or trivialization of a complex challenge that endangers addressing a challenge that not only produces suffering and discomfort, but is also a serious and prevalent health problem.

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Long-Term Careq Finbarr C Martin, Kings’ College London, London, United Kingdom Katie Robinson, University of Nottingham, Nottingham, United Kingdom © 2020 Elsevier Inc. All rights reserved.

Introduction: Why Long-Term Care Is Needed LTC Needs and Provision Typology of Care Settings Some International Comparisons and Time Trends The Clinical Profile of Care Home Residents Principles of Care: Preservation of Dignity; Ethical and Legal Challenges Models of Healthcare Assessment and Care Planning From Assessment to Care Planning The Management of Medical Conditions Administering Medications Responding to Changes in the Resident Deprescribing Vaccination End of Life Care Some Key Clinical Challenges in Nursing and Daily Care Evidence and Guidance Eating and Drinking and Weight Loss Infections Oral hygiene Continence Contractures and Positioning Pressure area care Dementia Care Preserving Function and Participation Promoting Physical Activity Promoting Physical Activity Whilst Preventing Falls Regulations, Standards and Quality What Is Quality? Quality measurement systems Future Trends and Research Needs References Further Reading Relevant Websites

332 333 333 334 335 336 336 337 338 338 338 339 339 339 339 340 340 340 341 341 341 341 342 342 342 342 342 343 343 343 345 345 346 347

Introduction: Why Long-Term Care Is Needed Globally, greater numbers of people are living to advanced old age. People are living their lives differently. Patterns of disease morbidity are changing. Among older people, this is evident with health and disability being increasingly shaped by aging related changes along with and also modifying the impact of the common noncommunicable long-term conditions. Whereas cardiovascular diseases, cancers and chronic respiratory diseases are the leading causes of mortality, age-dependent disorders such as dementia, stroke, chronic obstructive pulmonary disease, and vision impairment have a higher impact on disability than on mortality. The long-term care costs associated with these disabling conditions outweigh health expenditure. Disability-adjusted life years (DALYs) per head are 40% higher in low-income and middle-income (LMIC) regions, accounted for by the increased burden per head of population arising from cardiovascular diseases, sensory, respiratory, and infectious disorders. Dementia is the most important independent contributor to disability for older people in LMICs (Sousa and Ferri, 2009). Declines in intrinsic capacity, such as locomotion and cognition, and the consequent challenges to maintaining functional ability provide an alternative framework for describing the health and care needs of those needing long-term care than the traditional disease

q

Change History: March 2019. Finbarr C. Martin has updated the text throughout the article.

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orientated perspective. The World Health Organisation World Report on Ageing and Health (World Health Organisation, 2015) suggested that long-term care consists of: .activities undertaken by others to ensure that people with or at risk of a significant ongoing loss of intrinsic capacity can maintain a level of functional ability consistent with their basic rights, fundamental freedoms and human dignity.

The report suggested two mechanisms:

• •

optimizing the recipient’s trajectory of intrinsic capacity compensating for losses of capacity by providing the environmental support and care necessary to maintain functional ability at a level that ensures well-being.

In a later section we describe the care and clinical activities necessary to achieve these objectives. This is challenging and skilled work. Furthermore, the age structure of populations, particularly in high and medium income countries and increasingly in low income countries, means there are fewer younger nonemployed family members available to provide regular care. In high income countries, migrant workers are becoming very important providers of this care, both in domestic and institutional settings, with obvious consequences for LMICs.

LTC Needs and Provision Global data on the need and unmet need for long-term care are incomplete. Women are more likely to be care dependent than men of the same age, for a combination of reasons including disease prevalence and social factors (Rodrigues et al., 2009). More adverse life conditions in LMICs result in higher rates of care dependency for those ages 65–74, (as high as 50%) compared to high income countries such as Switzerland at 5%. Rates vary but less between high income countries. Long-term care (LTC) systems are rudimentary in most LMICs, and national level data reveal large gaps in both provision and access. Addressing this deficiency is a central plank of the WHO’s Global strategy and action plan on ageing and health (World Health Organization, 2016). The OECD estimates that public spending on long-term care varies more than 10-fold when expressed as a proportion of gross domestic product (GDP). The highest is 4.5% in the Netherlands: others include 2.1% in Japan, 0.5% in the United States and 0.3% in Hungary, 1.3% being the OECD 30 average. This variation is much greater than is seen for healthcare spending. It reflects large differences in the balance between formal provision and informal care (usually provided by families) and the share of costs that people pay out of pocket. Analysis across 20 European countries identified four clusters based on relative proportions of (1) public expenditure on LTC (related to GDP and the need for care), (2) the share of private expenditures on LTC, (3) use of informal care (number of users related to the number of persons aged 65 and older), and (4) support for informal caregivers (an indicator that counts support measures for informal caregivers (Kraus et al., 2010). Interestingly, high income countries with fairly similar population demographics are spread across these clusters suggesting that public policy has a key role in determining the systems in place. Residential (institutional) care facilities are a major though variable component of LTC systems. Our main focus in this article is on residential care although many of the clinical and ethical challenges we describe are the same when care is provided “at home.”

Typology of Care Settings The WHO describes long-term care institutions as “nursing and residential care facilities which provide accommodation and longterm care as a package. They include specially designed institutions or hospital-like settings where the predominant service component is long-term care and the services are provided for people with moderate to severe functional restrictions.” This definition excludes highly supported independent living [sheltered] housing). Internationally, different terms are used: Table 1 shows these terms and the associated characteristics of the care provided. Each of these may provide care until the end of life, with or without palliative care expertise, but we will not consider here the emerging hospice movement, designed specifically to provide palliative and end of life care. Some also provide temporary care for rehabilitation. For example skilled nursing care facilities in the United States and nursing homes in the Netherlands provide postacute care, both being important strategically in their health care systems. In response to inconsistency in the use of the term “nursing home” an international consensus group convened by the International Association of Gerontology and Geriatrics and the AMDA Foundation documented the various roles ascribed in the literature to nursing homes and proposed the following definition (Sanford et al., 2015):

334 Table 1

Long-Term Care Differences in the spectrum of institutional long-term care facilities Nursing home

Residential home Care home without nursing Assisted living facility

Size

Care home with nursing Skilled nursing facility Long-term care hospital Variable

Model of care Care staff

Health orientated, predominantly medical model Registered nurses and care assistants

Personal care

Performed by staff

Nursing presence General nursing tasks Specialized nursing tasks

Usually 24 h Usually performed by staff Variable: usually rely on an external community resource Variable, sometimes as members of staff. Variable from designated staff to standard primary care (see text) Higher

Alternative terms

Allied health professionals Physicians Costs to funder

Variable, more often provided in adapted domestic settings Social care model, often in less clinical environment Senior supervisory staff need not be nurses: care assistants Usually staff, sometimes with additional external resources Episodic, usually not required to live in Usually rely on an external community resource Always rely on an external community resource Usually external with ad hoc access Usually standard primary care Lower

A nursing home • is a facility which provides 24-h functional support for people who require assistance with personal Activities of Daily Living (ADLs) and instrumental Activities of Daily Living (IADLS) and have identified health needs • may or may not be staffed with healthcare professionals • provides long-term care and/or rehabilitation as part of hospital avoidance or to facilitate early hospital discharges • does not function as a hospital ward and is not hospital based • may play a role in providing palliative and/or hospice care at end of life.

We focus here only the long-term care role of these institutions.

Some International Comparisons and Time Trends The history of these institutions differs internationally. Some have developed from workhouse type origins where isolated old and/ or destitute people were accommodated with a minimum of care, almost a custodial punishment. In countries without that history, they may have emerged from basic community hospitals. In high income countries, they are now a major component of the welfare system. Many are now providing highly specialized services, for instance for older people with dementia. WHO Europe has collated bed numbers from most countries in the Europe Region (World Health Organisation (Europe Region)). Rates proportional to populations are highly variable. Despite demographic change, totals increased little in the Nordic states, the United Kingdom, the eastern or south east states of Europe since 2000 but over 25% in France and Germany. The OECD has published bed numbers from 33 countries worldwide, demonstrating marked variation proportional to older populations (see Table 2). This table also shows temporal trends since 2011, confirming variation between and within continents. In the 2015 European Ageing Report, the European Commission and the Economic Policy Committee stated that coping with the challenge posed by an aging population will require determined policy action in Europe, particularly in reforming pension, health care and long-term care systems (European Commission, 2015). A research project financed under the 7th EU Research Framework Programme, ANCIEN (Assessing Needs of Care in European Nations) involving 20 EU member states provided estimates of future need for, supply and use of LTC by older Europeans (Geerts et al., 2012). Within this, a comparative study of future nursing and residential care beds in four European countries demonstrated significant differences, for example a projected doubling of need from 2010 to 2060 in the Netherlands, approximately a steady state in Germany and 50% increase (from a low base) in Poland. These projections were based on data on current use, demographic projections and estimations of available informal care and disability prevalence. These projections can be only indicative as they are significantly sensitive to assumptions about mortality and disability rates, both of which have changed in recent decades. Where the data exists, it demonstrates the trend over recent years for care home residents on admission to be older and less functionally able. This is consistent with the relative decrease in some countries of institutional bed numbers, which may be partly explained by public policy which has strengthened community based alternatives so that the threshold for needing institutional

Long-Term Care Table 2

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Numbers of beds in nursing and residential care facilities Beds per 1000 persons aged
65 (thousands, to 3 figures) % Change from 2011

Country

Beds total (thousands, to 3 figures)

2016 (USA 2015)

Netherlands Canada France Australia United Kingdom Hungary United States of America Japan Korea Poland Turkey

219 341 653 189 545 83.4 1654 829 168 72.4 52.3

71.0 56.9 52.0 51.6 46.5 46.5 34.7 24.0 24.8 12.0 8.1

Decrease

9.4 12.6 6.1 13.0 4.4 5.6

Increase þ 7.4 þ 7.1 þ 8.1

þ 9.2 þ 8.0

Source: Organisation for Economic Co-operation and Development OECD. Long term care. Available from http://www.oecd.org/els/health-systems/long-termcare.htm (accessed October 31, 2018).

care is higher, as in the United Kingdom (Green et al., 2017) although lack of supply or lack of available public or personal funding is likely an additional factor in some countries. An additional explanation may be changes in dependency rates when expressed as population over 65 years (despite general increases in disability life expectancy). Despite the pressing need to develop national policies and programs to fund and provide adequate LTC services and facilities, many countries have no or inadequate preparations in place. One exception is Japan, with the world’s longest life expectancy of 84 years in 2015 and falling birth rates. Restricted state funding and failure of informal and family care to keep up with need was reflected in lengthening and clinically unnecessary acute hospital stays. Many countries face comparable challenges. Japan introduced a new long-term care insurance system in 2000 providing a universal and needs-based comprehensive care system (Campbell et al., 2016) funded from general taxation and social insurance premiums, which for younger working adults are shared with employers. In this context of sustainable funding, a provider market has developed. Globally, as far as LTC needs are concerned, massive progress is needed to achieve the WHO aspiration of universal access to healthcare.

The Clinical Profile of Care Home Residents Most people in care homes need help with personal care in daily life. Onder et al. (2012) reported the SHELTER study, a 12 months prospective study of 4156 residents in a nonrandomized sample of 57 nursing homes (NHs) in 7 EU countries (the Czech Republic, England, Finland, France, Germany, Italy, the Netherlands) and Israel, using the InterRAI Long-term Care Facility assessment tool (interRAI LTCF). The mean age was 83.4, 73% were female. ADL disability and cognitive impairment was observed in 81.3% and 68.0% of residents, respectively. Behavioral symptoms (27.5% of residents), falls (18.6%), pressure ulcers (10.4%), pain (36.0%) and urinary incontinence (73.5%) were common. These rates were higher than those for older people receiving care at home (Carpenter et al., 2014) although home care recipients in Italy and France had levels of cognitive and physical impairment similar to the NH residents in the Netherlands, Czech Republic and Germany demonstrating different thresholds across Europe for institutional rather than home based care. A larger UK survey of 16,043 people resident in 244 care homes (75% with onsite nursing) identified rates of cognitive impairment and incontinence of over 70%, and 27% were immobile, confused and incontinent (Bowman et al., 2004). Dementia may be present in over half of residents. Depression is also common, as is malnutrition, which becomes more prevalent during admission. Common long-term conditions such as COPD and heart failure contribute to fatigue and immobility. Residents are on often multiple medications, with widespread evidence in surveys of inappropriate polypharmacy. Increasingly LTC facilities may provide more sophisticated technologies. For example, a UK survey in 2009 reported that 9000 care home residents were receiving tube feeding, mostly via percutaneous endoscopic gastrostomy tubes (PEG tubes) and this is likely common internationally although its use may be controversial in the context of end of life care. The clinical course of people in need of long-term care is highly variable. Some transition from relative independence to receive palliative care for a short final phase of life, but others have more protracted needs following disabling injury or illness and may, with adequate care, stabilize for long periods. Depending on local care home admission criteria and policies, mortality rates are high. From a total of 2444 resident deaths in 38 homes in England over a 3-year period, 56% were within

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12 months of admission (Kinley et al., 2014). A primary care based database study including 9772 care homes in 293 English and Welsh general practices reported 26.2% at 1 year (approximately 10-fold higher rate than similar aged community dwellers).

Principles of Care: Preservation of Dignity; Ethical and Legal Challenges Older people continue to have aspirations to well-being and respect regardless of declines in physical and mental capacity. The WHO guiding principles of long-term care emphasize the right of any older person, despite dependency for care, to “realize their continuing aspirations to well-being, meaning and respect,” and secondly, to have access to receive efforts to minimize further losses and compensate for those which are irreversible. From this perspective, standards of care are variable and often poor. At its extreme, poor care amounts to elder abuse, whether caused by ignorance, inadequate staffing or wilful harm. The incidence of abuse is difficult to establish. A major study conducted in care homes in England (PANICOA) using an observational ethnographic approach plus nearly 500 interviews in 43 care homes found that the risk of physical assault to residents from care staff was low, but residents were potentially at risk of assault from others’ challenging behavior if this was not managed effectively by care staff. Overall, the weakest areas related to the maintenance of dignity and privacy in personal care and facilitating a sense of meaning and purpose in residents’ lives. Key factors affecting the experiences of residents were around leadership, staff training and support, the care culture and the relationship between care homes and their surrounding health and social care communities. Care homes are more likely to achieve these objectives with relationship-centered approaches to care, allied to understanding the resident’s attitude towards living in care homes (Bradshaw et al., 2012). This approach is exemplified in many care homes in England by the My Home Life project which works with care homes to improve the daily experience of both staff and residents. Similar findings and initiatives based on this perspective exist internationally. Many care home residents lack the capacity to understand or consider or communicate the detail required for informed consent and shared decision making. In this situation, local legal or ethical guidance usually exist. In most countries, discussions with relevant others such as family is advised to ascertain what might be in the patient’s best interests, taking into account any previously stated views, legal advance directives, and cultural factors. In some legal jurisdictions there are procedures which enable the consent for healthcare decisions to be made by nominated individuals on the resident’s behalf. In others, cultural norms afford this right to family members to make decisions without legal underpinning.

Models of Healthcare Generally, care homes without nursing (residential homes) rely on the standard primary, community and hospital services for healthcare, which of course vary internationally in terms of scope, quality and cost to the user. Local arrangements may ease access such as with scheduled visits from community nurses, for example for insulin injections or tissue viability care, pharmacists for assistance with medication management or general medical practitioners for acute illness events, but there is no specific model of care. Specialist homes for dementia care exist in many high income countries including the Netherlands, Japan, and the United Kingdom and they usually have enhanced access to mental health expertise. Nursing homes are more self-sufficient in daily nursing needs. A recent consensus process suggested the range of competencies necessary for the work (Stanyon et al., 2017). Some homes have in-house allied health professionals most commonly physiotherapy or, if the focus is dementia care, occupational therapy or clinical psychology. In most countries medical care is from whatever national pattern of primary care services exist but this may be replaced or supported by additional medical input with various levels of additional expertise. Table 3 describes some of these arrangements with examples. A survey of training requirements and existence of standards of medical care across Europe showed the lack of either in most countries, the notable exceptions being the Netherlands where a specialty of elderly care physicians has been developed (Briggs et al., 2015). There are initiatives in several countries to incentivize greater participation (time, etc.) by general practitioners but in general this is only moderately effective and there is a lack of recognition internationally of the specialist nature of the work with this most vulnerable group of medically complex older people.

Table 3

Characteristics of medical support for care home residents

Medical input

Specialist training/qualifications needed

Example

Elderly care physicians (work in NHs only) General practitioners General practitioners Medical directors

Postgraduate training and qualification with additional training without mandatory additional training Supervisory role without full medical care responsibility

Netherlands France, Ireland, Turkey United Kingdom, Italy, Sweden United States

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In several countries with an established speciality of geriatric medicine or old age psychiatry, such as in the United Kingdom, New Zealand and Singapore, there are moves to develop models which provide systematic access to these specialists whilst promoting the primary role of general practitioners in daily medical care. Access however may be insufficient to sustain improvements in care processes without well developed collaborative age-appropriate multidisciplinary working across the provider divide of the care home and the local health services (Goodman et al., 2016).

Assessment and Care Planning It is clear from the above description that planning daily care and therapeutic interventions must be based on a comprehensive assessment of each resident, before or soon after admission. Proactive care also involves anticipating health related challenges to quality of life and function likely to occur in the last year or so of life. Some are associated with the specific conditions and functional limitations evident in many new residents and include, but are not limited to these:

• • • • • • • • • •

Limb contractures associated with spasticity and limited active movement Pressure damage including ulceration Persistent coughing, aspiration and aspiration pneumonia Pain Breathlessness Poor sleep Undernutrition and dehydration Low mood and depression Anxiety Behavioral and psychological symptoms associated with dementia

The clinical purposes of the assessment are shown in Table 4. Later sections describe the clinical activities in more detail. Assessment may also be used to predict resource utilization for reimbursement purposes, and for quality monitoring purposes. There is general consensus on the domains which are important to asses to meet these clinical and administrative purposes, but consistency within and between countries is lacking in practice. For this reason, some have introduced mandatory approaches including the use of specific assessment technologies. Table 4

Purposes of assessment of residents receiving long-term care

General purpose

Summary description of issues and tasks

Identifying abilities and needs

Planning immediate and ongoing daily caredcomplementing the residents’ abilities so as to meet basic needs as a minimum and building on this to enhance safety, functionality, and participation. This is achieved through a full comprehensive geriatric assessment and multidisciplinary discussions, taking into account the resident’s priorities, psychosocial resources, and culture Identifying the need for skilled nursing care: what, when and then who is scheduled to provide this. Identifying the need for additional professional support, e.g., allied health professional input to designing how to provide optimum daily care and to plan therapeutic interventions in the short or medium term, dental care for caries or loose teeth. Identifying the need for therapeutic intervention for long-term conditions and clarifying feasible and balanced therapeutic objectives, taking into account the impact of frailty and multimorbidity on the benefits, risks and burdens of treatments. Planning the need for physician visits. Identifying the likely challenges to the resident’s quality of life and function, including prevention of falls and injuries. Including details in daily care plan, the environment and healthcare inputs. Planning what observations such as vital signs, presence of pain, bowel habit, etc., should be incorporated into staff daily routines., and agreeing triggers for referral to senior nurses or other clinicians, and regular review schedule, Agreeing in the context of feasible benefits, the likely limits of clinical activity, e.g., remain for treatment in the NH, transfer to acute hospital and then with/without use of intensive medical facilities, These may include ceilings of care but also preferred place of care during the stage of dying.

Identify health care goals Identifying specific tasks and procedures Additional healthcare needs Managing long-term medical conditions

Preventing problems Plan management of these challenges Ongoing assessment and review Ceilings of care Advance care plans

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The most widely used of these standardized tools currently is the InterRAI Longterm Care Facility assessment tool (InterRAI LTCF). This a comprehensive assessment and care planning process, which “.enables comprehensive, standardized evaluation of the needs, strengths, and preferences of persons receiving short-term postacute care in skilled nursing facilities as well as persons living in chronic care and nursing home institutional settings.” This tool has deep roots. The 1987 US Nursing Home Reform Act mandated the development of a standardized “minimum data set,” or MDS. The Health Care Financing Administration (now Centers for Medicare and Medicaid Services) commissioned a team of researchers to develop the MDS. Many of these researchers later became founders of interRAI. The MDS was originally implemented in approximately 17,000 US nursing homes in 1990–91, was revised (Version 2.0) in 1994–95, and was implemented in all U.S. nursing homes in 1996 as a requirement for nursing home participation in the Medicare and Medicaid programs. The current MDS 3.0 is not an interRAI product, although interRAI still holds the copyright outside the United Sates for many assessment items in that instrument. InterRAI is used in research in many countries, and in some countries, regions, provinces or states it is mandated. In Canada it is used in almost all provinces but Quebec. It is also used in Europe (Belgium, England, Finland, France, Germany, Iceland, Italy, the Netherlands, Norway, Spain, Sweden, Switzerland), Asia (Hong Kong, Korea, and Japan), and the Pacific Rim (Australia, New Zealand). The interRAI LTCF is linked by algorithms to Resource Utilization Groups (RUGs) which have been validated in a number of countries, and is used in some countries for reimbursement (e.g., the United States). MDS 3.0 generates 64 RUGs and also a revised set of Quality Indicators and Quality Monitors. Widespread use has enabled comparative studies of resident casemix and outcomes of care in Europe (Onder et al., 2012) and is used for quality assurance and quality improvement in the United States and elsewhere (Frijters et al., 2013). Whereas interRAI tools are directly linked to care planning, many other tools are stand alone, and a plethora of national or local guidance and policies will influence the response of care staff to their assessments. Provider chains usually mandate a particular approach for all their facilities of the same kind.

From Assessment to Care Planning Putting the needs and priorities of the individual resident at the center of care planning requires the clinical team being able to explain these issues sufficiently clearly so that the individual, perhaps supported by family, can consider their priorities and identify the goals of care. Usually the priorities and goals will be weighted towards minimizing mental and physical discomfort and retaining some degree of autonomy. Autonomy does not equate to independence. By definition, individuals needing long-term care, in an institution or at home, have reduced capacity and depend upon others for aspects of basic and instrumental activities. Promoting autonomy in this context is about preserving, as far as is possible, the ability to make choices about who, what, and when things happen.

The Management of Medical Conditions For the resident, the objectives of healthcare are similar to those at other stages of life: optimizing day to day quality of life, limiting functional dependency and preventing avoidable death. But living with frailty and/or dementia and/or complex multi-morbidity alters the priorities of each of these objectives. It is a mistake to uncritically extrapolate the evidence of benefits, risks and burdens of medical treatments from clinical trials carried out with participants without these characteristics, and in other contexts. Conventional medical long-term condition management may or may not contribute to any of these three objectives. Each situation needs individual consideration and judgment. This involves judgments about the contribution of the various, usually numerous factors to these outcomes and then the potential of clinical interventions to modify them. Prolonging life may be less important, and indeed unrealistic. Does a bit more dependency matter? Are a few extra months of life important? What mental or physical symptoms are the most troublesome? The principles of “Choosing Wisely” developed by the ABIM Foundation (American Board for Internal Medicine) are particularly important in this context as many residents are entering their final year of life and some evidence based treatments require longer time periods to achieve benefits but may produce adverse effects or be burdensome in the short term. Guidance has been produced by professional organizations specializing in older people, such as the American Geriatrics Society. General guidance on an approach to assessment and decision making when prescribing for long-term conditions in the context of multimorbidity has been provided by the England based National Institute for Health and Care Excellence (NICE). Based on a comprehensive assessment and shared decision making, a set of healthcare objectives for each individual can be determined. Some examples are shown in Table 5.

Administering Medications Providing medicines in standard formats may be problematic, because of swallowing difficulty or cognitive impairment. Administration by the parenteral route or orally in liquid form with thickening agents may be preferable. Efficacy of medicines can be altered by modification and pharmacy advice is usually necessary but a degree of pragmatism is also important. When medicines

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Examples of modified therapeutic objectives for residents in last year/years of life

Condition

Priority

Diabetes mellitus

Avoidance of ketosis and hypoglycemia Not optimization to reduce vascular complications Balance the sensory and social pleasure of eating and drinking with the risks of aspiration Minimize breathlessness but less need to impact prognosis Therefore beta blockers associated with fatigue may be best avoided

Dysphagia Heart failure

considered necessary to achieve agreed goals are resisted by a resident who lacks capacity, careful consideration should be given to covert administration. If done this should be explicitly discussed, justified and recorded in clinical records. In some countries, ethical or legal guidance is available.

Responding to Changes in the Resident There is also need for reactive care, responding to concerns of the resident but in practice more often to the concerns of family or staff. Subtle changes in behavior, alertness or facial expression are usually evident to those closest to the resident, but they may lack the confidence or the language to report them. Thus, relationship building and trust is an essential requisite for effective reactive care. Detailed conversation with care givers generally pays dividends. Clinical skill is needed to distinguish new events or illnesses from the anticipated trajectory for the resident. For example, people approaching end-stage dementia do not stop eating overnight, but they may do so if they develop oral thrush (infection with the fungus Candida albicans), parotitis related to dehydration or a tooth abscess. Agitated behavior may be induced by hallucination but may be pain related and treatable (Corbett et al., 2014). Fecal incontinence rarely precedes urinary incontinence in patients except when impaction or primary gut problems supervene. The conventional approach to clinical diagnosis often involves investigation requiring blood or other bodily samples, and attendance at specialized facilities for X-rays, etc. Any of these may be more burdensome for a frail older person needing long-term care, particularly since clinical instability results in this being more frequent. So it is necessary to take a measured approach to the level of certainty required for safe clinical care. Clinical skills become paramount and reliance on investigations should be proportionate to the burden and the potential added value of objective confirmation.

Deprescribing Changes in clinical condition evident at regular review or due to an acute illness should prompt a medication review for several reasons. The benefit/burden/adverse event balance changes according to the clinical condition and proximity to death of the individual. Medications justified for longer term benefit may need to be temporarily stopped if:

• •

contraindicated in the context of acute illness (e.g., risk of delirium) they become impossible to administer because of drowsiness or inability to swallow.

Vaccination Vaccination has an important part to play with older people although the efficacy may be reduced in frail residents. The priorities are influenza, pneumococcus and herpes zoster. Vaccinating care home staff against influenza in times of moderate influenza activity can reduce deaths, health service use, and hospital admissions in residents (Hayward et al., 2006; Lemaitre et al., 2009) and promoting this is public policy in several countries.

End of Life Care Most residents in LTC facilities are in the final years or months of life, but the proportion that die in their care home rather than in an acute hospital varies internationally. There is a widespread movement to facilitate “dying in place” and this includes care home residents, for whom a final acute hospital admission is usually futile and unpleasant. However, the skills existing in care homes to provide high quality end of life care are highly variable and the attitudes of residents, families and staff may not be supportive. The specific clinical and psychosocial attitudes and skills to enable older residents to die with dignity and comfort are discussed elsewhere. For residents who may need palliative care, a systematic review concluded that the interRAI PC (palliative care) and the McMaster Quality of Life Scale are suitable CGA tools to evaluate need (Hermans et al., 2014).

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If a greater number of older residents are to be offered this possibility, then willingness and an ability to recognize the dying process will be needed. It is instructive to consider the clinical trajectory before death of older people receiving LTC. A seminal study in the United States by Lynn and Adamson suggested that (Lynn and Adamson, 2003).

• • • •

20% followed progressive illnesses such as cancer with a clear transition from treatment to palliative end of life care 20% were related to progressive long-term conditions with intermittent exacerbations (such as COPD) with decreasing speed and completeness of recovery where attention to the disease specifics were gradually replaced by a palliative approach 20% were sudden 40% were described as “progressive dwindling, often associated with dementia.”

Age and number of comorbidities are weaker predictors of mortality for care home residents compared to community dwellers (Shah et al., 2013), probably reflecting the role of moderate or severe multisystem frailty. Incorporating ADL functioning and health stability increased predictiveness for residents who died within a year of admission to nursing homes in Iceland from 1996 to 2006 (Hjaltadóttir et al., 2011). A subsample of 500 residents from five European countries in the above mentioned SHELTER study examined the accuracy of prognostication of individuals who died within 6 months of their last assessment, which included a query on their likelihood of death. 86.4% of residents did not receive an accurate prognosis. Residents with cancer, fatigue, dehydration, or an impaired or artificial mode of nutritional intake were more likely to be accurately prognosticated. There was significant variation in accuracy between countries (ten Keppel et al., 2018). Thus better awareness of the clinical course of the final months of life is important for clinicians as well as care home staff. Care home residents with advanced dementia commonly experience pneumonia, febrile episodes, and eating problems and these complications are associated with high 6-month mortality. Distressing symptoms and burdensome interventions are also common among such patients, but a longitudinal observational US study showed that residents with health care proxies who have an understanding of the prognosis and clinical course were less likely to receive aggressive (and usually futile) care near the end of life (Mitchell et al., 2009). This emphasizes the importance of proactive discussion about death and dying including advance care planning. In general, the more frail the population, the more tricky it is to predict the time of onset of dying as although frail people are more likely to have ADL dependency 1 year before death, they have a slower rate of functional decline than those dying of disease progression (Cohen-Mansfield et al., 2018). Furthermore when physiological reserves are almost insufficient, chance becomes a factor in timing of death. Thus clinical expertise is required in recognizing the final phase of life, for example the features characteristics of late stage dementia. Helpful guidance on this has been provided, incorporating use of the Global Deterioration Scale (Mitchell, 2015). Transforming care homes’ culture and skills to enable good end of life care is a complex process but can be successful (Kinley et al., 2017).

Some Key Clinical Challenges in Nursing and Daily Care Evidence and Guidance The list above of predictable adverse events which threaten the health and quality of life of individuals needing LTC illustrate the challenges faced by caring staff and health professionals. Despite this care sector being larger than hospital activity, there is only a small body of relevant evidence about how best to perform these activities. In the United States, AMDA, previously the American Medical Directors Association but now renamed the Society of Post-Acute and Long-Term Care Medicine, has produced comprehensive guidance on a full range of care challenges and conditions. In England, NICE has issued a rage of guidance and quality standards relevant for or focused specifically on older people in care homes including: oral nutrition support including enteral tube feeding; medicines management; promotion of mental wellbeing generally and specifically by occupational therapy and physical activity interventions; delirium prevention; dementia management; falls prevention; prevention of healthcare acquired infections; end of life care; oral health and hygiene. Other relevant guidance is available from specialist professional sources such as on nutritional assessment and support from BAPEN.

Eating and Drinking and Weight Loss Weight loss towards the end of life is a common but difficult challenge. A diagnostic assessment including assessment of swallowing difficulties is essential. It is important to identify potentially treatable causes such as mouth ulcers, poor dentition or painful presbyoesophagus, but also to recognize the features of cognitive dysphagia and its significance in advanced dementia. This would prompt a review of healthcare goals towards avoidance of distressing choking during pleasure orientated feeding and away from an objective of maintaining body weight or perfect hydration.

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Offering food and drink is basic care but medical interventions to replace normal oral intake by infusions, nasogastric tubes or PEG feeding require consideration of burdens, benefits and risks. Because of the social and cultural significance of eating and drinking, discussions with families and care providers can be challenging because the various parties come to it with different understandings and knowledge of these factors. For example, it is not unreasonable for a lay person (or unqualified care provider) to believe that inadequate fluid intake must cause distress and that this can best be alleviated by fluid in an infusion whereas the clinical evidence of benefit for this at the end of life is lacking. So information and reassurance as well as sensitivity to culture and family values is necessary.

Infections The epidemiology of infections in the care home setting in the United States has been reviewed by Dwyer et al. (2013). From a total incidence of 11.8%, the most common are urinary (UTIs), respiratory (including pneumonia) and soft tissue including skin (cellulitis). Historic rates in the United States were much higher and it is likely that higher rates exist in most countries, as actions necessary to minimize the incidence are often poorly instituted. Prevention of infection is important because of the prevalence of impaired immunity and physicochemical barriers to infection. An example of the latter is postmenopausal atrophic urethritis and vaginitis associated with an increased risk of lower urinary tracts infections (UTIs) and vaginal candidiasis respectively. Fungal infections in skin creases is common if personal hygiene is not adequate, particularly in the most frail or residents with type 2 diabetes.

Oral hygiene Poor dentition and dry mouth are common and contribute to a range of potentially painful conditions: dental abscess, parotitis, gingivitis, oral thrush. Poor oral hygiene increases the incidence of lung infection associated with aspiration and good hygiene can reduce the incidence.

Continence Both urinary and fecal incontinence are common among LTC recipients. Limitations of mobility, awareness or communication are more important than intrinsic bladder or bowel disturbances, highlighting that pro-active care can reduce the burden. The usual measures regarding diet and fluids may not ensure adequate bowel transit in immobile individuals, so constipation, fecal impaction and resultant impaction are common and may present misleadingly with “overflow” loose stools. Good “basic” personal care can reduce the distress and skin damage that may result. The use of catheters, often to reduce skin damage associated with urinary incontinence is associated with bacteriuria almost universally and frequently with infection. Avoidance of catheter associated UTIs requires their judicious use, excellent hygiene during handling and scheduled replacement perhaps 3–6 monthly, although the optimum frequency is not definite. Prompted voiding is the most evidenced approach to urinary incontinence which is often a mix of urgency and pelvis stress, and compounded by poor mobility. Carers can be trained to use this approach with residents with or without cognitive impairment, and so reduce the number of incontinent episodes but perseverance and adequate staffing are needed (Roe et al., 2015).

Contractures and Positioning A contracture can be defined as “any degree of loss in an active or passive range of motion in a joint, or an increase in the resistance to passive movement” (du Toit, 2018). Contractures in care home residents are common; however inconsistency of definition contributes to variable prevalence estimates. Wagner and Clevenger (2010) reported that two thirds of a cohort of 273 nursing home residents suffered at least one contracture, most commonly affecting the shoulder and knees. Contractures have significant impact on resident due to pain at rest and on movement, loss of mobility and impaired participation in activities. There are multiple risk factors: immobility, reduced consciousness, musculoskeletal conditions such as arthritis, pain, extrapyramidal rigidity and spasticity (Bartoszek et al., 2015). The presence of joint contractures is increasingly used as an indicator to assess the quality of care in long-term care setting. Reversing the contracture is unlikely, so prevention is key: this requires a multifactorial approach that begins with identification and amelioration of potential risk factors. This may include (du Toit, 2018):

• • • •

supporting activity and participation in functional activities passive stretching which may be carried out by trained care staff use of orthotic equipment appropriate seating and positioning for those who are sedentary in a chair or bed.

A systematic review of interventions for the prevention of contractures in older people (17 studies of which four were conducted in nursing homes) suggested benefit from active assisted stretching (five of nine studies) but highlighted that better evidence is needed for bed positioning and passive movement (Saal et al., 2017). Raising awareness of the impact, identification and prevention of contractures for care home residents through education and training is an area of developing research.

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Pressure area care The cause of pressure damage to skin and subcutaneous tissues is restricted blood flow. This may result directly from hard surfaces or by shearing of skin associated with slipping, more likely if the weight of the individual slips but the skin is sticky and remains in place. Prevention requires frequent attention to skin and positioning with adjustment as necessary. A variety of mattress types exist with variable methods to reduce and redistribute pressure and thus alleviate compression of subcutaneous and skin blood supply. Treatment of pressure damage is beyond the scope of this article.

Dementia Care Since many and in some instances most or all residents in a care home have degrees of cognitive impairment and various forms of dementia, understanding the impact of this on residents and their care needs is fundamental to providing residential LTC. The care needed will vary according to the individual’s character, cognition, mobility and any associated behavioral or psychological symptoms. The latter are often associated with anxiety, depression, boredom, loneliness or pain. Pain may also induce agitation and responds better to analgesics than to antipsychotic medication. There has been extensive experimentation and innovation in environmental design and social activity approaches to modifying the experience and behavior of individuals with dementia. Qualitative exploration identified that care home residents with dementia considered activities that addressed their psychological and social needs as the most meaningful activities. This was in contrast to family members and care staff who prioritized activities that maintained physical abilities as more meaningful (Harmer and Orrell, 2008).

Preserving Function and Participation Promoting Physical Activity Promoting physical activity as part of long-term care may help maintain function, improve sleep, reduce anxiety and depression and improve quality of life. For those with more limited mobility it may prevent hypostatic pneumonia, improve peripheral circulation and prevent pressure damage. However, levels of sedentary behavior are high. Accelerometry data revealed that residents in one UK care home spent 79% of their day sedentary with only 20% of time spend doing low-light levels of activity (Barber et al., 2015). Such trends are echoed internationally. Guidance that is appropriate for healthy community-dwelling older people such as from the World Health Organisation may have limited applicability for care home residents. An expert task force developed recommendations for physical activity specific to long-term care settings recognizing the importance of considering heterogeneity among residents and individual needs and preferences (de Souto Barreto et al., 2016). Guidance separated into two strands:

• •

Increasing overall physical activity levels in daily life Exercise training for a sub group of residents who are dependent in basic activities of daily living but capable of ambulating/ rising from a chair.

Barriers to participation occur at the level of the resident, the environment and the organization. Much of the work on physical activity in care home settings has focused on time limited structured exercise programs. A Cochrane review of physical rehabilitation for LTC residents appraised 67 trials including 6300 resident, concluding that rehabilitation can improve ADL or at least slow functional decline (Crocker et al., 2013). Variability in programs precluded conclusions on the most effective components. More recently different types of exercise programs have been evaluated. For example, in residential care facilities in Sweden, highintensity weight bearing functional exercise supervised by two physiotherapists demonstrated improvements in balance and a slowing in the decline of ADLs in older adults with mild-moderate cognitive impairment, but not those with Alzheimer’s dementia (Toots et al., 2016). In contrast, chair based exercise is commonly encouraged and considered by care staff as a safe and accessible approach (Robinson et al., 2015) but the health benefits are not established. Structured exercise programs with selected residents and external resources may have limited sustainability and long-term impact. Whole home approaches that develop a culture of activity built into daily routines, and tailored to individual characteristics and attitudes are more likely to be sustainable. Care assistants supporting sit-to-stand exercises during their morning and evening shifts was trialed in nursing homes in Canada, slowing the decline in function and mobility. Collaborative approaches that meaningfully involve residents, care staff and families in the development and implementation of physical activity are more successful and sustainable.

Promoting Physical Activity Whilst Preventing Falls Care home residents fall five times more often than older frail people at home, nearly 1 in 10 suffering a fracture (Rapp et al., 2009), many being admitted to hospital and up to one in five will die within the year as a result of a falls related injury. These people suffer pain, immobility and fear of further falls with high personal and financial costs. Carers whether informal or employed at home or in a care home, suffer guilt and anxiety.

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Guidance on the management of falls of older community dwelling people advocate for a person-centered approach where individual risk factors are identified with tailored action taken to reduce risks. Synthesis of evidence specifically from long-term care settings provides much less clarity with multifactorial interventions “likely to be beneficial” but benefit for progressive strength and balance training programs not demonstrated (Cameron et al., 2012). Feasibility work in UK care homes highlighted challenges with participating in strength and balance programs with 30% of recruited residents unable to take part in such programs and a mean attendance of 41% of sessions in those residents able to participate (Whitney et al., 2017). An on-going trial in the United KingdomdFalls in Care Homes is evaluating a multifactorial assessment and intervention program providing much needed research specific to this setting. Despite the lack of robust evidence for falls management in long-term care settings, residents, clinicians, care home staff and families are dealing with the very emotive subject of falls on a daily basis. A key challenge is balancing risk with supporting activity and participation. Residents who fear falling may reduce activity, thus further reducing their balance. Care staff and family may also take a protective approach. Fear of litigation may influence decision making of care staff and managers. Balancing safety with independence and autonomy is a complex issue influenced by multiple factors, and needs to be tackled using a pragmatic, person centered approach which is supported by the best available evidence and shared decision making and responsibility. Identifying and assessing the risk of falls should be a regular pro-active approach that considers the resident holistically. Reflecting on the exact circumstances of a fall may enable refinements to the daily care plan to anticipate or avoid the most risky behaviors, without the need for restraint. Identifying patterns of falls can enable learning and better practice but reporting and monitoring falls can be seen as a negative process designed to attribute blame. The challenge is to support a safety culture without restricting liberty.

Regulations, Standards and Quality Regulating and determining quality in long-term care is dependent on the model of funding and how it is delivered and regulation needs to fit the purpose of the type of care. Mor et al. (2014) provided a detailed international comparison of the different approaches to regulating the quality of long-term care and suggested that the following need consideration: Who is subject to the regulation? What are the standards of care that are required? How will regulation be enforced? In summary there are three main approaches:

• • •

Professionalism based; where professional organizations are responsible for ensuring staff who work in long-term care have the appropriate levels of education, training and qualifications. Examples of countries which adopt this approach are Germany and Japan. Inspection based regulating systems; where government organizations are responsible for determining standards of care and carrying out inspections to monitor adherence to these standards. Examples of countries that adopt this approach are the United Kingdom and the Netherlands. Data measurement and reporting; where there is a standardized approach to reporting on key components of quality that can be used by consumers to assess quality. This approach is often used in addition to an inspection based system. Examples of counties adopting this approach are the United States and Canada.

What Is Quality? In order to measure quality in long-term care, we need to firstly define and determine what is meant by quality. There are several potential perspectives to consider including:

• • • • • •

system level efficiency, sustainability and resource use general professional and clinical guidance and standards views of residents/proxies staff views and satisfaction research evidence of what influences quality of life stakeholder views.

No quality measurement system can address all these simultaneously. Quality of life of a resident may be difficult to capture, and aspirations of families and advocates are not always the same as residents. Research is ongoing to establish the optimal proxy approach. Historically quality of care received by the resident was often viewed in terms of disease specific outcome and safety such as pressure ulcers, malnutrition and weight loss. There is a shift to consider the importance of quality of life and resident well-being, emphasizing the importance of person centered care.

Quality measurement systems The European Union developed a “European Charter of the rights and responsibilities of older people in need of long-term care and assistance” in conjunction with Age Platform, a federation of age advocacy organizations. This covers 10 themes:

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• • • • • • • • • •

Right to dignity, physical and mental well-being, freedom and security Right to self-determination Right to privacy Right to high quality and tailored care Right to personalized information, advice and informed consent Right to continued communication, participation in society and cultural activity Right to freedom of expression and freedom of thought/conscience: beliefs, culture and religion Right to palliative care and support, and respect and dignity in dying and in death Right to redress And a list of responsibilities including respect for carers and for self-support as feasible

This was subsequently used to develop a “European Quality Framework for long-term care services” by the European Partnership for the Wellbeing and Dignity of Older people, and supported by an on-line toolkit produced by Age Platform Europe (https://www. age-platform.eu/publications/dignity-and-wellbeing-older-persons-need-care-00). The My Home Life program in England proposed a framework for care homes based on extensive work with residents, families and care homes staff, identifying eight domains as shown in the box.

• • • • • • • •

Managing Transitions Maintaining Identity: a sense of personal identity and engage in meaningful activity Creating Community: optimizing relationships, belonging, purpose, etc. Sharing Decision-making: facilitating involvement and informed risk-taking etc. Improving Health and Healthcare: adequate access to healthcare services Supporting Good End of Life Keeping Workforce Fit for Purpose – training, attitudes etc. Promoting a Positive Culture - leadership, management, expertise etc.

The American Association for Retired Persons (AARP) adopted the AARP scorecard based on the following (Reinhard et al., 2011):

• • • • •

Affordability and access Choice of setting and provider Quality of life and quality of care Support for family caregivers Coordination of LTC with medical services

In Europe, the Centre for European Policy published results of the ANCIEN project (Assessing Needs of Care in European Nations) which compared five European countries’ LTC systems. It incorporated factors at individual and system level such simplicity of access and equity, system support for informal caregivers, and integration with healthcare and social services and coordination. As previously mentioned, the RAI MDS has generated a set of quality standards (RAI-MDS 2.0 Quality Indicators). The above mentioned SHELTER project in Europe compared quality of care based on interRAI-LTCF using thresholds and a Quality Indicator sum measure. Quality varied considerably between the eight countries even after case risk adjustment (Frijters et al., 2013). A systematic review of the use of these quality indicators however concluded that caution and additional data sources are needed to provide a reliable indication of quality of care (Hutchinson et al., 2010). In the Netherlands, a national quality measurement system, the National Prevalence Measurement of Quality of Care (LPZ, 2016) involves a single day snapshot of health states along with indications of care processes. Data is submitted on line and reports generated at the level of the resident, the unit or the whole facility. This enables national comparisons and monitoring the impact of improvement efforts over time. The indicators cover pressure ulcers and their prevention, continence, malnutrition, falls, physical restraints and pain. Other markers of quality may relate to processes such as staffing levels, skill mix and workforce development. High quality longterm care requires a highly trained and skilled diverse work force, however nonprofessional care staff often have low levels of education and training and are paid below the living wage. Nonprofessional staff are suggested by the Alzheimer’s Association (Gilster et al., 2018) to be the “single most important determinant of quality dementia care” and the same importance could be applied across all long-term care residents. The OECD concluded in 2013 (Organization for Economic Cooperation and Development, 2013) that the measurement of quality in long-term care lags well behind the health sector. More effective monitoring of long-term care quality, and the development of robust, comparable measures, should be a priority for OECD countries.

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Future Trends and Research Needs There is much to be done in developing and evaluating models of healthcare support to care homes. The majority remain independent institutions, with tenuous links to social and healthcare systems. There has been a clear move to articulate and then measure standards of care and healthcare in care homes with an increasing emphasis on promoting autonomy, dignity and quality of life. There is also a need to improve understanding and clinical practice. An international expert consensus process identified the following research priorities (Morley et al., 2014):

• • • • • •

Care of people with cognitive impairment/dementia and the management of the behavioral and psychological symptoms of dementia within the nursing home End-of-life care Nutrition Polypharmacy Developing new approaches to putting evidence-based practices into routine practice in nursing homes Research into innovative educational approaches, addressing why best practices are difficult.

Broadening the role of care homes in the health and social care ecosystem and developing the provider culture from custodial care to recuperative care may play a part in the future (De Mazieres et al., 2017).

References Barber, S.E., Forster, A., Birch, K.M., 2015. Levels and patterns of daily physical activity and sedentary behavior measured objectively in older care home residents in the United Kingdom. Journal of Aging and Physical Activity 23 (1), 133–143. https://doi.org/10.1123/japa.2013-0091. Bartoszek, G., Fischer, U., Grill, E., et al., 2015. Impact of joint contracture on older persons in a geriatric setting: A cross-sectional study. Zeitschrift für Gerontologie und Geriatrie 48, 625–632. Bowman, C., Whistler, J., Ellerby, M., 2004. A national census of care home residents. Age and Ageing 33, 561–566. Bradshaw, S.A., Playford, E.D., Riazi, A., 2012. Living well in care homes: A systematic review of qualitative studies. Age and Ageing 41 (4), 429–440. https://doi.org/10.1093/ ageing/afs069. Briggs, R., Holmerová, I., Martin, F.C., O’Neill, D., 2015. Towards standards of medical care for physicians in nursing homes. European Geriatric Medicine 6 (4), 401–403. Cameron, I.D., Gillespie, L.D., Robertson, M.C., et al., 2012. Interventions for preventing falls in older people in care facilities and hospitals. Cochrane Database of Systematic Reviews 12, CD005465. Campbell, C., Ikegami, C., Gori, F., et al., 2016. How different countries allocate long-term care benefits to users: A comparative snapshot. In: Long-term care reforms in OECD countries: Successes and failures. Policy Press, London. Carpenter, G.I., Gambassi, G., Topinkova, E., et al., 2014. Community care in Europe. The Aged in Home Care project (AdHOC). Aging Clinical and Experimental Research 16, 259–269. Cohen-Mansfield, J., Skornick-Bouchbinder, M., Brill, S., 2018. Trajectories of end of life: A systematic review. The Journals of Gerontology: Series B 73 (4), 564–572. Corbett, A., Husebo, B.S., Achterberg, W.P., 2014. The importance of pain management in older people with dementia. British Medical Bulletin 111, 139–148. https://doi.org/10. 1093/bmb/ldu023. Crocker, T., Forster, A., Young, J., et al., 2013. Physical rehabilitation for older people in long-term care. Cochrane Database of Systematic Reviews (2), CD004294. https://doi.org/ 10.1002/14651858.CD004294.pub3. De Mazieres, C.L., Morley, J.E., Levy, F., et al., 2017. Prevention of functional decline by reframing the role of nursing homes? The Journal of Nursing Home Research 3, 105–110. Dwyer, L.L., Harris-Kojetin, L.D., Valverde, R.H., et al., 2013. Infection in long-term care populations in the United States. Journal of the American Geriatrics Society 61, 342–349. European Commission, The 2015 Ageing Report: Economic and budgetary projections for the 28 EU Member States (2013–2060), Brussels, 2015. http://ec.europa.eu/economy_ finance/publications/european_economy/2015/ (accessed November 10, 2018). Frijters, D.H.M., van der Roest, H.G., Carpenter, I.G.I., et al., 2013. The calculation of quality indicators for long term care facilities in 8 countries (SHELTER project). BMC Health Services Research 13, 138. https://doi.org/10.1186/1472-6963-13-138. Geerts, J., Willemé, P., Comas-Herrera, A., 2012. Projecting long-term care use in Europe. In: Geerts, J., Willemé, P., Mot, G. (Eds.), Projecting long-term care use and supply in Europe, ENEPRI Research Report No. 116. Centre for European Policy Studies (CEPS), Brussels. Gilster, S.D., Boltz, M., Dalessandro, J.L., 2018. Long-term care workforce issues: Practice principles for quality dementia care. Gerontologist 58, S103–S113. https://doi.org/ 10.1093/geront/gnx174. Goodman, C., Dening, T., Gordon, A.L., et al., 2016. Effective health care for older people living and dying in care homes: A realist review. BMC Health Services Research 16, 269. https://doi.org/10.1186/s12913-016-1493-4. Green, I., Stow, D., Matthews, F.E., Hanratty, B., 2017. Changes over time in the health and functioning of older people moving into care homes: Analysis of data from the English Longitudinal Study of Ageing. Age and Ageing 46, 693–696. https://doi.org/10.1093/ageing/afx046. Harmer, B.J., Orrell, M., 2008. What is meaningful activity for people with dementia living in care homes? A comparison of the views of older people with dementia, staff and family carers. Aging & Mental Health 12 (5), 548–558. https://doi.org/10.1080/13607860802343019. Hayward, A.C., Harling, R., Wetten, S., et al., 2006. Effectiveness of an influenza vaccine programme for care home staff to prevent death, morbidity, and health service use among residents: Cluster randomised controlled trial. British Medical Journal 333 (7581), 1241. Hermans, K., Mello, J.D.A., Spruytte, N., et al., 2014. A comparative analysis of comprehensive geriatric assessments for nursing home residents receiving palliative care: A systematic review. Journal of the American Medical Directors Association 15 (7), 467–476. Hjaltadóttir, I., Hallberg, I.R., Ekwall, A.K., Nyberg, P., 2011. Predicting mortality of residents at admission to nursing home: A longitudinal cohort study. BMC Health Services Research 11, 86. http://www.biomedcentral.com/1472-6963/11/86.

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Hutchinson, M., Milke, D.L., Maisey, S., et al., 2010. The resident assessment instrument-minimum data set 2.0 quality indicators: A systematic review. BMC Health Services Research 10, 166. Kinley, J., Hockley, J., Stone, L., et al., 2014. The provision of care for residents dying in UK nursing care homes. Age and Ageing 43 (3), 375–379. https://doi.org/10.1093/ageing/ aft158. Kinley, J., Stone, L., Butt, A., Kenyon, B., Santos Lopes, N., 2017. Developing, implementing and sustaining an end-of-life care programme in residential care homes. International journal Palliative Care 23 (4). https://doi.org/10.12968/ijpn.2017.23.4.186. Kraus, M.M., Riedel, E., Mot, P., et al., 2010. A typology of long-term care systems in Europe, ENEPRI Research Report No. 91. Centre for European Policy Studies, Brussels. Lemaitre, M., Meret, T., Rothan-Tondeur, M., et al., 2009. Effect of influenza vaccination of nursing home staff on mortality of residents: A cluster-randomised trial. Journal of the American Geriatrics Society 57, 1580–1586. Lynn, J., Adamson, D.M., 2003. Living well at the end of life, adapting health care to serious chronic illness in old age. Rand Health, Santa Monica, CA. Mitchell, S.L., 2015. Advanced dementia. The New England Journal of Medicine 372, 2533–2540. Mitchell, S.M., Teno, J.M., Kiely, D.K., et al., 2009. The clinical course of advanced dementia. The New England Journal of Medicine 361, 1529–1538. Mor, V., Leone, T., Maresso, A. (Eds.), 2014. Regulating long-term care quality: An international comparison. Cambridge University Press, New York, NY. Morley, J.E., Caplan, G., Cesari, M., et al., 2014. Key priorities for nursing homes research: International survey of nursing home research priorities. JAMDA 15, 309–312. ten Keppel, M., Bregje, D., Onwuteaka-Philipsen, H., et al., 2018. Are older long term care residents accurately prognosticated and consequently informed about their prognosis? Results from SHELTER study data in 5 European countries. PLoS One 13 (7), e0200590. Onder, G., Carpenter, I., Finne-Solveri, H., et al., 2012. Assessment of nursing home residents in Europe: The Services and Health for Elderly in Long TERm care (SHELTER) study. BMC Health Services Research 12, 5. https://doi.org/10.1186/1472-6963-12-5. Organization for Economic Cooperation and Development (2013) A good life in old age? Monitoring and improving quality in long-term care. Available from http://www.oecd.org/ health/health-systems/a-good-life-in-old-age-9789264194564-en.htm (accessed November 6, 2018) Rapp, K., Lamb, S.E., Klenk, J., et al., 2009. Fractures after nursing home admission: Incidence and potential consequences. Osteoporosis International 20, 1775–1783. Reinhard SC, Kassner E, Houser A, and Mollica R (2011) A state scorecard on long-term services and supports for older adults, people with physical disabilities, and family. Available from https://assets.aarp.org/rgcenter/ppi/ltc/ltss_scorecard.pdf (accessed October 23, 2018) Robinson, K.R., Gladman, J.R.F., Masud, T.M., Logan, P., Hood, V., 2015. Chair based exercise: A survey of care homes in Nottinghamshire. East Midlands Research into Ageing Network, Nottingham. Rodrigues, M.A., Facchini, L.A., Thumé, E., Maia, F., 2009. Gender and incidence of functional disability in the elderly: A systematic review. Cad Saude Publica 25 (Suppl. 3), S464–S476. https://doi.org/10.1590/S0102-311X2009001500011. 20027393. Roe, B., Flanagan, L., Maden, S., 2015. Systematic review of systematic reviews for the management of urinary incontinence and promotion of continence using conservative behavioural approaches in older people in care homes. Journal of Advanced Nursing 71, 1464e1483. Saal, S., Beutner, K., Bogunski, J., et al., 2017. Interventions for the prevention and treatment of disability due to acquired joint contractures in older people: A systematic review. Age and Ageing 46, 373–382. Sanford, A.M., Orrell, M., Tolson, D., et al., 2015. An international definition for “Nursing Home”. Journal of the American Medical Directors Association 16, 181–186. Shah, S.M., Carey, I.M., Harris, T., De Wilde, S., Cook, D.G., 2013. Mortality in older care home residents in England and Wales. Age Ageing 42, 209–215. Sousa, R.M., Ferri, C.P., Acosta, D., et al., 2009. Contribution of chronic diseases to disability in elderly people in countries with low and middle incomes: A 10/66 Dementia Research Group population-based survey. Lancet 374, 1821–1830. de Souto Barreto, P., Morley, J.E., Chodzko-Zajko, W., et al., 2016. Recommendations on physical activity and exercise for older adults living in long-term care facilities: A taskforce report. Journal of the American Medical Directors Association 17, 381–392. Stanyon, M.R., Goldberg, S.G., Astle, A., Griffiths, A., Gordon, A.L., 2017. The competencies of registered nurses working in care homes: A modified Delphi study. Age and Ageing 46 (4), 582–588. du Toit, D., 2018. Prevention of contractures in older people living in long-term care settings. Nursing Older People 30, 24–30. https://doi.org/10.7748/nop.2018.e1023. Toots, A., Littbrand, H., Lindelöf, N., et al., 2016. Effects of a high-intensity functional exercise program on dependence in activities of daily living and balance in older adults with dementia. Journal of the American Geriatrics Society 64, 55–64. Wagner, L.M., Clevenger, C., 2010. Contractures in nursing home residents. Journal of the American Medical Directors Association 11, 94–99. Whitney, J., Jackson, S.H.D., Martin, F.C., 2017. Feasibility and efficacy of a multi-factorial intervention to prevent falls in older adults with cognitive impairment living in residential care (ProF-Cog). A feasibility and pilot cluster randomised controlled trial. BMC Geriatrics 17 (1), 115. https://doi.org/10.1186/s12877-017-0504-6. World Health Organisation (2015) World report on ageing and health, WHO, Geneva. Available from http://www.who.int/ageing/en/ (accessed October 20, 2018). World Health Organisation (Europe Region) European Health Information Gateway, number of nursing and elderly home beds, WHO, Copenhagen. https://gateway.euro.who.int/en/ hfa-explorer-#78k5Yj9IVn (accessed March 15, 2019). World Health Organization (2016) Global strategy and action plan on ageing and health. WHO, Geneva. Available from: http://www.who.int/ageing/global-strategy/en/ (accessed October 12, 2018)

Further Reading Croft, J., 2017. Enabling positive risk-taking for older people in the care home. Nursing and Residential Care 19 (9), 515–519. Hermans, K., De Almeida Mello, M.J., Spruytte, N., et al., 2014. A comparative analysis of comprehensive geriatric assessments for nursing home residents receiving palliative care: A systematic review. Journal of the American Medical Directors Association 15, 467–476. https://doi.org/10.1016/j.jamda.2014.01.002. Hirschfeld, M. (Ed.), 2013. Key policy issues in long-term care. World Health Organisation, Geneva. Ikezoe T, Asakawa Y, Shima H, Kishibuchi K, and Ichihashi N (2013) Daytime physical activity patterns and physical fitness in institutionalized elderly women: An exploratory study. Archives of Gerontology and Geriatrics 57(2): 221–225. doi:https://doi.org/10.1016/j.archger.2013.04.004. Epub 2013 May 9. PubMed PMID: 23664785. Larizgoitia, X., 2011. Approaches to evaluating LTC systems. In: Brodsky, J., Habib, J., Neyens, M., van Haastregt, J.C., Dijcks, B.P., et al. (Eds.), Effectiveness and implementation aspects of interventions for preventing falls in elderly people in long-term care facilities: A systematic review of RCTs, pp. 410–425. Journal of the American Medical Directors Association, 12:6. Sorenson C and Mossialos E (2007) Measuring quality and standards of long-term care for older people. European Commission Directorate-General Employment, Social Affairs and Equal Opportunities Unit E1 – Social and Demographic Analysis. Available from https://pdfs.semanticscholar.org/9207/2b98a62e7ddaf586770db3611df1cd943a57.pdf Umegaki, H., Yanagawa, M., Nonogaki, Z., Nakashima, H., Kuzuya, M., Endo, H., 2014. Burden reduction of caregivers for users of care services provided by the public long-term care insurance system in Japan. Archives of Gerontology and Geriatrics 58 (1), 130–133. https://doi.org/10.1016/j. archger.2013.08.010. Van Kooten, J., Smalbrugge, M., van der Wouden, J.C., Stek, M.L., Hertogh, C.M.P.M., 2017. Prevalence of pain in nursing home residents: The role of dementia stage and dementia subtypes. Journal of the American Medical Directors Association 18, 522e527. World Health Organisation, 2010. Global recommendation on physical activity for health. World Health Organisation, Switzerland.

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Relevant Websites https://gb.lpz-um.eu/endLPZ. http://www.nice.org.uk/guidance/qs13/dNational Institute of Health and Care Excellence. http://myhomelife.org.uk/news-and-media/resourcesdThe National Care Homes Research and Development Forum. https://www.ceps.eu/search?keywords¼ANCIEN&type¼AlldPerformance of Long-Term Care Systems in Europe. http://www.interrai.org/long-term-care-facilities.htmldInterRai. https://www.age-platform.eu/sites/.../22495_guide_accompagnement_EN_low.pdfdAGE Platform Europe. http://www.oecd.org/els/health-systems/long-term-care.htmdOrganisation for Economic Co-operation and Development (OECD). http://myhomelife.org.uk/dMy Home Life. http://www.choosingwisely.org/dThe ABIM Foundation (American Board for Internal Medicine). https://geriatricscareonline.org/ProductTypeStore/clinical-guidelines-recommendations/8/dAmerican Geriatrics Society. www.nice.org.uk/guidance/ng56dNational Institute for Health and Care Excellence. https://paltc.org/product-store/full-set-clinical-practice-guidelinesdClinical Practice Guidelines, American Medical Directors Association (AMDA). https://www.nice.org.uk/guidance/ng48/resources/oral-health-for-adults-in-care-homes-pdf-1837459547845dOral Health for Adults in Care Homes, National Institute of Health and Care Excellence. http://www.who.int/ageing/publications/Falls_prevention7March.pdfdWorld Health Organization.

Lung Cancer Rafael Lucas Costa de Carvalho, Pedro Henrique Cunha Leite, Fla´vio Pola dos Reis, Eserval Rocha Ju´nior, and Ricardo Mingarini Terra, University of São Paulo Medical School, São Paulo, Brazil © 2020 Elsevier Inc. All rights reserved.

Introduction Epidemiology Risk Factors Tobacco and Smoking Air Pollution Asbestos Radon Infections Lung Cancer Classification Screening for Lung Cancer Clinical Manifestations Diagnostic Techniques Staging TNM System T Status N Status M Status Noninvasive Staging Invasive Staging Staging Groups Treatment Early Stages Locally Advanced Disease Metastatic Disease Small Cell Lung Cancer Palliative Care Conclusions References Further Reading

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Abbreviations AIS Adenocarcinoma in situ ALK Anaplastic lymphoma kinase CI Confidence interval CRT Chemoradiotherapy CT Computed tomography EBUS Endobronchial ultrasound EUS Endoscopic ultrasound EGFR Epidermal growth factor receptor HIV Human immunodeficiency virus IASLC International Association for the Study of Lung Cancer LCC Large cell carcinoma LDCT Low-dose chest CT NSCLC Nonsmall cell lung cancer PD-L1 Programmed death-ligand 1 PET Positron emission tomography SCLC Small cell lung carcinoma

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TKI Tyrosine-kinase inhibitors TTNA Transthoracic needle aspiration WHO World Health Organization

With population aging, the incidence of lung cancer has increased, as age and smoking remain the main risk factors. In the same way, the therapeutic arsenal has expanded with the emergence of minimally invasive surgery, such as video-assisted and robotics, new modalities in radiotherapy and promising new target-directed drugs and immunotherapy. Although treatment has advanced, prevention remains the most effective strategy to reduce mortality in lung cancer patients. Recently, randomized trials of low-dose CT scanning in the smoking population demonstrated that screening can identify early-stage asymptomatic lung cancer and reduce mortality. Appropriate staging, with imaging methods and minimally invasive procedures, is essential for choosing the appropriate treatment. This should be individualized considering, in addition to staging, status performance. Palliative care is always part of oncology care, but in elderly patients, often diagnosed at an advanced stage, it plays an even more important role since quality of life must be prioritized.

Introduction Epidemiology The most recent global statistical analysis estimates 1.8 million new cases of lung cancer were diagnosed worldwide in 2012, with 1.6 million deaths in the same year (Ferlay et al., 2013). Currently, the estimated number of new cases of lung cancer in the United States for 2018 is 121,680 for men and 112,350 for women, for a total of 234,030 cases. Lung carcinoma is the second most common cancer diagnosis by sex, behind prostate cancer for men and breast cancer for women. In 2018 in the United States, lung cancer accounted for 14% and 13% of new cancers in men and women, respectively (Siegel et al., 2018). Global trends in lung cancer epidemiology show that rates vary around the world, reflecting geographical differences in tobacco use and air quality (Torre et al., 2016). Additionally, lung cancer incidence is increasing worldwide (Ferlay et al., 2013). Cigarette smoking is much more prevalent in individuals with less than a high-school education than in college graduates: 32.1% versus 9.1% (Siegel et al., 2018). Individuals with a higher level of education are less likely to start smoking and are more amenable to quitting. Smokers with low education levels are less likely to even attempt to quit (Torre et al., 2016). Better educated people also have access to resources such as healthcare, leading to disparities in mortality and survival (Siegel et al., 2018). Regarding sex, historically more men than women smoke tobacco, and men have higher rates of incidence and mortality. Women took up smoking at a later period, mostly after the Second World War, and their rates of cessation have lagged behind those of men, leading to a much later peak in lung cancer incidence in women (Siegel et al., 2018). There is a higher rate of lung cancer in nonsmoking women than in nonsmoking men, a higher proportion of epidermal growth factor receptor (EGFR) mutations in female nonsmall cell lung cancer (NSCLC), and a higher incidence of adenocarcinoma with lepidic features in women (Patel, 2005). Older age is associated with cancer development due to biologic factors that include DNA damage over time and shortening telomeres. Accordingly, the median age of lung cancer diagnosis is 70 years for both men and women (Torre et al., 2016; National Cancer Institute, 2018); this subgroup is under-represented in clinical trials where the median age is typically around 60 years (Hutchins et al., 1999). Approximately 53% of cases occur in individuals 55–74 years old, and 37% occur in those older than 75 years (Torre et al., 2016). Older patients do not tolerate treatments as well as their younger counterparts, likely due to higher rates of comorbidities as well as decreased regenerative capacity and organ function. Providing optimal treatment for older patients is challenging. According to a pooled analysis of The Surveillance, Epidemiology, and End Results data, less than half of older patients receive guideline-concordant treatment. Yet, survival was increased in the patients who received guideline-concordant care (Nadpara et al., 2015).

Risk Factors Tobacco and Smoking The use of tobacco cigarettes is the single greatest risk factor for the development of lung cancer, with up to 90% of lung cancers attributed to smoking (de Groot et al., 2018). The risk of lung cancer increases with the duration of smoking and the number of cigarettes smoked per day (de Groot et al., 2018). One report estimated that the average male smoker has an
9- to 10-fold higher risk for developing lung cancer, whereas the risk for heavy smokers is at least 20-fold higher (U.S. Public Health Service, 1972). Cigarette smoking is believed more important than occupational exposures in the causation of lung cancer in the general population. The addictive component of tobacco is nicotine, a natural alkaloid that acts as an acetylcholine agonist and binds to nicotinic acetylcholine receptors in the nervous system. While nicotine itself is not a carcinogen, it upregulates nicotinic receptors and

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produces alterations in gene expression that foster tobacco dependence. Moreover, it is associated with the progression of existing lung tumors. Tobacco combustion produces at least 60 known carcinogens, of which the most significant are polycyclic aromatic hydrocarbons (de Groot et al., 2018). One in nine smokers eventually develops lung cancer. The cumulative lung cancer risk among heavy smokers can be as high as 30% compared with a lifetime risk lower than 1% in nonsmokers (Jemal et al., 2005). Secondhand smoke, also referred to as environmental tobacco smoke, can contribute to an increased risk for lung cancer with a dose-dependent relationship between the degree of exposure and the relative risk. One study showed that household exposure of 25 or more smoker-years before adulthood doubled the risk for lung cancer. Investigators estimated that at least 17% of lung cancers in nonsmokers are attributable to exposure to high levels of environmental tobacco smoke during childhood and adolescence (Janerich et al., 1990).

Air Pollution Air pollution has become a worldwide problem given the current staggering rate of globalization and industrialization. The effects of low levels of air pollution exposure over a longer period are harder to measure, especially the long-term and cumulative effects on the risk of lung cancer. Air pollution is worsening in developing countries; the highest concentrations of suspected particulates, sulfur dioxide, and smoke have been recorded in large cities of these countries (Dela Cruz et al., 2011; Pershagen, 1990).

Asbestos Asbestos is the most widely known and most common occupational cause of lung cancer. Asbestos is a class of naturally occurring fibrous minerals consisting primarily of two types: (1) serpentine (chrysotile) and (2) amphibole (amosite, crocidolite, and tremolite) (Driscoll et al., 2005). The risk of lung cancer associated with asbestos exposure is dose-dependent but varies with the type of asbestos fiber exposure. The lung cancer risk appears higher for workers exposed to amphibole fibers than for those exposed to chrysotile fibers. The relative risk for lung cancer related to asbestos exposure alone is 6-fold, and for cigarette smoking alone it is 11-fold; however, with exposure to both asbestos and cigarette smoke, the increase in risk may be as high as 59-fold (Weiss, 1999).

Radon Residential radon from soil accounts for the second most common risk factor for lung cancer, estimated to cause 10% of cases. Radon is a naturally occurring radioactive gas produced by uranium decay in the earth’s crust. It emits alpha particles, decaying to polonium and then bismuth. Radon can accumulate to unsafe levels in basements and lower building levels. Concurrent tobacco smoking increases the relative risk of lung cancer from radon (Krewski et al., 2005).

Infections Damage to the lungs from inflammation and infection is implicated in carcinogenesis. Lung cancer is the most common non-AIDSdefining malignancy in people with human immunodeficiency virus (HIV) infection. The HIV virus has not been implicated in oncogenesis, but studies suggest that immunosuppression can play a role. The higher smoking prevalence in the HIV population, with 42% of HIV-positive adults reported to be current cigarette smokers in 2009, may be a contributing factor (de Groot et al., 2018).

Lung Cancer Classification The 2015 World Health Organization (WHO) classification relies on immunohistochemical characterization in addition to light microscopy, allowing for subtyping that more judiciously guides treatment strategy and predicts clinical course. Additionally, it provides standardized criteria and terminology for lung cancer diagnosis based on small biopsies and cytology, which is critical given that most patients with lung cancer present with high-stage disease and are not surgical candidates (Janssen-Heijnen et al., 2001; Travis et al., 2015). AdenocarcinomadIn a contemporary series, adenocarcinoma was the most common type of lung cancer, accounting for
50% of lung cancer cases. The increased incidence of adenocarcinoma is thought to be due to the introduction of low-tar filter cigarettes in the 1960s, although such causality is unproven (Janssen-Heijnen et al., 2001). Patients with advanced lung adenocarcinoma and other nonsmall carcinomas not otherwise specified should have their tumors tested for the presence of a driver mutation (e.g., mutated EGFR, anaplastic lymphoma kinase (ALK) translocation, and, increasingly, other mutations) (Travis et al., 2015). Histological diagnosis requires evidence of either neoplastic gland formation, pneumocyte marker expression (TTF1 þ/ napsin), or intracytoplasmic mucin. There is significant variation in the extent and architecture of neoplastic gland formation, with major subtypes demonstrating an acinar, papillary, micropapillary, lepidic, or solid growth pattern, with either mucin or

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pneumocyte marker expression having prognostic significance when predominant within resections (Travis et al., 2015; Kish et al., 1989; Moran, 1995). Less common patterns include cribriform, colloid, enteric, and fetal. Squamous cell carcinomadIs predicated upon the presence of keratin production by tumor cells and/or intercellular desmosomes, or by immunohistochemistry consistent with squamous cell carcinoma (i.e., expression of p40, p63, CK5, or CK5/6 and desmoglein). Most squamous cell carcinomas (60–80%) arise in the proximal portions of the tracheobronchial tree through a squamous metaplasia-dysplasia-carcinoma in situ sequence (squamous carcinoma in situ), although they are increasingly presenting as peripheral lesions (Funai et al., 2003). Large cell carcinomadLarge cell carcinoma (LCC) is a malignant epithelial neoplasm lacking both glandular and squamous differentiation by light microscopy and immunohistochemistry and lacking cytologic features of small cell carcinoma. LCC usually presents as a large peripheral mass with prominent necrosis (Travis et al., 2015). Neuroendocrine tumorsdSeveral tumor types are grouped based upon shared neuroendocrine features (Travis et al., 2015). These tumors include small cell carcinoma, large cell neuroendocrine carcinoma, typical carcinoids, and atypical carcinoids. Additionally, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, a possibly preinvasive epithelial lesion, is included in this category (Travis, 2004). Within the group of pulmonary neuroendocrine tumors, typical and atypical carcinoids share several features and are similar to carcinoid lesions arising at other sites. Small cell carcinomas and large cell neuroendocrine carcinomas are clinically characterized by a more aggressive course and pathologically by a much higher mitotic rate than pulmonary carcinoids (11 or more mitoses per 10 high-power fields) (Travis et al., 2015). Small cell lung carcinoma (SCLC) shows a strong correlation with cigarette smoking and is extremely rare in persons who have never smoked. The nuclei are typically hyperchromatic and either has a dispersed “salt and pepper” chromatin or a homogeneously dispersed chromatin. The cells are fragile, and the tumors are generally extensively necrotic, both of which may contribute to the difficulty in establishing a histologic diagnosis. Tumor cells are usually positive for one or more of chromogranin or synaptophysin, although around 10% may be unreactive for neuroendocrine markers. Carcinoid tumors are neuroendocrine epithelial malignancies with a lower grade than large cell neuroendocrine or small cell carcinomas and can be further divided into typical or atypical carcinoid tumors.

Screening for Lung Cancer Prevention is the most effective strategy for reducing the mortality of lung cancer in the long term (US Department of Health and Human Services, 2014). Smoking cessation is considered the most effective method of prevention for current smokers, as 90% of lung cancers can be attributed to smoking (US Department of Health and Human Services, 2014). Ma et al. showed that more than 12,000 lung cancer deaths per year in the United States are potentially preventable (Ma et al., 2013). However, some features of lung cancer suggest that screening could be effective, for example, high morbidity and mortality, significant prevalence (0.5–2.2%), identified risk factors, and evidence that treatment is more successful in early-stage disease (Cole and Morrison, 1980; Patz et al., 2000). Several observational studies of low-dose computed tomography (CT) scanning have been published, which demonstrate that screening can identify early-stage asymptomatic lung cancer (Henschke et al., 2006; Swensen et al., 2005; Veronesi et al., 2014). The International Early Lung Cancer Action Program Investigators showed a stage shift, above 48–85% of screen-detected lung cancers were detected at stage I compared with 30–35% of clinically detected lung cancers, making possible the adoption of more effective treatment options (Henschke et al., 2006). Recently, some randomized trials of low-dose CT scanning demonstrated that screening can identify early-stage asymptomatic lung cancer and reduce lung cancer-related death among asymptomatic patients at high risk for lung cancer (National Lung Screening Trial Research Team et al., 2011; De Koning et al., 2018). The National Lung Screening Trial was an American randomized trial comparing annual screening by low-dose chest CT (LDCT) scanning with chest radiograph over 3 years and included persons aged 55–74 years with a history of at least 30 pack-years of smoking, current smokers, and those who had discontinued smoking within 15 years of enrollment. This study demonstrated that LDCT screening reduced mortality in a high-risk population compared with screening by radiograph. There was a relative mortality reduction of 20% (relative risk 0.80, 95% confidence interval [CI] 0.73–0.93) and an absolute reduction of 62 lung cancer deaths per 100,000 person-years (National Lung Screening Trial Research Team et al., 2011). The NELSON is a European controlled trial that enrolled 15,792 patients at high risk of developing lung cancer to undergo CT screening or no screening. CT screening was conducted at baseline and 1, 3, and 5.5 years after randomization. The follow-up period comprised a minimum of 10 years (De Koning et al., 2018). Results from the NELSON trial presented at the International Association for the Study of Lung Cancer’s (IASLC) nineteenth World Conference on Lung Cancer in Toronto, Canada showed that CT screening reduced the risk of lung cancer-related deaths by 26% (95% CI 9–41%) resulting in a rate ratio of 0.74 in men. Apparently, women had a greater benefit, with a rate ratio for lung cancer-related death of 0.30–0.61, depending on the year of follow-up. Furthermore, 69% of detected lung cancer was stage I, and surgical treatment was significantly more prevalent in patients who underwent CT screening than in patients in the control arm (68% vs. 25%; P < .001) (De Koning et al., 2018).

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The United States Preventive Services Task Force recommends LDCT screening for lung cancer; annual screening for men and women aged 55–80 years with a smoking history of at least 30 pack-years who currently smoke or quit smoking within the past 15 years provides a beneficial trade-off between benefits and harms (Humphrey et al., 2013).

Clinical Manifestations Patients who present with clinical signs or symptoms due to lung cancer usually have advanced disease. Symptoms result from the local effects of the tumor, from regional or distant spread, or from paraneoplastic syndromes. Approximately 75% of nonscreened patients have one or more symptoms at the time of diagnosis. The most common symptoms are cough (55%), dyspnea (45%), pain (38%), and weight loss (36%). Older lung cancer patient can expect a high symptom burden, particularly from fatigue and dyspnea, associated with the highest rates of comorbidities including; cardiovascular disease (23%), chronic obstructive airways disease (COPD) (22%), and other malignancies (15%). Indeed, the prevalence of comorbidity among lung cancer sufferers is significantly higher in patients aged > 70 years. (Kocher et al., 2015). CoughdA cough is present in 50–75% of lung cancer patients at presentation and is more common in squamous cell and small cell carcinomas due to their tendency to involve the central airways. Moreover, these carcinomas may cause postobstructive pneumonia (Kocher et al., 2015). HemoptysisdHemoptysis is reported by 20–50% of patients who are diagnosed with lung cancer, although bronchitis is the most common cause of this symptom (Kocher et al., 2015). It occurs more commonly with centrally located tumors such as squamous cell tumors and SCLC. Chest paindChest pain is present in
20–40% of patients presenting with lung cancer. Usually, pleuritic pain may be the result of direct pleural or chest wall involvement; however, obstructive pneumonitis or a pulmonary embolus related to a hypercoagulable state may also cause chest pain (Kocher et al., 2015). DyspneadDyspnea occurs in 25–40% of cases (Kocher et al., 2015). It may be due to extrinsic or intraluminal airway obstruction, obstructive pneumonitis or atelectasis, lymphangitic tumor spread, tumor emboli, pneumothorax, pleural effusion, pericardial effusion with tamponade, or unilateral paralysis of the diaphragm due to damage to the phrenic nerve (Piehler et al., 1982). HoarsenessdHoarseness results from malignancies involving the recurrent laryngeal nerve along its course under the arch of the aorta and back to the larynx (Ramadan et al., 1998). Pleural involvementdPleural involvement can manifest as pleural thickening and by pleural effusion. Patients with malignant effusions are considered incurable and are managed palliatively. Although malignant pleural effusions can cause dyspnea and cough,
25% of patients who have lung cancer and pleural metastases are asymptomatic (Maskell and Butland, 2003). Superior vena cava syndromedSuperior vena cava syndrome occurs more commonly in patients with SCLC than with NSCLC. Obstruction of the superior vena cava causes a sensation of fullness in the head and dyspnea. During a physical exam, dilated neck veins, a prominent venous pattern on the chest, facial edema, and a plethoric appearance are evident (Eren et al., 2006). Horner’s syndromedHorner’s syndrome is caused by involvement of the paravertebral sympathetic chain and the inferior cervical (stellate) ganglion. It consists of ipsilateral ptosis with narrowing of the palpebral fissure, miosis, enophthalmos, and anhidrosis. The prevalence is about 14–50% in patients with superior sulcus tumors (Kratz et al., 2017). Pancoast syndromedPancoast syndrome occurs in lung cancers arising in the superior sulcus. It is characterized by pain (usually in the shoulder, and less commonly in the forearm, scapula, and fingers), Horner’s syndrome, bony destruction, and atrophy of the hand muscles (Kratz et al., 2017). Extrathoracic metastasesdLung cancer can spread to any part of the body tissue. Metastatic spread may cause the presenting symptoms or may occur later in the course of the disease. The most frequent sites of distant metastasis are the liver, adrenal glands, bones, and brain (Toloza et al., 2003). Paraneoplastic syndromedParaneoplastic effects of tumors are remote effects that are not related to direct invasion, obstruction, or metastasis. The most common paraneoplastic effects in lung cancer are hypercalcemia, syndrome of inappropriate antidiuretic hormone secretion, neurologic syndromes, hypertrophic osteoarthropathy, dermatomyositis and polymyositis, and Cushing’s syndrome (Thomas et al., 2004).

Diagnostic Techniques Lung cancer diagnoses cannot be made without definitive pathology. Therefore, it is necessary to select the most favorable biopsy site and obtain an adequate sample for microscopic examination. With a correct strategy, it is possible to obtain sufficient sample for supplemental immunohistochemical and genetic analyses (Rivera et al., 2013). The selection of a biopsy modality considers its yield for a target lesion in the context of patient safety, outcome, and values (Rivera et al., 2013). Below, we describe the main diagnostic methods for lung cancer. BronchoscopydBronchoscopy is the recommended test to obtain a pathological diagnosis of centrally-located tumors with biopsy of any visible lesion. The presence of an endobronchial lesion on CT is strongly associated with a positive tissue diagnosis on bronchoscopy (Rivera et al., 2013). Age does not present a barrier to the application of this technique. A prospective study showed that tolerance to the procedure was independent of age (Lechtzin et al., 2000). Moreover, a review of flexible bronchoscopy in the elderly found no evidence to suggest that age affects performance or the outcome of this procedure (Hehn and Haponik, 2001).

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CT-guided thoracic biopsydTransthoracic needle aspiration (TTNA) is a diagnostic option in patients suspected of having lung cancer who have a peripheral lesion and who require tissue diagnosis before further management can be planned. CT guidance is used to obtain tissue by core needle biopsy or fine needle aspiration as it has high rates of sensitivity and specificity (90% and 97%, respectively) (Rivera et al., 2013). Complications include a 15% risk of pneumothorax and a 1% risk of major hemorrhage. The risk factors for major complications during TTNA include emphysema, small lesion, greater depth of needle penetration, and multiple needle passes (Wiener et al., 2011). A prospective study of transthoracic fine needle biopsy in over 500 patients detected a low morbidity and mortality, despite the inclusion of patients up to 94 years of age with over 60% showing varying degrees of emphysema radiologically. The tolerance of the procedure was also good, allowing discharge after 30 min (Dennie et al., 2001). Video-assisted thoracoscopic surgerydAn important tool in the diagnosis of lung cancer, video-assisted thoracoscopic surgery allows high-quality visualization of the pleura and lung and biopsy of tissue through small incisions without rib spreading. This approach requires general anesthesia and a dual-lumen endotracheal tube. This technique makes it possible for the surgeon to perform a biopsy of suspicious areas of pleura under direct vision or to resect indeterminate lung nodules or mediastinal lymph nodes (Rivera et al., 2013).

Staging Regarding oncological diseases, staging is the bedrock of therapeutic management and a basic predictor of prognosis. Correctly identifying the anatomical extense of the disease as well as the average survival of that population directly influences the extent of investment in invasive procedures to direct efforts to seek healing or palliation. This decision is especially important for the elderly population that already has a reduced life expectancy and other aggregate comorbidities (Dettterbeck, 2018).

TNM System The basic structure of lung cancer staging is based on the TNM system where T characterizes the primary tumor, N lymph node involvement, and M the presence of metastatic disease. This classification was created and maintained by the American Joint Commission on Cancer and the Union for International Cancer Control with the support of the IASLC (Table 1) (Detterbeck et al., 2017). Table 1

Lung cancer staging.

T (primary tumor) T0 T1

T2

T3

Tis T1a(mi) T1a T1b T1c T2a T2b

T4

N (regional lymph nodes) N0 N1 N2 N3 M (distant metastasis) M0 M1a M1b M1c

No primary tumor Carcinoma in situ (squamous or adenocarcinoma) Tumor 3 cm Minimally invasive adenocarcinoma Tumor 1 cm Tumor >1 but 2 cm Tumor >2 but 3 cm Tumor >3 but 5 cm or tumor involving: visceral pleura, main bronchus (not carina), atelectasis to hilum Tumor >3 but 4 cm Tumor >4 but 5 cm Tumor >5 but 7 cm or invading chest wall, pericardium, phrenic nerve or separate tumor nodule(s) in the same lobe Tumor >7 cm or tumor invading: mediastinum, diaphragm, heart, great vessels, recurrent laryngeal nerve, carina, trachea, esophagus, spine; or tumor nodule(s) in a different ipsilateral lobe No regional node metastasis Metastasis in ipsilateral pulmonary or hilar nodes Metastasis in ipsilateral mediastinal/subcarinal nodes Metastasis in contralateral mediastinal/hilar, or supraclavicular nodes No distant metastasis Malignant pleural/pericardial effusion or pleural/pericardial nodules or separate tumor nodule(s) in a contralateral lobe Single extrathoracic metastasis Multiple extrathoracic metastasis (1 or >1 organ)

Adapted from Detterbeck, F. C., Boffa, D. J., Kim, A. W., Tanoue, L. T. (2017). The eighth edition lung cancer stage classification. Chest 151(1), 193–203.

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Right Hemithorax

Left Hemithorax

1 Low cervical, supraclavicular and sternal notch nodes

1

2R Upper Paratracheal (Right) 2L

Trachea 2R

Trachea 4L

6

Superior Vena Cava Left Pulmonary Artery

4R 5

Left Main Bronchus 7

Superior Pulmonary Vein Inferior Pulmonary Vein 8

8

Azygos Vein

9R

2L Upper Paratracheal (Left) 3A Prevascular

Right Main Bronchus

3P Retrotracheal

Right Pulmonary Artery

4R Lower Paratracheal (Right)

Superior Pulmonary Vein

4L Lower Paratracheal (Left)

Inferior Pulmonary Vein

Esophagus 9L

Superior Vena Cava 3A

3P

Esophagus

5 Subaortic 6 Para-aortic 7 Subcarinal 8 Paraesophageal 9 Pulmonary Ligament

Fig. 1

Mediastinal lymphnodes.

T Status The T component is divided into five categories considering the size of the lesion, its relation to adjacent structures, the number of lesions, and their location. For the final staging, the characteristic that determines a higher category should be considered when more than one condition classifies the tumor; for example, a 2 cm tumor that invades the pericardium or phrenic nerve should be classified as T3. It should also be noted that the correct way to measure the size of the lesion for clinical evaluation (cstaging) is by high-resolution tomography taking into account only the solid area measured in the lung parenchyma window. Furthermore, when the surgical specimen is evaluated by the pathologist (p-staging), only the invasive component should be considered (Travis et al., 2016).

N Status The most important point of staging in lung cancer is lymph node status. There are four categories (Detterbeck et al., 2017) which, unlike other organs that take into account mainly the number of lymph nodes involved, are fundamentally based on the localization of nodal metastases. There are 14 stations that range from low cervical and supraclavicular lymph nodes to subsegmental intrapulmonary lymph nodes (Fig. 1). For patient pN0 (without lymph node involvement in a surgical specimen), the overall 5-year survival rate was around 60% independent of T, while for pN1 (hilar), pN2 (mediastinal), and pN3 (contralateral and/or supraclavicular) it was 37%, 23%, and 9%, respectively (P < .0001) (Asamura et al., 2015). The number of lymph nodes affected also has prognostic value; however, the outcome has not been fully measured. Especially for patients with N2 disease, it is known that the volume of disease, which can range from a single chain to the presence of a bulky mediastinal mass, is extremely important for the prognosis and definition of conduct.

M Status Distant metastases determine the final degree of disease dissemination and indicate the need for systemic therapy. An average survival of 11.4 months for the better of the scenarios (M1a) (Eberhardt et al., 2015). The most common metastatic sites are lungs, pleural surface, central nervous system, liver, adrenal glands, and bones (Fig. 2). It is worth mentioning that neoplastic pleural effusion (confirmed by cytology), often present in the diagnosis, characterizes the presence of systemic M1a disease.

Noninvasive Staging Especially in the elderly population, unnecessary invasive procedures should be avoided; therefore, one of the basic principles of staging should be the initial implementation of less complex and less invasive procedures. Careful physical examination for cervical and axillary lymph node enlargement, easily biopsied on an outpatient basis and without the need for general anesthesia, should always be performed and be able to complete staging without the need for further procedures to define therapeutic management.

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Fig. 2

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Common sites of lung cancer metastases.

The basic complementary exam for the evaluation of patients with lung cancer is high-resolution CT of the thorax. Lymph nodes measuring more than 1 cm across their small transverse axis on high-resolution CT are considered suspicious. High-resolution CT has a sensitivity and specificity of 51% and 86%, respectively (Silvestri et al., 2007). In patients with central lesions or tumors larger than 3 cm with suspicion of N1 involvement, the chance of N2/N3 involvement is around 20–25%, even in the absence of suspicious lymph nodes on CT. Thus, to increase the accuracy of the CT scan, the association with PET raises the sensitivity to 74%. For the functional evaluation of lymph nodes using the measurement of FDG uptake, a commonly accepted reference value for the suspected involvement of an SUV is 2.5. Another advantage of PET scan is the evaluation of extrathoracic metastases, especially bone metastases, when it is performed using a whole-body protocol (Silvestri et al., 2007). As PET-CT is unable to assess the presence of brain lesions due to the high natural uptake by the brain, performing magnetic resonance imaging of the skull is indicated for patients who present with neurological symptoms and has staging greater than T1N0M0 (Crino et al., 2010).

Invasive Staging While noninvasive tests can identify lymph nodes suspected of neoplastic involvement, they do not provide definitive diagnostic data and are often not sufficient to define treatment in cases of false-negatives and false-positives, specifically in populations where the incidence of inflammatory diseases is remarkable. Thus, the main guidelines for the management of lung cancer to reduce the number of futile thoracotomies and surgical procedures, especially in patients with undiagnosed N2 disease, indicate invasive staging of the mediastinum for cases of (Crino et al., 2010): -

tumor of central location (1/3 central of the hemithorax), tumor > 3 cm, mediastinal uptake in PET scan, and suspected lymph node in CT.

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Lung cancer stage grouping (eight edition).

T/M

N0

N1

N2

N3

T1a T1b T1c T2a T2b T3 T4 M1a M1b M1c

IA1 IA2 IA3 IB IIA IIB IIIA IVA IVA IVB

IIB IIB IIB IIB IIB IIIA IIIA IVA IVA IVB

IIIA IIIA IIIA IIIA IIIA IIIB IIIB IVA IVA IVB

IIIB IIIB IIIB IIIB IIIB IIIC IIIC IVA IVA IVB

Adapted from Detterbeck, F. C., Boffa, D. J., Kim, A. W., Tanoue, L. T. (2017). The eighth edition lung cancer stage classification. Chest 151(1), 193–203.

The method of histological evaluation of the lymph nodes will depend on the chain to be evaluated, as the aim is always to submit the patient to the least invasive procedure. Conventionally invasive mediastinal staging is done by mediastinoscopy. Mediastinoscopy is a surgical procedure performed under general anesthesia that ranges from a cervical incision to performing a tissue sampling biopsy of the mediastinal lymph nodes of the paratracheal and subcarinal chains (2R, 2L, 4R, 4L, and 7). This is a low-risk procedure performed by a thoracic surgeon with complication rates around 2% and a mortality rate of 0.08% (Hammoud et al., 1999). When access to the prevascular lymph node station (6) or the aortopulmonary window (5) is essential, other techniques such as anterior mediastinotomy (also known as the Chamberlain procedure), extended cervical mediastinoscopy, and even videothoracoscopy should be used (De Leyn et al., 2014). Echoendoscopy (endobronchial ultrasound [EBUS]/endoscopic ultrasound [EUS]) is a low-risk procedure, considered to be minimally invasive, that can be performed under mild sedation at a day hospital. Performing bronchoscopy (EBUS) with or without complementation by digestive endoscopy (EUS) by association with an ultrasound device at the end of the endoscopic apparatus requires appropriate training of the endoscopist team as well as a team of pathologists with experience in cytological evaluation of the material. Needle aspiration performed via these methods can obtain cytological material from practically all mediastinal lymph node stations with the exception of the prevascular chain (6). In the main development centers of the technique, its sensitivity and accuracy are 94.6% and 96.3%, respectively (Yasufuku et al., 2005).

Staging Groups After individual analysis of each TNM site and investigating each possible permutation of staging, it is possible to group similar prognostic patients representing equivalent disease-advancement points (Table 2). Thus, patients who are defined as stage I present tumors up to 4 cm without signs of lymph node dissemination. These patients represent the best prognosis with a 5-year survival ranging from 77% to 92% (depending on the staging subgroup) and exhibit the best survival after surgical treatment. Patients with lymph node involvement will be classified as at least stage II with 5-year survival ranging from 53% to 73%, and lymph node involvement in any mediastinal chain will be classified as stage III (5-year survival of 13–56%). Stage IV is reserved for patients with metastatic disease M1 with a maximum 5-year survival of 10% (Dettterbeck, 2018). It is worth noting that staging should not serve as a treatment guide but should reflect the prognosis of patients given appropriate treatment. Its main function is to unify the language of evaluation of patients with lung cancer, globalizing and facilitating the academic and assistance dialogue (Dettterbeck, 2018).

Treatment Early Stages Surgical treatment remains the best curative option for treatment of early-stage nonsmall cell lung cancer, and lobectomy plus mediastinal lymphadenectomy is the standard treatment for young and older patients (Rami-Porta et al., 2005). In contrast, it has been shown that the recurrence rate after a more limited resection (segmentectomy or wedge) is higher (Ginsberg et al., 1995). Between these options, segmentectomy is usually chosen since it is associated with better margins and lymphnode dissection (Table 3). However, specifically for older patients, data suggest that sublobar resections are applicable for peripheral tumors smaller than 2 cm, especially when they have limited pulmonary function, as they achieve similar survival rates when compared to lobectomy (Qiu et al., 2017; Mery et al., 2005).

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Treatment of nonsmall cell lung cancer.

Early stages Best option If >70 years, nodule 50% PDL1 < 50% No driver mutation and contraindication to immunotherapy Best option

Minimally invasive lobectomy þ lymphadenectomy Segmentectomy Stereotactic body radiation therapy Surgery after induction Chemoradiation Tyrosine kinase inhibitors (gefitinib, erlotinib, afatinib) ALK inhibitor (crizotinib) Pembrolizumab Pembrolizumab þ chemotherapy (platinum based) Platinum based combination chemotherapy

Sublobar resections are also considered adequate for treatment of ground glass opacities (Nakamura et al., 2004; Watanabe et al., 2002), which usually turn out to be noninvasive adenocarcinoma (Lee et al., 2014). This pathology is associated with 5-year diseasespecific and overall survival rates of around 99% (Sagawa et al., 2017). Care should be taken when proposing pneumonectomy for older patients as it is associated with relatively higher postoperative morbidity and mortality rates and worse 5-year overall survival when compared with limited resections or even with chemoradiotherapy (CRT) (Janet-Vendroux et al., 2015; Powell et al., 2009). Although this procedure may be necessary for central invasive tumors, when possible, lung-sparing techniques such as sleeve lobectomy should be applied (Gómez-Caro et al., 2011). Minimally invasive approaches should be favored since, when compared to thoracotomy, they provide the same oncological outcome with improved quality-of-life and pain control (Bendixen et al., 2016). In elderly patients, a video-assisted approach is associated with fewer and an overall reduced severity of complications as well as shorter hospital stay than for thoracotomy (Cattaneo et al., 2008). To consider a patient for surgery, it is mandatory to stratify the risk of perioperative complications with lung function tests. Patients with forced expiratory volume in the first second and diffusing capacity of the lungs for carbon monoxide values > 80% of the predicted pulmonary function tests and no other major comorbidities are considered fit for surgical treatment. Other patients benefit from exercise testing and split lung function, and maximal oxygen consumption < 10 mL/kg/min indicates a high risk for postoperative complications (Brunelli et al., 2013; Postmus et al., 2017). For patients with a high perioperative risk, including those with advanced age, stereotactic body radiation therapy is considered a good alternative as the tolerability is better compared to surgery, and the local control rate is around 90% over 5 years (Kreinbrink et al., 2017). In the elderly, this modality leads to an improvement in population-based survival of patients with peripherally located stage I, as well as a reduction in the number of untreated patients (Shirvani et al., 2014). Adjuvant chemotherapy with cisplatin-based doublets plays a role in treating early-stage lung cancer when neoplastic lymph nodes are involved, resulting in a 4–5% absolute survival improvement at 5 years (Cortés et al., 2015).

Locally Advanced Disease Treatment of locally advanced disease (T4N0M0 or TanyN2-3 M0) always involves more than one therapeutic modality and varies according to lymph node involvement (Postmus et al., 2017). When single station N2 can be demonstrated preoperatively through invasive mediastinal staging procedures, the best evidence suggests that surgery after induction chemoradiation should be considered. Using this strategy, overall survival and progression-free survival were improved for patients who underwent lobectomy but not pneumonectomy due to the high perioperative mortality rate associated with pneumonectomy (Albain et al., 2009). Resection followed by adjuvant chemotherapy and induction chemotherapy followed by surgery are also options (Postmus et al., 2017). In most locally advanced cases, when there is more than one N2 station or any N3, concurrent CRT in 2–4 cycles is the treatment of choice (Glatzer et al., 2016). Chemotherapy should be based on cisplatin associated with etoposide, vinorelbine, or, if nonsquamous histology, pemetrexed. Radiotherapy should be delivered in 60–66 Gy in 30–33 daily fractions (Postmus et al., 2017). Since it has been demonstrated that patients older than 65 years of age experience shorter overall survival, more toxicity, and a higher rate of death during concurrent CRT, sequential treatment is a viable and safer alternative in older patients (Stinchcombe

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et al., 2017). There is growing evidence that immunotherapy also has a role in treating stage III patients, since it has been shown that patients treated with durvalumab after concurrent chemoradiation had longer progression-free survival than those in the placebo group (Antonia et al., 2017).

Metastatic Disease Currently, there are multiple therapeutic options for the metastatic stage. While conventional doublet platinum chemotherapy remains an option for the first line in most patients, tumor genotyping and targeted chemotherapy have transformed the management of metastatic nonsmall cell lung cancer resulting in prolonged survival in a subgroup of patients (Seo et al., 2012). The recent development of immune checkpoint inhibitors has made immunotherapy of great importance in the treatment of lung cancer. Currently, programmed death-ligand 1 (PD-L1) immunohistochemistry is considered a mandatory test in all patients with advanced disease. When tumor PD-L1 expression is greater than 50%, pembrolizumab is the therapy of choice, since it is associated with a better objective response rate, progression-free survival, and overall survival than platinum doublet chemotherapy (Reck et al., 2016; Brahmer et al., 2017a). Continued follow-up of these patients has shown doubled median overall survival in the experimental arm, which emphasizes the efficacy of pembrolizumab (Brahmer et al., 2017b). The role of immunotherapy has been extended to patients with PD-L1 expression lower than 50%, since many studies have demonstrated the association of pembrolizumab and platinum-based chemotherapy or atezolizumab with albumin-bound paclitaxel to improve overall survival. The combination nivolumab/ipilimumab was also tested and, in patients with a high tumor mutation burden (more than 10 mutations per megabase), it was associated with longer progression-free survival than conventional chemotherapy (Gandhi et al., 2018; Paz-Ares et al., 2018). When immunotherapy cannot be used due to any cause, platinum-based chemotherapy with third generation cytotoxics (paclitaxel, gemcitabine, docetaxel, or vinorelbine) is the therapy of choice. For nonsquamous histology, a pemetrexed-based combination is also a therapeutic option (Novello et al., 2016). Oncogenic driver mutations refer to genetic mutations that are involved in the initiation and maintenance of carcinogenesis. Knowledge about cancer initiation and progression has enhanced with genomic and transcriptomic profiling (Luo and Lam, 2013). The best established oncogenic target for the management of advanced stage NSCLC is EGFR (Lynch et al., 2004). Multiple studies have shown that tyrosine-kinase inhibitors (TKI) such as gefitinib, erlotinib, and afatinib improve the overall response rate and progression-free survival in the EGFR-mutated population in all age groups (Maemondo et al., 2010; Mok et al., 2009; Rosell et al., 2012; Sequist et al., 2013). Osimertinib, a third-generation EGFR TKI, was developed to target the resistant exon 20T790M mutation which causes resistance in most patients over the course of treatment (Cross et al., 2014). Already useful as a second-line treatment for EGFR-mutated patients (Soria et al., 2018), it has been shown that it is also an option for first-line treatment in this subset, since it is associated with improved progression-free survival compared to gefitinib or erlotinib, especially in patients with central nervous system metastasis (Mok et al., 2017). Another established oncogenic target is ALK. As a first-line treatment option, crizotinib is associated with a better overall response rate and progression-free survival in ALK-rearranged patients. (Solomon et al., 2014). Newer ALK-inhibitors, ceritinib and alectinib, have been tested and shown to have excellent efficacy along with intracranial activity, thereby improving the overall response rate and progression-free survival compared to conventional chemotherapy (Cho et al., 2017; Hida et al., 2017). New medications have been tested for other oncogenic drivers such as rearrangement of ROS1 and the BRAF mutation, which were treated effectively with crizotinib (Shaw et al., 2014) as well as dabrafenib and trametinib (Planchard et al., 2017), respectively. In general, for patients older than 70 years without driver mutations, carboplatinum-based combination chemotherapy is the preferred option, since it has been shown to improved overall and progression-free survival (Santos et al., 2016). However, platinum-based chemotherapy causes more toxicity and treatment-related morbidity, including anemia, thrombocytopenia, emesis, diarrhea, and peripheral neuropathy (Langer et al., 2002). For patients ineligible for doublet chemotherapy with lower performance status, single-agent chemotherapy is considered the standard of care (Novello et al., 2016). Concerning immunotherapy, although studies dedicated to the elderly have not been published yet, no differences between patients younger and older than 65 years of age were noted in subgroup analyses regarding survival and toxicity (Reck et al., 2016). Therefore, immunotherapy should be considered according to standard recommendations.

Small Cell Lung Cancer About 40% of all SCLC patients are older than 70 years, and 10% are older than 80 years (Owonikoko et al., 2007). Without treatment, the overall survival is limited to weeks to a few months (Glatzer et al., 2017). Five year overall survival for SCLC is only 6.6%; for limited and extensive disease it is 12.1% and 1.6% (Glatzer et al., 2017), respectively. The standard treatment for limited disease SCLC is concurrent CRT (Radovicco et al., 2018), and chemotherapy regimens are the same for younger and older patients (Rossi et al., 2005). Age does not affect the efficacy of combined treatment (Corso et al., 2015). Older patients appear to benefit similarly from treatment compared to younger patients but with increased toxicity (Siu et al., 1996). A meta-analysis observed no survival benefit regarding treatment for patients over 65 years of age, but this subgroup analysis should be interpreted with caution (Pignon et al., 1992). No randomized phase III studies have compared combined CRT to chemotherapy alone in an older population with limited disease SCLC (Radovicco et al., 2018). Corso et al. showed that CRT has better results

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than chemotherapy alone in older patients after stratification for comorbidities, nodal status, radiation once/twice daily, or concomitant/sequential treatment (Corso et al., 2015). The incidence of central nervous system metastasis in patients with SCLC is high. Approximately 10% of patients present lesions at diagnosis, and about 50% will present within 2 years. Chemotherapy drugs have low efficacy in overcoming the blood-brain barrier, with a response rate around 27% compared to 73% for other systemic lesions. Therefore, prophylactic radiotherapy of the skull is indicated for patients who have localized disease and who have a good response to treatment, leading to an increase in 3-year survival. It is worth emphasizing that, especially in the elderly population, the deleterious effects of prophylactic cranial irradiation are not yet well established; however, they present a high risk of neurocognitive depreciation when compared to the nonelderly population and should, therefore, be carefully indicated (Aupérin et al., 1999; Eaton et al., 2013; Früh et al., 2013). The treatment of advanced disease is often palliative. The response to cisplatin-based chemotherapy is high with a response rate of 70%; however, the overall median survival is less than 10 months and the median progression-free survival is 5.5 months. A meta-analysis of 36 articles showed an increase in overall survival associated with an etoposide and cisplatin regimen, making the combination of these two drugs the first-line treatment. Thoracic radiotherapy is not routinely indicated for cases of advanced disease with metastatic lesions, and prophylactic cranial irradiation remains controversial. However, an improvement in survival and a significant reduction in the risk of symptomatic brain metastases from 40.4% to 14.6% (odds ratio 0.68; 95% CI 0.52– 0.88) have been shown (Radovicco et al., 2018). Nevertheless, these treatments are associated with a reduction in the quality of life and lead to important side effects, mainly in the elderly population; therefore, they are dispensable for patients with a low performance status and should be discussed in a multidisciplinary setting for elderly patients.

Palliative Care Palliative care, focusing on management of symptoms and psychosocial support potentially improves quality of care and reduce the use of medical services (Ferris et al., 2009). As a worldwide leading cause of death from cancer (Ferlay et al., 2013), metastatic lung cancer is a debilitating disease that results in a high burden of symptoms and poor quality of life (Lutz et al., 2001). Studies have found that among patients with advanced stage disease early palliative care integrated to standard oncologic treatment led to significant improvement in quality of life, mood and even longer survival (Temel et al., 2010).

Conclusions Lung cancer is a complex affection that mostly affects older people. Its variety of clinical presentations and therapeutic possibilities show how important it is to individualize care in each situation. Proper staging is essential not only to estimate survival but to compare treatments in different populations and to choose the best individual therapy. Targeting improvement in quality of life and palliation of symptoms is essential, either in the early stages, combined with treatments that aim prolonged survival or cure, or in advanced stages, when they become priorities.

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Further Reading Novello, S., Barlesi, F., Califano, R., Cufer, T., Ekman, S., Levra, M.G., et al., 2016. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 27 (Suppl_5), v1–v27. Postmus, P., Kerr, K., Oudkerk, M., Senan, S., Waller, D., Vansteenkiste, J., et al., 2017. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 28 (Suppl_4), iv1–iv21. Radovicco, M., et al., 2018. Multidisciplinary treatment of lung cancer in older patients: A review. Journal of Geriatric Oncology 10 (3), 405–410.

Malabsorption Syndrome in the Elderly Murat Akarsu and Mehmet Hursitoglu, Saglik Bilimleri University, Istanbul, Turkey © 2020 Elsevier Inc. All rights reserved.

Introduction Ideal Weight in Elderly Gastrointestinal System Changes With Age Digestion of Essential Nutrients in Elderly Malabsorption of Lipids Malabsorption of Carbohydrates Malabsorption of Proteins Malabsorption of Vitamins, Minerals and Micronutrients Some Specific Diseases That May Cause Malabsorption Celiac Disease Tropical Sprue Short-Bowel Syndrome Bacterial Overgrowth Syndromes Pancreatic Disease Whipple’s Disease Clinical Features of Malabsorption in Elderly Laboratory Investigations Diagnosis of Fat Malabsorption Diagnosis of Protein Malabsorption Diagnosis of Carbohydrate Malabsorption Other Malabsorption Tests Other Useful Laboratory Tests Radiological Inspection Treatment of Malabsorption in Elderly References

363 364 364 364 364 365 365 365 367 367 368 368 368 368 369 369 369 369 369 369 370 370 370 370 370

Introduction World Health Organization (WHO) defines elderly as persons aged 65 years old and older. Persons aged between 65 and 74 years old are called as late adults, aged between 75 and 84 years old are considered as older age while patients
85 years old are considered as advanced old age. So
65 years old persons are accepted as elderliness (Forman et al., 1992). This age related definition is somewhat confusing since there are so many persons in this age group who are still active with normal health status. So; functional impairment should also be important in defining the elderly people. There are some suggestions from researchers to accept persons older than 75 years as elderly (Ouchi et al., 2017). According to the previous reports, aging population is increasing worldwide. United Nations reports show that the older population is growing faster than the total population in all over the world. The number of elderly people is tripled over the last 50 years. Surprisingly, this number will increase more than this rate during the next 50 years (Harmankaya et al., 2015). Malnutrition is very common in this aging population. Since decreased intake and maldigestion are more implicated in this group, other factors such as malabsorption, are ignored. We will try to review and discuss somewhat ignored this topic here below. Impairment of absorption of nutrients by the body is called malabsorption. Generally three steps are required for normal absorption of the nutrients. These are luminal and brush border processing, absorption into intestinal mucosa, and lastly transport into the circulation (Forman et al., 1992). Genetic, usually in childhood and early adolescent, and/or acquired (at any age) defects in one or more above steps will lead to malabsorption. It should be mentioned that, although maldigestion is a different entity from malabsorption, its presence may lead to or facilitate the occurrence of malabsorption too. Malabsorption syndrome is usually associated with steatorrhea. Steatorrhea is an increased fat content of the stool (usually > 6%). So this is an important symptom and or sign of malabsorption. It should be mentioned that primary lactase deficiency status is a different condition that is not associated with steatorrhea. Diarrhea is frequently associated with or is a consequence of the diminished absorption of one or more dietary nutritions. Diarrhea either in the presence or absence of steatorrhea, may be secondary to the intestinal diseases. Celiac disease is associated with both extensive morphologic changes in the small-intestinal mucosa and reduced absorption of several dietary nutrients; in contrast, the diarrhea of steatorrhea is the result of the effect of nonabsorbed dietary fatty acids on intestinal ion transport.

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Ideal Weight in Elderly Body mass index (BMI) is usually used to determine the ideal weight of individuals. It is calculated by dividing the current weight (kg) by the square of height (m) and expressed as kg/m2. In younger people and adults, a BMI < 18.5 is considered as underweight, a BMI of 25–29.9 considered as overweight, and a BMI > 30 is considered as obese (Kenney, 2018). With advanced age, person loses muscle mass. This is called sarcopenia which will lead to functional impairment in such age group. As muscle mass decreases, fat tissue of the body centralizes. This increased fat in the elderly will lead to a slight increase of the weight. So in older people, the upper limit of normal BMI is 27 but not 25 kg/m2 (see Table 1) (Zeliha Fulden and Merve, 2015).

Gastrointestinal System Changes With Age In our daily practice, we have noted increased dental problems and oral cavity hygienic problems in the functionally impaired elderly persons. Although gastrointestinal (GI) bleeding and neoplasms are more common in the advanced age, motility and functional disorders of GI are also frequent in this age group (Firth and Prather, 2002; Holt, 2007). Some physiological changes are seen in all parts of GI tract. Xerostomia (dryness of the mouth) is common in this age group. In esophagus, there may be a reduction in upper esophageal resting pressure, reduction in lower esophageal relaxation, delayed esophageal emptying, reduced myenteric ganglion cells and increased thickening of the smooth muscle layer of the esophagus. Although there is no significant physiological changes in the large intestine, there may be delayed emptying of the stomach and decreased small bowel transit time (Holt, 2007). Previous study reports speculated that the small bowel villous height and surface area are decreased in the elderly compared with the young; but careful examination of the jejunal biopsies of healthy elderly volunteers does not support this (Corazza et al., 1986). Even if there are abnormalities in the upper intestinal villus architecture, they are usually associated with the underlying disease and not because of aging (Holt, 2007). Small intestinal bacterial overgrowth is somewhat more common in the elderly. Decreased gastric acidity and prolonged intestinal transit time are precipitant to this condition (Firth and Prather, 2002). This bacterial overgrowth in the intestine may lead to secondary malabsorption of some nutrients.

Digestion of Essential Nutrients in Elderly Malabsorption of Lipids Behind being a source of energy supply in the elderly people, lipids are also important in the absorption of fat-soluble nutrients, such as vitamins. Oral uptake of lipid rich nutrients is associated in the pathophysiology and development of obesity, DM, cardiovascular diseases and some malignancies. So these comorbidities could negatively affect the health of elderly people and physical activity as well. It is adviced to supply 25–30% of the energy by fat in this age group. This fat supply should be adjusted as 8–10% of polysaturated type and less than 15% of monosaturated fats (Holt, 2007). Three types of fatty acids compose fats: long-chain fatty acids (LC-FAs), medium-chain fatty acids (MC-FAs) and short-chain fatty acids (SC-FAs). Dietary fat is exclusively composed of long-chain triglycerides (LCTs), glycerol that is bound via ester linkages to three LC-FAs. While the majority of dietary LC-FAs have carbon chain lengths of 16 or 18, all fatty acids with carbon chain length of greater than 12 are metabolized in the same manner; saturated and unsaturated fatty acids are handled identically. The need for n 3 and n 6 fatty acids in elderly men is different from elderly women. The adviced amount of these two types of fatty acids in men is 1.6 and 14 g, respectively; while in women this amount is 1.1 and 11 g, respectively. It is also adviced to not exceed 300 mg of cholesterol intake by daily foods (Holt, 2007). According to WHO; the average intake of dietary fat is 120–150 g/day. The total fat load delivered to the small intestine is significantly higher due to the secretion of significant amounts of lipids in bile every day. Absorption of dietary lipid requires three integrated processes: intraluminal or digestive phase; mucosal or absorptive phase; and delivery or postabsorptive phase. An

Table 1

Normal body mass index (BMI) levels in different age groups.a

Age (year)

BMI(kg/m2)

19–24 23–34 35–44 45–54 55–65 65þ

19–24 20–25 21–26 22–27 23–28 24–29

a

According to WHO.

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abnormality at any site involved in these processes can cause steatorrhea. Therefore, it is essential that any patient with steatorrhea should be evaluated to identify the specific physiologic defects in overall lipid digestion/absorption, as therapy will be determined by the specific etiology.

Malabsorption of Carbohydrates Carbohydrates in the diet are found in the form of starch and such as glucose, lactose and sucrose disaccharides. Carbohydrates are only absorbed as monosaccharides in the small intestine. Disaccharides and starch are first decomposed into monosaccharides by pancreatic amylase and intestinal brush border disaccharides before they are absorbed. Monosaccharide absorption is provided by the sodium glucose co-transporter-1 (SGLT-1). Lactose malabsorption is a clinically important disorder in carbohydrate absorption. It is adviced by WHO that 55–60% of the daily energy in the elderly to be met from carbohydrates. This equals to a daily carbohydrate intake of about 130 g. Carbohydrates are found in foods in simple or complex forms. Simple carbohydrates should not exceed 10% of total carbohydrates. Carbohydrates, like cereals and dried legumes, consist of complex sources. Because of a decrease in tolerance to carbohydrates in elderly persons, complex carbohydrates may be a good source for vitamins, minerals and pulp in such age group (Turkey Ministry of Health, 2015). Constipation is an important problem in geriatrics. It may be due to many reasons such as lack of sufficient fluid intake, low rate of non-starch polysaccharide intake, polypharmacy and decreased activity. With an increase in the intake of liquid and fibrous foods, the amount of pulp intake also increases. Pulp is not present in fruits. It could be found in almost all foods, except meat and milk. It is a rich source of vitamins and fiber. It has a beneficial role in blood sugar lowering and cholesterol metabolism. The recommended intake amount of pulp in elderly is 21–29 g/day, respectively (Turkey Ministry of Health, 2015).

Malabsorption of Proteins Proteins are usually found in foods as polypeptides and require extensive hydrolysis to dipeptides and tripeptides and amino acids before absorption. Proteolysis occurs in both the stomach and the small intestine; it is mediated by pepsin which is secreted as pepsinogen by gastric chief cells and by trypsinogen and other peptidases secreted from pancreatic acinar cells. Proteins are absorbed by separate transport systems for dipeptides and tripeptides and for different types of amino acids, dibasic and neutral. Changes in protein or amino acid digestion and absorption are rarely observed clinically. Functional limitations and inadequacy in the geriatric population are due to a decrease in total muscle mass and function (Melton 3rd et al., 2000; Baumgartner et al., 1998). The loss of type 2 muscle fibers is evident in sarcopenia, which is known as age-related muscle atrophy. In recent years, it has been understood in studies in geriatric patients that; sarcopenia is actually due to the deterioration of protein synthesis and protein catabolism balance of muscle tissues. In other words, protein catabolism exceeds its synthesis in this condition. Skeletal muscle constitutes 40–50% of total muscle mass and is the primary tissue for basal body energy metabolism and movement (Haran et al., 2012). While the protein content of muscle mass decreases with aging, the amount of fat in the muscle tissue increases. Insufficient protein intake and lack of physical activity are important factors in the reduction of muscle mass. Exacerbation of diseases or comorbid diseases may also affect the amount of protein (Fielding, 2013). Aging does not have any negative effect on the basal rate of skeletal muscle protein synthesis. However, it has been shown that there is a decrease in response to anabolic stimulation after contraction or feeding (Rennie, 2009). It is recommended that 10–15% of the total nutrient content of the geriatric age group consists of proteins (or about 0.8–1 g/kg body weight). If supplied from animal source, 0.8 g/kg is enough; while if it is of vegetable sources, 1 g/kg is required. The general opinion is that it should not decrease below 0.75 g/kg. The need to essential amino acids in geriatric patients should also be mentioned (see Table 2) (Zeliha Fulden and Merve, 2015).

Malabsorption of Vitamins, Minerals and Micronutrients Due to the decreased diversity and intake of foods by elderly people, they usually suffer from deficiency of micronutrients as well. Micronutrients are important in maintaining health and preventing non-communicable diseases. The inability to acquire micronutrients is associated with a decrease in immune functions in elderly people. Table 2

Recommend intake amounts of some macronutrients in elderly people.a

Macronutrients

Male

Female

Lipids (g/day) Carbohydrates (g/day) Proteins (g/kg/day)

120–150 >130 0,8-1

120–150 >130 0,8-1

a

According to WHO.

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There is a positive correlation between the socio-economic status and micronutrient intake. As socio-economic condition deteriorates, micronutrient insufficiency increases. Compared with 65–74 age group; most people over the age of 85 years, experience around 10% reduction in intake of many nutrients. Several studies have reported decreased intake and absorption of foliate, vitamin B12, iron and zinc with aging (Anon, 1992; Lowen, 1998). Aging is accompanied by antioxidant vitamin deficiencies, such as carotenoids, tocopherols and vitamin C. It is also associated with the insufficiency of trace elements, such as selenium and zinc. The inadequacy of these trace elements could cause deterioration of protective mechanisms against oxidative stress (Doets et al., 2011). The rate of vitamin B12 deficiency in the elderly is about 10–20%. The main cause of this deficiency is decreased intake. It may also occur due to atrophic gastritis. In the geriatric population over 80 years of age; atrophic gastritis is seen in a rate of 40–50%. Gastric acid is required to digest B12-rich foods. Animal proteins, although rich in vitamin B12, are more expensive, more difficult to chew and can have adverse effects on blood lipids. Overgrowth of bacteria in the intestine is another factor that reduces the bioavailability of vitamin B12. Vitamin B12 malabsorption may cause neurological, psychological and hematological disorders by affecting different organ systems (including nervous system) (Mursu et al., 2011; Pennypacker et al., 1992). Therefore, it is important to eat foods rich in vitamin B12 in geriatric patients and vitaminB12 deficiency must be supplemented additionally if required (Table 3) (Food and Nutrition Board and Institute of Medicine, 1998). The absorption of vitamin B12 occurs in four events; intragastric, duodenal and jejunal, ileal, and enterohepatic circulation events. Gastric events consist of two steps; first step is the release of this vitamin from food proteins and the second step is binding of the released vitamin B12 by the R-protein. In the second duodenal and jejunal event, degradation of R-protein by pancreatic enzymes and binding of vitamin B12 by intrinsic factor (IF), that is released from the stomach, takes place (Gallagher et al., 1979). In pernicious anemia, secretion of IF due to atrophic gastritis is not reduced, but gastric acid secretion decreases which also affects the absorption of vitamins. As in folic acid absorption, diseases that affect small intestine will decrease the absorption of vitamin B12. Low intake of vitamin C in the elderly is associated with senile cataract, atherosclerosis, cancer, and with decreased cognitive functions. Vitamin C deficiency is more common in older people. It is essential for the hydroxylation of proline and lysine, the collagen precursors for wound healing in elderly. Chronic intake of vitamin C in high doses facilitates the formation of renal stones and leads to diarrhea as well (Bendich and Langseth, 1995). Vitamin E; is an oil-soluble antioxidant present in the cell membrane. Vitamin E deficiency may lead to hemolytic anemia, peripheral neuropathy, and ophthalmoplegia. If adequately supplied in the elderly, it could lead to an improvement in cell-mediated immune reaction and could slow age-related cataract development (Meydani et al., 1997). Vitamin A is a fat-soluble vitamin. Its deficiency could occur in the presence of protein calorie malnutrition or with the diseases associated with diarrhea. Replacement should be recommended when its deficiency is detected. However, it should be kept in mind that hepatic toxicity can easily develop in older people when it is replaced in high doses. Vitamin K is also a fat-soluble vitamin and fat malabsorption leads to its deficiency. It is thought that vitamin K may have effects on bone mineralization. Studies showed a decrease in fracture rate of postmenopausal women when vitamin K deficiency is treated. It is required in an amount of 90–120 mg daily. Vitamin K deficiency is rare, but should be known that its requirement is increased in bleeding status. Deficiency of copper may cause fatigue, malaise, hypochromic anemia, osteoporosis, and cardiovascular diseases. It is necessary in the function and activity of copper-containing enzymes. Copper deficiency is not common in elderly people (Kohlmeier, 2003). The daily requirement for copper in persons aged 70 years and older is about 700 mg/day (Choung et al., 2007).

Table 3

Requirements of some nutrients in the elderly men and women.a

Micronutrients

Male

Female

Vitamin A(mcg/day) Vitamin B1 (mg/day) Vitamin B2 (mg/day) Vitamin B12 (mcg/day) Folate (mcg/day) Niacin (mg/day) Vitamin C (mg/day) Vitamin D (IU/day) Vitamin E (mg/day) Ferrum (mg/day) Calcium (mg/day) Vitamin A(mcg/day) Magnesium(mg/day) Zinc (mg/day)

900 1,2 1,3 2,4 400 16 90 400 15 10 1200 900 350 11

700 1,1 1,1 2,4 400 14 90 400 15 10 1200 700 280 10

a

Turkey Ministry of Health, Department of Primary Health Care, Hacettepe University Department of Nutrition and Dietetics. To Turkey Specific Nutrition Guide. http://www.beslenme.gov.tr/content/files/publications/books/other_books/nutrition_rehberi.pdf (accessed on May 2015).

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Calcium is an essential nutrient. Along with aging, the absorption of calcium from the gastrointestinal tract is also significantly affected. In contrast, the endocrine system provides bone mineral balance by increasing calcium absorption and regulating urinary calcium excretion. Thus, calcium is usually kept within normal limits (Chernoff, 2005). In elderly people aged between 70 and 90 years, calcium absorption decreased by 30%, compared to younger adults. In order to prevent osteoporosis, calcium consumption of 1200 mg in men and women over 50 years is recommended. Calcium has a relation with osteoporosis, colon cancer and hypertension (Chernoff, 2005). Calcium is exclusively absorbed by active-transport processes in the proximal small intestine (especially the duodenum) in contrast; the active transport mechanisms for both cobalamin and bile acids are performed only in the ileum. Magnesium requirement is similar in elderly and young adults which is about 350 mg/day in men and 280 mg/day in women. Its absorption is not decreased even in the presence of atrophic gastritis. In hypomagnesemia; diminished immune functions, electrolyte imbalances, osteoporosis, muscle atrophy, other neuromuscular, cardiovascular and renal dysfunctions may be seen (Lindeman and Johnson, 2014). Zinc deficiency in people over 70 years of age was shown to be around 40%. Iron can reduce the bioavailability of zinc by interacting with it. Cereals and phytates affect the absorption of zinc also. Zinc malabsorption is associated with physiological stress, trauma and muscle weakness, dermatitis, cognitive impairment, lack of concentration, loss of taste, delay in wound healing, and impaired memory. Zinc deficiency is associated with pressure ulcers, an increase in age-related degenerative diseases, and with a state of impaired immune functions that are characterized by fragility. Although aluminum is an essential nutrient, its excess may lead to Alzheimer’s disease in the elderly. Aluminum overdose may develop in older people, especially due to the high content of antacids and some anti-ulcer drugs (Chernoff, 2000). Although a small amount of aluminum absorption is expected, absorption increases with genetic predisposition, advanced age or mucosal damage (Chernoff, 2005). Skeletal muscle disorders manifested by muscle pain, fatigue, proximal weakness, and serum creatine kinase (CK) elevations have been reported in patients with selenium deficiency. Selenium, with its antioxidant properties, can be used to improve immune functions. The upper normal limit of daily selenium intake is 400 mg, and when taken in higher doses, toxicity symptoms such as nausea, vomiting, hair loss, irritability, peripheral neuropathy and fatigue may be seen (Chernoff, 2005). A large number of human studies in which consumption of fresh yogurt (with live yogurt cultures) was compared with consumption of a pasteurized product (with heat killed bacteria), demonstrated better lactose digestion and absorption in subjects that consumed yogurt with live cultures as well as reduction of gastrointestinal symptoms (Savaiano et al., 1984). Probiotics are the microorganisms that help in the preparation of small bowel homeostasis. Probiotics have been shown to be useful in improving age-related immune system defects and in reducing the severity and incidence of infectious diseases in the elderly (Pedrosa et al., 1995). Nutrients’ absorptions are affected by age. Animal studies showed an alteration in ileal uptake of fatty acids in vitro. In human studies, there is a little change of fatty absorption which may be because of large reserve capacity of human intestine in healthy people. This decreased absorption may become more prominent with increased severity of functional defects. Another important mechanism of malabsorption is the associated pancreatic insufficiency condition. This condition is usually silent and without apparent pancreatic disease. It is mostly attributed to the age related vascular insufficiency (Holt, 2007). Although Celiac disease (CD) is a disease of youngs, it may be asymptomatic and/or with minimal symptoms that lead to be not diagnosed until late ages. It should be suspected in individuals with increased risks (presence of dermatitis herpetiformis, family history of CD, presence of type 1 DM, etc.). If patient with a known CD presented with malnutrition and/or malabsorption, development of malignancies (lymphoma) should be expected and diagnosed accordingly in the elderly.

Some Specific Diseases That May Cause Malabsorption Celiac Disease Celiac disease is a common cause of malabsorption of one or more nutrients. Although CD was originally considered largely a disease of white individuals, especially in recent observations on people of European descent, it has been established as a common disease in all patients with protein malnutrition. The most common symptom of celiac disease on first presentation is diarrhea (Green and Jabri, 2003). Celiac disease is widespread worldwide and its prevalence is 1% globally. The prevalence of CD in geriatric patients is not known clearly but we estimate that it is lower than the general population. The incidence of CD has increased in the last 50 years. The etiology of CD is not known but immunologic, genetic and environmental factors are important. Johnson et al. detected that 34% of newly diagnosed CD patients was over 60 years of age (Johnson et al., 2008). A small number of individuals have classical symptoms and manifestations related to nutrient malabsorption along with a varied natural history; the onset of symptoms can occur at all points from the first year of life through the eighth decade. A much larger number of individuals have “atypical CD.” Although CD is diagnosed during childhood and young adulthood, it should be considered in the differential diagnosis of geriatric patients in the presence of symptoms. CD is associated with malignant diseases (Öngen et al., 2016). Physicians should suspect CD in patients with pronounced or early osteoporosis, unexplained low serum iron determinations or iron deficiency anemia, or low serum folic acid measurements (McIntyre and Long, 1993; Pare et al., 1988). In the absence of symptoms, the diagnosis often is made by tests for the antibody to tissue transglutaminase. Even if symptoms of malabsorption are

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present, elderly individuals display less severe complaints than younger adult patients with celiac disease, thus, the disease is very overt and often is not diagnosed until serologic tests or small bowel biopsy are performed (Gillberg et al., 1984). Serologic testing for tissue transglutaminase has not been standardized at the present time, so that small bowel biopsy confirmation is important to establish the diagnosis. The usual colonic symptoms that are seen in patients with celiac disease that result from the passage of unabsorbed macronutrients and bile acids into the large intestine are muted in the elderly, who may complain only of vague dyspepsia (Swinson and Levi, 1980). When the diagnosis of CD is made, the treatment of elderly patients, as in the young individuals, is initiating a gluten-free diet. However, elderly patients may find it difficult to change their lifestyle. The patient may be inclined to neglect the maintenance of a gluten-free diet, so in order to achieve a satisfactory diet regimen it is often necessary for the intense participation of trained dieticians. In elderly patients with CD, osteopenia may be the underlying disease. Particular attention should be paid to the management of calcium and vitamin D homeostasis in these patients. It should be noted that a strict gluten-free diet will also increase bone density.

Tropical Sprue Tropical sprue (TS) is a poorly understood syndrome that affects both expatriates and natives in certain but not all tropical areas and is manifested by chronic diarrhea, weight loss, steatorrhea and nutritional deficiencies, including those of both cobalamin and foliate. Tropical sprue affects 5–10% of the population in some tropical areas. Chronic diarrhea in a tropical environment is most often caused by infectious agents, including G. Labia, Y. Enterocolitica, C. difficile, C. parvum and C. cayetanensis. Tropical sprue should not be entertained as a possible diagnosis until the presence of cysts and trophozoites has been excluded in three stool sample. The TS case reports in the elderly population are so scarce. However, post-infectious tropical sprue cases with malabsorption at the 5th and 6th decade have been reported (Lim, 2001).

Short-Bowel Syndrome Short-bowel syndrome is a descriptive term for the myriad clinical problems that follow resection of various lengths of small intestine or, on rare occasions are congenital (e.g. microvillus inclusion disease). Short-bowel syndrome can occur in persons of any age, from neonates to the elderly. Three different situations in adults mandate intestinal resection; (1) mesenteric vascular disease, including atherosclerosis, thrombotic phenomena and vaculitis; (2) primary mucosal and submucosal disease (e.g. Crohn’s disease) and (3) operations without preexisting small-intestinal disease (example: after trauma).

Bacterial Overgrowth Syndromes Small intestinal bacterial overgrowth may induce occult malabsorption in the elderly, although the frequency of this disorder has been disputed (Holt, 2001; Saltzman et al., 1994). Bacterial overgrowth syndromes comprise a group of disorders with diarrhea, steatorrhea and macrocytic anemia whose common feature is the proliferation of colonic-type bacteria within the small intestine. This bacterial proliferation is due to stasis caused by impaired peristalsis (junctional stasis), changes in intestinal anatomy (anatomic stasis) or direct communication between the small and large intestine. These conditions have also been referred to as stagnant bowel syndrome or blind loop syndrome which leads to small bowel bacterial contamination (particularly with E coli species) and consequently may cause malabsorption. It may well be, therefore, that the elderly people with malnutrition due to poor diet are also more susceptible to such bacterial contamination. Through studies of motor activity in the elderly some delay in gastric emptying was demonstrated, but little effect in overall small and large bowel transit was determined (Tabaqchali et al., 1968). Hypothyroidism, depression and Parkinson’s disease and the use of certain drugs such as antidepressants, analgesics and calcium channel antagonists may also slow gastrointestinal transit (O’Mahony et al., 2002).

Pancreatic Disease Many studies comparing elderly individuals with young people show that minor decrements in pancreatic enzyme output occur with advancing age. Pancreatic insufficiency with sufficient reduction in function and enzyme secretion to produce malabsorption may become apparent in the elderly without a previous history of pancreatic disorders. In a study, approximately 75% of the pancreatic insufficiency in the elderly is of unknown etiology. The same study also showed that vascular insufficiency was the major cause of pancreatic insufficiency in the elderly population (Amman and Sulser, 1976). In geriatric patients, immune-mediated lymphocytic chronic pancreatitis is thought to play a role in etiology (Nahon Uzan et al., 2005). Pancreatic insufficiency may occur in geriatric patients as a result of chronic alcohol consumption. Biliary pancreatitis is more common in the elderly than in young people. However, it rarely causes chronic atrophic pancreatitis. Diabetes mellitus may also cause malabsorption in the elderly population on the basis of pancreatic insufficiency. Obstructive pancreatitis due to malignancies may lead to chronic pancreatitis and malabsorption in geriatric patients.

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Most patients with severe pancreatic insufficiency present with voluminous oily stools, near-normal serum albumin levels, and a normal xylose tolerance test. Tests of pancreatic insufficiency as the cause of malabsorption may be invasive and specific, noninvasive and indirect, or anatomical. Fecal elastase determination has been utilized to evaluate subclinical overt reductions in exocrine pancreatic function in elderly individuals.

Whipple’s Disease Whipple’s disease (WD) is a chronic multisystemic disease associated with diarrhea, steatorrhea, weight loss, arthralgia and central nervous system and cardiac problems; which is caused by the bacterium Tropheryma whipplei. Until the identification of T. whipplei by polymerase chain reaction the hallmark of whipple’s disease had been the presence of PAS-positive macrophages in the small intestine and other organs with the evidence of disease. WD could be seen at any age. But it is so rare before 30 years old and usually it is diagnosed at age 50. It rarely causes malabsorption (Desnues et al., 2006).

Clinical Features of Malabsorption in Elderly Patients will have signs and symptoms of the underlying disease(s) such as malignancy, pancreatic insufficiency, celiac disease, and etc. Weight loss is one of the major symptoms of malnutrition and/or malabsorption. As we mentioned above, ideal body weight and BMI should be determined according to the patient’s age. Patients may have diarrhea, floating, or epigastric discomfort. In vitamin B12 and/or folic acid deficiency, patients will have the signs and symptoms of megaloblastic anemia. In Vitamin B12 deficiency, patients may have dementia and other neurological symptoms and signs of cobalamin deficiency in the absence of anemia even. So, high level suspicion is required in such patients.

Laboratory Investigations If a patient has signs of malabsorption, both upper and lower GI investigations are required accordingly including endoscopic evaluations. Sometimes performing such invasive tests in some elderly patients is challenging. Generally patients should be investigated according to the underlying disease conditions and underlying nutrient malabsorptions. Investigating the cause(s) of anemia and weight loss is so important (whether is due to malnutrition and/or malabsorption). Even if blood vitamin B12 level is normal, in highly suspected conditions, other tests (such as serum homocysteine level) should be performed. If patient has associated iron deficiency, mean corpuscular volume (MCV) of the red blood cells may be normal or decreased. Peripheral blood smear examination of such patients may show dimorphic picture and/or hyper segmented neutrophiles (an important sign of vitamin B12 and/or foliate defiance). In calcium absorption defects, patients will have osteopenia and osteoporosis. Parasitic infections are so common in dependent elderly patients, so these infections should be excluded in the elderly with appropriate tests.

Diagnosis of Fat Malabsorption Fat test in stool: In the person who receives 100 g oil per day, steatorrhea is mentioned when more than 6 g of fat is detected in the stool. Determination of fat in feces is done qualitatively and quantitatively. The determination of fat by qualitative method is based on the addition of Sudan III on the stool and evaluation of it by a microscopic examination. Normally there is less than 6 g oil excretion in 24 h. In severe steatorrhea (e.g.: exocrine pancreatic insufficiency) there is 30–50 g/day of fat excretion in feces), while in moderate steatorrhea (e.g.: gluten enteropathy), there is a 10–20 g/day excretion of fat in feces.

Diagnosis of Protein Malabsorption Fecal nitrogen could be measured. But this is a difficult method. Severe hypoproteinemia is rarely seen in small bowel diseases. Bacterial overgrowth can be seen in protein losing enteropathy. The presence of muscle fibers in stool microscopy indicates inadequate digestion and could be an alarming sign of protein malabsorption.

Diagnosis of Carbohydrate Malabsorption Carbohydrate malabsorption is seen in isolated congenital enzyme deficiencies. Therefore, the diagnosis is made before the geriatric period. Due to bacterial fermentation in carbohydrate malabsorption, the fecal pH is below 5.5. Oral lactose tolerance test: 50 g of lactose containing 180 mL water is ingested by the patient. Then blood samples are taken at 30 min intervals during 2 h period. If blood glucose is less than 1.1 mmol/L; hypolactase condition is suspected. Lactose/H2 breath test: Based on the colonic bacterial feminization of lactose. The patient is given 50 g of lactose. Breath H2 is measured at 30–60-90 and 120 min. An increase of less than 20 ppm indicates malabsorption (Firth and Prather, 2002).

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Other Malabsorption Tests D-Xylose test: 25 g D-xylose dissolved in 400 mL water will be given to patient orally. Patient’s urine samples will be collected during a 5 h period. Xylose urine and blood levels are measured. Normally, more than 5 g of 25 g D-xylose (i.e. 20%) should be excreted in urine within 5 h. This amount may be reduced in the elderly, in patients with kidney diseases, and in cases of bacterial overgrowth. This test is rarely used in these days. Schilling Test: Vitamin B12 absorption test and also an ileum function test. As is known, vitamin B12 taken with food is combined with IF in the stomach and absorbed by active transport in ileum. For this test, radioactive labeled vitamin B12 and also unlabeled vitamin B12 intramuscularly are administered orally for this test. If the amount of vitamin B12 given in the urine is less than 8% within 24 h, vitamin B12 malabsorption is possible. If malabsorption is improved with IF administration, the diagnosis is pernicious anemia. If it improves with pancreatic enzymes, it is due to pancreatic insufficiency. Bacterial overgrowth should be considered if it improves with antibiotics. Malabsorption is not improved in ileal resections. This test also is rarely used in these days. Serological Tests: CD4 measurement should be performed for the diagnosis of HIV enteropathy. CD antibodies tests are indicated in the diagnosis of CD. C-reactive protein and ESR may be increased in the conditions of malignancy and chronic inflammation.

Other Useful Laboratory Tests The effects of malabsorption on the elderly are more severe. In particular; albumin, Na, Ca, Mg, Zn, Fe, total cholesterol, vitamin B12, foliate and vitamin A decreases are more frequent in the serum. Alkaline phosphatase may increase. If serum albumin level is below 2.5 g/dL; diffuse intestinal diseases such as intestinal lymphangiectasia, CD, WD, vasculitis, bacterial overgrowth, chronic radiation enteritis or severe pancreatic insufficiency should be investigated. Osteomalacia may be considered if Ca is low and ALP is high.

Radiological Inspection Radiological examination of the small intestine using intestinal contrasts may provide important information. In evaluation of the patient with default or suspected malabsorption, the most common parts to examine are esophagus, stomach and duodenal ampulla. The dosage is important in barium administrations to the geriatric patients with malabsorption. Mostly, gastrointestinal radiologists prefer to modify the procedure as applying small doses in series instead of performing small simultaneous examination, during evaluation of the mucosa of the small intestine and ileum. In enteroclysis esophagus and stomach are investigated with large amount of barium. Also diagnostic features initially disclosed by radiologists to demonstrate the presence of current barium suspensions of small bowel disease that are rarely seen. The barium contrast examination of the small intestine by the experienced radiologist can provide important information. A normal barium contrast study does not exclude the possibility of small intestinal disease. However, a small intestinal array remains useful for investigating anatomical abnormalities such as stricture and fistulas (such as CD) or blind loop syndrome.

Treatment of Malabsorption in Elderly Management and treating of malabsorption in elderly patients is not possible everytime. Managing the underlying etiology or disease is so important. Replacement of the deficient nutrient is so important part of the management of patient’s symptoms. But it should be bearded in mind that; if the underlying etiology is not treated completely, maintenance replacement of the deficient nutrients may be required. In order to ensure an adequate and balanced diet in the geriatric age group, the number of meals should be increased and food diversity should be ensured. Food intake should be regulated according to the eating habits of the patient. It should be ensured that the four main nutrients are found at each meal as much as possible. Attention should be paid to the loss of weight. Enough energy should be supplied to overcome weight loss. Considering the decrease in the sense of thirst in the elderly, the amount of fluid taken, especially the amount of salt taken should be reduced. Cooking should be paid attention to and cooking methods such as frying should be avoided. Consumption of foods with high pulp content such as cereals, dried legumes, vegetables and fruits should be encouraged. Chewing difficulties are common in the elderly. For this reason, meals should be prepared in a soft and juicy form. Instead of doughy desserts, lighter and milky desserts should be offered.

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Baumgartner, R.N., Koehler, K.M., Gallagher, D., et al., 1998. Epidemiology of sarcopenia among the elderly in New Mexico. American Journal of Epidemiology 147 (8), 755–763. Bendich, A., Langseth, L., 1995. Health effects of vitamin C supplementation: Review. Journal of the American College of Nutrition 14, 124–136. Chernoff, R., 2000. Trace elements and minerals in the elderly. In: Bogden, J.D., Klevay, L.M. (Eds.), Clinical nutrition of the essential trace elements and minerals: The guide for health professionals. Humana Press Inc, Totowa, p. 3. Chernoff, R., 2005. Micronutrient requirements in older women. The American Journal of Clinical Nutrition 81 (5), 1240S–1245S. Choung, R.S., Locke 3rd, G.R., Schleck, C.D., et al., 2007. Cumulative incidence of chronic constipation: A population-based study 1988-2003. Alimentary Pharmacology & Therapeutics 26 (11  12), 1521–1528. Corazza, G.R., Frazzoni, M., Gatto, M.R., Gasbarrini, G., 1986. 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Current Gastroenterology Reports 3, 322–327. Lindeman, R.D., Johnson, M.A., 2014. Mineral requirements. In: Chernoff, R. (Ed.), Geriatric nutrition: The health Professional’s handbook, 3rd edn. Jones & Bartlett Learning, Boston, pp. 79–94. Lowen, D., 1998. Wound healing. In: Matarese, L.E., Gottschlich, M.M. (Eds.), Contemporary nutrition support practice: A clinical guide. WB Saunders, Philadephia, pp. 583–589. McIntyre, A.S., Long, R.G., 1993. Prospective survey of investigations in outpatients referred with iron deficiency anaemia. Gut 34, 1102–1107. Melton 3rd, L.J., Khosla, S., Crowson, C.S., et al., 2000. Epidemiology of sarcopenia. Journal of the American Geriatrics Society 48 (6), 625–630. Meydani, S.N., Meydani, M., Blumberg, J.B., Leka, L.S., Siber, G., et al., 1997. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomised controlled trial. JAMA 277, 1380–1386. Mursu, J., Robien, K., Harnack, L.J., et al., 2011. Dietary supplements and mortality rate in older women: The Iowa Women’s health study. Archives of Internal Medicine 171 (18), 1625–1633. Nahon Uzan, K., Levy, P., O’Toole, D., Belmatoug, N., Vullierme, M.P., et al., 2005. Is idiopathic chronic pancreatitis an autoimmune disease? Clinical Gastroenterology and Hepatology 3, 903–909. O’Mahony, D., O’Leary, P., Quigley, E.M., 2002. Aging and intestinal motility: A review of factors 54 that affect intestinal motility in the aged. Drugs & Aging 19, 515–527. Öngen, B., Aksungar, F., Tiftikçi, A., et al., 2016. A rare association: Celiac disease and multiple myeloma in an asymptomatic young patient / Asemptomatik genç bir hastada çölyak hastalıgı ve multipl myelom’un nadir birlikteligi. Turkish Journal of Biochemistry 41 (5), 367–372. https://doi.org/10.1515/tjb-2016-0053. Retrieved from 27 May 2019. Ouchi, Y., Rakugi, H., Arai, H., Akishita, M., Ito, H., et al., 2017. Joint Committee of Japan Gerontological Association (JGLS) and Japan Geriatrics Society (JGS) on the identification and classification of elderly people. Those who define the elderly as 75 years or older: An offer from the Japan Global Society Association and the Japan Geriatrics Association Joint Committee. Geriatrics & Gerontology International 17 (7), 1045–1047. Pare, P., Douville, P., Caron, D., Lagace, R., 1988. Adult celiac sprue: Changes in the pattern of clinical recognition. Journal of Clinical Gastroenterology 10, 395–400. Pedrosa, M.C., Golner, B.B., Goldin, B.R., et al., 1995. Survival of yogurt-containing organisms and lactobacillus gasseri (ADH) and their effect on bacterial enzyme activity in the gastrointestinal tract of healthy and hypochlorhydric elderly subjects. The American Journal of Clinical Nutrition 61 (2), 353–359. Pennypacker, L.C., Allen, R.H., Kelly, J.P., et al., 1992. High prevalence of cobalamin deficiency in elderly outpatients. Journal of the American Geriatrics Society 40 (12), 1197–1204. Rennie, M.J., 2009. Anabolic resistance: The effects of aging, sexual dimorphism, and immobilization on human muscle protein turnover. Applied Physiology, Nutrition, and Metabolism 34 (3), 377–381. Saltzman, J.R., Kowdley, K.V., Pedrosa, M.C., Sepe, T., et al., 1994. Bacterial overgrowth without clinical malabsorption in elderly hypochlorhydric subjects. Gastroenterology 106, 615–623. Savaiano, D.A., Abou ElAnouar, A., Smith, D.E., et al., 1984. Lactose malabsorption from yogurt, pasteurized yogurt, sweet acidophilus milk, and cultured milk in lactase-deficient individuals. The American Journal of Clinical Nutrition 40, 1219–1223. Swinson, C.M., Levi, A.J., 1980. Is coeliac disease underdiagnosed? BMJ 281, 1258–1260. Tabaqchali, S., Hatzioannou, J., Booth, C.C., 1968. Bile-salt deconjugation and steatorrhoea in patients with the stagnant-loop syndrome. Lancet 2, 12–16. Turkey Ministry of Health, Department of Primary Health Care, Hacettepe University Department of Nutrition and Dietetics. Nutrition Guide for Turkey. http://www.beslenme.gov.tr/ content/files/publications/books/other_books/nutrition_rehberi.pdf (accessed on May 2015) Zeliha Fulden, S., Merve, Y., 2015. Aging and healthy nutrition. Ege Journal of Medicine 54 (Supplement), 1–11.

Malnutrıtıon ın Older Peopleq Ugur Kalan, Kayseri Education and Research Hospital, Kayseri, Turkey; and Ermenek State Hospital, Karaman, Turkey Ferhat Arık, Kayseri Education and Research Hospital, Kayseri, Turkey; and Tomarza Yasar Karayel State Hospital, Kayseri, Turkey Pinar Soysal, Kayseri Education and Research Hospital, Kayseri, Turkey; and Bezmialem Vakif University, _Istanbul, Turkey © 2020 Elsevier Inc. All rights reserved.

Malnutrıtıon Definition of Malnutrition Causes of Malnutrition Results of Malnutrition Basic Concepts of Malnutrition Energy Balance Protein Fat Carbohydrate Fiber Fluid Trace Elements and Vitamins Body Composition Evaluation of Nutritional Status Anthropometric Measurement Methods Screening and Assessment Tests The Calculation of Daily Energy and Protein Needs in the Elderly Treatment Access to Nutrition in the Elderly Enteral Nutrition Therapy Immunonutrition Products Parenteral Nutrition Treatment Indications and Contraindications for Parenteral Nutrition The Method of Administration of Parenteral Nutrition The Contents of Parenteral Nutrition Solutions Carbohydrates Lipids Aminoacids Immunonutrition Micronutrients Monitoring of Parenteral Nutrition The Evidences of Parenteral Treatment in the Elderly Complications of Parenteral Nutrition Catheter-related complications Metabolic complications Infectious complications References Further Reading

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Malnutrıtıon Definition of Malnutrition Healthy nutrition is essential for people to grow, develop and survive. Physiological changes, chronic diseases, gastrointestinal problems, oral and dental problems, polypharmacy, economic and social problems affect the nutrition negatively (Arıoglu, 2013). 35%–40% of the elderly cannot feed on a daily basis to meet their daily energy needs, two out of three elders are skipping one meal and this is defined as “Anorexia of aging” (Morley, 1997). Only 1–2.5 years after the onset of weight loss for any reason in the elderly, the mortality rate increases by 9%–38% (Marton et al., 1981).

q

Change History: March 2019. Kalan, Arık, and Soysal prepared the update. Author has made changes to table 4 and reference vellas B (1999).

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Malnutrition is the pathological changes that occurs resulting from the lack of one or more nutrients. There are some physical and metabolic changes in the body when there is insufficient intake of macronutrients ingredients (proteins, carbohydrates and lipids) and/or micronutrients (trace elements and vitamins). The European Society for Clinical Nutrition and Metabolism (ESPEN) and British Association of Parenteral and Enteral Nutrition (BAPEN) define malnutrition; as a pathological condition that leads to noticeable deterioration in the body (body measurements and composition) and body functions of the energy, protein, and other nutritional items more or less in the intoxicating body, thereby reducing survival (Lochs et al., 2006a). Malnutrition is defined as “inadequacy of food intake or irregular nutrition, deterioration of body composition and body mass index, resulting in decreased physical and mental functions, and worsening of the clinical course of the disease” in the ESPEN guidelines in 2017 (Cederholm et al., 2017). In the same year, the main diagnostic criteria for malnutrition were defined by the ESPEN report, and subtypes have been identified; disease related malnutrition/inflammation (þ), disease related malnutrition/inflammation (), non-disease related malnutrition (Cederholm et al., 2015). It is aimed that these general criteria can be applied independently from the clinical state and etiology. A similar approach to defining diagnostic criteria has also been demonstrated by the American Society for Parenteral and Enteral Nutrition (ASPEN) and the Nutrition and Dietetic Academy (White et al., 2012). Studies have shown that in geriatric patients there is an inverse proportional relationship between nutritional status and mortality, infections, pressure scars, length of hospitalization and recovery (Sobotka et al., 2009).

Causes of Malnutrition 50%–70% of the elderly had a risk of malnutrition when they were hospitalized. This has been associated with decreased appetite, gastrointestinal system diseases, chronic diseases and increased catabolic response due to these reasons (Hiesmayr et al., 2009). The causes of malnutrition are shown in Table 1. Diseases associated with aging and malnutrition related diseases include cancer, depression and social isolation, dementia, stroke, other neurological diseases leading to cognitive impairment, gastrointestinal and endocrine system disorders. Sarcoma, osteoporosis, physical dependence and self-care deficiencies can be occurred during all of these diseases and nutritional status gets worse (Morley, 1997; Saka et al., 2010). The most important causes of loss of appetite in the elderly; social isolation, dementia, depression, chronic diseases and medications. In fact, in the presence of progressive cognitive impairment, all of these factors are occurring, and on the other hand difficulty swallowing occurs as the disease progresses. This also facilitates the development of malnutrition (Hays and Roberts, 2006). As daily activities and instrumental daily activities decrease, patients become more dependent, depression develops and the amount of food taken orally decreases (Cabrera et al., 2007). Malnutrition is mainly caused by comorbidities (chronic diseases, oral and dental health disorders, depression and related drugs) in early stage of dementia. Skipping meals, inability to reach food (increased dependence) and more rarely swallowing problems begin to emerge in mid stage of dementia. The most important problem with advanced dementia is difficulty swallowing. As dementia progresses, which then expresses as symptoms such as coughing or choking, clearing the throat, grimacing when swallowing, exaggerated movements of the mouth or tongue, refusal to swallow or holding food in the mouth or spitting food out.

Table 1

Causes of Malnutrition in Elderly

Social factors Poorness Inability to access food Lack of social support Unable to shop Social isolation Medicines Loss of appetite Dry mouth Nausea and vomiting Taste/odor disorder Diseases Oral and dental problems Gastrointestinal diseases Dementia Parkinson Cerebrovascular diseases Infections Endocrine disorders

Antibiotics, digoxin, opiates, metformin, antidepressants Diuretics, anticholinergics Antibiotics, digoxin, opiates, bisphosphonates, anti-parkinsonian, antidepressants, anti-dementia ACEi, spironolactone, iron, opiates, allopurinol Malignancies Heart failure Chronic obstructive pulmonary disease Chronic renal failure Depression Alcoholism Other acute and chronic diseases

ACEi, angiotensin converting enzyme inhibitor.

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Results of Malnutrition Malnutrition in geriatric cases is a big problem accompanied by important biological, physiological, social and financial consequences. Malnutrition may demonstrate itself with weight loss, loss of muscle mass and functions (sarcopenia), which causes the loss of strength in geriatric cases, fall, hip fracture and longer healing duration in such situations. The results of malnutrition are summarized in Table 2. Such cases lead to negative circumstances such as long-term and frequent hospitalization, increased use of medicine and difficulty in care, placement in nursing home, deterioration in the quality of life and cost increase. Besides, it is indicated that malnutrition is an independent risk factor in terms of mortality rate.

Basic Concepts of Malnutrition Energy Balance The minimum amount of energy consumed by a person at rest for chemical events in the body is called the basal metabolic rate (resting energy expenditure, REE). REE varies with height, weight, sex and age. The decrease in the age-related basal metabolic rate depends on a decrease in muscle mass and adipose tissue with slower metabolism rate substituted for muscle mass. REE increases in the ratio of metabolic stress which increases in the presence of infection and inflammation related excessive cytokine response. It is necessary to intake calories in the amount corresponding to daily energy consumption through nutrients taken orally. In addition to daily energy need, the intake of essential food items which are necessary for intracellular metabolic functioning is important. As the consumption of any food item less than enough can lead to malnutrition, malnutrition and obesity can coexist. In recent years, the incidence of “obese malnutrition” has been increasing in the elderly. Especially, rapid muscle breakdown depending on catabolic process occurs with the decrease of food intake in the elderly who were obese and had an acute illness beforehand, and sarcopenia develops over time. That situation is called sarcopenic obesity. Decubitus may develop in long-term in patients. Besides, when considered from this point of view, being obese becomes a risk factor. Nutrients are used in the construction and repair of tissues in addition to the continuity of body functions. A complete diet should comprise of proteins, vitamins, essential elements and water which are necessary for the tissues and metabolism as well as sufficient carbohydrate and fat to meet daily energy need.

Protein The recommended 0.8 g/kg of daily protein requirement is largely based on studies with young males, and this level of protein intake may not be sufficient for many older people. It should be kept in mind that protein intake will decrease prominently in patients whose oral intake decreases because protein sources in comparison with carbohydrate and fat are generally tasteless and bitter. However, it is reported that protein intake via gastrointestinal hormones can provide increased appetite (Peuhkuri et al., 2011). Daily protein requirement increases prominently in many diseases. Even if protein restriction is suggested for chronic renal failure patients before the renal replacement treatment, it is determined that renal failure progresses faster in case of restriction (Menon et al., 2009). In a recent multicenter study, it is identified that reaching both 0.95 g/kg protein and 30 kcal/kg energy goals are beneficial especially for the treatment of deep bedsores (Iizaka et al., 2015). The recommended daily protein intake for the elderly is around 0.9–1.2 g/kg. Although there are many studies related to the clinical benefits of high protein intake, informations about the safety of long-term high protein intake are inadequate. In cases of malnutrition, trauma, surgery and hospitalization, the need for daily protein may vary and increase significantly depending on the severity of the medical condition (> 1.2–1.5 g/kg/day) (Wolfe et al., 2008). The presence of gastric acid is important for the efficient absorption of proteins from the gastrointestinal tract. Until quite recently, it was reported that there was a significant decrease in the acid production from the stomach as a result of atrophy Table 2

Results of Malnutrition in Elderly

Impairment of immune system functions The tendency to infections Delay in wound healing Tendency to pressure sores Sarcopenia Falling and hip fractures Osteoporosis Dehydration Reduced kidney function Specific macro and micronutrient deficiencies

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associated with aging. However, nowadays it is acknowledged that this situation is not a result of normal aging and it is usually connected with Helicobacter pylori-positive chronic gastritis (Iijima et al., 2004). During critical diseases, the daily protein requirement is significantly increased. Generally, it is suggested that to give protein at the level of 1.2–1.5 g/kg/day. In a prospective observational cohort study that examined the patients with mechanic ventilation, it has been found that one-month mortality was reduced 50% in patients who achieved both sufficient energy and protein (> 1.2 g/ kg/day) goal. In addition, it is also noted that there is no significant reduction in mortality in patients who achieved only the energy goal (Weijs et al., 2012).

Fat It is recommended that the fat intake in the diet should not exceed 30% of the total energy. Furthermore, polyunsaturated and monounsaturated fats should be preferred (Institute of Medicine, 1998). In the meantime, it is suggested that all kinds of fat products should be encouraged in order to be able to complete sufficient calorie need in people with malnutrition.

Carbohydrate Usually, the 55% of the total energy should be provided from carbohydrates. In particular, it is recommended to consume the whole grains and avoid simple sugars. To prefer the whole grains may also have beneficial effects on intestinal functions because they increase fiber consumption.

Fiber Consuming fibrous nutrients is beneficial for intestinal functions when it is accompanied by adequate fluid intake. Adequate fiber consumption was shown to be protective against cardiovascular disease, diverticulosis and diabetes. Fibrous food consumption if not accompanied by adequate fluid intake can lead to paradoxical constipation. For men and women over the age of 70, it is recommended to consume respectively 21 g and 30 g of fiber per day (Institute of Medicinee, 1998). Additionally, to increase fiber consumption gradually is an important issue. In general, increases such as 5 g/day/week can be well tolerated. Faster increases can lead to indications such as gas increase and bloating, which can lead to malnutrition.

Fluid The daily fluid requirement can be estimated as 1 mL/1 kcal or roughly 30 mL/kg. The fluid requirement of an individual should be arranged in such a way that dehydration and overload are avoided by taking into consideration the accompanying diseases and hydration conditions. The elders are under risk in terms of both hyponatremia and hypernatremia because their ability to both concentrate and dilate the urine can reduce. For this reason, daily fluid requirements should be carefully determined.

Trace Elements and Vitamins The minerals and vitamins in foods are molecules which are not energy source alone but are vital for various body functions. Significant metabolic derangements and functional impairments occur in their deficiencies. Sodium, potassium, chlorine, calcium, phosphorus, iron, zinc, magnesium and iodine are important minerals. Vitamin D and group B vitamins are particularly prominent vitamins in the elderly. Vitamin D is found in very few foods. It is synthesized from cholesterol in the body and replacement therapy is administered in its deficiency. Also, milk and milk products enriched with vitamin D attain a place in the market. Vitamin D is thought to play a role in the development of cardiovascular system diseases, immunodysfunction, multiple sclerosis and cancer in addition to bone and muscle metabolism. Vitamin B12 is found in the foods of animal origin and is an essential vitamin because it is not produced in the body. It is necessary for nervous system functions and hematopoietic system. In its deficiency, serious neurological damage as well as anemia and cytopenes may occur. It can disrupt the existing dementia clinic and may even facilitate the development of dementia alone.

Body Composition The proportions of body fats and other non-fat tissues to each other represent body composition. The main goal is to be able to estimate or measure the body’s fat percentage and muscle mass in the most accurate way. The most practical method to determine is anthropometric measurements. These include weight, body mass index (BMI), extremity circumference (arm or calf) and skinfold thickness measurements. In recent years, more objective data about body composition can be obtained via some devices. One of them is bioelectrical impedance analysis (BIA). The BIA is the measurement of resistance of body tissues to a harmless electric current in a small amount. Electrical currents are more easily transmitted through body tissues containing much water (blood, urine, and muscles) than other tissues (such as bone, fat, or air). With this method, the speed and power of the electric currents passing through the body are

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measured and these results with informations such as height, weight, sex are used to determine the body fat percentage of a person.Other methods include dual energy X-ray absorptiometry (DEXA), computed tomography (CT) and magnetic resonance imaging (MRI).

Evaluation of Nutritional Status The risk of malnutrition is often ignored when clinical problems in the elderly in the community, in the care home, or in the hospital are examined. Especially, the nutritional risk in inpatients in addition to high rates of malnutrition can further increase. The detailed evaluation of the nutritional status is not practically possible for each elder. For this reason, screen tests which can expose risky individuals within the population in a short period of time were developed. When risky individuals are identified, more detailed evaluation for these individuals is possible. In the evaluation of the nutritional status, there is physical examination findings including the anamnesis which reveals the nutritional status of the person, the system interrogation and various anthropometric measurements. The amount of food consumed by a person, in last days and months, food selectivity, appetite, weight loss, existing diseases, gastrointestinal symptoms, oral health, physical and cognitive disorders and psychological mood disorders should be questioned separately in a detailed anamnesis. Each of them and the food intake disorders they may cause can result in malnutrition. This information is also questioned in the screen and evaluation tests currently being used and the nutritional status is being tried to be determined with the scores given by them.

Anthropometric Measurement Methods According to ESPEN guidelines, the desired BMI range in the geriatric age group is 20–24.9 kg/m2 (Wolfe et al., 2008). The below of this value is described as low weight and the above is described as high weight. People are defined as overweight when their BMI is between 25 and 29.9 kg/m2, as obese between 30 and 39.9 kg/m2 and as morbid obese  40 kg/m2. The International Dietetic and Nutritional Terminology guide (American Dietetic Association) accepts over 65-year-old individuals with a BMI < 23 kg/m2 as underweight and recommends nutritional evaluation to these people (Van Heukelom et al., 2011). Extreme environmental measurements are also used for anthropometric evaluation. The upper arm circumference can be measured from the midpoint of the distance between the shoulder and the elbow. When it is < 23 cm in males and < 22 cm in females, it can be evaluated in favor of low body composition (Powell-Tuck and Hennessy, 2003). The calf diameter in the elderly is considered an important indicator in the evaluation of muscle mass. If the diameter of the calf is < 31 cm, it can be considered as a decrease in muscle mass. This data will be misleading in the presence of subcutaneous tissue edema (Bonnefoy et al., 2002). Body fat ratio can be predicted by measurement of skin thickness made from specific regions of the body with special caliper. One of them is triceps skinfold thickness (TSF) measurement. Behind the arm, from the middle point between the olecranon and the acromion by releasing the arms at side, the thickness of the skin is measured by pinching it. Using the TSF with the upper arm circumference, it is stated that an estimated measurement of upper arm muscle mass can be performed, and as the individual’s BMI increases, the margin of error increases (Lukaski, 1997).

Screening and Assessment Tests Some tests as well as anthropometric measurements are used to determine the nutritional status of the patients. Nutritional Risk Screeningd2002 (NRS-2002) is a comprehensive screening test developed by ESPEN (Kondrup et al., 2003) (Table 3). Basically, it is graded by questioning the current clinical disease, weight loss in the last months, nutrition status in the last 1 week, body mass index, general condition and age. It is stated that the Mini-Nutritional Assessment (MNA) test is more likely to be more appropriate for outpatients and patients staying in care institutions in the elderly population. The first part (short form) is a screening test consisting of six questions. The total score is obtained by asking 12 more questions in the second part (assessment) to the people with low score ( 11) from the first part. Normal nutritional status when total score is 23.5 and above, the risk of malnutrition when the score is between 17 and 23, malnutrition when the score is < 17 are mentioned (Guigoz et al., 2002). The “Malnutrition Universal Screening Tool” (MUST) is a screening test in which patients are evaluated in four steps. In the first three steps, BMI, weight loss in the last 3–6 months and acute illness situation accompanied by the decrease in oral intake are questioned. In the last part, scores from the first three steps are added (Vera Todorovic, 2003). Recently, two new tests have begun to be used in the elderly population. These are Geriatric Nutritional Risk Index (GNRI) and Short Nutritional Assessment Questionnaire 65 þ (SNAQ65 þ). In GNRI, serum albumin level, current weight and ideal weight are used for malnutrition risk assessment (Bouillanne et al., 2005). A laboratory test that can be used to diagnose malnutrition is not yet available. The most commonly used serum proteins (albumin, prealbumin, transferrin, retinol binding protein) are more important in follow-up than in diagnosis. In particular, serum proteins behave like negative acute phase in all types of infectious and inflammatory disease and their synthesis decrease, which is a problem during the assessment of the nutritional status of a person. For this reason, it is appropriate to evaluate it with other acute phase indicators (especially CRP). Also, in some chronic diseases such as chronic liver disease and chronic renal failure, synthesis disorder or loss may give false positive results (Saka et al., 2010; Mueller et al., 2011).

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Nutritional Risk Screeningd2002 (NRS-2002) Step 1: Initial Screening

Yes

No

1 Is BMI 5% in 3 months or food intake below 50-75% of normal requirement in preceding week Moderate Weight loss > 5% in 2 months or Score 2 BMI 18,5-20,5 þ impaired general condition or food intake 25-60% of normal requirement in preceding week Severe Weight loss > 5% in 1 month or Severe Head injury, bone marrow transplantation, intensive care Score 3 BMI < 18,5 þ impaired general condition or Score 3 patients (APACHE>10) food intake 0-25% of normal requirement in preceding week Score: þ Score: ¼ Total score: Age: If > 70 years old, add 1 to total score ¼ age adjusted total score Score >¼ 3: The patient is nutritionally at risk and a nutritional care plan is initiated. Score 4 week) tube feeding (Lochs et al., 2006b).

Access to Nutrition in the Elderly EN way, which is physical, should be priorly preferred in the presence of malnutrition. Hence, gastrointestinal system progresses its normal functions. Oral, enteral, nasoenteral and enterocutaneous nutrition are the kinds of EN. Nasogastric or nasointestinal feeding tube can be used for nasoenteral way. Silicon or polyurethane types of these tubes should be preferred. Enterocutaneous ways include percutaneous endoscopic gastrostomy (PEG), percutaneous endoscopic jejunostomy (PEJ), percutaneous endoscopic transgastric jejunostomy (PEG-J), surgical gastrostomy, and surgical jejunostomy. The parenteral way should be preferred when it is not possible to use the enteral way. The EN is contraindicated in the presence of peritonitis, intestinal obstruction, ileus, excessive vomiting and high-output fistule (especially localized in the middle part of the gastrointestinal system). During EN, the integrity of the gastrointestinal system should exist. Isoosmolar products should be selected for the patients with multiple organ dysfunction and enough sodium should be added with these products. Isoosmolar products should be given as an infusion during the jejunum feeding and hypotonic solution should not be infused. In the individuals taking enterocutaneous EN, injectors and nutrition bag should be replaced every 24 h and they should be cleaned only with warm water. Tablet shape drugs should be given with an injector by powdering and diluting. Then, at least 50 mL of water should be given in order to prevent PEG clogging. If the patient is continuously feeding with the pump, at least 50 mL of water should be given every 2–3 h. If medicine will be given, water should be given absolutely both before and after the drug. Patients fed by intermittent applications should be given at least 50 mL of water after each application. Residue control should be done if symptoms such as nausea, vomiting, diarrhea, distension are present after the feeding. Parenteral feeding can be preferred in the presence of a nonfunctional gastrointestinal system, in the situations that intestines need to be rested and EN cannot be tolerated, severe pancreatitis, large gastrointestinal system resections (short bowel syndrome, especially in the < 100 cm residence) and high-flow fistulas (Mueller et al., 2011; Lochs et al., 2006b). If all of the daily energy needs cannot be provided by EN, it should be supplemented with PN. Appropriate products should be selected in the presence of metabolic disorders such as diabetes, hyperlipidemia, etc., and also the protein content of the product should be increased for survival in the increase of protein catabolism.

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Enteral Nutrition Therapy Standard products are used in the majority of all patients given EN on product. Each ml of these products contains 1 kcal. They can be easily tolerated due to their low osmolarity. Energy sources are carbohydrates (50%–60%) and fats (30%–40%), respectively. They are enriched with trace elements and vitamins in parallel with the daily needs. Diabetic products contain low glycemic index carbohydrates (fructose, isomaltose and maltodextrin), additionally, they are rich in fat and fiber. Higher energy products have 1.2–2.0 kcal/mL and higher osmolarities. It is used in patients with high energy deficit and in situations where fluid restriction is necessary. Protein-rich products (60–100 g/L) can be used in patients who are under metabolic stress and whose protein degradation or use is accelerated or needed. Products containing insoluble fiber help with gastrointestinal motility and they can be used in the presence of acute and chronic diarrhea with their prebiotic effects. Soluble fibers have positive effects on enterocyte feeding, microbiota and glucose-insulin metabolism by converting into short-chain fatty acids in the colon. Immunonutrition products are the products that are enriched with one or more than one of glutamine, arginine, eicosapentaenoic acid (EPA), leucine and tissue RNA. They are developed for people with cancer and chronic inflammatory disease. As they have anti-oxidant properties, they protect the individual from harmful effects of the exaggerated immune response by suppressing the proinflammatory cytokines and increasing the anti-inflammatory cytokines. They increase protein synthesis. Its protective effects on gastrointestinal system enterocytes has been shown with the antioxidant effect of glutamine. Arginine is used in wound healing as it promotes collagen synthesis (Wu, 2009). EPA can reduce cancer cachexia with appropriate EN when used 1.5 g and over. Leucine and metabolite beta-hydroxy-beta-methylbutyrate increase protein synthesis and reduce protein degradation (Nissen et al., 1996). Medium chain fatty acids can be used as a source of high energy in inflammatory diseases of the gastrointestinal system, especially in the presence of malabsorption at various levels. They do not need the formation of bile and micelles, they are absorbed actively and come directly to the liver with the portal circulation, and then they go through the systemic circulation. There should also be long chain fatty acids which are essential to the products (Wu, 2009). When enteral product is preferred, the patient’s acute and chronic diseases, metabolic status and compliance are taken into account. Serious problems such as product rejection, complications (vomiting, diarrhea, etc.), getting tired of aroma and not trusting the product can occur during the long-term use of enteral products.

Immunonutrition Products Immunonutrition is the use of functional molecules that can modulate the immune system during nutrition therapy. Each type of stress condition causes an increasement of proinflammatory cytokines. Tumor necrosis factor (TNF-alpha), IL-1 and IL-6 are the cytokines that increase. The main immunonutrition items are arginine, omega (u)-3 fatty acids, glutamine, leucine and nucleotides. These products cannot be present in enteral nutrients on their own but can be as a mixture in commercial products. Glutamine and u-3 fatty acids have parenteral forms. Glutamine is not an essential amino acid. It has been shown to become essential in hypercatabolic situations. The glutamine requirement exceeds the synthesis capacity in cases of severe stress such as sepsis, trauma, burns, malnutrition, no oral feeding prolonged > 7 days and surgical wounds healing. This causes glutamine to take the definition of “essential amino acid linked to the situation”. Under these conditions, the addition of glutamine may be necessary (Singer et al., 2009). However, in randomized clinical trials, parenteral glutamine and antioxidant treatment in intensive care patients have been shown not to improve clinical outcomes (Heyland et al., 2013). 2015–2016 ASPEN, ESPEN and Canada guidelines do not recommend the use of parenteral glutamine in critically ill patients (McClave et al., 2016). Arginine plays an important role in nitrogen transport, storage and excretion through the urea cycle. The effects of glutamine and arginine on the immune system are similar (Wu, 2009). Arginine like glutamine is a non-essential amino acid and it may become essential in the catabolic stress. It acts in the formation of nitric oxide. There is conflicting data about the use of arginine in severe sepsis. In the ASPEN 2016 guideline, routine arginine use in sepsis cases is not recommended. Polyunsaturated fatty acids (PUFAs) are defined by the length and degree of saturation of carbon chains. PUFAs identified as u-3, u-6 are important in inflammation and infection modulation. The prevalence of coronary artery disease was revealed to be low in the societies whose diet is rich in u-3 PUFAs. In postoperative surgery adult ICU patients, the use of arginine in combination with fish oil as enteral is recommended at moderate and low levels of evidence (McClave et al., 2016). Soy-based intravenous fat emulsions are recommended in intensive care patients in parenteral treatment at a low level of evidence (McClave et al., 2016). It was revealed that the parenteral replacement of u-3 fatty acids does not reduce mortality and infectious complications, but reduces the length of hospital stay (Palmer et al., 2013).

Parenteral Nutrition Treatment In hemodynamically unstable cases, enteral feeding should not be preferred in the presence of GIS dysfunction, excessive vomiting, short bowel syndrome and high-flow fistula. In such cases PN can be applied. The appropriate way for PN is the central venous access. Lower osmolarity products can also be delivered by peripheral venous access.

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PN products do not contain all micronutrients in appropriate quantities. For this reason, support may be necessary in prolonged treatments. The metabolic complications of PN are much more frequent. Especially, in patients with long-lasting severe malnutrition, extracellular and intracellular volume changes based on sudden osmolar load, serum electrolyte imbalance (sodium, potassium, phosphorus, magnesium, calcium), acute renal failure, acute heart failure, ARDS, arrhythmias and sudden death may develop. Acute heart failure and central nervous system disorders based on the deficiency of vitamin B1 (thiamin) and encephalopathy (Wernicke Korsakoff syndrome) may develop. All these clinical conditions that may develop after PN are referred to as “Refeeding Syndrome” (Solomon and Kirby, 1990). Although the EN is the basic method of nutritional support, total parenteral nutrition (TPN) alone when EN is not available at all or as addition to EN when it is used partially can be used. In this cases, oral, enteral and parenteral nutrition can be complement of each other. In PN, the patient should always be evaluated in terms of EN.

Indications and Contraindications for Parenteral Nutrition PN is indicated in the situations that the nutritional requirements of the patient cannot be met by the enteral route and EN is contraindicated or tolerated constrictedly, and by this way adequate nutrition of the patients can be provided. PN support should be provided if it is not possible to feed the patients with oral/enteral nutrition for > 3 days or the patient cannot adequately feed with the EN even though it lasts longer than 7–10 days (Lochs et al., 2006b; Wei et al., 2015). In rare cases in which gastrointestinal system passage is absent or the intestines need to be rested, there is an indication for PN if the patient is thought to be unable to feed for about 5–7 days or if malnutrition is present. EN support can also be given to many patients with an indication for PN. The most important reason for PN support is the lack of dysfunction or passage of the gastrointestinal system. Indications for PN are shown in Table 5 (Sobotka et al., 2009). The major disadvantage of PN is that metabolic and infectious complications are more than enteral ways (Lochs et al., 2006b). Inflammatory bowel diseases usually cause malnutrition. Especially in acute exacerbations, PN should be administered if there is no indications for absolute PN, if the patient cannot tolerate EN or if EN is insufficient. In acute exacerbations, PN may be given alone or in addition to EN. Indications for PN may arise during the complications (obstruction, perforation, short bowel, etc.) in the course of the disease. Short-bowel syndrome is a malabsorption disorder caused by a lack of functional small intestine. The primary symptom is diarrhea, which can result in dehydration, malnutrition, and weight loss. Short bowel syndrome may be mentioned when the present small bowel is < 200 cm in length (Pironi et al., 2016). There is not enough small bowel length for the absorption of food items. It is important that the length of the small bowel ending with a stoma is  100 cm for the maintenance of EN (Sobotka et al., 2009; Pironi et al., 2016). The most common cause of short bowel syndrome is large bowel resections due to mesenteric ischemia. Crohn’s disease, the complications of abdominal operations and malignancies can also cause short bowel syndrome. Long-term PN at home may be necessary in the patients with chronic intestinal failure (Pironi et al., 2016). In the presence of severe pancreatitis, the patient is in the catabolic process. The suitable dose for EN or PN is 25–35 kcal/kg/day. In acute pancreatitis, it is recommended to switch to EN as soon as possible. EN is recommended in mild pancreatitis. In recent studies and severe necrotizing pancreatitis, enteral treatment should be performed at first if possible. In the last decade, the nutritional approach has shifted from parenteral to enteral (Tenner et al., 2013).

The Method of Administration of Parenteral Nutrition The establishment of PN formulas, starting long-term central venous catheterization safely, asepsis in the preparation and delivery of solutions, the provision of antisepsis and the correction of metabolic disorders has increased the applicability of TPN. PN support can be achieved through central and peripheral vessels. While planning PN, the appropriate choice of venous access and the placement and care of the catheter are very important. Both methods have advantages and disadvantages. The most important difference between the peripheral and the central products is the osmolarity. Table 5

Indications for Parenteral Nutrition

Intestinal Obstruction Gastrointestinal fistulas Intra-abdominal infections Radiation enteritis Severe mucositis Short bowel syndrome Severe hemodynamic impairment and mesenteric ischemia Severe gastrointestinal bleeding In cases where enteral nutrition cannot be tolerated

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The most important difference between the products applied in both pathways is the calories and fat they contain in a unit volume. While products peripherally administered have 0.6–0.7 kcal/mL, those administrated centrally have approximately 1 kcal/mL. Therefore, there is a difference between their osmolarities. The osmolarities of the products administrated peripherally are below 850 mOsm/L. Furthermore, the amount of macro and micronutrient ingredients in the product determine the increase in osmolarity. Subclavian vein is usually preferred in central PN. The central venous line allows for the use of solutions with high osmolarity. Thus, the targeted protein and calories can be given to the patient with a lower volume. For peripheral venous access, palpated and visible veins are used. Peripheral venous access should be preferred, in patients whose nutrition support treatment is expected not to exceed 2 weeks or who the central route cannot be used (Sobotka et al., 2009; McClave et al., 2016). Calories over 1400–1500 kcal/day are not recommended for peripheral administration (Sobotka et al., 2009; McClave et al., 2016). TPN solutions can be prepared as “multi-bottle systems” and “all-in-one systems” (Driscoll, 1995). In the all-in-one system, all the components of PN are in one reservoir. The single bag systems allow all food items including water, electrolytes, trace elements and vitamins. The advantages of all-in-one systems include better nutritional balance, reduced cost during preparation, process and infusion, reduced costs of intravenous routes, injectors, needles and connection systems, reduced risk of contamination, metabolic complications and infection risk (Driscoll, 1995). Multi-bottle systems in which the fat, carbohydrate, protein and electrolytes are given with separate bottles are now abandoned. TPN should provide all necessary nutrient elements in the required quantities. The detection of daily energy and protein requirements is necessary for the proper energy intake and especially for the prevention of superalimentation.

The Contents of Parenteral Nutrition Solutions Carbohydrates Only glucose is currently used as a carbohydrate PN solutions. Glucose is the major carbohydrate in circulation and is used by all the cells in the body. Under stress conditions, the high speed of gluconeogenesis cannot be effectively reduced by glucose infusions. In addition, glucose intake and consumption degenerate due to changing blood glucose levels, glucosuria and the effects of regulatory hormones. Excess glucose loads create an additional stress table. For this reason, the recommended maximum infusion rate in adult patients is 3–5 mg/kg/min (Boullata et al., 2014; McMahon et al., 2013).

Lipids Intravenous lipid solutions are largely developed by the structure of intestinal chylomicron. Preparations containing a mixture of soybean, long chain fatty acids and medium chain fatty acids have been used for 25 years. Depending on the clinical situation, u-3 fatty acids such as fish oil can also be added. The amount of lipid in PN solutions should account for the 30–50% of the nonproteinbound calorie (Singer et al., 2009). Lipid quantities should be regulated in patients with hypertriglyceridemia. Lipids should be administered with very slow infusion (0.1 g/kg/h) in patients under intense stress (Pertkiewicz et al., 1999). In PN, it is not recommended to add lipid emulsion with in cases of shock, multiple organ failure, severe acidosis (pH < 7.1) and severe hypoxemia (McClave et al., 2016; Singer et al., 2009).

Aminoacids At different concentrations, there are amino acid solutions (5%–15%). PN solutions contain the various combinations of eight essential amino acids and non-essential amino acids. Crystallized amino acid solutions, which contain the whole of the essential amino acids, are used in the PN (Sobotka et al., 2009). However, they do not contain non-essential amino acids in the sufficient amount. The main reason for this is the problems related to the use of cysteine, glutamine and taurine in natural forms. Protein intake at the level of 1–1.2 g/kg/day in the elderly is recommended (Roza and Shizgal, 1984; Lochs et al., 2006b).

Immunonutrition It is described in detail above. Stable dipeptides which contain glutamine that can be administered intravenously are being produced. u-3 fatty acids, which is another immunonutrition product, can be administered intravenously.

Micronutrients They support the immune system by participating in the maintenance of natural barriers (skin-mucosal integrity), antibody production and cellular immunity (Maggini et al., 2007). Vitamins A, B6, C, D and E vitamins and folic acid, iron, zinc and selenium make contribution to the cytokine mediated immune response and the production of cytokines and prostaglandins. Micronutrient replacement is recommended at the level of evidence C in all types of patients. Vitamins and trace elements should be added shortly before the administration to PN solutions due to stability problems. The recommended doses for adults are 9.1 mg/day for vitamin E, 200 mg/day for vitamin C and 70–400 mg/day for selenium. It is not recommended that the use of selenium, zinc and antioxidants via parenteral pathway in the sepsis (Wolfe et al., 2008). The supply of water and electrolytes is an important part of TPN. Patients should be evaluated every day for dehydration, edema or ileus, and also biochemistry and electrolytes tests should be performed.

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Monitoring of Parenteral Nutrition The patients should be monitored to evaluate the nutritional status and to prevent the complications. Vital signs, intakes and outputs, weight, blood glucose, serum creatinine, electrolytes, calcium-phosphorus-magnesium levels, liver function tests, serum triglyceride and cholesterol levels, prealbumin levels should be regularly monitored (Table 6) (Sobotka et al., 2009). Blood glucose levels should be regularly monitored and hypoglycemia should be avoided. Target blood glucose levels should be 140–180 mg/dL (McMahon et al., 2013). In the follow-up of nutritional status, serum proteins can be used. The use of serum prealbumin level is suitable because of its short half-life. Serum albumin is not as reliable as serum prealbumin because its half-life is long and its distribution is influenced by many factors. C-reactive protein (CRP) and prealbumin should be evaluated together.

The Evidences of Parenteral Treatment in the Elderly While the PN treatment is being regulated, the treatment should be set according to the patient’s disease activity, metabolic status, physiological characteristics, and recovery status. Insulin sensitivity reduces 43% in geriatric patients and the risk of developing diabetes increases 16% (Sullivan et al., 2005). Lung volume and capacity reduce. Extra glucose supplementation may not only impair blood glucose regulation, but may also lead to respiratory failure, hepatosteatosis, cholestasis, and liver dysfunction (Wei et al., 2015). The ability of fatty acid oxidation in the elderly is similar to that of young adults. Thus, controlled glucose support may be provided by increasing the lipid content in PN treatment (Bates et al., 1998). The daily intake of 1.2–1.5 g/kg protein and physical activity are useful in elderly patients with normal renal function (Wolfe et al., 2008). In comparison with adults, the vitamin and mineral intake of patients over the age of 65 are 40% lower (Bates et al., 1998). The necessary vitamins and minerals must be added to the PN treatment (Sobotka et al., 2009).

Complications of Parenteral Nutrition The complications of PN are more than the enteral route. Complications of PN support therapy can be classified under three headlines.

Catheter-related complications In the early period, complications could be occurred during the central venous catheter insertion. Arrhythmia, pneumothorax, hemothorax, catheter hemorrhage, embolism, cardiac tamponade and chylothorax. The main complications of late complications are central venous thrombosis and catheter bacteremia (Cowl et al., 2000). Aseptic techniques should be adhered to in placement and care of the catheter under appropriate conditions to reduce catheter related complications.

Metabolic complications Metabolic complications of PN can be divided into deficiency states, acute metabolic complications and chronic (long-term) metabolic complications. Hyperglycemia and hypopotassemia are the most common complications of acute phase. Hypernatremia, hyponatremia, hyperlipidemia and hypoglycemia can also be seen (Sobotka et al., 2009). These complications may occur in the acute care or chronic care patient. “Refeeding” syndrome may develop due to the rapid and excessive nutrition in chronic malnourished, especially fragile aged. In these patients, 30%–40% of daily energy requirements should be initially provided and gradually increased (Solomon and Kirby, 1990). Late-stage metabolic complications include bacterial overgrowth in the bowel, chronic diarrhea, cholestasis, hepatosteatosis, gallstone formation, renal oxalate stone formation, and metabolic bone diseases (McClave et al., 2009). Table 6

Recommended Monitoring Parameters for Patients with Parenteral Nutrition

Weight and anthropometry Hydration state Oral intake status Psychological status Full blood count Liver function tests Kidney function tests Electrolytes Albumin Trace elements A, E, D and B12 vitamins and folic acid Bone mineral density measurement

Every visit

Once every three months

Once a year

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Infectious complications Catheter-associated infection is the most frequent complication, although intrinsic or extrinsic contamination of TPN fluid or administration sets or local catheter site infection also occur. Catheter entry site often constitutes an infection source. Most of the infectious complications of TPN therapy can be prevented with meticulous attention to aseptic technique. It is recommended that catheters used in central or peripheral feeding can be used only for feeding purposes (Sobotka et al., 2009; McClave et al., 2009). In multi-lumen central catheters, one of the passages must be used only for nutrient solutions. In the presence of a catheter infection, catheter must be withdrawn and culture should be taken from the catheter end, the access site, and the catheter (Graham et al., 1991).

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Nutritional risk screening (NRS 2002): A new method based on an analysis of controlled clinical trials. Clinical Nutrition 22 (3), 321–336. Lochs, H., Allison, S.P., Meier, R., Pirlich, M., Kondrup, J., et al., 2006a. Introductory to the ESPEN guidelines on enteral nutrition: Terminology, definitions and general topics. Clinical Nutrition. Lochs, H., Dejong, C., Hammarqvist, F., Hebuterne, X., Leon-Sanz, M., et al., 2006b. ESPEN guidelines on enteral nutrition: Gastroenterology. Clinical Nutrition 25 (2), 260–274. Lukaski H (1997) Sarcopenia: Assessment of muscle mass. The Journal of Nutrition 127(5 Suppl): 994S–997S. Maggini, S., Wintergerst, E.S., Beveridge, S., Hornig, D.H., 2007. Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses. The British Journal of Nutrition 98 (Suppl. 1), S29–S35. Marton, K.I., Sox, H.C.J., Krupp, J.R., 1981. Involuntary weight loss: Diagnostic and prognostic significance. Annals of Internal Medicine 95 (5), 568–574. McClave, S.A., Martindale, R.G., Vanek, V.W., McCarthy, M., Roberts, P., et al., 2009. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of critical care medicine (SCCM) and American society for parenteral and enteral nutrition (A.S.P.E.N.). Journal of Parenteral and Enteral Nutrition 33 (3), 277–316. McClave, S.A., Taylor, B.E., Martindale, R.G., Warren, M.M., Johnson, D.R., et al., 2016. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). Journal of Parenteral and Enteral Nutrition 40 (2), 159–211. McMahon, M.M., Nystrom, E., Braunschweig, C., Miles, J., Compher, C., 2013. A.S.P.E.N. clinical guidelines: Nutrition support of adult patients with hyperglycemia. Journal of Parenteral and Enteral Nutrition 37 (1), 23–36. Menon, V., Kopple, J.D., Wang, X., Beck, G.J., Collins, A.J., et al., 2009. Effect of a very low-protein diet on outcomes: Long-term follow-up of the modification of diet in renal disease (MDRD) study. American Journal of Kidney Diseases 53 (2), 208–217. Morley, J.E., 1997. Anorexia of aging: Physiologic and pathologic. The American Journal of Clinical Nutrition. Mueller, C., Compher, C., Ellen, D.M., 2011. A.S.P.E.N. clinical guidelines: Nutrition screening, assessment, and intervention in adults. Journal of Parenteral and Enteral Nutrition 35 (1), 16–24. Nissen, S., Sharp, R., Ray, M., Rathmacher, J.A., Rice, D., et al., 1996. Effect of leucine metabolite b-hydroxy-b-methylbutyrate on muscle metabolism during resistance-exercise training. Journal of Applied Physiology 81 (5), 2095–2104. Palmer, A.J., Ho, C.K.M., Ajibola, O., Avenell, A., 2013. The role of u-3 fatty acid supplemented parenteral nutrition in critical illness in adults: A systematic review and metaanalysis. Critical Care Medicine 41, 307–316. Pertkiewicz, M., Slotwinski, R., Majewska, K., Szczygiel, B., 1999. Clinical evaluation of amino acid solution. Polski Merkuriusz Lekarski 7 (41), 211–214. Peuhkuri, K., Sihvola, N., Korpela, R., 2011. Dietary proteins and food-related reward signals. Food & Nutrition Research 55.

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Pironi, L., Arends, J., Bozzetti, F., Cuerda, C., Gillanders, L., et al., 2016. ESPEN guidelines on chronic intestinal failure in adults. Clinical Nutrition 35 (2), 247–307. Powell-Tuck, J., Hennessy, E.M., 2003. A comparison of mid upper arm circumference, body mass index and weight loss as indices of undernutrition in acutely hospitalized patients. Clinical Nutrition 22 (3), 307–312. Roza, A.M., Shizgal, H.M., 1984. The Harris Benedict equation reevaluated: Resting energy requirements and the body cell mass. The American Journal of Clinical Nutrition 40 (1), 168–182. Saka, B., Kaya, O., Ozturk, G.B., Erten, N., Karan, M.A., 2010. Malnutrition in the elderly and its relationship with other geriatric syndromes. Clinical Nutrition 29 (6), 745–748. Singer, P., Berger, M.M., Van den Berghe, G., Biolo, G., Calder, P., et al., 2009. ESPEN Guidelines on Parenteral Nutrition: Intensive care. Clinical Nutrition 28 (4), 387–400. Sobotka, L., Schneider, S.M., Berner, Y.N., Cederholm, T., Krznaric, Z., et al., 2009. ESPEN guidelines on parenteral nutrition: Geriatrics. Clinical Nutrition 28 (4), 461–466. Solomon, S.M., Kirby, D.F., 1990. The refeeding syndrome: A review. Journal of Parenteral and Enteral Nutrition 14 (1), 90–97. Sullivan, P.W., Morrato, E.H., Ghushchyan, V., Wyatt, H.R., Hill, J.O., 2005. Obesity, inactivity, and the prevalence of diabetes and diabetes-related cardiovascular comorbidities in the U.S. 2000-2002. Diabetes Care 28 (7), 1599–1603. Tenner, S., Baillie, J., Dewitt, J., Vege, S.S., 2013. American college of gastroenterology guideline: Management of acute pancreatitis. The American Journal of Gastroenterology 108 (9), 1400–1415. Van Heukelom, H., Fraser, V., Koh, J.C., McQueen, K., Vogt, K., et al., 2011. Implementing nutrition diagnosis: At a multisite health care organization. Canadian Journal of Dietetic Practice and Research 72, 178–180. Vera Todorovic CRaME (2003) The “MUST” Explanatory Booklet: A Guide to the “Malnutrition Universal Screening Tool” (‘MUST’) for Adults, 5–22 p. Wei, J., Chen, W., Zhu, M., Cao, W., Wang, X., et al., 2015. Guidelines for parenteral and enteral nutrition support in geriatric patients in China. Asia Pacific Journal of Clinical Nutrition 24 (2), 336–346. Weijs, P.J.M., Stapel, S.N., De Groot, S.D.W., Driessen, R.H., De Jong, E., et al., 2012. Optimal protein and energy nutrition decreases mortality in mechanically ventilated, critically ill patients: A prospective observational cohort study. Journal of Parenteral and Enteral Nutrition 36 (1), 60–68. White, J.V., Guenter, P., Jensen, G., Malone, A., Schofield, M., 2012. Consensus statement: Academy of nutrition and dietetics and American society for parenteral and enteral nutrition: Characteristics recommended for the identification and documentation of adult malnutrition (undernutrition). Journal of Parenteral and Enteral Nutrition. Wolfe, R.R., Miller, S.L., Miller, K.B., 2008. Optimal protein intake in the elderly. Clinical Nutrition 27, 675–684. Wu, G., 2009. Amino acids: Metabolism, functions, and nutrition. Amino Acids 37, 1–17.

Further Reading Gomes, F., Schuetz, P., Bounoure, L., Austin, P., Ballesteros-Pomar, M., et al., 2018. ESPEN guidelines on nutritional support for polymorbid internal medicine patients. Clinical Nutrition 37 (1), 336–353. Vellas, B., Guigoz, Y., Garry, P.J., et al., 1999. The mini nutritional assessment (MNA) and its use in grading the nutritional state of elderly patients. Nutrition 15, 116–122. Volkert, D., Beck, A.M., Cederholm, T., Cruz-Jentoft, A., Goisser, S., et al., 2018. ESPEN guideline on clinical nutrition and hydration in geriatrics. Clinical Nutrition. Weimann, A., Braga, M., Harsanyi, L., Laviano, A., Ljungqvist, O., et al., 2006. ESPEN guidelines on enteral nutrition: Surgery including organ transplantation. Clinical Nutrition 25 (2), 224–244.

Maximal Human Lifespan Jean-Marie Robine, French National Institute of Health and Medical Research (INSERM), CERMES3, Paris, France; and École Pratique des Hautes Études (EPHE), MMDN, Montpellier, France Franc¸ois R Herrmann, Division of Geriatrics, Department of Rehabilitation and Geriatrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland © 2020 Elsevier Inc. All rights reserved.

Introduction Living 1000 Years, a Very Old Scientific Objective The Very Long Emergence of Scientific Definitions of Concepts and Terms Associated With Longevity The Distribution of Lifespan Age and Trajectories Trends Over Time The Multiplication of Publications Data and Observations, the Case of France The Dynamics of Longevity Why the Future Can Be Different? References Further Reading

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Introduction The existence of a limit to the length of human life as well as the potential value of this limit is a controversial topic at least since Man writes on this subject. Indeed, one of the known fragments of the work of Hesiod (8th century BC), reported by Plutarch (circa AD 46-120), contains a strange poem whose interpretation has constantly mobilized the best minds. One of the first translations into English is due to Philemon Holland in 1603. Nine ages of men in their flower, doth live The railing Crow: foure times the Stag surmount The life of Crowes: to Ravens doth nature give A threefold age of Stags, by true account: One Phœnix lives as long as Ravens nine: But you faire Nymphes, the daughters verily Of mighty Jove and of nature divine, The Phœnix yeeres 10-fold do multiply.

Hesiod, reported by Plutarch (Plutarch, 1603).

The study of the longevity of humans and animals has mobilized successively through the centuries Aristotle (384–322 BC), Pliny the Elder (AD 23–79), Paracelsus (1493–1541), Nostradamus (1503–1566), Joubert (1529–1583), Bacon (1561–1626), Donne (1572–1631), Digby (1603–1665), Browne (1605–1682), Fontenelle (1657–1757), Voltaire (1694–1778), Buffon (1707–1788), Smellie (1740–1795), Flourens (1794–1867), and Holland (1788–1873) for citing a few of them.

Living 1000 Years, a Very Old Scientific Objective In the manuscript, De Vijs Mortis, et de Senectute Retardanda, atque Instaurandis Viribus, found in the 1980s, Bacon notes that all that can be nurtured continuously and, by feeding, being fully restored, is just like the flame of Vesta, potentially eternal (Bacon, Circa 1620). He expressed a similar idea in Historia Vitae et Morbis, published in 1623 and translated into English as early as 1638, namely that “which can be repaired by Degrees, without a Totall waste of the first Stocke, is potentially eternal” (Bacon, 1638). Bacon is not the first to look for ways to prolong life but he distinguishes himself from alchemists and lays the foundations of modern science. Through his work New Atlantis, published after his death, his ideas are at the origin of the foundation in 1660 of the Royal Society. Prolongation of life, rejuvenation and postponement of old age are clearly among the initial objectives of the Society (Haycock, 2006). Henry Oldenburg (c. 1618–1677), the first Secretary of the Royal Society has published in the Philosophical Transactions a letter from a certain Jean de Martel, Professor of Anatomy at the University of Aix-en-Provence, who claims that in developing our understanding of the causes of natural death (as opposed to death by disease), “we might procure for ourselves an Age of continual Youth” (de Martel de Montauban, 1670).

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Several authors of the 17th and 18th centuries have discussed the reasons for the decrease in longevity of men, which reached about 1000 years before the Flood and is now only 60 or 70 years in the 17th century (Maynwaring, 1670). For some, the earth is aging and there is little hope of recovering the longevity of our ancestors (Buffon, 1749; Vaughan, 1633). For others, it is God who fixes the life of the species to control the size of populations. Thus, He progressively reduced that of men according to the settlement of the earth (Derham, 1713). However, Descartes (1596–1650) is a good example of scholars who think we could regain the longevity of our ancestors. Digby reported that to a question about eternal life, Descartes would have answered “that to render a man immortal, was what he would not venture to promise, but that he was very sure it was possible to lengthen out his [i.e., man’s] life to the period of the Patriarchs” (Digby, 1682). Aubrey De Gray, editor-in-chief of Rejuvenation Research, is the modern representative of this line of thinking. Indeed, in 2004, he claimed that the first human to live 1000 years was probably already alive (de Grey, 2004). In 2005, the journal Science to celebrate its 125th anniversary has decided to explore the 125 major questions that scientists should attempt to answer in the next quarter century (Kennedy, 2005). How Much Can Human Life Span Be Extended? ranks sixth in the top 25 of these questions. The article in Science indicates at the same time that many demographers believe that the average life span will continue to increase for decades and “that many scientists believe that average human life span has an inherent upper limit, although they don’t agree on whether it’s 85 or 100 or 150” (Couzin, 2005). In short, in 2005, we still do not know much about the limits of human longevity. What is new is that in 2005 slowing aging and postponing aging related diseases seem more important than simply extending life. Such an approach contrasts with that proposed by Roy Walford (1924–2004) in the 1980s. He then proposed to distinguish between the average and maximum duration of life, and between techniques that improve overall health without prolonging life, and those that prolong life. In a writing published in French, Walford writes “Let’s not forget that, of the three classic dreams of man; the transmutation of metals, such as lead into gold, going to the moon or the planets, and increasing the length of life, the first two dreams have already been realized nowadays” (Walford, 1985a). This confirms that some researchers have not given up their dreams of immortality. Walford added “... it can be said, however, that it is now possible, and not just in a dream to extend human life to 130 or 150 years.” But we must also quote James Hart (c1580/90-1639) who wrote in the first decades of the 17th century “one may aske what is the ordinary period whereunto the life of man by meanes of art may be prolonged? Our ordinary Authours, as wee have said, assigne 100 or 120 [years]: but wee have a certaine sort of people, who in shew, would seeme to trancend vulgar understanding, and tell us strange things of the prolongation of mans life for many yeeres, farre beyond this above-mentionned period; and that by meanes of certaine medicines made of metals, of gold especially; and these be Paracelsus and his followers.” to ask “is it not a thing ridiculous, now in these later times, to extend the life of man-kinde to 1000, 900, or at least to 600 yeeres?” (Hart, 1633; Haycock, 2006). Immortality or eternal youth Immortality without eternal youth is not worth much. This is what the stories of Greek mythology tell us. In this way, Eos will end up abandoning to solitude his lover Tithon who has become so old and so desiccated (Homer).

The Very Long Emergence of Scientific Definitions of Concepts and Terms Associated With Longevity When, in 1749, Buffon concluded on the basis of all the knowledge acquired since Aristotle’s observations that “to take the human race in general, there is practically no difference in the duration of life; the man who does not die of accidental diseases lives everywhere ninety or a hundred years; our ancestors have not lived more, and since the age of David this term has not varied at all,” we do not really know what he is talking about (Buffon, 1749). The 18th century authors, like their predecessors, speak of ordinary longevity or common longevity without the meaning of words being defined. They do not have the language of modern statistics which allows since the works of Adolphe Quetelet (1796–1874) to describe with precision complex biometric phenomena such as the longevity of individuals (Quetelet, 1848, 1871). Yet Michel de Montaigne (1533–1592) had denounced this confusion from the end of the 16th century: “Do not flatter us with these beautiful words: we must on the adventure call earlier natural, what is general, common, and universal. To die of old age, it is a rare death, singular and extraordinary, and all the less natural as the others: it is the last and extreme kind of death: the further away it is from us, the less so it is: it is indeed the limit, beyond which we will not go, and which nature has prescribed, not to be exceeded: but it is his rare privilege to make us last until then” (Montaigne, 1595). Buffon did not devote more than a paragraph in 1749 to the idea that man can recover the longevity of the Patriarchs. He considers that the limits of life are fixed, at least, since the age of David. This is one of Buffon’s major contributions to the field of longevity. It will be repeated again in the 1980s by Roy Walford for whom maximum longevity has not changed since the time of the Romans and probably not since the appearance of Homo sapiens (Walford, 1985b), by Richard Cutler for whom there is always in each period of history, since the earliest times, a small number of individuals able to live up to 100 years and, thus, to realize the maximum longevity potential of the species (Cutler, 1985), by Leonard Hayflick who was still writing, at 4 years of the year 2000, that there is no evidence that maximum human longevity has changed for 100,000 years (Hayflick, 1996). For these biogerontologists of the late 20th century, the reasons are simple, namely our longevity is controlled by our genes. Thus, Cutler

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considers that, beyond 70 years, the environment no longer has a significant contribution to the causes of mortality and that the last ages reached are relatively independent of environmental conditions, including nutrition (Cutler, 1985). However, it will not be long after the publication of Buffon’s work that the idea of a fixed and immutable limit to the longevity of species is called into question by the Marquis de Condorcet (1743–1794), who wrote in 1795 in Esquisse d’un tableau historique des progrès de l’esprit humain [Sketch of a historical picture of the progress of the human mind] that “the distance between the moment when [Man] begins to live and the common time where naturally without disease, without accident he experiences the difficulty of being can it grow steadily?” (de Condorcet, 1795). This hypothesis triggered the thunders of Thomas Malthus (1766–1834) and led him to write his famous essay on the principle of population, published in 1798 (Malthus, 1798). For Malthus, only God could change these laws “but, without signs of such a change (and these signs do not exist), it is equally unscientific to imagine that the life of man can be prolonged beyond any given limit, than to imagine that the attraction the earth will gradually turn into repulsion and the stones will eventually rise instead of falling, or at some point the Earth will fly to some sun more generous and warmer.”

The Distribution of Lifespan Back to Buffon. In 1777 he completed his list of supercentenarians with, among other cases, the case of the Danish ChristianJacobsen Drachenberg “who died in 1772, aged 146 years ...,” before generalizing to all animals: “it is because there must be in all species, and consequently in the human species, as well as in that of the horse, some individuals whose life is prolonged to double the ordinary life, that is to say, at one hundred and sixty years instead of eighty. These privileges of Nature are, in truth, placed far and wide for time, and at great distances in space; these are the jackpots in the universal lottery of life; nevertheless, they are sufficient to give even the eldest old men the hope of an even greater age.” (Buffon, 1777). The variability of lifespans, especially in the absence of disease, is an idea that will have a hard time making its way. Thus, following the publication of James Fries’s theories on “Rectangularization of the survival curve” and “Compression of morbidity” (Fries, 1980), Hayflick considers that if we are able to eliminate the losses associated with age without touching the biological clock itself, “the result would be a society whose members would live full, physically vigorous, youthful lives until death claimed them at the stroke of midnight on their one-hundredth birthday” (Hayflick, 1981). For almost all authors of the 17th and 18th centuries, the ordinary life span, which must be understood as a limit and not as a central value, is not incompatible with the existence of octogenarians, nonagenarians and even centenarians, the small number of individuals who access the broken arches of the Mirzah Bridge (Addison, 1711). Hart (1633) notes “[to] attaine to 100 is no wonder, having my selfe knowne some of both sexes.” The inhabitants of the New World are even supposed to live longer, 300 years for the natives of Florida (Hart, 1633) or Brazil (Temple, 1701). Buffon seems clearly to reject these cases in 1749 (Buffon, 1749) when he formulates his general proposition on human longevity “... the man who does not die of accidental diseases lives everywhere ninety or a hundred years ....”. However, he accepts the existence of supercentenarians stating “[There are] men who have lived beyond the ordinary term; and, without speaking of these two old men, of whom mention is made in the Philosophical Transactions, of which one has lived a hundred and sixty-five years [i.e., Henry Jenkins], and the other one hundred and forty-four [i.e., William Parr], we have a large number of examples of men who lived for a hundred and even a hundred and twenty years ...”. Abraham de Moivre (1667–1754) appears well isolated in his refutation of ages over 90, (Moivre, 1725; Moivre, 1756). However the argument had to carry and in 1740 Nicolas Struyck (1687–1769), refuses to detail the ages superior to 100 years (Struyck, 1740); what he specified in 1753 in response to critics of Süssmilch (1707–1767): “It is intentionally that I did not separately note people of each age over 100 years, because in the register [i.e., from London] in 1739, mention is made of a person who has reached the age of 138, which I cannot admit without decisive proof” (Struyck, 1753). Süssmilch, in the 1741 edition of the Divine Order, had not only accepted this age but also stressed that it was not “the farthest term we can reach,” before mentioning the inevitable Parr and Jenkins (Süssmilch, 1741). However, Süssmilch stressed the exceptional side “It appears from the London survey that out of 2 to 300 thousand people, only one was 138 years old. I believe that one would not find his like on millions, because such an age is a half-miracle.” He seems to be drawing a credible frontier somewhere between 200 years old, an age that “still seems to be going, especially since [he] is only 30 years away from Jenkins’ age” and 500 years, “everyone will assign a small place among the tales to the story of the Wandering Jew, as well as that of the American prince Hultazob, who gave himself for 500 years.” Buffon confirms both in his works (Buffon, 1749, 1777) the life span of the patriarchs that would have reached nearly 1000 years, the ordinary limit of 80 or 90 years for the common people and the existence of supercentenarians who can reach 160 years old. But these are theoretical values of human longevity. Thus before introducing the life tables of M Dupré de SaintMaur (1695–1774), Buffon indicates that he changes the level of analysis. After having studied the longevity of the human race in general, he will study that of the present populations. He then states: “Man, as we know, dies at any age; and although in general it may be said that the duration of his life is longer than that of the life of almost all animals, it cannot be denied that it is at the same time more uncertain and more variable...” Here we find the origin of the distinction still present among aging biologists between life span, characteristic of species, and life expectancy, which is the fraction lived by different populations. We had to wait until the lecture of Wilhelm Lexis (1837–1914) on the normal duration of the human life, given in Paris in 1878, for a first clarification of the distribution of human lifespans (Lexis, 1878). Lexis extends to the duration of life the “remarkable researches of Quetelet [who] have made known to us this interesting fact that individuals belonging to a given nationality [i.e., a given population], are more or less exact copies of a model with definite proportions, and that individual differences of this type, taken in large numbers, are grouped around the average, according to the well-known law of errors accidental.” To determine

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this typical duration, “that popular opinion vaguely estimates to be seventy to eighty years,” Lexis rules out premature mortality. He observes thus that “in any generation supposed to be sufficiently numerous, a certain group will realize in its average life the normal type with deviations conforming to the formula called by Quetelet the binomial law” (Quetelet, 1848). Applied to France, his method shows a concentration around a center of density, set at 72.5 years for men and 72 years for women, “representing the normal length of life (in France).” Jacques Bertillon (1851–1922) immediately welcomed the conceptual and methodological advance “[Lexis has] established a maximum probability of death in these years immediately after birth, then another maximum around 72–73 years. Indeed, our results lose much of their precision, when we confound probabilities so greatly different as we do by calculating the average life span [i.e., life expectancy at birth]. In France, it is about 40 years old; though it is precisely one of the ages when death occurs most rarely. There is, therefore, in the affirmation of this average something that strangely swears with what everyone knows. The true probability of death is not to die at age 40, but to die in the first years of life, or beyond age 65, 70, and 75. It would therefore be useful for us to consider these two age groups apart: and those who have been seriously called to live, and those who have only appeared on the world stage” (Bertillon, 1878). Lexis burned politeness to Karl Pearson (1857–1936). Let us recognize him, however, the introduction of the modern term of mode: “We may term that occurrence, which happens not necessarily a majority of times, but more frequently than any other’ mode” (Pearson, 1897). From now on, the distribution of deaths by age will be described with all modern statistical terminology. Almost all authors of the 17th and 18th century have proposed a range of ages of about 10 years (60 or 70 years for Maynwaring in 1670, 70 or 80 years for William Petty (1623–1687) in 1672, 90 or 100 years for Buffon in 1749, indicating that they perceived some variability in the notion of ordinary life, if not knowing how to theorize it. On the other hand, it seems obvious to all, from Graunt (1662) to Pearson (1897), that this ordinary life is immutable, at least since the time of David. They do not even mention it except to confirm it (Buffon, 1749; Derham, 1713; Maynwaring, 1670; Süssmilch, 1765). Petty wanted in the years 1676–1679 establish a hierarchy between living beings or Scale of Creatures, ranging from the most basic animals to God, through Man (Reungoat, 2004). His list of questions included in particular the question of what is the lifespan in humans compared to other animal species, a question which is not unlike Hesiod’s poem which opens this article, and the question of how to distinguish those who die of old age from those who die of disease. Petty observes, for example, that the longevity of the elephant (80 or 90 years) is close to that of Man, and justifies, with the other characteristics of the animal, that it occupies the second place after Man on the “animal scale.” For Buffon, this ordinary lifespan, characteristic of species, is a constant that nothing or almost nothing varies. “...it will be even more clearly recognized that the duration of life depends neither on habits, nor on manners, nor on quality of food; that nothing can change the laws of mechanics, which regulates the number of our years, and that we can hardly alter them except by excesses of food or by too great a diet.” There is only one exception “If there are some differences in the length of life, it seems that it must be attributed to the quality of the air.” Buffon’s ideas are going to have a huge impact in the world of biology. Let us quote for example Flourens who wrote in 1856 “Everything in the animal economy, is subject to fixed laws...” (Flourens, 1856). These ideas are still very much present in aging biologists who consider, or considered until very recently, that the longevity of species is a fixed or quasi-fixed biological characteristic, independent of the environment, while the average life, observed for a particular population, depends mainly on the physical and social environment in which this population lives, this environment being more or less favorable to the expression of the potential longevity of the species.

Age and Trajectories It is well established, at least since the publication in 1694 of the life table of Edmond Halley (1656–1742) in the Philosophical Transactions that mortality increases with age (Halley, 1693). Johann Heinrich Lambert (1728–1777) is perhaps the first one to note in 1772 that mortality ceases to increase from a high age that he sets at 80 years (Lambert, 1772). He reports that Pehr Wilhelm Wargentin (1717–1783) found identical results for Sweden before writing: “It can be concluded that the one who had vital force for 90 or 100 years and who abandons his activities towards the 80th year less exposes his remaining vital force to the risk of being diminished since he is resting more and reducing worries for the times to come” (Lambert, 1772). Buffon notes in 1777 the same point of inflection towards 80 years. Mortality growth slows down and tends to a fixed value. “If we can bet one against one, that a man of eighty years will live three years more, we can bet the same for a man of eighty-three, eighty-six, & may be the same for a man of ninety. We therefore always have, in the oldest age, the most advanced, the legitimate hope of three years of life...” This is the description before the hour of a logistic trajectory tending towards a plateau of mortality. Benjamin Gompertz (1779– 1865), revived in 1825, in his famous article on the exponential progression of mortality with age, the possibility of a mortality trajectory tending towards a plateau and concludes that there would be no limit to human longevity (Gompertz, 1825). Harald Westergaard (1853–1936) analyzing life tables in Germany and Norway at age 90 and above notes in 1899 that “about 1/3 of [these] aged persons died within a year, but the mortality seems to be decreasing instead of increasing according to age.” He proposed two mechanisms (Westergaard, 1899) which “may explain the curious bending at extreme old age of the mortality curve, and the fact that a few persons now and then reach an astonishing age like Drakenberg or others.” Firstly, “Evidently there is a sort of selection going on... A thousand old men of ninety are perhaps to be separated in several classes each with its own vitality differing more or less from the average, some of them to be compared to men of 70 or 80, whereas others have very few chances of life.” Secondly, the oldest survivors “lead a quiet vegetative life, without much excitement and with hardly any strain on their small bodily and mental strength.” Therefore, “Life goes on calmly like a quiet brook, till at last it is interrupted in some way or other, and death comes with hardly any agonies.” Westergaard underlines that “It is evident that a person like Drakenberg

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could hardly have existed if 50 per cent or more of the old persons alive died every years.” Irving Fisher (1867–1947) draws on these works (Fisher, 1927) and those of Hornell Hart (1888–1967) to introduce in 1927 his two questions on the limits of human longevity: 1. “If there exists a natural limit to human life of, say, 100 years, how far we expect to increase the duration of life? 2. How far, if at all, may we extend the alleged natural limit of 100 years?” Hart believes that the recent acceleration in life expectancy increase over time can be maintained and concluded that, by the year 2000 the average duration of human life will be 100 years and that many babies will then be born destined to live 200. The main raison is the acceleration in scientific progress, discoveries, number of investigators and funds at the service of scientists in health and medical fields (Hart, 1926). Fisher observed, as Westergaard, that after the age of 85 years the rate of mortality increase actually decreases. “Now, if there exists any definite limit to human life the situation ought to be the reverse. The force of mortality ought to grow heavier and heavier and the curve representing it ought to bend, not toward the horizontal, but toward the vertical, approaching an impassable barrier or “asymptote.” . but if we assume that the mortality of centenarians is not over 50% per annum, which is conservative so far as our scanty facts go, we would have at least one centenarian out of a thousand reaching 110 years and of those who reach 110, one out of thousand reaching 120, and so on indefinitely. ... Such a “law” of mortality does not seem unreasonable. What I am stressing is that we must apparently, give up the concept of any definite life span and substitute the concept merely of chance of survivorship which diminishes indefinitely but with no known or knowable limit.” Fisher notes that “If we assume this 100 years as the limit, we must substitute for Hart’s parabolic law of progress an entirely different type of curve the specifications for which may be: (1) that we start off at the present average duration of life in the United States, 58 years, and with the present rate of life lengthening, 4,1/2 years per decade; (2) that this average shall approach 100 years as a limit; and (3) that its rate of increase, relatively to the possible room for improvement still left, shall be maintained at 10 per cent, or about the present rate.” Starting with a life expectancy of 58 years in 1922, the results of such a forecast are 72 years in 1960, 75 years in 1970, 82 years in 2000, 94 years in 2100, 98 years in 2200 and then approaching the unattainable limit, 100 years (Fisher, 1927). Here Fisher seems to confuse the maximum life span, i.e., the limit of the human longevity, and the life expectancy defined as a mean of all actual life spans, except if he considered that all life spans can approach 100 years without any variability as suggested by Fries (1980) and Hayflick (1981) in the 1980s. According to Fisher “there are five lines of evidence which taken together, seem to be fairly conclusive that the possible life span of man is much more than the century,” i.e., (1) the rate of mortality increase with age decreases after the age of 85, (2) there are still many life-shortening influences to be removed such as germs and poor hygiene, (3) the mortality rates, contrary to prior experience, are beginning to diminish even at the upper age group, (4) we know authentic cases of people who have lived well above 100 years, and (5) modern biology, with reference to the work of Alexis Carrel (1873–1944), found the life cells and many tissues potentially immortal (Pearl, 1922). Among these lines of evidence, two are very new as they suggest that mortality can decrease over time while all above scholars, but Condorcet (see the next section), considered that mortality and longevity do not change over time. For Fisher, it is clear that “all death are, always were, and always will be, accidental in nature and that by safeguarding against bullets, poisons, and germs we can theoretically extend life indefinitely.” It is really tempting to bring this sentence closer to some sentences of Francis Bacon cited at the beginning of this article. Fisher even envisions a kind of transhumanism “It may be that a super-hygiene, a gland transplantation or other device or devices yet unknown will some day open up these new vistas.” Major Greenwood (1880–1949) and Joseph O. Irwin (1898–1982) came back in 1939 to the mortality trajectory by age and “the possibility that with advancing age the rate of mortality asymptotes to a finite value.” According to them, this trajectory could be due to the fact that the elderly are sheltered from the most common risks, “A statistical rate of mortality might show no increase with age, if the demands made on the vital forces diminished pari passu with the decay of vigour,” thus taking up the ideas of Lambert (1772) and Westergaard (1899). Finally, Alexander Comfort (1920–2000), wrote in 1964 in his treatise Agingdthe Biology of Senescence “Extreme records in man, occurring in excess of statistical probability, are chiefly of interest in suggesting that after a certain age the rate of increase in the force of mortality is not maintained, either by reason of selection or from other causes” (Comfort, 1964). In 1979, Vaupel developed with Manton and Stallard a first biodemographic model explaining such a mortality trajectory through the individual heterogeneity in frailty (Vaupel et al., 1979), the frailest die first progressively increasing within the survivors the proportion of more robust individuals. Such mechanism can tend to a mortality plateau if the elimination of the frailest offsets the expected mortality increase with age and even to a decrease in mortality, as “observed” by Westergaard in 1899, if the decrease in mortality level brought by the elimination of the frailest is larger than the expected mortality increase with age, leading Vaupel and his co-authors to propose also a quadratic trajectory in 1998 (Vaupel et al., 1998).

Trends Over Time Let us return to the famous sentence of Condorcet which characterizes the third time of the future progress of the human mind, after the elimination of infectious diseases and other diseases “Without doubt Man will not become immortal but the distance between the moment when he begins to live and the common time when naturally without disease, without accident he experiences the difficulty of being cannot it grow constantly?” The words are chosen. They echo those of the sentence of Buffon’s in 1749 “to take the human race in general...; the man who does not die of accidental diseases lives everywhere ninety or a hundred years; our ancestors have not lived more, and since the age of David this term has not varied at all.” Condorcet speaks, like Buffon, about

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human longevity in absence of disease. For these two authors, the natural or ordinary longevity of the human species corresponds to what we would today call the potential longevity of the human species. But what can explain an extension of this potential longevity if diseases and accidents have been eliminated previously? Condorcet, quite simply, senses that the potential longevity of man has no fixed value. It must depend in part on the general environmental conditions and the progress he anticipates, concerning preventive medicine, nutrition, conditions and lifestyles, should increase it. Condorcet takes the opportunity to develop the two meanings of the word indefinite. “Indeed, this average duration of life, which must constantly increase as we sink into the future, may be augmented by a law such that this duration is continually approaching a limited extent without ever being able to reach it, or well according to a law such that this same duration can acquire in the immensity of the centuries a greater extent than any definite quantity assigned for limit. In the latter case, the increments are really indefinite, in the most absolute sense, and there is no limit beyond which they must stop. In the first, they are still in relation to us if we cannot fix this term that they can never reach and which they must always approach, especially if we only know that they must not stop, we do not even know in which of these two senses the term indefinite is to be applied; and this is precisely the term of our present knowledge of the perfectibility of the human species, such is the sense in which we may call it indefinite. Thus, in the example we are considering here, we must believe that this average duration of human life must constantly increase if physical revolutions do not oppose it, but we do not know what is the term that must never be passed, we do not even know whether the general laws of nature have determined one beyond which it cannot extend.” Even if we have to wait until the 1920s to measure it, the facts will prove Condorcet right. If we still do not really know what is meant and how to measure the “ordinary longevity,” we now know how to measure the typical or normal longevity in a population using the mode (Lexis, 1878; Pearson, 1897). While Lexis, in line with the work of the past, thought that the modal age at death should be stable over time, Greenwood and Irwin showed in 1939 that in fact this value is increasing. They defined it as a variable and considered that minimizing adverse environmental factors should allow more individuals to reach the modal age at death (Greenwood and Irwin, 1939). Kannisto confirmed in 2001 that the modal age at death is increasing and that this increase is accompanied by a reduction in the dispersion of the ages at death occurring after the mode. These observations will allow Kannisto to formulate the hypothesis of an “invisible wall” against which mortality would be compressed as the modal age at death, perceived as the normal age at death, increases (Kannisto, 2001). Studies suggest that the dramatic increase in modal age at death, which has been observed in low-mortality countries since the 1950s, is not always accompanied by a reduction in the dispersion of the ages at death occurring beyond the mode (Bongaarts, 2005). The two hypotheses, “compression of mortality” or “shifting mortality,” explored today correspond exactly to the two scenarios imagined by Condorcet in his manuscript dated October 4, 1793. We can use his own words to say “this is precisely the term of our present knowledge” about the limits of human longevity. Numerous indicators have been proposed to measure the dispersion of the individual lifetimes and hence the compression or not of mortality. They were reviewed by Wilmoth and Horiuchi in 1999. Kannisto himself proposed new indicators in Kannisto (2000). See also Robine (2001), Zhang and Vaupel (2009), Vaupel et al. (2011), and Basellini and Camarda (2019), articles to which reference will be made with interest.

The Multiplication of Publications Today, with the considerable increase in the number of researchers interested in longevity and the multiplication of scientific journals, it is impossible to cite all the studies on the maximum life span. However, the questions and hypotheses remain the same between those who think that the limits of longevity are strongly constrained by the biological characteristics of the human species (Carnes et al., 2013; Da Silva Antero-Jacquemin et al., 2015; Dong et al., 2016; Hanayama and Sibuya, 2016; Le Bourg, 2012; Le Bourg and Vijg, 2017; Olshansky, 2018; Vijg and Le Bourg, 2017) and those like Aubrey de Gray (Ben-Haim et al., 2018; de Grey, 2004) who believe that Man may soon live several 100 years, between those who think that mortality tends to a plateau (Barbi et al., 2018) and those who think that in fact mortality continues to increase with age and that observation of a plateau is due to the poor quality of the data (Gavrilov and Gavrilova, 2019a,b; Gavrilov et al., 2017). Many of the contributions are technical and relate to the choice of modeling mortality rates, the data quality and/or the size of the samples. Very often at their reading, we don’t know exactly what are they talking about and how to measure it. While it is understandable that in the 16th or 17th century theoretical or theological reflections prevailed in view of the scarcity of available observations, this is no longer the case today and the analysis of the available data must be a prerequisite for any reflection on the limits of human longevity.

Data and Observations, the Case of France To illustrate what the analysis of available data shows, we use French data for four reasons, i.e., (1) France displays a high level of longevity, (2) the country is of a reasonable size, nearly 65 million residents in 2019, (3) data on ages at death are of good quality thanks to a systematic registration at birth for a long time and (4) finally France has long time series. We use French empirical data on age at death, from age 0 to 110 and over, dating back to 1816, from the Human Mortality Database (HMD, 2019) and, in addition, empirical data on lifetimes who have reached or exceeded 105 years, from the International Database on Longevity (IDL, 2019) which aims at gathering a large number of data both of quality and unbiased, i.e., corresponding to well-defined populations in space and time. The use of the two databases is complementary and should lift the censorship at the age of 110 years operated by

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Fig. 1 Actual distribution of the individual ages at death observed in France in 1997 (left panel) vs. the modeled distribution of the ages at death according to the French life table for the year 1997 (right panel). While the left panel displays 257.510 deaths, the life table on the right panel is computed for 257.510 births for ease of comparison, France, 1997, females. Sources: HMD and IDL.

HMD. We limit ourselves to women’s data because women not only live longer than men, but also seem to precede them by about 30 years in the current demographic transitions. Thus, in 2016, the last year for which French data are available in HMD, life expectancy for women is 6 years higher than for men, 85.3 years versus 79.3 years, a value achieved by women in 1984, i.e., 32 years before men. Fig. 1 presents the mortality data available for 1997, the year in which Jeanne Calment, the world’s oldest human, passed away (Robine et al., 2019). On the left panel, the actual mortality data observed in 1997, on the right panel the death series from the French life table for the same year. The figure shows the value of the main indicators for characterizing human longevity. 257,510 female deaths were reported to the French civil status bureaus in 1997. The three central values of the distribution of the ages at death, the mode, the mean and the median, are not superimposed because the distribution is not symmetrical. The highest number of deaths was recorded at the age of 87. This is the modal age of observed deaths (Lexis, 1878; Pearson 1897). The mean age at death (arithmetic mean of the ages at death) is 79.7 years, 7 years below the modal age. In fact, 50% of the deaths occurred after the age of 84 was reached. This is the median age at death. It should be noted that the arithmetic mean of ages at death falls in the age group 78–81 years for which relatively few deaths were reported because these ages correspond, in 1997, to the 1915–1919 low birth cohorts. HAPaL30, the Highest Age Providing at Least 30 deaths, is the indicator we have chosen for the “ordinary” limit of human longevity, excluding extreme and “extraordinary” empirical values (Robine et al., 2019). In 1997, HAPaL30 was 106 years. The Maximum Reported Age at Death (MRAD) reached the same year 122 years with the death of Jeanne Calment, value surely “extraordinary.” The panel on the right shows the series of deaths from the period life table, constructed from the mortality rates observed at each age in 1997. This distribution of deaths results in a life expectancy at birth of 82.3 years. Under this law of mortality, 50% of deaths occur after the age of 85 and the most frequent age at death is 89. This is the modal age of the death series from the table. This life table, being closed at age 110 in HMD, ages at deaths above this value, such as the MRAD observed in 1997, are censored. An indicator, such as HAPaL30, does not make sense with life table data because the number of deaths depends on the radix of the table, here chosen at 257.510 to facilitate the graphical comparison between the two panels but which, by convention, is generally a multiple of 10, i.e., 10,000 or 100,000. It should be noted that on the right panel, the distribution of the ages at death is much more regular than on the left panel. In particular, there is no longer any impact of the 1915–19 low birth cohorts. Mortality modeling has removed the impact of the differential size of the successive birth cohorts. Fig. 2 displays again data from period life tables but for the years at both ends of the available time series, namely 1816 and 2016. This makes it possible to measure changes over 200 years in the central indicators of the distribution of the individual lifespans in France. Between 1816 and 2016, female life expectancy (LE) at birth increased by 44 years and the age reached by at least 50% of newborns (median) by 42 years, respectively, from 41.1 to 85.3 years for LE and 46 to 88 years for the median, while the modal age at death only increased by 18 years, from 72 to 90 years. In 1816, LE and the median age at death are clearly

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distinguished from the most common age at death, i.e., the modal age (M). In 2016, the three indicators got closer together. If we consider that M, the most frequent age at death, is the best indicator we have for the ordinary longevity, (here defined as the typically observed longevity, see Montaigne, 1595), these trends suggest that more and more people benefit from ordinary longevity. This tremendous concentration of lifetimes around our ordinary longevity indicator, M, is primarily due to the near disappearance of infant mortality and the sharp reduction in premature mortality between 1816 and 2016. But as we have seen above, the period life tables do not provide indicators of the limits of ordinary longevity. Based on French empirical data, we explored 3 other indicators before choosing HAPaL30, the Highest Age Providing at Least 10 deaths (HAPaL10) and the Highest Reported Ages at Death (HRAD) ranking 10th (HRAD10) and 30th (HRAD30). They give indications between MRAD and HAPaL30 with HRAD10 being closer to MRAD and HRAD30 closer to HAPaL30. HAPaL10 falls in between HRAD10 and HRAD30. Fluctuations from year to year decreases from MRAD showing the largest fluctuations to HAPaL30 showing the smallest annual fluctuations. Fig. 3 displays at the same time all longevity indicators from 1816 to 2016: (1) life expectancy (LE) at birth that infant mortality is pulling down and that may not be the best indicator of ordinary longevity (Bertillon, 1878), (2) the age reached by 50% of the newborns, median age at death, which by construction remains close and mostly above the mean age at death, (3) the modal age at death (M), (4) the age reached by 10% of the newborns, l(10), which ecologists use as indicator of species longevity (Vaupel, 2003), the small size of the samples/populations often preventing them from having statistical indicators closer to the possible limits of ordinary longevity, (5) the Highest Age Providing at Least 30 deaths, HAPaL30, presented above and indicator chosen of the limits of ordinary longevity, and (6) the Maximum Reported Age at Death (MRAD), highest value observed in France each year and validated by IDL, extraordinary value or not, but taken here as an empirical measure of Maximum Life Span. To our surprise, it is HAPaL30, the indicator of the limits of ordinary human longevity, which fluctuates the less between 1816 and 2016. Its trajectory is very simple. From 1816 to 1946, he fluctuates around 99 years, reaching 24 times 100 years and 12 times 98 years, the rest of the time it reached 99 years, 94 times, except in 1817 when he displays 101 years. From 1947, it rose linearly to reach 109 years in 2016, an increase of about 1.5 years every 10 years. It thus increased by 2 years between 2006 and 2016 as well as between 1946 and 1956. We can conclude that there is in France no sign of a slowdown in the growth of the limits of human longevity that has begun after WW II. Life expectancy at birth (LE) and the age reached by 10% of the newborns, l(10), are the least fluctuating indicators since WW II. They both suggest a slowdown in the increase in longevity since the 2000s. In the post-war period, life expectancy at birth and the median age at death are much closer to the most frequent age at death. The four indicators, (LE(0), Median, M and l(10)), show the same trend towards slower gains in ordinary longevity. The comparison between M and l(10) suggests that the age reached by 10% of the newborns would be more of an indicator of ordinary longevity than an indicator of the limits of longevity. The most fluctuating indicators over the entire period are MRAD, of course, which retains only one individual observation per year among hundreds thousands observations and M which retains only one age per year among a hundred possible ages. During the 19th century life expectancy at birth and the age reached by 50% of the newborns fluctuate the most. At the beginning of the 21st century, it is MRAD that varies the most.

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In France, life expectancy first came closer to the ordinary longevity, indicated by the most common age at death (M), before it began to increase itself during the 20th century, however with strong fluctuations until WW II. Since WW II, HAPaL30, the Highest Age Providing at Least 30 deaths, is also increasing. From now on, all the indicators increase except the erratic MRAD. Twenty-seven years separate LE(0) and HAPaL30 in 1966, 25 years in 1976, 22 years in 1986, 20 years in 1996, 18 years in 2006 and finally 17 years in 2016, illustrating an ongoing concentration of individual lifetimes around the ordinary longevity. However, this concentration occurred much more before the mode (M), the difference between M and the EV (0) decreasing from 39 years in 1816 to 4.7 years in 2016, than after the mode, the difference between M and HAPaL30 decreasing from 20 years in 1816 to 12 years in 2016. This 12-year gap in 2016 had already been reached as early as 1946. Since then it has fluctuated around 11 years, a difference recorded 36 times between 1946 and 2016 compared to 22 times for 12 years and 11 times for 10 years. These results, indicating that the increase in ordinary longevity observed since the beginning of the 20th century is accompanied by an equivalent increase in the limits of ordinary longevity since the end of the Second World War, is not favorable to the Kannisto hypothesis of the existence of an invisible wall on which mortality would be compressed (Kannisto, 2001). Fig. 4 displays the distribution of the gaps, in years, between the limits of the ordinary human longevity, indicated by HAPaL30, and the Maximum Reported Age at Death (MRAD). Out of 201 observations, the difference is 7 years in 25.4% of cases, between 6 and 8 years in 52.2% of cases and between 5 and 9 years in 79.6% of cases. The two most extraordinary values are 1 year in 1989 where MRAD reached only 106 years and 16 years in 1997 when Jeanne Calment dies at the age of 122. Recall, however, that HMD censors ages at death over 109 years and IDL only complements it from the 1980s. Finally, note that the values of the MRAD are surely exaggerated over a good part of the 19th century. Fig. 5 illustrates this suspicion with the female death rates at age 100. We can see that these rates increase throughout the 19th century, while the mortality rates at age 85 taken as controls do not change during the period. The annual mortality rates at age 100 increase in HMD from 30.4% in 1816 to 49% in 1895. The most likely explanation for this increase in mortality at age 100 is an improvement in statistics with the development of their use (Robine, 2016). Subsequently, these rates fluctuate a little below 50% until 1946 when they begin to decrease for reaching the rate of 32.7% in 2004, year which enjoys a significant “harvesting effect” following the heat wave of 2003. Since that year, the mortality rates at age 100 stagnate in France around the value of 32%, joining several countries that experience a stagnation of mortality rates at age 100 since several years (Drefahl et al., 2012; Robine and Cubaynes, 2017). This development contrasts with the continuing decline in mortality rates at age 85.

The Dynamics of Longevity In this last section we perform some simple simulations to illustrate the dynamics of longevity. In a first step, we have modeled the mortality trajectory by age for each extinct French birth cohort, using the actual probabilities of death from age HAPaL30 minus

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50 years to HAPaL30, with three models following (1) a Gompertz trajectory, (2) a logistic trajectory and (3) a quadratic trajectory. As it was impossible to fit quadratic models with actual data starting 50 years before HAPaL30, we keep for the next step only (1) Gompertz and (2) logistic trajectories. In a second step, we examined whether the parameters of the Gompertzian and logistic models changed over time with clear trends. As it is not the case, we decided to use only the parameters of the modeling of the most recent extinct birth cohort, i.e., the cohort born in 1903. This choice is reinforced by the fact that the mortality rates at age 100 and over seem to stagnate since the year 2004 in France. In a third step we use the 1903 Gompertzian and logistic mortality trajectories to simulate the survival after the age of 100 years for the successive cohorts of people reaching age 100 according to the French forecast from the year 2016 to the year 2070 (Blanpain and Buisson, 2016). We made only one simulation for each year from 2016 to 2070. In each simulation, we simulated the survival to the next age or the death before the next anniversary for each individual present at the beginning of the year at age 100. The number of individual simulations for each year was determined by the number of forecasted centenarians according to the central scenarios of the French forecasts. On the one hand, our design is a big simplification of the reality as in the future several neighboring birth cohorts will compete each year for providing the yearly MRAD. On the other hand, the future will be unique and not the average of 1000 or 500.000

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simulations. We are not looking for the expected HAPaL30 or the expected MRAD but for one illustration of the future, respecting both the Gomperzian and the logistic mortality trajectories modeled for the birth cohort born in 1903 and the forecasted size of the group of female centenarians from the year 2016 to the year 2070. Fig. 6 illustrates this future with a Gomperzian mortality trajectory with age while Fig. 7 illustrates this future with a logistic modeling. The results of the two simulations displayed on Figs. 6 and 7 are quite similar. Both suggest a kind of level-off for MRAD around 115 years (114.8) with a Gomperzian mortality trajectory (GMTwA) and 116 years (115.7) with a logistic mortality trajectory (LMTwA). The highest MRAD simulated is 119 years in 2050 with GMTwA and 120 years in 2046 with LMTwA. Respectively, the lowest MRAD simulated is 112 years in 2017, 2018, 2026, and 2041 with GMTwA and in 2018 with LMTwA. However HAPaL30, our indicator of the limits of the ordinary longevity, keeps increasing over the period with both trajectories but at a slower pace. With both trajectories it stands at 112 years in 2070. It reached this value for the first time in 2058 with GMTwA and in 2051 with GMTwA. For the last 15 years of the simulation, HAPaL30 seems to remain at the same level. On average, from 2017 to 2070, HAPaL30 increases by 0.6 years per decade while during the period from 1946 to 2016, it increased by 1.4 years per decade.

Why the Future Can Be Different? The above simulations provide a fair illustration of what could be the French longevity performances in the coming future (1) if the mortality level at age 100 and over remains identical to the one observed for the cohort born in 1903 and (2) if the number of people reaching 100 years in the coming decades coincide with figures forecasted by the French statistical bureau from 2013 to 2070. The 1903 female birth cohort reached 100 years in 2003 and was observed until extinction in 2017 at the age of 114 years. The mortality trajectory with age, observed over the 50 single ages preceding HAPaL30, has been used to model the mortality trajectory of each cohort until extinction according to both a Gompertzian and a logistic model. According to the central scenarios of the French forecasts, the number of centenarians (100 years old), present in the French population at the beginning of the year will increase from 6997 women in 2013 to 56,951 women in 2070 (Blanpain and Buisson, 2016). Our illustration is based on this eight times increase in the number of centenarians. The future performances of longevity will be different from this illustration because the later is based on probabilities only. These performances can tend to be lower/higher in the future if the level of mortality increases/decreases before and after the age of 100 years and, especially, if the number of new centenarians is smaller/larger than forecasted.

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Moving from France, a country with 65 millions of inhabitants, to the world with 7.5 billions inhabitants is moving by a scale factor higher than 100. The United Nations forecast that 6,214,000 women will be aged 100 years and above in 2070 (United Nations, 2019). Using the French proportion of women aged of 100 years within the age group 100 and over in 2070 (30%), we can estimate the global number of centenarian women to 1,851,000 in 2070 which is more than 30 times the number of French centenarian women that we used for the last year of our French simulations. We used this ratio to estimate the global number of centenarians (100 years old) from 1950 to 2100. Then based on these estimates, we simulated HAPaL30 and MRAD to illustrate a possible longevity future at the global level, with both a Gompertzian and a logistic mortality trajectories (see Fig. 8). Everything else being equal, i.e., the level and the mortality trajectories with age, the huge expected increase in the number of centenarians at the global level, over the next 80 years, should lead to a continuous increase in HAPaL50, the indicator we selected for the limits of the ordinary longevity, at least until 2070 where it seems to stabilize at a level of 117 years with GMTwA and 118 years with LMTwA. About MRAD, extreme values, we have no reason to believe that they will behave in the future differently from what we observed in France in the period 1946–2016, as in Fig. 4. However, we note in our global illustration (Fig. 8) that MRAD reaches 121 years three times, in 2075, in 2090 and in 2100, and 120 years six times with GMTwA and 124 years in 2075, 123 years in 2040 and 122 years five times with LMTwA. This continuous increase in indicators aimed at identifying the limits of human longevity does not preclude the idea of biological constraints. It incorporates the weight of the environmental factors as the inevitable inertia of a phenomenon that now develops over more than a 100 years. Study of the interactions between “biological” phenomena and ecological and anthropic factors is one of the major challenges of 21st century biology if we want to understand the plasticity of the longevity of species, in particular of the human species, under the actual historic conditions, an idea that has been opposed by almost all scholars since the beginning of time. On the other hand, the observation of a stagnation of HAPaL30, our indicator of the limits of ordinary longevity, in France from 1816 to 1946 echoes the writings of scholars from the 16th to the 19th century for whom ordinary longevity had not changed since the Flood. This article is not intended to close the debate on the limits of human longevity, but to inform of what has already been discussed and the origin of the ideas put forward, as well as the need to look at the empirical facts.

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Demography 16 (3), 439–454. Vaupel, J.W., Zhang, Z., van Raalte, A.A., 2011. Life expectancy and disparity: An international comparison of life table data. BMJ Open 1 (1), e000128. Vijg, J., Le Bourg, E., 2017. Aging and the inevitable limit to human life span. Gerontology 63 (5), 432–434. Walford, R., 1985a. Biologie et sociologie de la prolongation de la vie [biology and sociology of the prolongation of life]. Les Cahiers du MURS 2, 75–91.

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Further Reading Basellini, U., Camarda, C.G., 2019. Modeling and forecasting adult age-at-death distributions. Population Studies 73 (1), 119–138. Canudas-Romo, V., 2008. The modal age at death and the shifting mortality hypothesis. Demographic Research 19 (30), 1179–1204. Canudas-Romo, V., 2010. Three measures of longevity: Time trends and record values. Demography 47 (2), 299–312. https://doi.org/10.1353/dem.0.0098. Cheung, S.L.K., Robine, J.-M., Tu, E.J.-C., Caselli, G., 2005. Three dimensions of the survival curve: Horizontalization, verticalization, and longevity Extension. Demography 42 (2), 243–258. https://doi.org/10.1353/dem.2005. Christensen, K., Doblhammer, G., Rau, R., Vaupel, J.W., 2009. Lancet 374 (9696), 1196–1208. https://doi.org/10.1016/S0140-6736(09)61460-4. Finch, C.E., Kirkwood, T.B.L., 2000. Chance, development and aging. Oxford University Press, New York. Horiuchi, S., Ouellette, N., Cheung, S.L., Robine, J.-M., 2013. Modal age at death: Lifespan indicator in the era of longevity extension. Vienna Yearbook of Population Research 11, 37–69. Kannisto, V., 2001. Mode and dispersion of the length of life. Population 13 (1), 159–171. Le Bourg, E., Vijg, J., 2017. The future of human longevity: Time for a reality check. Gerontology 63 (6), 527–528. Olshansky, S.J., 2018. From lifespan to healthspan. JAMA 320 (13), 1323–1324. Robine, J.-M., 2019. Successful aging and the longevity revolution. In: Fernandez-Ballesteros, R., Benetos, A., Robine, J.M. (Eds.), The Cambridge handbook of successful aging. Cambridge University Press, Cambridge, pp. 27–38. Vallin, J., Meslé, F., 2009. The segmented trend line of highest life expectancies. Population and Development Review 35 (1), 159–187. Vaupel, J.W., 2010. Biodemography of human aging. Nature 464, 536–542. https://doi.org/10.1038/nature08984. Vijg, J., Le Bourg, E., 2017. Aging and the inevitable limit to human life span. Gerontology 63 (5), 432–434. Wilmoth, J.R., Horiuchi, S., 1999. Rectangularization revisited: Variability of age at death within human populations. Demography 36 (4), 475–495.

Mediterranean Diet and Longevity Ligia J Dominguez and Mario Barbagallo, University of Palermo, Palermo, Italy © 2020 Elsevier Inc. All rights reserved.

Introduction History and Definition of the Mediterranean Dietary Pattern Assessment of Mediterranean Diet Adherence AgingdMediterranean Diet Effects on Longevity and Incident NCDs Mortality Cardiovascular Disease Obesity, Metabolic Syndrome, Type 2 Diabetes Cancer Cognitive Decline, Dementia, and Depression Bone Health Frailty Sustainability Molecular and Metabolic Mechanisms Conclusions References Further Reading

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Introduction In the past 150 years, a demographic revolution has taken place as never in history. At the end of the 19th century, life expectancy in Europe, one of the world regions with the largest aging population, was about 35 years, similar to people living in Ancient Rome when it was around 30 years according to historic sources. (Harman, 2001) Today, many people from Japan and most European nations live beyond 80 years. The recently published World Report on Aging and Health of the World Health Organization, states that now most people worldwide can expect to live beyond 60 years (Beard et al., 2016). A key determinant among the multiple factors that may have contributed to this extraordinary demographic event has been the decline in mortality from infectious diseases. However, increased life expectancy did not rely only on child mortality decline, because mortality patterns also changed in old age with increasing life expectancy after the age of 50 years (Beard et al., 2016). Decreasing rates of infectious diseases have been accompanied by an expansion in diseases more frequently seen in old age, such as cardiovascular disease (CVD), cancer, and neurodegenerative diseases. This apparent puzzle between lengthening the average duration of life and increasing degenerative diseases is not surprising, because if the organism lives longer, risk factors have more time to provoke diseases, such as CVD and cancer, not only in industrialized nations but also in developing and underdeveloped countries. Thus, mortality attributable to chronic diseases, so called noncommunicable diseases (NCDs), has grown steadily and continues to grow throughout the world. Not only mortality but also morbidity, disability and deterioration of the quality of life are growing in association with the development of these frequent diseases (Harman, 2001). The NCDs are more frequently seen in old age, hence, relentless aging of the world population in the last 150 years, is one of the cardinal factors to explain the explosion of NCDs that we are witnessing. The consequences for health, health systems, their workforce, and budgets are profound (Beard et al., 2016). The achievements of medicine might aim not only at the extension of life but also at ensuring an old age as free as possible of morbidity and disability. A key contributor of this alarming scenario has been identified in the unfavorable changes in lifestyle of entire populations, which involve a greater incidence of risk factors, associated with the increased life expectancy. This allows a greater number of people to be in age groups vulnerable to cardiovascular events, type 2 diabetes (T2D), cancer, and neurodegenerative diseases. The sedentary lifestyle, the lack of exercise, the unbalanced diet, overeating and cigarette smoking will be the true architects of the increased incidence of obesity, diabetes, dyslipidemia and hypertension, all powerful risk factors for CVD and some types of cancer. A large body of research data has consistently shown that certain dietary patterns, such as the traditional eating habits and lifestyle unique to the Mediterranean basin (Mediterranean diet, MeDiet), may play a fundamental role in the prevention and treatment of chronic diseases and improved longevity. MeDiet has been included in the 2015–20 Dietary Guidelines for Americans as a healthy dietary pattern (Tagtow et al., 2016). This dietary prototype has been linked to greater nutrient adequacy in both observational and intervention studies, helping to address under-consumption of calcium, potassium, magnesium, and fiber, nutrients that have been identified as of public health concern. MeDiet, as a dietary pattern focused on the consumption of plant-based food, but that admits low amounts of animal food, and favoring local and seasonal food production, emerges as an eating model that

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could address both environmental and health concerns. The traditional MeDiet must be understood as not only a cluster of foods, but also as a cultural model that involves the way food is produced, selected, processed, and distributed, as well as other elements of lifestyle. These features have led to the inscription of MeDiet on the list of intangible cultural heritage of humanity by UNESCO in 2010 (Dernini and Berry, 2015). Regrettably, current diets in the Mediterranean countries are moving away from the traditional MeDiet regarding the amounts and proportions of food groups. This is due to the widespread diffusion of westernization and globalization of food production and consumption, related to the homogenization of eating behavior in the modern area. The aim of this chapter is to review the trajectories of MeDiet from its origins in the 1950s until today; and to emphasize the different approaches and evidence that have come to light in the last six decades regarding the link between the adherence to this healthy dietary pattern and longevity with decreased mortality and morbidity derived from chronic diseases associated with aging.

History and Definition of the Mediterranean Dietary Pattern The ecological evidence of results from the Seven Countries Study beginning in the 1950s, before globalization made its influence on lifestyle, including diet, first introduced the concept of MeDiet, as conceived today in nutritional research (Keys, 1995). Southern European participants from olive-tree growing areas of the Mediterranean basin showed life expectancies, which were among the highest in the world, while incident coronary heart disease (CHD), cancer, and other chronic diseases were among the lowest. Rather than a specific dietary pattern, a collection of eating habits traditionally followed by these populations first defined the traditional MeDiet, which are rooted ever since prehistory and history, in the same places where they are found in modern times. The study of this persistence has fascinated historians, physicians, scholars of food and agro-pastoral activities, of the migrations of large and small populations, and of the wars consequent to them. Through the history of humanity, societies have learned to develop a multitude of different ways of combining the foods available in that particular geographical area. The traditional eating patterns are the result of this long and jagged path. Some types of traditional eating patterns, such as the Mediterranean or the Japanese, have shown an association with a lower frequency of CVD, cancer, and neurodegenerative diseases. The term Mediterranean diet, together with the nutritional value, is permeated with a deep symbolic meaning, a unique way of being in this region, cradle of the oldest civilizations, scene of the bloodiest wars, and point of departure of the three monotheistic religions that have marked the face of History. It is clear that the mechanism by which traditional eating models were developed did not occur only in the Mediterranean basin. Nevertheless, only in this area there are sufficient historical, literary, and traditional testimonies to allow verification of hypotheses, comprising archeological vestiges, such as food remains, especially in the tombs, artifacts used for eating, ceramics, objects for cooking, and vessels for food transportation. In addition, there are papyri, terracotta tablets, parchments, wall inscriptions, and literary sources of classical authors, from Homer onwards (Fig. 1). To describe the main characteristics of what is today called Mediterranean dietary pattern, even if generic, we may say that this nutritional model, that has remained constant over time and space, is mainly, but not exclusively, plant-based. It comprises an abundant consumption of seasonal and colorful vegetables, poorly tampered with by culinary interventions, fresh fruit of the season consumed at the end of every meal, nuts and seeds (as snacks and as part of recipes), legumes several times per week, unprocessed cereals every day, high consumption of olive oil as the main source of fat (for cooking and added raw for seasoning), moderate amount of fish (in the past it has been a function of sea distance but it has been generally at a moderate consumption 2–3 times/week), herbs and spices to season recipes, dairy products (milk, yogurt, cheese) allowed daily in limited quantities, eggs (3–4/week), sweets made with sugar or honey, but only a few times a week, red meat and meat products with extreme moderation, drinking plenty of water, as opposed to wine, which is consumed in moderation with meals always respecting beliefs of each community (Dernini and Berry, 2015). A distinctive feature of MeDiet is the use of unprocessed nutrient-dense foods, in stark contrast to “empty calories” of westernized diets rich in processed food that are full of calories but poor in nutrients, undeniably associated with an increased risk of overweight and obesity (Fig. 2). Together with dietary choices, the MeDiet is part of lifestyle, and comprises historical knowledge, practices, skills, and traditions, transmitted from generation to generation, ranging from the landscape to the table, and providing a sense of belonging and continuity to the community. Mediterranean tradition offers a cuisine rich in colors, aromas, and memories, emphasizing the flavors and the harmony with nature, as well as the importance of cooking and eating together with family and friends. Crucial bases of the traditional MeDiet have been climate, flora and hardship. The role played by physical activity, in the more general context of the relationship between the MeDiet and lifestyle, is fundamental (Table 1 and Fig. 3). It is interesting to recall the origin of the concept of MeDiet that today has become so common. In 1948, the Greek government, worried about the need to improve the economic, social and health conditions of the population in the postwar period, invited the Rockefeller Foundation to undertake an epidemiological study on the eating habits of the islanders of Crete, where traditions had remained intact throughout the centuries. American epidemiologists, led by Leland G. Allbaugh, interviewed a sample of the population, chosen at random, obtaining information on various parameters related to lifestyle. Concerning nutrition, plant foods constituted over 60% of the total daily caloric intake, well above the 37% documented in that period in the United States. The surprising observation was that the Cretans consumed a daily amount of fat similar to that of American citizens, about 107 g

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Fig. 1 Traditional olive oil jars and press from 20th century BC (left) and ancient Minoan frescoes with wine drinking vessels from 15th century BC (wright) in the Knossos palace (Crete).

Fig. 2 Food pyramids of Mediterranean and Western diet. As illustrated by the pyramids, the basis of the Mediterranean diet (in green) is minimally represented in the Western diet, while the consumption of red and processed meats, sweets, industrial- and fast-food (in red) constitute the majority of consumption in the Western diet, while is minimally represented in the Mediterranean diet. High-fat dairy products, refined grains, and potato (yellow) are also frequently consumed in the Western diet, as opposed to the Mediterranean diet where other healthy foods are consumed instead.

Mediterranean Diet and Longevity Table 1

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Dietary characteristics of the traditional Mediterranean dietary pattern and lifestyle

Mediterranean dietary pattern

• • • • • • • • • • • • • • • • • •

A variety of fresh fruits and vegetables; legumes, nuts, seeds every day. Bread and other grain products (pasta, rice), mostly whole. Herbs and spices to season food. Cold pressed extra-virgin olive oil as the main source of fat. Fresh fruit everyday as dessert; sweets, cakes and dairy desserts only on occasion. Frequent consumption of fish and seafood (2–3 times/week). Dairy products on a daily basis, mainly yogurt (less often small portions of local cheese). Eggs (high quality proteins) 2–4 per week. Red and processed meat consumed unfrequently, in moderate portions, if possible as a part of stews and other recipes (1–2 every month). Drinking plenty of water. Wine in moderation with meals (
1 drink/day for women and 1–2 drinks/day for men), (respecting beliefs of each community and former habits). Foods that have undergone minimal processing, that are fresh and locally produced. Direct connection with nature. Tasty cooking. Moderation in portion size. Moderate physical active every day is just as important as eating well. Meals and cooking in the company of others. Adequate rest (enough night sleeping time and eventually for small periods of time during the day [siesta]).

Fig. 3 Nutritional and lifestyle components of the Mediterranean dietary pattern, which has been associated with improved longevity and reduced incident age-related chronic diseases.

a day, but with differences as regards the quality of fat consumed: mainly olive oil in the Cretans and saturated fatty acids (SFA) of animal origin in Americans. The eating habits of the Cretans, as observed in the 1950s and 1960s, resulted in an excellent health standard, better than what could be expected from a population not yet influenced by the “advances” of Western societies and exposed, as then believed, to the harmful effects of poor food, social and public hygiene. The model of the MeDiet was born from these considerations, which led to the execution of the Seven Countries Study by Keys (1995) and the creation of the term. Curiously, at the time of the study, Cretan peasants complained to the interviewers of their meat-poor diet, still unaware at that time that one of the reasons for their excellent health was the low consumption of meat combined with the hard work of the fields. Indeed, the notion that food in excess is poorly

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suited to a healthy life has been common knowledge even in times of shortage when fatness was pursued and considered the best expression of health. Nonetheless, in those years, people would not easily believe a physician who would recommend the benefits of a frugal diet, made of foods considered “poor” and of low intake of meat, fats and sugars, combined with continuous physical activity, which at that time was considered degrading. The knowledge of “good food to eat” and to grow has often been accompanied by limited availability and misery for so much of the population. Next to what was to be defined in the future the healthiest diet in the world, has been the availability of food at the limit of survival, where parsimonious eating and using what nature offered was not only a choice of life but also a necessity. However, it is also true that ancient Greeks, for social and political reasons, did not like to binge, which was stigmatized, both on a moral and on a physical level. They believed that what makes men is the measure, the rule, while appetites were considered typical of brutes and beasts. As a matter of fact, Plato considered gluttony, or the folly of the belly, a crime against the Republic. In summary, MeDiet means moderate consumption of dietary healthy choices, but in the context of ancient habits deeply rooted in the cultural and historical features of those peoples of rural societies who have benefited, without being aware, for centuries. This diet is not only health promoting, confirmed by compelling evidence, but also delicious, which can help a greater number of people to follow it more easily.

Assessment of Mediterranean Diet Adherence The evidence put forward by the Seven Countries Study was largely an ecological observation. Lately, an operational definition was necessary in order to perform and make comparisons among different epidemiological studies in diverse populations to assess the health effects of conformity with the MeDiet. Trichopoulou et al. proposed the most commonly used operational definition of adherence to the traditional MeDiet through a simple score in 1995 (Trichopoulou et al., 1995), that was afterwards updated (Trichopoulou et al., 2003). In brief, this score assigns one point for each one of six beneficial components that are consumed (vegetables, fruits and nuts, legumes, cereal, fish, ratio of monounsaturated fatty acids [MUFA] to SFA) with the use of the sex-specific median as the cut-off. For components assumed to be detrimental (meats, and dairy products, which are rarely low-fat in Mediterranean countries), the consumption of an amount lower than the sex-specific median for that population is considered as one point added to the score, while a higher amount has a value equal to zero. For alcohol, one point is added to the score for men who consume 10–50 g/day and to women who consume 5–25 g/day. Thus, the total score ranges from 0 (minimal adherence to MeDiet) to 9 (maximal adherence) (Trichopoulou et al., 2003). Because this score is based on sample medians, it is highly dependent on the specific characteristics of the sample. This may entail a limitation for the comparison of diverse samples and the transferability of results among different populations. An alternative score (Mediterranean Diet Adherence Screener [MEDAS]) has been validated using absolute/normative cut-off points for the consumption of specific food groups (predefined servings/day or servings/week) and was effectively used in the PREDIMED (Prevención con Dieta Mediterránea) intervention trial (Estruch et al., 2018). Both, MEDAS and the 9-point MeDiet score similarly predicted macronutrient distribution and disease incidence or mortality (diabetes incidence, CVD or all-cause mortality) (Dominguez et al., 2013). Table 2 shows the points considered by MeDiet score and by MEDAS. There are, however, some disparities in the definition of MeDiet, and several other scores have been proposed. The Table 2

Two Mediterranean dietary pattern scores of adherence

MEDAS a (0–14 points) (Estruch et al., 2018; Dominguez et al., 2013) 1. 2. 3. 4. 5. 6. 7. 8.

Olive oil as main culinary fat 4 tablespoons/day olive oil 2 servings/day vegetables 3 servings/day fruits 3 servings/week legumes 3 servings/week fish 3 servings/week nuts 2 servings/week olive oil sauce with tomato, garlic, and onion (“sofrito”) 9. Preference for poultry > red meats 10. 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL),

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Fig. 3 Trends in death rates by age group and primary cancer site, from 1975 to 2015. Adapted from Noone, A., Howlader, N., Krapcho, M., Miller, D., Brest, A., Yu, M. et al. (2018). SEER Cancer Statistics Review, 1975–2015. Bethesda, MD: National Cancer Institute. Seer [Internet]. Available from: https://seer.cancer.gov/csr/1975_2015/. 

•

R (renal insufficiency)dcreatinine clearance < 40 mL/min (measured or estimated by validated equations) or serum creatinine > 177 mmol/L (> 2 mg/dL),  A (anemia)dhemoglobin value of > 20 g/L below the lower limit of normal, or a hemoglobin value < 100 g/L,  B (bone lesions)dat least osteolytic lesions on skeletal radiography, computed tomography (CT), or fusion 18Ffluorodeoxyglucose positron-emission tomographyd(18F-FDG PET/CT), any one or more of the following biomarkers of malignancy referred as SLiM acronym:  S (sixty)dclonal bone marrow plasma cell percentage
60% with clonality established by showing kappa/lambda lightchain restriction on flow cytometry, immunohistochemistry, or immunofluorescence,  Li (light chains)dinvolved to uninvolved serum free light chain ratio
100 (measured in the serum Freelite assay),  M (magnetic resonance)dmore than one focal lesions on magnetic resonance imaging studies, each of them at least 5 mm in size.

Premalignant Stages In most cases symptomatic multiple myeloma is preceded by premalignant stages termed monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) (Landgren et al., 2009; Weiss et al., 2009). The diagnosis of MGUS requires the presence of monoclonal protein < 30 g/L, clonal bone marrow plasma cells < 10% in the trephine biopsy and the absence of hypercalcemia, renal failure, anemia, and bone lesions (all CRAB features must be absent). It accounts for over 50% of all plasma cell dyscrasia and is present in roughly 3–4% of the population over the age of 50 years (Kyle et al., 2010, 2006). The rate of progression to MM is about 0.5–1% per year (Kyle et al., 2002), with the risk influenced by some factors including the type and serum concentration of monoclonal protein and percentage of clonal bone marrow plasma cells. SMM is an intermediate clinical stage between MGUS and multiple myeloma defined as serum monoclonal protein
30 g/L or urinary monoclonal protein
500 mg per 24 h and/or clonal bone marrow plasma cells 10–60%, and as with MGUS absence of myeloma defining events mentioned above. The risk of progression to malignant disease in the first 5 years after diagnosis is much higher, at about 10% per year, with a downward trenddapproximately 3% per year for the next 5 years, and 1% per year for the last 10 years (Kyle et al., 2007). The cumulative probability of progression is reported as 73% at 15 years. It is a very biologically heterogenous group, consisting of patients with a very low rate of progression comparable with MGUS, as well as patients who progress with clinical symptoms within the first 2 years of diagnosis (Landgren and Waxman, 2010) (Fig. 4). The biologic transition from normal plasma cells to multiple myeloma precursor disease, and then to multiple myeloma consists of many overlapping oncogenic events but these events are not all present in each affected individual. The two major early events include

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Fig. 4 Criteria for diagnosis of multiple myeloma and preceding premalignant stages. Based on Rajkumar, S.V., Dimopoulos, M.A., Palumbo, A., Blade, J., Merlini, G., Mateos, M. et al. (2014). International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncology 15(12), e538–e548. Elsevier Ltd; Available from: https://doi.org/10.1016/S1470-2045(14)70442-5.

Fig. 5 Biological events related to progression to multiple myeloma. Adapted from Korde, N., Kristinsson, S.Y., Landgren, O. (2011). Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): Novel biological insights and development of early treatment strategies. Blood 117(21), 5573–5581.

immunoglobulin heavy chain gene loci (IgH) translocations [mainly: t(4;14), t(14;16), t(6;14), t(11;14), and t(14;20)] and hyperdiploidy, although most malignant plasma cells have only one of these two genetic changes. In the subsequent stages of myelomagenesis clonal plasma cells gain further secondary translocation involving MYC, copy number variations (CNV) and somatic mutations (such as mutations in KRAS, NRAS, BRAF, P53) (Korde et al., 2011; Manier et al., 2016) that lead to disease progression (Fig. 5).

Etiopathogenesis Etiopathogenesis of multiple myeloma is still not fully understood. MM is thought to be heterogenous multifactorial disease, encompassing a wide variety of risk factors that concern numerous life aspects (Sergentanis et al., 2017). Confirmed risk factors

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include age, male sex, black race and MM among first-degree relatives. Concerning lifestyle risk factors, only obesity and overweight are associated with increased MM incidence and elevated risk for transformation of MGUS to MM, with no evidence of protective role of physical activity (Jochem et al., 2014; Wallin and Larsson, 2017). Regarding occupational exposure, there is an increased risk of MM among farmers, firefighters and hairdressers that is probably associated with the exposure to pesticides containing dichlorodiphenyltrichloroethane (DDT), phenoxyacetic acid and chlorophenols, to metal dust, aromatic hydrocarbons, aldehydes, asbestos and silica, as well as to chemicals from hair dyes, shampoos, conditioners and hair sprays (LeMasters et al., 2006; Perrotta et al., 2008; Takkouche et al., 2009). With regard to comorbidities, autoimmune diseases such as ankylosing spondylitis and pernicious anemia are associated with significantly increased MM risk (Shen et al., 2014). Interestingly, the treatment of autoimmune diseases (e.g. steroids) may also play a role in MGUS and MM pathogenesis. There is no evidence of negative impact of acute and chronic inflammatory diseases, although in these cases immune system may be deregulated (Alexander et al., 2007). Concerning medications, prior use of insulin, prednisone, and, perhaps, gout medication might promote increased occurrence of multiple myeloma. Conversely, statins, estrogen replacement therapy, and certain medical conditions might protect against multiple myeloma development (Landgren et al., 2006b). While taking into consideration family history, increased risk of MM is observed in relatives of MM patients, especially in first-degree relatives, relatives of the patient aged
65 at diagnosis, relatives of the female patient, female relatives and in African-American families (Landgren et al., 2006a; VanValkenburg et al., 2016). In summary, probably exposure to the environmental risk factors modifies the genetic predisposition to the disease development.

Staging System The clinical outcome of antimyeloma therapy is heterogenous, with overall survival ranging from a few months up to 10 years. Therefore, IMWG created a useful tool named revised International Staging System (R-ISS) to stratify patients with newly diagnosed MM (NDMM) effectively with respect to the relative risk to their survival (Palumbo et al., 2015a). It includes the following three prognostic parameters: (1) ISS stage based on serum b2-microglobulin level (b2m) and serum albumin level, (2) chromosomal abnormalities (CA) detected by fluorescent in situ hybridization (FISH), and (3) serum lactate dehydrogenase level (LDH). Concerning CA, the presence of del(17p), translocation t(4;14), or translocation t(14;16) commonly identifies high-risk patients. The combination of ISS stage III, high-risk CA, and elevated serum LDH are associated with a significantly poorer prognosis (Table 1). The R-ISS staging system has a prognostic impact when analyzed in age subgroups (patients  65 and > 65 years old) and as well as in subgroups with different treatment strategy [autologous stem-cell transplantation (ASCT) and non-ASCT]. Therefore, it is recommended to use it in clinical practice (Table 2).

Geriatric AssessmentdFrailty Score In newly diagnosed elderly patient geriatric assessment should be done to define the frailty profile as it predicts survival and treatment toxicities. Frailty is an increased vulnerability resulting from aging-associated loss of ability to cope with everyday or acute

Table 1

Staging system of multiple myeloma.

Prognostic factor ISS stage I II III CA by FISH High risk Standard risk LDH Normal High R-ISS stagednew model for risk stratification in MM I II III

Criteria Serum b2-microglobulin the upper limit of normal ISS stage I and standard-risk CA by FISH and normal LDH Not R-ISS stage I or III ISS stage III and either high-risk CA by FISH or high LDH

Adapted from Palumbo, A., Avet-Loiseau, H., Oliva, S., Lokhorst, H.M., Goldschmidt, H., Rosinol, L. et al. (2015a). Revised international staging system for multiple myeloma: A report from international myeloma working group. Journal of Clinical Oncology 33(26), 2863–2869.

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Prognostic impact of R-ISS in general population and by age groups.

Median progression-free survival Median progression-free survival in patients 65 years old Median progression-free survival in patients >65 years old Median overall survival Median overall survival in patients 65 years old Median overall survival in patients >65 years old

R-ISS I

R-ISS II

R-ISS III

66 months 70 months 47 months not reached not reached not reached

42 months 47 months 29 months 83 months 87 months 70 months

29 months 34 months 17 months 43 months 42 months 46 months

Based on Palumbo, A., Avet-Loiseau, H., Oliva, S., Lokhorst, H.M., Goldschmidt, H., Rosinol, L. et al. (2015a). Revised international staging system for multiple myeloma: A report from international myeloma working group. Journal of Clinical Oncology 33(26), 2863–2869.

stressors. However, the group of elderly MM patients is highly heterogeneous and among adults of the same age, physical and cognitive functions can be highly variable. Chronologic age, performance status, and brief physician assessment of the clinical status of the patient are not sufficient to characterize the frail population properly. Frailty score in MM proposed by IMWG is based on age, comorbidities, and cognitive and physical conditions, using in its scoring system previous three tools of geriatric assessment: the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL), and the Charlson Comorbidity Index (CCI). The scoring scale in each tool mentioned above is divided into subclasses with different values (0, 1 or 2). The additive total score (after summing up those values from each tool and a value of age) enables to classify the patient as fit, intermediate-fitness or frail (Palumbo et al., 2015b) (Tables 3 and 4). Frail patients have increased risk of progression, non-hematologic adverse events during antimyeloma therapy, treatment discontinuation and death. Therefore, both R-ISS and frailty score should be considered in elderly patients with NDMM as a strategy of treatment outcome prediction. Although evidence-based geriatric assessment-guided treatment recommendations are still lacking, IMWG highlights that fit patients can receive full-dose, triplet therapies or even more intensive approach including auto-HSCT. Intermediate-fitness patients may benefit from doublet treatments or less intense triplets, while frail individuals should undergo a gentle, reduced-dose doublet therapy or even a palliative/supportive treatment alone.

Treatment Primary Therapy In most cases multiple myeloma treatment is based on systemic therapy (chemotherapy) and autologous hematopoietic stem cell transplantation (auto-HSCT). To date, the main criterion for treatment decisions is age (Cavo et al., 2011). Depending mainly on the age at the time on MM diagnosis the patient is considered as eligible or non-eligible to tolerate high-dose therapy (HDT) followed by auto-HSCT. Although there is no formal definition of young MM patient who is transplant-eligible, it is often operatively

Table 3

Geriatric assessment in multiple myeloma-scoring system. Age

Score

75 0

76–80 1

ADL >80 2

>4 0

IADL 4 1

>5 0

CCI 5 1

1 0


2 1

Palumbo, A., Bringhen, S., Mateos, M.V., Larocca, A., Facon, T., Kumar, S.K. et al. (2015b). Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report. Blood 125(13): 2068–2074.

Table 4

Patient status according to the additive total score.

Additive total score

Patient status

0 1
2

Fit Intermediate-fitness Frail

Based on Palumbo, A., Bringhen, S., Mateos, M.V., Larocca, A., Facon, T., Kumar, S.K. et al. (2015b). Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report. Blood 125(13): 2068–2074.

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defined as being  65 years. However, IMWG highlights that age is not the only one factor taking into consideration while planning antimyeloma treatment and therefore patients who are older than 65 years may undergo auto-HSCT. Practically, in some selected individuals up to 70–75 years who are classified as fit patients, auto-HSCT still is an option and can be performed safely.

Transplant-eligible patients When the patient is qualified as eligible for transplantation, it should be performed in the first line (up-front) treatment. Typically, prior to the transplantation procedure the patients receive a limited number of cycles of induction therapy to reduce tumor cell mass and bone marrow plasma cell infiltration before collection of peripheral blood stem cells. Nowadays, novel agents such as proteasome inhibitors (PIs) e.g. bortezomib, carfilzomib, ixazomib, and immunomodulatory derivatives (IMiDs) e.g. thalidomide, lenalidomide, pomalidomide, proven to be more effective in comparison to conventional chemotherapy used in the past, are used as in induction regimens preceding autotransplantation to enhance the depth of response before auto-HSCT and further improve outcomes after transplantation. Achievement of at least complete remission as proven to be one of the strongest predictors of long-term outcomes is the main aim of current treatment strategies. In case of failure to achieve at least very good partial response after first auto-HSCT, it is suggested to consider second ASCT (Table 5). Concerning the induction regimens, it is recommended to use triplets. National Comprehensive Cancer Network (NCCN) categorized all MM treatment regimens as “preferred,” “other recommended,” or “useful under certain circumstances” (Kumar et al., 2018). In the last update to the NCCN Guidelines treatment of NDMM transplant-eligible patients, that was listed as preferred option include the following bortezomib-based triple-drug regimens: bortezomib/lenalidomide/ dexamethasone (VRd) and bortezomib/cyclophosphamide/dexamethasone (VCd) (Table 6). In young patients with high-risk MM and poor long-term prognosis allogeneic stem cell transplantation as a frontline therapy or as a salvage treatment after the failure of the first-line chemotherapy still may be an option. However, it should be considered only when the risk of allotransplantation-related threats is lower than the risk of disease progression, even in the era of novel effective agents (Lokhorst et al., 2010). Very fit patients aged 65–75 years may follow the same protocol like young individuals. If the patients are unsuitable for highdose melphalan in conditioning they may undergo reduced-intensity auto-HSCT with preceding bortezomib-based induction and conditioning with melphalan in half-reduction dosage (Palumbo et al., 2014).

Table 5

IMWG uniform response criteria for multiple myeloma.

Response

IMWG criteria

Stringent complete remission (sCR)

CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and 90% reduction in serum M-protein plus urine M-protein level 50% reduction of serum M-protein and reduction in 24 h urinary M-protein by >90% or to 50% reduction in the size of soft tissue plasmacytomas is also required Not meeting criteria for CR, VGPR, PR, or progressive disease Increase of
25% from lowest response value in any one or more of the following: • Serum M-component and/or (the absolute increase must be
0.5 g/dL) • Urine M-component and/or (the absolute increase must be
200 mg/24 h) • Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL • Bone marrow plasma cell percentage; the absolute percentage must be
10% • Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas • Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder At least one of the following is required: • Development of new soft tissue plasmacytomas or bone lesions • Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion • Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L] • Decrease in hemoglobin of
2 g/dL [1.25 mmol/L] • Rise in serum creatinine by 2 mg/dL or more [177 mmol/L or more]

Complete remission (CR) Very good partial response (VGPR) Partial response (PR) Stable disease (SD) Progressive disease (PD)

Relapse

Adapted from IMWG Uniform Response Criteria for Multiple Myeloma. http://imwg.myeloma.org/international-myeloma-working-group-imwg-uniform-response-criteria-for-multiplemyeloma/.

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Primary therapy for transplant-eligible patients.

Preferred regimens • Bortezomib/ lenalidomide/ dexamethasone • Bortezomib/ cyclophosphamide/ dexamethasone Other recommended regimens • Bortezomib/ doxorubicin/ dexamethasone • Carfilzomib/ lenalidomide/ dexamethasone • Ixazomib/ lenalidomide/ dexamethasone Useful in certain circumstances • Bortezomib/ dexamethasone • Bortezomib/ thalidomide/ dexamethasone • Lenalidomide/ dexamethasone • Bortezomib/ thalidomide/ dexamethasone/cisplatin/doxorubicin/cyclophosphamide/etoposide (VTDPACE) Adapted from Kumar, S.K., Callander, N.S., Alsina, M., Atanackovic, D., Biermann, J.S., Castillo, J. et al. (2018). Multiple Myeloma, version 3.2018: Featured updates to the NCCN guidelines. Journal of the National Comprehensive Cancer Network 16(1), 11–20.

Table 7

Primary therapy for transplant-noneligible patients.

Primary therapy for transplant-non-eligible patients Preferred regimens • Bortezomib/lenalidomide/dexamethasone • Lenalidomide/low-dose dexamethasone • Bortezomib/cyclophosphamide/dexamethasone Other recommended regimens • Carfilzomib/lenalidomide/dexamethasone • Carfilzomib/cyclophosphamide/dexamethasone • Ixazomib/lenalidomide/dexamethasone Useful in certain circumstances • Bortezomib/dexamethasone Adapted from Kumar, S.K., Callander, N.S., Alsina, M., Atanackovic, D., Biermann, J.S., Castillo, J., et al. (2018). Multiple Myeloma, version 3.2018: Featured updates to the NCCN guidelines. Journal of the National Comprehensive Cancer Network 16(1), 11–20.

Transplant-non-eligible patients Bortezomib/lenalidomide/low-dose dexamethasone is listed as preferred regimen for transplant-non-eligible patients, especially those who are frail or elderly with standard-risk features. For high-risk patients bortezomib/melphalan/prednisone protocol is a treatment of choice. Although triplet-drug regimens are gold standard in MM treatment, elderly or frail patients may be treated effectively with doublet regimens (e.g. lenalidomide/low-dose dexamethasone continuously until progression). Dexamethasone should be implemented in low doses as the use of high-dose dexamethasone was proven to result in higher toxicity and mortality rates, especially in patients aged
65 years (Table 7).

Maintenance Therapy NCCN recommends lenalidomide in monotherapy as preferred maintenance regimen, stressing the need to assess the benefits of long-term use of lenalidomide in the context of potential adverse events, including severe neutropenia, risk for secondary hematological malignancies and solid tumors. Bortezomib is listed as an “other recommended” as it is well tolerated and enables to achieve higher overall response rate after auto-HSCT in transplant-eligible patients and after bortezomib-based induction in transplant-noneligible individuals (Table 8).

Relapsed/Refractory Multiple Myeloma The choice of treatment in the next lines, in case of refractory disease or relapse after achieving a remission, depends on the clinical context such as prior treatment and duration of response. Therapeutic options include systemic therapy with the use of traditional chemotherapeutics and novel drugs (proteasome inhibitors, immunomodulators, monoclonal antibodies),

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Maintenance therapy.

Preferred regimens • Lenalidomide Other recommended regimens • Bortezomib Kumar, S.K., Callander, N.S., Alsina, M., Atanackovic, D., Biermann, J.S., Castillo, J. et al. (2018). Multiple Myeloma, version 3.2018: Featured updates to the NCCN guidelines. Journal of the National Comprehensive Cancer Network 16(1), 11–20.

auto-HSCT for transplant-eligible patients who did not receive autotransplantation as part of the up-front treatment, and in patients who achieved a long remission after the first auto-HSCT, as well as experimental therapy in clinical trials. In case of late relapse (> 6 months after completion of the previous therapy), patients may be retreated with the same regimen. Triplets remain gold standard, however frail elderly patients may benefit from double-regimens, with the possibility to add the third drug after the improvement of the patient’s general condition. Patients with an aggressive relapse may need multidrug combinations including traditional chemotherapeutic agents as VTD-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide). IMWG and NCCN guidelines remain useful tools supporting therapeutic decisions, however as far as multiple myeloma is a heterogenous disease the final decision should be individually tailored to find a balance between the efficacy and toxicity of the regimens, especially in the population of elderly patients.

Difficult to TreatdRare Conditions in the Spectrum of Multiple Myeloma Solitary Plasmacytoma Solitary plasmacytoma (SP) is a local mass of neoplastic monoclonal plasma cells with no or minimal (< 10%) bone marrow plasmacytosis, and no sign of systemic plasma cell proliferative disorder which may present as a single bone lesion, solitary bone plasmacytoma (SBP), or as a soft tissue mass, extramedullary plasmacytoma (EMP) (Caers et al., 2018). SP is a rare condition with a cumulative incidence of 0.15/100.000, accounting for less than 5% of plasma cell malignancies. There is a twofold male predominance observed, with higher incidence in African Americans and incidence rate increasing exponentially by advancing age. Median age at the moment of SP diagnosis is 55 years (Kilciksiz et al., 2012). Diagnostic criteria of pure SP include biopsy-proven clonal plasma cell infiltration of the lesion of bone or soft tissue, no evidence of clonal plasma cells in bone marrow, normal result of skeletal survey (except for the primary solitary lesion), no additional lesions found on spine and pelvic magnetic resonance imaging (or computed tomography) and no features of end-organ damage (CRAB criteria). SBP comprises 70% of all SP cases and occurs predominantly in red marrow-containing bones (vertebrae, femurs, pelvis, ribs). EMP may develop in any tissue, but is primarily found in the head and neck region (most frequently in the sinonasal area), gastrointestinal tract and lungs. Imaging studies should include MRI to determine the extent of local disease and PET to exclude the presence of additional malignant lesions and systemic involvement. Concerning EMP, reactive processes, carcinoma and lymphoma should be considered in a differential diagnosis. Both SBP and EMP are treated locally. Fractionated radiotherapy is a cornerstone (Soutar et al., 2004). Surgery, followed by radiotherapy, should be considered in patients with pathological fractures, large, well-defined soft tissue lesions, or high risk of complications. Chemotherapy, using the same protocols as for MM, including high-dose chemotherapy followed by auto-HSCT in younger patients, is indicated in case of refractory disease and/or relapse. Patients presenting with SBP have a higher risk of developing symptomatic multiple myeloma in comparison to those diagnosed with EMP. 3-year progression rate is 10% for all SP cases, elevated in case of minimal bone marrow involvementdup to 20% in EMP and to 60% in SBP. Furthermore, it is proven that in a period of 10 years after the initial diagnosis approximately 30% of patients with EMP and 50% of patients with SBP develop MM. So far only minimal bone marrow plasmacytosis has been indicated as a prognostic factor of progression to MM. Considering the potential risk of progression to MM, local recurrence and development of new plasmacytomas, follow-ups are required (Suska et al., 2018) (Figs. 6 and 7).

Plasma Cell Leukemia Plasma cell leukemia (PCL) is the most aggressive variant of the monoclonal gammopathies (Fernández De Larrea et al., 2013). It can be classified as either primary (pPCL) (accounting for 60–70% of all PCL cases) while present ‘de novo’ in patients with no evidence of previous MM, or secondary (sPCL) in case of leukemic transformation of relapsed/refractory multiple myeloma, with still increasing incidence observed. The diagnosis is based on the presence of more than 20% plasma cells of the total white blood cell count in peripheral blood and an absolute plasma cell count greater than 2  109/L (Fig. 8). PCL concerns 2–4% of patients with MM. sPCL occurs in 1–2% of late-stage myeloma. As for MM, PCL is more common in African Americans than in Whites. pPCL is observed in younger patients than MM. In trephine biopsy bone marrow in extensively

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Fig. 6 18F-fluoro-ethyl-tyrosine (18F-FET) fusion positron-emission tomography (PET/CT). Solitary extramedullary plasmacytoma of palatine tonsil. Focal increase in 18F-FET uptake in the left palatine tonsil. Usually, 18F-fluorodeoxyglucose (18F-FDG) in used as a tracer in PET, however it is less specific to neoplastic cells, with highly uptake in inflammatory cells. Sinonasal region is often affected by inflammatory process, therefore in this case 18-FET was used a tracer, as it is not incorporated in inflammatory cells.

Fig. 7 18F-fluoro-ethyl-tyrosine (18F-FET) fusion positron-emission tomography (PET/CT). Posttreatment status. No focal increase in 18F-FET uptake in the left palatine tonsil.

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Fig. 8 Peripheral blood film: 90% plasma cells, a bluish background, rouleaux, occasional nucleated red blood, and low platelets. Adapted from Moiz, B. and Ali, S.S. (2012). Plasma cell leukemia in pregnancy. Blood 120(18), 3633. Available from: http://www.bloodjournal.org/content/120/18/ 3633.abstract.

infiltrated by clonal plasma cells with highly pathological morphology, that results in the reduction of the space for other cell lines (red blood cells and platelets). Clinical course of PCL is very aggressive according to the high tumor burden, with profound anemia, thrombocytopenic hemorrhagic diathesis and hypercalcemia. Extramedullary involvement may present as organomegaly, predominantly hepatomegaly, splenomegaly and lymphadenopathy, and even palpable extramedullary soft-tissue plasmacytomas. Interestingly, the presence of osteolytic lesions is not so common as in MM. Age
60 years, platelet count  100  109/L and peripheral blood plasma cell count
20  109/L (factors of pPCL prognostic index) are independent predictors of worse survival in pPCL (Jurczyszyn et al., 2018b). Leukemic transformation of MM to sPCL is a complex, multistep process. Thus, pPCL and sPCL are two clinically and biologically different entities with the same features of high level of plasma cells circulating in the peripheral blood and poor prognosis, without significant improvement observed in MM in the past decade. Therapy should be initiated immediately after diagnosis. The main aim of the induction is to reduce the number of neoplastic plasma cells rapidly to minimize the risks contributing to early death. Systemic therapy with chemotherapeutics and novel agents, followed by transplantation is the cornerstone. In pPCL patients  50 years old with a suitable donor, a myeloablative allogeneic transplantation can be considered. Otherwise, a tandem auto-HSCT with the following reduced-intensity conditioning allogeneic transplantation if a related or an unrelated donor is available can be considered. Transplantation should be preceded by the induction therapy with bortezomib-based regimens combined with classical chemotherapeutics including alkylating agents or anthracyclines. In transplant-non-eligible pPCL patients bortezomib-based induction regimen is the treatment of choice. Treatment of sPCL or relapsed pPCL depends on the type of and response to previous therapy. Fit patients may be qualified for intensive salvage multidrug chemotherapy and/or bortezomib-based protocols, followed by stem cell transplantation in transplant-eligible patients. In unfit patients and fit individuals but not responding to intensive chemotherapy palliative approach should be implemented. There are no specific response criteria for PCL, therefore according to the primarily leukemic nature of the disease IMWG recommends to combine in the treatment response evaluation acute leukemia and MM requirements. sPCL is usually a terminal stage of MM with a median OS of 1–2 months (Jurczyszyn et al., 2018a). The survival of patients with pPCL is substantially better than in sPCL, with median OS of 7–12 months utilizing conventional chemotherapy. Five-year survival rate is less than 10%. Early mortality within the first months from diagnosis, reflecting the aggressiveness of the disease, is the main problem. Considering the poor outcomes observed in both groups pPCL and sPCL, novel therapy with higher efficacy is needed.

Emergencies and Supportive Care Bone Disease Multiple myeloma is characterized by osteolytic lesions that are detected in 70% to 80% of patients at diagnosis and increase the risk for skeletal-related events such as pathologic fractures and spinal cord compression (Terpos et al., 2013) (Fig. 9). Bone disease in MM results from increased activity of osteoclasts which are responsible for bone resorption, and reduced function of osteoblasts stimulating bone formation. It is a highly disabling event that can cause pain impairing quality of life. The main

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Multiple small, uniform, sharply demarcated osteolytic lesions with no sclerotic margin or periosteal new bone formation involving the skull.

group of drugs used in bony disease are bisphosphonates (BPs) such as zoledronic acid and pamidronate, that are the inhibitors of osteoblasts-mediated bone resorption. In each patient with osteolytic bone lesions revealed on conventional skeletal survey, who is receiving antimyeloma therapy, with adequate renal function, BPs should be initiated, preferable intravenously, and at 3- to 4-week intervals. For patients with a solitary lytic lesion and no evidence of osteoporosis, BP therapy is not indicated. BPs are generally well tolerated in patients with MM. Most common adverse events associated with BP administration include: hypocalcemia and hypophosphatemia, gastrointestinal symptoms in case of oral BPs administration, and inflammatory reactions at the injection site in intravenous BPs. Renal impairment and osteonecrosis of the jaw (ONJ) are less frequent but potentially serious complications. Calcium and vitamin D3 supplementation should be used to maintain calcium homeostasis. Patients should undergo a dental check-up, accompanied by optimal everyday dental hygiene to avoid ONJ. In some cases, orthopedic surgery is needed. For symptomatic painful vertebral compression fractures balloon kyphoplasty is the procedure vitally improving quality of life. Radiation therapy is mainly used in solitary plasmacytoma and symptomatic spinal cord compression. As a palliative approach low-dose radiotherapy is indicated in uncontrolled bone pain associated with lytic lesions and as prevention from impeding pathological fractures.

Anemia Anemia is characterized by the low hemoglobin level. It is present in approximately 75% of MM patients at the time of diagnosis. There are several factors contributing to development of anemia in MM, including bone marrow infiltration by myeloma cells with the erythropoietic line (erythrocyte precursors) displacement, deficiency of erythropoietin that normally is responsible for erythropoiesis stimulation, decreased erythrocyte precursor cells reactivity to erythropoietin, and impaired iron utilization due to increased production of hepcidin associated with chronic inflammation in the course of myeloma. It may be also a result of hematologic toxicity of the antimyeloma treatment (chemotherapy or/and radiotherapy). Anemia can be observed at any stage of MM. Red blood cell transfusions is a standard treatment in moderate and severe symptomatic anemia, aiming to increase the hemoglobin level rapidly. The administration of erythropoiesis-stimulating agents such as erythropoietin (Epo)-a and b as well as darbepoetin, may result in the decrease in transfusion frequency and quality of life improvement. However, it can also lead to serious side-effects: thromboembolism and hypertension, therefore it has to be used with caution. Routine iron supplementation is not recommended, and administered intravenously can be effective only in absolute or functional iron deficiency.

Renal Impairment Mild renal impairment (RI) defined as a decrease of glomerular filtration rate concerns at least 25%–50% of MM patients during the course of the disease. The pathophysiology of RI in MM is very complex (Dimopoulos et al., 2016). The main underlying

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mechanism is cast nephropathy which results from the high serum concentration of immunoglobulin free light chains. Because of its excessive amount, absorption mechanisms of this kind of monoclonal protein in the proximal tubule are overwhelmed. As a consequence, FLCs can cause direct injury to proximal tubular cells through the induction of pro-inflammatory cytokine production and other pathways leading to tubular cell death. The excessive light chains reach the distal tubules, where they form tubular casts with Tamm-Horsfall protein (THP) (physiologically secreted into the urine by epithelial cells of the nephron), subsequently leading to tubular obstruction, tubular atrophy and tubular-intestinal fibrosis (Figs. 10 and 11). In addition to this, other factors as hypercalcemia (defined as high calcium level in the blood serum), hyperuricemia (abnormally high level of uric acid in the blood), urinary tract infections, dehydration, and amyloid light chain (AL) amyloidosis (a condition characterized by the deposition in the glomeruli of fibril-forming free light chains) may also contribute to the deterioration of kidney function. Finally, therapy-driven nephrotoxicity may occur as contrast-induced nephropathy (following intravenous iodinated contrast administration in imaging techniques) or acute kidney impairment caused by the use of nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs, loop diuretics and antibiotics of the aminoglycoside group. MM patients with RI at presentation should be considered a medical emergency. Antimyeloma treatment should be initiated immediately. Bortezomib-based regimens plus high-dose dexamethasone are the first choice, as far as bortezomib is proven to be safe and effective in MM patients with RI. In case of contraindications to use bortezomib, immunomodulatory derivatives such as thalidomide and lenalidomide should be considered, with adequate dose adjustment according to renal function. It

Fig. 10 Mechanisms of FLC-induced acute kidney injury. Adapted from Terpos, E., Kleber, M., Engelhardt, M., Zweegman, S., Gay, F., Kastritis, E. et al. (2015). European myeloma network guidelines for the management of multiple myeloma-related complications. Haematologica 100(10), 1254– 1266.

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Fig. 11 Mechanism of cast nephropathy. Adapted from Lam, A.Q., Humphreys, B.D. (2012). Onco-nephrology: AKI in the cancer patient. Clinical Journal of the American Society of Nephrology 7(10), 1692–1700.

must be emphasized that high-dose chemotherapy with auto-HSCT may be performed even in patients requiring dialysis (there are no contraindications), however the patient should be aware of a higher toxicity of this procedure due to the kidney failure. Additionally, supportive care is of key importance. A proper management include adequate hydration, urine alkalinization, and treatment off hypercalcemia. It is crucial to treat urinary tract infection early and effectively, and to avoid nephrotoxic agents listed previously. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB), also known as angiotensin II receptor antagonists, used in hypertension and heart failure, should be administrated with caution as they act on the arterioles of glomeruli.

Peripheral Neuropathy Peripheral neuropathy (PN) in multiple myeloma can be caused by the disease itself or by certain therapies, including thalidomideand bortezomib-based regimens. It is found in up to 20% of MM patients at the time of diagnosis, and up to 75% may experience treatment-emergent neuropathy. MM-associated PN, in most cases mild intensity, is primarily sensory or both sensori-motor. It may result either from the presence of a monoclonal protein itself, or osteolytic lesions, pathological fractures, leading to the compressions of the spinal cord or spinal nerves. The main symptoms include paresthesia, numbness, burning sensation and weakness, and occur predominantly symmetric. In contrast, treatment-induced PN is usually symmetric and distal, with some differences in details depending on the treatment regimes. PN from thalidomide is dose-dependent and often permanent, and may occur even after treatment cessation. Its mechanism may be related to the inhibition of the NF-kB signaling pathway, which leads to increased programmed cell death. Bortezomib-induced PN is related to dose, schedule and mode of administration (intravenous vs subcutaneous), with symptoms progressing proximally, however, in most cases it is reversible. Probably, it results from mitochondrial dysfunction (cell energy centers) (Fig. 12). Risk factors for the development of neuropathy include: diabetes mellitus, overweight, alcohol abuse, previous chemotherapy (such as vincristine, cisplatin), vitamin D deficiency, viral infections, as well as polymorphisms of some genes, e.g. inflammatory proteins genes or neuronal regulation genes. In the treatment-related PN prophylaxis is of key importance. Subcutaneous (rather than intravenous) and weekly (instead of twice a week) bortezomib application significantly reduce peripheral neuropathy, without affecting the final therapy outcome. Potential treatment-emergent PN prophylaxis may also include: magnesium and vitamin supplementation, especially multi-B complex with B1, B6 and B12, folic acid and vitamin E, amino acid supplements, fish oils, omega-3 fatty acids. All MM patients with treatment protocols based on the potentially neurotoxic drugs should be routinely monitored for signs of PN with validated tools. Early reduction or temporary discontinuation of the neurotoxic drug should be adopted, as a gold standard of care.

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Fig. 12 Principal mechanism of neuronal damaged induced by bortezomib. Adapted from Grammatico, S., Cesini, L., Petrucci, M.T. (2016). Managing treatment-related peripheral neuropathy in patients with multiple myeloma. Blood and Lymphatic Cancer: Targets and Therapy 6, 37–47.

Co-analgesics (which are not typical painkillers, but under certain conditions may present analgesic effects or enhance the effect of analgesics) including gabapentin, pregabalin, amitriptyline and duloxetine are indicated as a treatment of neuropathic pain. Additionally, neuro-rehabilitation through physical and occupational therapy might be considered (Richardson et al., 2011).

Venous Thromboembolism There is an increase incidence of venous thromboembolism (VTE) in MM patients, approximately 8-22/1000 person years. Risk factors are related to the disease itself, patient status and implemented antimyeloma treatment. Patient-related risk factors include:

• • • • • • • • • • •

advanced age, VTE in the past medical history, inherited thrombophilia, obesity (Body Mass Index
30), central venous catheter in situ, immobility, paraplegia, dehydration, comorbidities (cardiac, diabetes, RI, chronic inflammatory disease, concomitant presence of myeloproliferative disorders), infections, surgery (within 6 weeks).

Myeloma-related factors include:

• • • •

hyperviscosity syndrome, disease burden, renal impairment in the course of the disease, hypercoagulability status induced by inflammatory cytokines.

Treatment-related factors include:

• • •

the use of immunomodulatory derivatives: thalidomide-, lenalidomide- and pomalidomide- based regimens, particularly when combined with high-dose steroids or doxorubicin multiagent chemotherapy, concomitant use of erythropoietin.

The type of the frontline therapy matters. The incidence of VTE during upfront ranges from 1% to 2% with conventional therapies such as melphalan and prednisone, and it is doubled by the initiation of conventional chemotherapy e.g. with doxorubicin, while the use of immunomodulatory derivatives in combination with dexamethasone or chemotherapeutic agents increases the risk of up to 70% in case of no anticoagulation, and is the highest he first 4 months of therapy. Each MM patient required thromboprophylaxis. In patients who have no or the only one risk factor for VTE listed above aspirin is considered an adequate and sufficient anticoagulation therapy. In individuals with at least two risk factors low molecular weight

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Fig. 13 Incidence rates of microbiologically defined infections in patients with multiple myeloma following disease diagnosis. Adapted from Teh, B.W., Harrison, S.J., Worth, L.J., Spelman, T., Thursky, K.A., Slavin, M.A. (2015). Risks, severity and timing of infections in patients with multiple myeloma: A longitudinal cohort study in the era of immunomodulatory drug therapy. British Journal of Haematology 171(1), 100–108.

heparin (LMWH) with the prophylactic dose adjusted according to renal function, administrated subcutaneously or full-dose warfarin (vitamin K antagonist oral anticoagulant) can be used. It should be continued for at least first 4 months, until disease control is achieved or as long as the risk of thromboembolism remains high, then switch to aspirin prophylaxis is possible. In case of VTE development, antimyeloma treatment should be discontinued, and they full anticoagulation therapy should be implemented. Taking oral anticoagulants, which are vitamin K antagonists, requires systematic monitoring of INR, a normalized prothrombin time (international normalized ratio), being one of the blood coagulation parameters, to keep this value in proper ranges. Of note, INR value may vary depending on the content of foods high in vitamin K. To date, novel non-vitamin K antagonist oral anticoagulants (NOAC) such as rivaroxaban, apixaban, dabigatran, are not recommended in MM.

Infections Infections are the main cause of death in MM patients. The risk of a bacterial infection is 7-fold higher and for viral infections 10fold higher in MM patients compared to healthy individuals of the same sex and age. The increased risk of infection in MM results from the nature of the disease itself (dysregulation of the immune system), implemented therapy (melphalan in high dose, multidrug chemotherapy, cumulative dose of steroids), disease-related complications such as end-organ damage in active disease (especially renal failure) and age-related conditions, including frailty status as well as physical dysfunction (immobilization). Haemophilus influenzae, Streptococcus pneumoniae, Gram negative Bacilli, influenza virus and herpes zoster virus are the most frequent pathogens. There are two main peaks of the bacterial infection incidence ratedfirst, the highest, at 4–6 months following disease diagnosis, and a smaller one at 70–72 months from diagnosis. Equally, the incidence rate of viral infection had a bimodal distribution with peaks at 7–9 months and 52–54 months following disease diagnosis (Fig. 13). In terms of prophylaxis, vaccination against influenza virus is recommended for both patients and their contacts. Moreover, vaccination against Streptococcus pneumoniae and Haemophilus influenzae is recommended, but with unclear efficacy due to impaired immune response observed in MM. Live vaccines are contraindicated. Antiviral prophylaxis is mandatory in patients receiving proteasome inhibitors, even at least 6 weeks after treatment discontinuation, and during transplantation procedure. Because of increased infection rate reported during lenalidomide- and pomalidomide-based protocols, it is also recommended to administer antibiotic prophylaxis at least for the first 3 months of the therapy, following local institutional guidelines. Routinely, prophylactic immunoglobulin replacement is not recommended, but it can be useful under certain circumstances in patients with severe recurrent bacterial infections and hypogammaglobulinemia (reduced gamma globulin fraction, which include antibodies responsible for the defense against pathogens).

New Developments Investigators are now turning to immunotherapy in clinical trials for multiple myeloma. There are a lot of innovative approaches such as CAR-T cells [a type of white blood cellsdT cells, with engineered chimeric antigen receptor (CAR)] and bispecific antibodies which are engineered to simultaneously target and bind to two different antigens, including Bispecific T Cell Engagers (BiTEs) designed to help engage T cells to target and destroy malignant cells. To date, encouraging results have been observed in targeting cluster of differentiation (CD)19 and B cell maturation antigen (BCMA) (Berahovich et al., 2018). Using CAR-T against a surface antigen on myeloma cells seems to mediate efficient tumor cell death even in heavily pretreated patients, however only in

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Fig. 14

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The process of CAR-T cell development. Adapted from National Cancer Institute. www.cancer.gov.

a proportion of them. Moreover, the responses are short because of the lack of CAR-T cells persistence and the tumor immune escape with loss of CD19 and BCMA are observed. There are still too many question marks, therefore this interesting therapeutic modality should be used only in the context of clinical trials (Fig. 14).

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Incidence of multiple myeloma in Great Britain, Sweden, and Malmö, Sweden: The impact of differences in case ascertainment on observed incidence trends. BMJ Open 6 (1). BMA House, Tavistock Square, London, WC1H 9JR: BMJ Publishing Group. e009584. Available from: http:// www.ncbi.nlm.nih.gov/pmc/articles/PMC4735168/. Wallin, A., Larsson, S.C., 2017. Body mass index and risk of multiple myeloma: A meta-analysis of prospective studies. European Journal of Cancer 47 (11), 1606–1615. Elsevier. Available from: https://doi.org/10.1016/j.ejca.2011.01.020. Waxman, A.J., Mink, P.J., Devesa, S.S., Anderson, W.F., Weiss, B.M., Kristinsson, S.Y., et al., 2010. Racial disparities in incidence and outcome in multiple myeloma: A populationbased study. Blood 116 (25), 5501–5506. Available from: http://www.bloodjournal.org/content/116/25/5501.abstract. Weiss, B.M., Abadie, J., Verma, P., Howard, R.S., Kuehl, W.M., 2009. A monoclonal gammopathy precedes multiple myeloma in most patients. 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New Ages of LifedEmergence of the Oldest-Old Marja Jylha¨, Faculty of Social Sciences (Health Sciences) and Gerontology Research Center (GEREC), Tampere University, Tampere, Finland © 2020 Elsevier Inc. All rights reserved.

Introduction: The Emergence of the Oldest-Old Population Who Are the Oldest-Old? Health and Functioning Among the Oldest-Old Morbidity, Functional Status and Self-Rated Health Time Trends in Health and Functioning Predictors of Mortality The Complex Interactions of Increasing Longevity, Postponed Death and Health in the Last Years of Life Long-Living Men and Long-Living WomendTwo Different Stories Multiple Ages of Old AgedQuality of Life in the Fourth Age Conclusions: New Ages of LifedNew Definitions of Success? References

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Introduction: The Emergence of the Oldest-Old Population The past few decades have seen the emergence of a new, important population group in society: the oldest-old, that is, people over the age of 85, 90 or even 100. There have always been extremely old individuals, but until recently they were few and far between. Historically, longevity has always been highly valued. The Bible, for instance, mentions several improbably old individuals, including Abraham who died at the age of 175 and Noah who lived to be 950. In real life the emergence of the oldest-old population is a relatively recent phenomenon. Because of the sharp rise in the number of old people and the symbolic value of a 100 year-long life, most of the attention has focused on centenarians. According to Robine and Cubaynes (2017), the number of centenarians started to rise in the 1960s in Sweden, France and Denmark, and in the 1980s in Japan. Since 1990, the number of centenarians in the world has multiplied by 1.7–2.0 every 10 years, and it is projected that by 2100 it will be 50 times higher than in 2015. In absolute numbers, this means an increase from 96,000 in 1995 to 25 million centenarians in 2100. Yet centenarians account for only a small proportion of older people and even of the oldest-old. The groups with the greatest impact on the population structure and health and welfare are people aged 85 þ and 90þ, whose numbers are rising sharply. In the Nordic countries of Iceland, Finland, Norway, Denmark, and Sweden, for example, the population aged 90 þ increased remarkably from 1990 to 2014 (Jørgensen et al., 2018). The growth was lowest in Iceland where the number of both female and male nonagenarians doubled, and highest in Finland where the number of female nonagenarians multiplied by 3.2 and that of males by 3.6. In Finland, it is projected that from 2012 to 2060 the number of people aged 85 þ will multiply by 2.7; the number of people aged 90 þ by 3.7; and the number of centenarians by 7.5 (Statistics Finland (a) Official Statistics of Finland (OSF): Population projection [e-publication], 2019). The growth of the oldest-old population is a result of declining mortality in childhood, youth and middle age and the consequent increase in the number of people reaching old age; and of declining mortality in old age, which has increased the length of time that people are spending in old age. While life expectancy (LE) at birth started to rise after the mid-18th century, first mainly as a result of declining childhood mortality and since the 1930s also because of falling adult mortality (Robine and Cubaynes, 2017), mortality in the age group 65–79 did not begin decline more sharply until after the 1920s, among males even later, and in the age groups 80 þ only after the second world war (Kannisto et al., 1994; Meslé and Vallin, 2011). In all the Nordic countries the proportion of birth cohorts surviving until 90 has greatly increased between those born in 1900 (cohorts who reached their 90th birthday in 1990) and 1923 (reaching 90 in 2013). The proportion of survivors in the 1923 cohort was highest in Sweden, 25.8% for females and 12.6% for males (the figures for the 1900 cohort were 13.5% and 5.4%, respectively), and lowest among females in Denmark (19.3% for the 1923 cohort and 12.7% for the 1900 cohort) and among males in Finland (6.9% for the 1923 cohort and 2.2% for the 1900 cohort). The odds of reaching age 90 thus roughly doubled in 13 years. This dramatic change, rightly characterized as a longevity revolution, has happened quite rapidly, but it has often been overshadowed by the growing total number of people reaching retirement age. Yet there are many reasons why the growth of real longevity warrants research attention in its own right and why it is important to know more about the oldest-old population. As the growth of populations aged 65–74 is set to slow in many countries, the oldest-old will account for an ever larger share of the total older population. The oldest-old today remains a poorly understood age group. This chapter describes the general characteristics, health and functioning, quality of life and individual experiences of the oldest-old. The oldest-old is here defined as the population aged 85 or older, that is, individuals who have exceeded the average life expectancy and the modal age of death in most low-mortality countries. Yet the main focus of discussion here is on nonagenarians (90 þ) and centenarians (100 þ). Based on the findings, I will

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discuss the need to update our understanding of life stages and good aging with the lengthening of old age. In contrast to the third age, a stage of life characterized by Peter Laslett as freedom, activity and fulfillment, the following “fourth age” is apparently marked by “dependency and decrepitude” (Laslett, 1997). If this is true, should the lengthening of life be regarded as a misfortune? Rowe and Kahn (1997) define successful aging as a low probability of disease and disease-related disability, high cognitive and physical functioning, and active engagement with life. To what extent does this apply to the oldest-old? If it doesn’t apply at all, should we understand longevity as human failure?

Who Are the Oldest-Old? The oldest-old populations are only a small remaining segment of their birth cohorts or the cohorts at a younger adult age. Therefore, the older the cohort, the greater the power of selection has been during the life course. As mortality is known to be higher in men than women and in lower than in higher social classes, it is obvious that the proportion of men and the proportion of lower social classes is smaller among the oldest-old than in the same cohort in middle age. Zajacova and Burgard (2013) demonstrated the impact of selection in the Health and Retirement Study and Assets and Health Dynamics of the Oldest-Old cohorts. They showed that the distribution of baseline characteristics such as wealth, education and smoking status differed among survivors from one time point to another during the follow-up: the surviving participants were those who at baseline had higher education, higher wealth and were less likely to smoke. It is likely that selection mostly impacts factors that are not highly dependent on higher age, and it is more powerful in countries where survival to the oldest-old ages is rarer. But we should not overestimate the impact of selective mortality on the characteristics of the oldest-old population. Although mortality over the whole life course is higher in lower social classes and among those with less healthy lifestyles, studies with representative population samples show remarkable heterogeneity among the oldest-old for characteristics that are known to be subject to selective mortality. The oldest-old come from different occupational and educational backgrounds (Enroth et al., 2013b; Zeng et al., 2017a; Herr et al., 2018) and have different lifestyle habits such as smoking (Nybo et al., 2003), and include married, widowed, separated and single individuals. Even in countries with strong traditions of institutional care, at least half of those aged 90 þ live in ordinary homes in the community (Christensen et al., 2013; Enroth et al., 2013b). This heterogeneity is also true for centenarians (Hazra et al., 2015) as noticed by Ursula Lehr already in 1991 (Lehr, 1991) when the number on centenarians still was low. Yet there are clearly more women than men among the oldest-old. In 2015 the female/male sex ratio among centenarians in the world was 3.7, but this figure is expected to decrease to 1.9 by 2100 (Robine and Cubaynes, 2017). In the Nordic countries, the sex ratio in the population 90 þ ranged from 2.0 in Iceland to 3.8 in Finland in 1990, and from 2.1 in Iceland to 3.6 in Finland in 2014 (Jørgensen et al., 2018).

Health and Functioning Among the Oldest-Old Morbidity, Functional Status and Self-Rated Health Health in very old age is a function of the dynamic interplay of survival and morbidity over the whole life course. One line of thinking maintains that as the oldest-old are the fittest survivors of their birth cohort and have a robust genetic makeup, they are likely to be healthy even at very old age. Another line of thinking says that as people live to a very old age, they are exposed to risks of aging-related diseases and therefore are likely to be frail and disabled. I would suggest that both these ways of thinking are relevant and that their importance is dependent on the health indicator in question. It is plausible that long-living individuals are those who have managed to avoid several major health problems and who were healthier than their shorter-living age peers at younger ages. On the other hand, several major conditions are strongly agerelated and share many molecular mechanisms with processes of biological aging. For these conditions, health selection before old age is likely to have less impact than for conditions whose incidence peaks at younger ages. Yet selection works not only at younger ages but also among the oldest-old. Therefore, we need to recognize the existence of a continuous dynamic process extending from good health through worse health to death throughout the life course. This “wave” is likely to start later and advance more slowly among those who live a very long live. There are many ways to extreme longevity. Evert et al. (2003) described these routes by categorizing centenarians as escapers, delayers and survivors according to their health history before reaching very old age. Escapers were individuals who reached their 100th birthday without a diagnosis of major age-associated diseases, delayers were individuals who did not have age-related illnesses before the age of 80, and survivors had an age-related disease before the age of 80. A few studies indicate that at the earlier stages of the life course, those who live to high ages are healthier than their age peers who die younger, and that the onset of chronic conditions occurs later among them (Andersen et al., 2012; Doblhammer and Barth, 2018). Using Danish nationwide registers, Engberg et al. (2009) showed that centenarians experienced less hospitalizations during their younger adult years than their shorter-living age peers at the same age. Yet the “wave” is there for the very old as well, and survival in this stage of life is strongly dependent on the absence of dementia and chronic heart disease (Doblhammer and Barth, 2018). Reliable information on the prevalence of health and functioning in the oldest-old is still rather scarce as many studies are hampered by selection bias and reach only the healthiest members of the base population. The most credible data comes from studies with a well identified base population and a high response rate (Box 1).

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Box 1 Studying the oldest-old: methodological challenges Studying the oldest-old involves some unique features that partly explain why we still do not know very much about this age group and why research findings about health and functioning in particular vary so widely. Recruitment is often an early challenge as some of the potential participants live in care homes, are unable to give their informed consent, or are unable to answer the interview questions or to participate in face-to-face examinations for health reasons. When the potential participants have been reached and they have agreed to participate, special arrangements may be needed for data collection because of the high frequency of cognitive problems, sensory impairment and fatigue. Therefore, unless the necessary data can be drawn from register sources, the process of data collection will be more laborious and time consuming than with younger age groups (Davies et al., 2010). In population studies describing the characteristics of the oldest-old age groups, one major question is whether the samples collected are representative of the base population, that is, whether the findings can be generalized to the whole population. The first question is whether the sampling frame covers the whole population of interest, that is, does the target population comprise all the nonagenarians in the area or country concerned. This depends on whether there is a way to identify all nonagenarians in a reliable way in population registers using personal identification numbers, municipal inhabitant registers, or the like. Furthermore, convincing evidence shows that in order to produce generalizable findings, it is necessary to include individuals living in care homes and accept proxy interview answers for those who for health reasons are unable to answer the questions themselves (Kelfve et al., 2013). This, again, is problematic in the case of questions concerning individual experiences such as self-rated health or life satisfaction. Indeed, it is virtually impossible to draw generalizable findings that represent the whole oldest-old population for individual feelings and experiences; the best we can hope to achieve are findings describing those who are able to participate in the interviews.

Even when institutionalized individuals and proxies are included, eligible individuals who do not participate are likely to be in poorer health than the participants. In the Vitality 90 þ study, which included all individuals in the target area and age group irrespective of health and place of residence and which showed a response rate of around 80%, those who did not participate were significantly more likely to die during the 3 months after data collection than those who did participate, suggesting that they were in poorer health at the time of the study (Vitality 90 unpublished information). It is reasonable to assume then that even the best population-based studies paint an overly positive picture of the health and functioning of nonagenarians and centenarians. In advanced age, functional status is by far the most important descriptor of health and most important determinant of quality of life, independence and need for care. Population-based studies show that octogenarians, nonagenarians and centenarians are heterogeneous groups in terms of functioning. The Newcastle 85 þ study reported that 31% of women and 58% of men aged 85 were independent in ADL and IADL (Jagger et al., 2011). In the Danish 1905 birth cohort, 41% of women and 50% of men were independent in five activities of daily living (ADL) at the age of 93–94, while 22% of women and 19% of men were dependent in at least three individual activities (Nybo et al., 2001). In a sample of almost 3000 individuals aged 90–99 in China, 34% of women and 56% of men were independent in ADL and cognitive functioning (Li and Zhang, 2018). In the Vitality 90 þ study, 73% of women and 85% of men were independent in ADL, and 31% and 61%, respectively, were independent in mobility (Jylha et al., 2013). In a French sample of 512 participants aged 90 þ, 37% of women and 24% of men were dependent in ADL, while the figures for IADL were 72% and 60%, respectively (Herr et al., 2016). Among centenarians, the frequency of disability is higher. In the Tokyo Metropolitan Study (Gondo et al., 2006), 6% of women and 19% of men were independent on the Barthel index, which measures independence in basic activities, while 38% of women and 20% of men were totally dependent. In another Japanese study, nearly 80% of centenarian women and 60% of men needed help in daily activities (Arai et al., 2017). In the West Danish cohort born in 1901, 50% of centenarian women and 35% of men were dependent in three or more out of five ADLs, while 17% of women and 38% of men were independent in all five (Rasmussen et al., 2018). In Portugal, the Oporto study reported that centenarians were, on average, dependent in 5.6 ADLs out of seven (Ribeiro et al., 2016). Yet in a Chinese cohort born in 1903–09, 63% of women and 71% of men aged 100–105 were independent or dependent in only one of the six ADLs, while 28% of women and 23% of men were dependent in at least three (Zeng et al., 2017a). While assessments of functioning are based on relatively standard measures of ADL and mobility disability, the disease diagnoses covered vary from one study to another. In the Vitality 90 þ study in Finland (Halonen et al., 2019), the most frequent chronic conditions were heart disease (54% in women, 52% in men), hypertension (46% in women, 32% in men), dementia (42% in women, 39% in men), arthritis (41% in women, 28% in men) and depression (23% in women, 18% in men). In all, 74% of women and 60% of men had at least two chronic conditions. In England, primary care records were used to study chronic conditions among centenarians between 1990 and 2003 (Hazra et al., 2015). The most frequent chronic conditions were disorders of the nervous system and senses (63% for women, 49% for men), arthropaties and related disorders (44% and 35%), musculoskeletal and connective tissue diseases (59% and 44%), digestive diseases (42% and 37%) and hypertensive diseases (27% and 16%). According to the authors, geriatric syndromes tended to be less frequently recorded than other chronic morbidities. Dementia or impaired cognition or memory were recorded in 17% of women and 10% of men. Other major conditions were fractures or falls (65% in women and 33% in men), hearing impairment (30% in women and 25% in men) and vision impairment (16% in women and 12% in men). Approximately half of the women and 40% of men had at least three morbidities (excluding dementia). In the Oporto study in Portugal (Ribeiro et al., 2016), 88% of centenarians had three or more health problems out of the 15 queried. In the Danish 1885–86 cohort (Andersen-Ranberg et al., 2001), the most prevalent conditions at the age of 100 were urinary incontinence (60%), osteoarthritis (54%), hypertension (52%), dementia

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(51%) and angina pectoris or ischemia (28%). Centenarians had also experienced several earlier health events such as pneumonia, fractures, cardiac events or cancer. The mean number of diagnoses was 4.3. Only one participant did not have any diagnoses and 62% had at least three conditions. In the COOP study that involved centenarians from Japan, France, Switzerland, Sweden and Denmark, 51–78% of the participants were classified as frail and from 3% to 11% as robust (Herr et al., 2018). As most studies only cover a limited number of diseases, the figures are likely to underestimate the rate of multimorbidity. A Swedish study considering 60 categories of chronic disease, more than one third of individuals aged 90 years and older experienced seven or more diseases (Calderon-Larrañaga et al., 2017). Self-rated health, an individual evaluation summarizing several aspects of health and illness, is an important health indicator for the oldest-old. In most population studies, a majority of the oldest-old rate their health as average or better (Enroth et al., 2013a; Cevenini et al., 2014). With increasing age, the relation between self-rated health, on the one hand, and more objective indicators such as disease diagnosis and functional ability, on the other, changes as individuals adapt their evaluations to the higher expected levels of health problems (Jylhä, 2009). Therefore, in very old age people will accept higher levels of disease and disability in their assessments of “good” self-rated health. Even so self-rated health is associated with morbidity and functional status among the oldest-old, and is sensitive to changes in morbidity and functional status (Galenkamp et al., 2013). It is difficult to compare studies on health and functioning as they vary in terms of their basic population, sampling frame, sources of information, response rate, health conditions and functional dimensions included, and in the measures used to assess these conditions. Some conclusions can be drawn, however, based on the most reliable data available. First, in the oldest-old, among those aged 85 to over 100, both chronic health conditions and functional disability are frequent. At the age of 85, less than one in 10 have no chronic conditions, and there are hardly any centenarians who have no diagnoses. A clear majority have at least two to three diagnoses. Both vital diseases such as ischemic heart disease and conditions that are likely to cause functional problems and lower quality of life, such as arthritis, are common. Problems in vision and hearing are likewise frequent. There is even more variability in findings on functional status. Roughly, 40–70% of those over 85 but under 100 are independent in activities of daily living, meaning that they are able to dress and undress, eat and move around indoors without help. Difficulties occur more frequently in IADL and outdoor mobility. Among centenarians the proportion of those who are independent in basic daily activities varies from less than one in ten to more than half. Even among the oldest-old, age matters in respect of physical functioning. Even beyond age 90, additional years mean an increased likelihood of disability (Christensen et al., 2008; Li and Zhang, 2018). As physical disability is a strong predictor of death and therefore individuals with the highest rate of disability are subject to mortality selection, the decline of functioning with age is less pronounced in cross-sectional studies that show survivors in different age groups than in longitudinal studies that follow cohorts of individuals over time. The prevalence of major chronic disease does not increase as steeply with age as the prevalence of disability. Yet a recent registerbased longitudinal study by Doblhammer and Barth (2018) showed a regular association between age and major chronic conditions such as heart disease, depression and dementia even between the ages of 95 and 100. In this study, 28% of those who survived beyond age 100 had dementia at age 95, and 54% at age 100, while among those who died at age 95, 55% had dementia at this age. Dementia appeared to reach a maximum of approximately 70% in the group who died at the age of 97–99. Corrada et al. (2010) showed an exponentially increasing incidence of dementia between the age groups of 90–94, 95–99, and 100þ. Dementia is by far the most important individual chronic condition among the oldest-old (Box 2).

Time Trends in Health and Functioning The big question about longer old age and increasing real longevity is whether the years gained are healthy or disabled. Does increasing longevity mean that the oldest-old are healthier than before, or are they surviving in poor health and with disabilities? Again, only few high quality studies are available, as several identical data collections on representative samples in the same population are needed to reach reliable results. Examples of relevant studies are provided in Table 1. Between two cohorts of centenarians born in Denmark in 1895 and 1915, the proportion of non-disabled women increased and the proportion of severely disabled women decreased. No significant differences were found among men, but the proportion of non-disabled men was somewhat lower and that of severely disabled men higher in the latter cohort (Rasmussen et al., 2018).

Box 2 An example of population-based studies with the oldest-old: the Vitality 90D project The Vitality 90þ study in Tampere, Finland, has used identical survey methods in 2001, 2003, 2007, 2010, 2014, and 2018 to study the whole population aged 90 years or over irrespective of health and place of residence (Jylhä, Enroth and Luukkaala, www.gerec.fi/vitality). Before these six surveys, home-dwelling individuals were studied in 1995, 1996, and 1998. In all waves, response rates have been around 80% of the base population. Proxies have been used where individuals were unable to answer the questions for health reasons; this has been the case for 13–24% the of participants in different waves. The data include altogether 8840 nonagenarian participants and 5935 observations. Surveys have been linked with national registers on mortality and the use of social and health care services. The data allows for analyses of time trends and individual changes in health and functioning, changes in disability-free life expectancy, as well as predictors of mortality, and long-term care. Sub-studies include face-to-face examinations, blood tests and qualitative interviews.

New Ages of LifedEmergence of the Oldest-Old Table 1

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Cohort differences in the health and functioning of the oldest-old.

Study

Women

Men

Centenarians born in 1895 vs. 1915 in Denmark (Rasmussen et al., 2018)

ADL disability Y

93-Year-olds born in 1905 vs. 95-year-olds born in 1915 (Christensen et al., 2013)

ADL disability Y Cognitive functioning [ Grip strength – Chair stands Y ADL disability Y Cognitive functioning Y Chair stands Y ADL disability Y Mobility disability (Y) Total sample, sex-adjusted: ADL disability (Y)

No ADL disability ([) Moderate ADL disability Y Severe disability ([) ADL disability Y Cognitive functioning [ Grip strength – Chair stands Y ADL disability Y Cognitive functioning Y Chair stands Y ADL disability Mobility disability

Nonagenarians born in 1988–1905 vs. 1909–18 and centenarians born in 1893–98 vs. 1903–08 in China (Chinese Longitudinal Healthy Longevity Study, Zeng et al., 2017b) Nonagenarians born in 1911, 1913, 1917,1921, 1924, and 1928 in Tampere, Finland (Enroth, unpublished) 90–99-years-old in 1991–93 vs. 2007–10 in Sweden (the Kungsholmen project and the Swedish National Study on aging and Care in Kungsholmen, Angleman et al., 2015) Age group 85 years in 1998, 2004 and 2008 in the United States (the Health and Retirement Study, Hung et al., 2011)

Total sample, sex-adjusted ADL disability Y ADL disability Y

Findings from selected large population studies. [ means that the condition was more frequent in the latter cohort, Y means that the condition was rarer in the latter cohort. Brackets () mean a minor non-significant difference.

Another Danish study also compared two cohorts 10 years apart, those born in 1905 at the age of 93 and those born 1915 at the age of 95 (Christensen et al., 2013). The latter cohort scored better in cognitive functioning and in activities of daily living. However, the findings for physical performance were mixed: there were no differences in grip strength and the earlier cohort did better in the chair stand test. In China, Zeng et al. (2017b) compared cohorts aged 80–89, 90–99, and 100–105 years 10 years apart. They reported less ADL disability but worse physical performance and cognitive capacity for the latter cohorts. In Finland, the Vitality 90 þ study found little change in levels of disability between 2001 and 2018 among individuals aged 90 þ, but findings suggest a minor but significant improvement in ADL and mobility for women in the latest years (Enroth, Raitanen, Halonen, Tiainen and Jylhä, unpublished). A Swedish study similarly reports basically stable levels of disability in nonagenarians between 1991 and 2010, with a slight tendency to improvement (Angleman et al., 2015). In the Health and Retirement Study in the US, ADL and IADL disability declined between 1998 and 2008 (Hung et al., 2011). The Vitality 90 þ study also calculated trends in disability-free life expectancy at the age of 90 (Fig. 1). Disability was defined as dependence in any of the five ADL and mobility activities measured. Between 2001 and 2014, disability-free LE increased somewhat

Fig. 1 Disabled and disability-free life expectancy for men and women at the age of 90 from 2001 to 2014. Data on disability come from surveys in the Vitality 90þ Study, life table data from: Statistics Finland, (2019), Statistics Finland (b) Official Statistics of Finland (OSF): Deaths [e-publication]. ISSN¼ 1798-2545. Helsinki: Statistics Finland [referred: 28.3.2019]. Access method: http://www.stat.fi/til/kuol/index_en.html.

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in both genders, but more so in women. However, among women in particular, disabled LE also increased. No clear trend was observed in disability-free LE as a percentage of total LE at the age of 90, but it was slightly higher in 2014 than in 2001. In the US, the increase in total LE between 1970 and 2010 at the age of 85 was roughly equally distributed between disabled and non-disabled years in men, but among women the number of non-disabled years increased by twice as much as disabled years. The percentage of non-disabled years also increased between 1990 and 2010 (Crimmins et al., 2016). Studies largely agree that the number of chronic diseases among the oldest-old either shows no time trends (Jylha et al., 2013) or increases over time (Hung et al., 2011), rather than decreases. The one possible exception is dementia for which some decline in both incidence (Matthews et al., 2016) and prevalence (Crimmins, 2015) has been observed.

Predictors of Mortality Mortality among the oldest-old is high but not random. Even at the age of 90, male gender, disability in ADL and mobility, impairment in cognition and poorer self-rated health predict mortality (Nybo et al., 2003; Tiainen et al., 2013; Cevenini et al., 2014). Individual studies have also identified such predictors as grip strength (Cevenini et al., 2014), hemoglobin and total cholesterol levels, low creatinine, CRP and Il1-ra (Cevenini et al., 2014; Jylhä et al., 2007). Findings concerning BMI, blood pressure and blood lipid values vary, and in some studies the associations point in a different direction than in the case of younger adults. It is debated whether this could be explained by selected samples, selective mortality (that is: the individuals in highest risk have already deceased) or reverse causation (that is: decreasing values associated with approaching death). In some studies the number of chronic conditions shows no association with mortality, but in others multimorbidity and dementia, and cardiovascular diseases in particular are important (Doblhammer and Barth, 2018; Halonen et al., 2019). Several studies have shown that even at very high age, socio-economic status, measured as level of education or previous occupational class, predicts the number of remaining years (Cevenini et al., 2014; Enroth et al., 2015) through their influence on health and functional status. Psychological factors such as an optimistic outlook have been found to have predictive power for survival in the oldest-old (Engberg et al., 2013; Cevenini et al., 2014).

The Complex Interactions of Increasing Longevity, Postponed Death and Health in the Last Years of Life Not only chronological age but also age at death is of importance to discussions of health and functioning in oldest-old populations. When individuals die at an increasingly old age, what do their last years of life look like and what are the circumstances of their death? Studies imply that health trajectories at the end of life are different for those who live a long life and those who die younger. Gill et al. (2010) showed that those who have lengthy periods of severe disability at the end of life, often associated with severe dementia, die on average 4 years later than those who lived without disability until the end of life. This implies that those who die at more advanced age, are more likely to suffer from dementia and disability in their last years. Aaltonen et al. (2017) identified four care profiles for those who died at the age of 70 and over. Between 1998 and 2013, as age at death increased by around 2 years, an increasing number of individuals had care profiles characterized by long periods of long-term care and a high prevalence of dementia. Out of all deaths at the age of 70 or older in Finland, the proportion who died at age 80 or older with a dementia diagnosis increased from 20% in 2001 to 31% in 2013 (Aaltonen et al. unpublished). Apparently, there is a trade-off between length of life and health in the last years of life (Robine, 2018). Longer lives do not mean healthier but instead more disabled last years of life, and one of the main contributors to this paradox is dementia. Empirical research is insufficient, but logically this may also imply a paradox for disease prevention and health promotion. If healthier lifestyles help individuals avoid major conditions such as cardiovascular diseases, cancer and dementia in middle and young old age, there will be increasing numbers of individuals at higher ages and therefore at high risk of developing dementia at the end of their long lives, as Masoro (1999, 30) pointed out.

Long-Living Men and Long-Living WomendTwo Different Stories Very old age is a different stage of life for men and women. In most countries, life expectancy is higher for women than men, and among nonagenarians and centenarians there is a female excess (Robine and Cubaynes, 2017). Paradoxically, women’s longer lives include more illness and disability: at the age of 85 or over, women regularly have more diseases and disabilities than men. The main reason is not a higher incidence of health problems, but the fact that women spend longer periods of life with disability (Tiainen et al., 2013; Kingston et al., 2014). It seems that gender differences are greater in disability than in morbidity. Yet the major cause of poor health, i.e., dementia, is more frequent in long-lived women (Arosio et al., 2017). Health is not the only dimension where the genders differ. In generations that are now at high old age, women tend to have a lower education. Due to their lower mortality and a tendency to marry older men, women are more often widowed, and more often live alone or in a care home than men who even in very old age more often live with their spouse (Engberg et al., 2008; Zeng et al., 2017b). So marked are these gender differences that, according to Arosio et al. (2017) “it is timely to put gender medicine on the agenda of the oldest-old.”

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Multiple Ages of Old AgedQuality of Life in the Fourth Age As older populations continue to grow and old age continues to lengthen, researchers introduced the idea of multiple stages of old age, emphasizing the uniqueness and advantages of the third age, that is, the years following the retirement age, in contrast to later fourth age. The dividing line between the third and the fourth age is determined not by chronological age alone, but also by physical, mental and also financial resources as well as by lifestyles. The transition is often set at around 85 years of age. Yet the theories have not much to say about the very old age, and what they tell about it is painted by dark colors. As the third age is described as a time of freedom, activity and fulfillment, the following fourth age is characterized by “dependency and decrepitude” (Laslett, 1997). These negative views seem to be supported by findings which show that only three or four out of ten older individuals say they want to live up to 100 years (Nosraty et al., 2012). Those who look forward to such a long life were most likely to be men, to have good functional ability and good self-rated health, and be older, that is, already closer to their 100th birthday. However interviews with the nonagenarian participants imply that the main reason for not wanting to live up to 100 lies not in depression or low life satisfaction. Instead, people seem to be realistic in their views, appreciating the long life lived but understanding that the years ahead will not necessarily be better than those that have gone (Nosraty et al., 2012 and unpublished data from the vitality 90 þ study). The concepts of third and fourth age precede the major increase in longevity and lengthening old age. As very long living very long lives continue to rise and very old populations continue to grow and become more diverse, it becomes necessary to elaborate a more differentiated view of the “fourth age” as a stage of life. Empirical findings imply a wide variation in social engagement, quality of life, and plasticity and adaptation in psychological well-being among the oldest-old. Declines of life-satisfaction have been found to be related to closeness of death rather than increasing age as such, and to happen mostly in a few years before death (Gerstorf et al., 2008). Most representative population studies have found that experiences of loneliness increase with age, but even at very old age only a minority feels lonely often or continuously. Rather than age as such, loneliness arises from losses in significant relationships, declining functional ability and also feelings of not being needed (Jylhä and Saarenheimo, 2010; Yang and Victor, 2011; Yang et al., 2018). Successful aging, if defined according to Rowe and Kahn (1997) as a combination of avoiding diseases and disability, maintaining high cognitive and physical function, and engagement with life, is rare, even if not impossible, in very old age. In a populationbased study with nonagenarians, < 3% met the criteria of being free of chronic disease including dementia, being independent in ADL and mobility, and being socially and psychologically engaged with life (Nosraty et al., 2012). Nonetheless 22% of women and 18% of men could be categorized as successful in sense that even if they had other disease they were free of dementia, they had satisfactory hearing and vision, they were independent in functioning and they had frequent contacts with family and/or friends. Importantly, “success” was clearly more frequent in social and psychological dimensions than the functioning and health. Similarly, von Faber et al. (2001) found that only 10% of the population aged 85 þ met all the physical, social, psycho-cognitive and well-being criteria of successful aging, but 45% had optimal scores for well-being. Recent qualitative studies have shed interesting light on very old peoples’ own views of good old age at a level of detail that would be hard to achieve in quantitative population-based studies. These studies suggest that to very old individuals themselves who almost necessarily experience some decline in health and functioning, “success” in aging seems to be understood as a process of adaptation rather than a state of being absolutely healthy. Reasonable health is seen as a prerequisite for good life, but rather than absence of disease this means adequate daily functioning. Studies emphasize the role of social relationships as a major element of good old age, and the meaning of these relationships is more important than their quantity (Komatsu et al., 2018; Tuominen and Pirhonen, 2019). A crucial concept in respect to good old age, from very old individuals’ own perspective, is autonomy or selfdetermination. Essentially, this does not necessarily require physical independence but rather autonomy in the ability to exercise choices, make one’s own decisions and sense a control over one’s life (Pirhonen et al., 2016; Komatsu et al., 2018). For nonagenarians or centenarians, even those with active life and good functional capacity, the proximity of the end of life is reality that is often voluntarily raised and discussed also in research interviews. Thoughts about death vary, of course, but studies imply that most very old people express concerns about death less often than concerns about the process or dying. In very old age, a prospect of good, painless death is an important ideal and an essential element of good old age (Nosraty et al., 2014; Fleming et al., 2016).

Conclusions: New Ages of LifedNew Definitions of Success? During the past few decades, increasing longevity has created a new distinct stage of life, the very old age, and transformed it from a rarity to normal, expected last period of human life. This development in human life course invites new research on health and quality of life of the oldest-old and a new understanding of good and dignified life. The very old age can be seen as a by-product of declining childhood and adult mortality. It is a result of an increasing likelihood to survive through childhood, through young adulthood and the middle age and finally, increase in survival at old age. Long life, always desired, has now been reached, but it is not clear whether our societies consider it as success or a burden. What we’d prefer is a very long, very healthy life, but that is not what we have got. Even if long-living individuals stay healthy for longer than their shorter-living age peers, there are only few nonagenarians without chronic diseases and very few centenarians without need for help in daily life. Longer lives seem to have brought along longer periods of frailty and disability at the very end of life.

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It is impossible to predict the future of disease prevention, geroscience and perhaps rejuvenation, and their impact on the length of and health in advanced old age. At present, the condition with the strongest impact on health and well-being of very old people is dementia. A cure for dementia or a way to prevent it would revolutionize the longevity landscape. Yet in the foreseeable future, even if the number of active and autonomous nonagenarians and centenarians is continuing to rise, only very few of them will reach their 95th or 100th birthday without health problems. On the other hand, even though a very long life as such seems not to be a goal for older individuals themselves, the oldest-old express reasonably high levels of self-rated health and life satisfaction. They seem to think that meaningful social relationship, autonomy, and self-determination are more important to good old age than the absence of disease or even physical independence. The new ages of life, perhaps, call for new definitions of successful aging and more diverse characterization of the fourth age. In the face of expanding longevity, both research and the broader society need to recognize the heterogeneity of very old age and the multiple pathways to good old age. “Success” for the oldest-old should mean autonomy and a meaningful life rather than just physical health and fitness. With the emergence of real longevity, societies must be prepared to face the challenge to guarantee older people’s full citizenship and to find ways in which to promote their active participation even when they have problems with health and functioning. Health and social care must adapt and meet the increasing needs for care during the last years of life (Kingston et al., 2018). Pioneering social gerontologist Mathilda White Riley (Riley and Riley, 1994) introduced the concept of structural and cultural lag to describe the mismatch in the society between the changes in the new age structure, on the one hand, and prevailing laws, practices and norms, on the other. With the increasing number of the oldest-old, this mismatch is a greater challenge than ever before.

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Nutrition, Inflammation, and Infection in the Genomics of Lifespan Caleb E Finch, University of Southern California, Los Angeles, CA, United States © 2020 Elsevier Inc. All rights reserved.

Introduction ApoE in the Genomics of Aging and Lifespan Inflammation Nutritional Approaches to Aging Conclusions Gene-Environment Interactions Are Emerging as Important in Population Differences in Lifespan Acknowledgments References Further Reading

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Introduction Diet is popularly considered as a major influence on lifespan and health at later ages. Largely neglected, however, is role of geneenvironment interactions (GxE) throughout life. This review focuses on human aging with necessary reference to rodent models that amply document these effects. Most readers may share my understanding that cardiovascular disease (CVD), cancer, and dementia have long pre-clinical phases rooted early in life that may be retarded or accelerated by lifestyle. While diet receives major attention as an environmental or life style factor of choice, little is known about its GxE interactions in human populations. Because inflammation has deep roles in chronic diseases of aging (Franceschi et al., 2018; Finch, 2007) and because nutrition influences inflammatory processes (Custodero et al., 2018), an important agenda in aging research is how diet alters GxE interactions. Inbred mice show the potentially huge scale of GxE interactions for dietary influences on lifespan. Diet restriction alters the lifespans of inbred mice, with up to 5-fold differences by genotype and sex (Liao et al., 2010). ApoE alleles will be discussed as the most common allele system that influences lifespan and two major diseases of aging, Alzheimer’s disease (AD) and cardiovascular disease (CVD). Despite the associations of ApoE4 with AD and CVD, the “bad” apoE4 allele can be advantageous in highly infectious environments. My selection of studies for discussion emphasizes large numbers of subjects - many well-known studies are underpowered for the heterogeneity of the populations sampled.

ApoE in the Genomics of Aging and Lifespan The lifespan is strongly heritable at the species level: if you have human genes you will never experience aging like a mouse, with menopause at 12 months and likely death from aging by 30 months. However, within species, gene variations contributes a minority of individual differences (Finch and Tanzi, 1997). Identical twin lifespans show heritability of about 30% or less (Finch and Tanzi, 1997; Herskind et al., 1996; Passarino et al., 2016), while at later ages heritability can be slightly higher in long-lived families and centenarians (Murabito et al., 2012). Specific diseases of aging, such as cardiovascular disease (CVD) and Alzheimer’s disease (AD) are also associated with gene variants (Newman and Murabito, 2013; Passarino et al., 2016). Gene expression shows similarly low heritability, assessed in white blood cell RNA (Häsler et al., 2017) and DNA methylation (van Dongen et al., 2016). Alleles of the apolipoprotein E gene (ApoE) were first associations of a common gene system with lifespan (Box 1). ApoE is a major transporter of cholesterol systemically to the liver and in the brain to neurons. Relative to ApoE3, the majority allele in human populations (Table 1 below), lifespan is typically lengthened by ApoE2, but shortened by ApoE4 (Schachter et al., 1994; Kulminski et al., 2011). These longevity associations are well established. In a genome-wide meta-analysis of 600,000 parents, Joshi et al. (2017) validated the life shortening risk of ApoE4, together with recognized longevity genes including FOXO3 and other insulin system genes. Humans are the only mammal known to have a multiallelic system for the ApoE gene, which originated from an ancestral apoE4-like gene shared with great apes (Mahley, 2016; Fullerton et al., 2000). The evolution of the novel human ApoE3 can be understood in the evolution of transitions to the meat-rich diets of humans (Finch and Stanford, 2004). Potential ApoE-diet interactions in in premature arterial and cognitive aging of ApoE4 carriers were elegantly shown by Drenos and Kirkwood (2010) to account for natural selection against apoE4, the ancestral human allele, and for the expansion of ApoE3 and E2 in human populations. CVD was the first disease association of ApoE4, cited in Sing and Davignon (1985, b). More recently and in the largest sample reported from Europe, North America, and Asia, CVD was increased above E3/E3 by 29% in E3/E4 and by 45% in E4/E4; this metaanalysis of 30 studies included 11,804 CVD patients and 17,713 controls (Xu et al., 2016). Preclinical atherosclerosis is also

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Box 1 Apolipoprotein E (ApoE) and linked genes on chromosome 19 Thirty five years ago, apoE gene variants were definitively associated with differences in blood cholesterol (C) (Sing and Davignon, 1985, b). For simplicity, I do not include apoE2, which is 3-fold in E3/E4 heterozygotes. The ApoE locus is close to four other genes on chromosome 19 (Box 1) that show cross-talk in AD risk, as indicated by different distributions of genetic variants in AD versus age-matched controls (Kulminski et al., 2018). These AD signatures were consistent across 5 different AD studies that included the Framingham Heart Study (FHS) and Offspring (FSHO) cohorts. Most of the SNPs alter gene expression (eQTLs). Plasma triglyceride elevations are strongly associated with CVD (Handelsman and Shapiro, 2017), as well as associated with vascular contributions to risk of all cause dementia (Schilling et al., 2017). ApoE4 has strong impact on plasma triglycerides, especially after ingesting fatty foods (Fig. 1) (Carvalho-Wells et al., 2012). This study excluded current cigarette smokers; the use of statins or other medications that influence blood lipids; anti-oxidants, and frequent eating of oily fish; frustratingly, this critical information reported separately. Although triglycerides are targets of nutritional intervention by omega-3 fatty acids (Handelsman and Shapiro, 2017), ApoE alleles have not been considered in most studies of omega-3 fatty acids and other nutritional interventions for CVD risk. Moreover, most diet-aging studies of European populations discussed below did not include ApoE alleles. This is a key gap because the ApoE4 allele prevalence in Western Europe varies twofold, north to south. Lifespans show parallel trends, with a 2.3 year spread from the top-ranked Italy (third in world) to Finland (26th). Do these longevity differences arise from genes, environment, or GxE interactions? Recent findings show benefits of ApoE4 in infectious environments with high pathogen loads. Contrary to the shorter lifespans of ApoE4 carriers in developed countries, for example, the Framingham Heart Study population (Fig. 2A), in a rural African population with endemic chronic and acute infections ApoE4 did not decrease survival (Van Exel et al., 2017) (Fig. 2B). Besides better survival, E4 carriers also had more children. South America provides two further examples of ApoE4 benefits. Children carrying ApoE4 in Brazilian slums, are more resistant to diarrhea and have better cognitive development (Oriá et al., 2010), while adult Tsimane farmer-foragers in Bolivia have better cognition during high parasitemia for ApoE4 carriers (Trumble et al., 2017) [I am co-author of the Ghanaian and Tsimane studies].

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TG, mmol/I 5.0

4.0

*

3.0

* *

** 2.0

**

1.0

0.0 0

60

120

180

240 300 Time (min)

360

420

480

Fig. 1 ApoE alleles and post-prandial plasma triglyceride levels. Plasma triglycerides (TG) were monitored after two meals in healthy UK adults, ages 20–70 years. with BMI 19–32 kg/m2; ApoE3 homozygotes, N ¼ 142; ApoE3/4 heterozygotes, N ¼ 65. After fasting overnight, subjects received breakfast (49 g fat, t ¼ 0) and lunch (29 g fat, 330 min), solid arrows. The E4 excess of plasma TG did not differ by age (Carvalho-Wells et al., 2012). For clarity, the graph omits ApoE2 carriers, whose triglycerides was close to ApoE4.

Fig. 2 ApoE4 has divergent impact on lifespan with low vs high loads of infection. (A) Framingham Heart Study survivors from age 50 (3924 since 1971) (Kulminski et al. 2011). (B) The Ghanaian population resides in remote villages of the Upper East Region, and subsists by traditional farming. Health care was minimal; endemic diseases include malaria, typhoid fever, tuberculosis, and intestinal helminths. Mortality of 4311 subjects during 7 years was 366 total deaths. The ApoE4 hazard ratio was 0.80 (0.69–1.05, CI; P ¼ 0.165) (Van Exel et al. 2017).

Inflammation Inflammation has become a core concept in aging and aging-related disease. Many inflammatory responses of the innate immune system arise in pathological lesions of aging such as cytokines, complement factors, and amyloids found in atheromas and senile plaques (Table 1). The individual burden of vascular disease is recognized as a major risk factor in cognitive decline and AD. The messenger RNAs for many these proteins also increase during aging (Finch, 2007). These broad inflammatory responses produce by-stander oxidative damage to proteins, lipids, and DNA. System-wide proinflammatory changes at later ages are illustrated by increased blood serum levels of IL-6, a proinflammatory cytokine (Fig. 3) and of C-reactive protein (CRP) a response to infections and CVD risk indicator (Fig. 4). These data are from the Long Life Family Study (LLFS) in the United States and Denmark, and from the InCHIANTI study from two small Italian towns (Box 2). They are among the few studies of IL-6 and CRP across adult ages based on longitudinal community samples. Surprisingly, no US-wide results are yet available from major population-based studies. For both LLFS and InCHIANTI, men incur greater increases of CRP and IL-6 at later ages than women. This male excess may be associated with greater mortality at later ages, but does not match the greater prevalence of morbidities in older women. We do not know how much of aging-related CRP elevation is due to CVD or subclinical infections.

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In Chianti 6

LLFS 10

Women

Women

4

IL6 pg/L

IL6 pg/L

5

3

5

1

40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89 90–94 95–99 100+

85+

75–84

65–74

50–64

0

40–49

0

Age 6

Age 10

men

men

4

IL6 pg/L

IL6 pg/L

5

3

5

1

85+

75–84

65–74

50–64

40–49

Age

40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89 90–94 95–99 100+

0

0

Age

Fig. 3 Plasma IL-6 from Italy (InCHIANTI, Ferrucci et al., 2005) and from the U.S. (Long Life Family Study, LLFS; Sebastiani et al. 2017, Suppl). For LLFS, solid bars show the 25th to 75th percentile and dashed lines represent extremes of data; the units of pg/mL correct an error in the original table (Paola Sebastiani, pers. comm.). For In Chianti, solid bars represent 95% confidence intervals. The twofold differences in plasma IL-6 levels between studies across the age range suggests that calibrations differ between the radioimmunoassays.

The absence of ApoE allele data for these two studies frustrates interpretation of aging-relevance, because ApoE4 can enhance inflammatory responses. In a study notable for comparisons normal and clinical patients, and transgenic mice, ApoE4 increased serum IL-1b, IL-6, IL-8, IL-10, IL-17, and TNFa responses to LPS (endotoxin) using in vivo and ex vivo assays in humans (Gale et al., 2014). Moreover, in hospitalized patients with severe sepsis, ApoE4 carriers had greater coagulation deficits (thrombocytopenia), In mice carrying human ApoE transgenes, the E4 mice also showed greater responses IL-6 and TNFa (the only cytokines assayed). An important gap in this exemplary study is the lack of data on CRP and its mouse equivalent, SAA. The origins of aging-related increases of inflammatory changes is poorly understood. Two classes of inflammatory stimulae are recognized: pathogen-driven inflammation from viruses, microbes, and parasites versus sterile inflammation from non-infectious toxins and fatty diets. Moreover, fat depots release IL-6 and other proinflammatory factors (Madani et al., 2009), aptly described as the inflammation highway in obesity (Johnson et al., 2012). Other sterile inflammogens from the environment include cigarette smoke and air pollution from urban traffic (Forman and Finch, 2018; Finch, 2018; Morgan and Finch, n.d.). Fast-responding innate immune responses (911 for emergency) can persist as chronic inflammation. Several acute phase cytokines also mediate the slower responses of adaptive immunity that target specific antigens recognized by B- and T cells. Some inflammatory responses are shared by infectious pathogenic and sterile inflammogens, such as in the TLR4 pathway responses to LPS (bacterial lipopolysaccharides) and urban air pollution particles (Wood et al., 2018). Aging-related morbidities are often associated with elevated plasma IL-6 and CRP, but correlation does not prove causality. A healthy subgroup of the Framingham Heart Study with minimal CVD also had minimal age-related increase of CRP; the

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Fig. 4 Plasma CRP from the United States (Long Life Family Study, LLFS; Sebastiani et al. 2017, Suppl). Solid bars show the 25th to 75th percentile and dashed lines represent extremes of data.

Box 2 Community-based studies of aging InCHIANTI (Invecchiare in Chianti) is a community-based study of normal and pathological aging in two small Tuscan towns, Greve in Chianti and Bagno Ripoli. Led by Luigi Ferrucci and Stefania Bandinelli since 1998. The initial cohort of 1270 persons aged 65 and older was expanded to age 20, with 30 or more men and women per decade. Cardiovascular Health Study (CHS): Risk factors in CVD and stroke in a community based sample of 2962 women and 2239 men examined yearly 1989–99. Recruited from Forsyth County, NC; Sacramento County, CA; Washington County, MD; and Pittsburgh, PA. The brain imaging study of Corlier et al. 2018 selected a subgroup aged 65 or older (139 men; 87 women) who were cognitively normal in 1991 and examined by MRI 9 years later. Framingham Heart Study (FHS) Incident CVD for three generations in this small city in eastern Massachusetts. Starting in 1948 with 5209 adults now includes three generations and ages from 13 and brain imaging. Long Life Family Study (LLFS). Started in 2005 by Kaare Christensen, Richard Mayeux, Tom Perls, and Paola Sebastiani, the LLFS analyzes genetics and other familial factors in healthy aging during exceptional lifespans of 4953 individuals from 539 families from United States (Boston, New York, Pittsburgh) and Denmark. Fewer than 1% of the FHS cohorts would be included in LLFS.

large sample size (1666 subjects) give confidence in these findings (Albert et al., 2003). Two careful studies further show the tangle of issues: InCHIANTI and the Cardiovascular Health Study Cohort (CHSC) (Box 2). Both are based on longitudinal observations during 9 years and considered multiple inflammatory markers. InCHIANTI considered possible associations of baseline elevations for serum CRP, IL-1b, IL1RA, IL-6, IL-18, and sTNFa-Rs with weakened kidney function (glomerular filtration rate, GFR) (Salimi et al., 2018). After adjustment for hypertension and other covariates, only the rate of increase of sTNFa-Rs remained strongly correlated with declining GFR and incident chronic kidney disease. Other reports associating kidney disease with elevated CRP and other inflammatory markers did not include as large a panel of inflammatory markers and aging-related covariates. ApoE alleles were not included in the InCHIANTI studies of kidney function. The potential interaction of ApoE with inflammatory markers is shown for brain aging in the Cardiovascular Health Study Cohort (Corlier et al., 2018). This study is notable for its inclusion of SNPs for ApoE and 10 other AD risk factors, but only CRP and IL-6 were available for blood inflammatory markers. A subset with high sustained baseline serum CRP had greater thinning of the cerebral cortex in four subregions afflicted by AD. However, ApoE4 carriers had lower levels of CRP. A mediation analysis suggested that elevated CRP was not the primary cause of cortical atrophy, but was downstream of undefined factor(s) linked to ApoE4. Both studies are exemplary for recognizing complex interactions of inflammatory processes and individual heterogeneity in the potential causal pathways. Despite the evidence for inflammatory processes in major diseases of aging, few antiinflammatory drug treatments have shown benefit in controlled trials, some of which were underpowered. For reference, the different phases of clinical trials used in the United States, with typical subject numbers are summarized in Box 3.

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Box 3 Phases of FDA drug trials As described by the Federal Drug Administration (FDA), after passing Phase I safety tests, Phase II typically includes 100–300 patients observed up to 2 years for biological efficacy and side effects. Some Phase II trials are case studies of selected patients, while others are randomized controlled trials (RCT), which are considered the most rigorous. About 33% of drugs from Phase II survive for further testing in Phase III with larger groups of 300–3000 for up to 4 years for efficacy and adverse reactions. Lastly in Phase IV, about 25% of phase III drugs are tested in “several thousand” volunteers for safety and efficacy.

Aspirin, the most widely used nonsteroidal antiinflammatory drug (NSAID), did not decrease heart attacks from CVD or CVD deaths in a large Phase III US trial with sufficient subject numbers. The Women’s Health Study of 39,876 women aged 45 lasting 10 years without a history of heart disease at entry. In a randomized design, half received 100 mg aspirin and 600 units of vitamin E (Ridker et al., 2005). Nonetheless, this and other randomized control trials of aspirin, while designed for CVD, also showed definitive reduction of cancer risks for breast, colorectal, and gastrointestinal (Bruno et al., 2018). For AD, a recent meta-analysis concluded benefits of aspirin (Zhang et al., 2018a, b), but this needs independent confirmation with randomized trials. No other NSAID treatment of clinical AD has shown consistent benefits (this fraught topic cannot be reviewed here). Because salicylate, the parent compound of aspirin, is produced by many plants (Duthie and Wood, 2011), clinically relevant anticoagulant levels may be ingested in fruits and tomatoes. More encouraging benefits to CVD have resulted from immunotherapy led by the CANTOS trial to decrease plasma IL-1b by passive immunization with canakinumab, a monoclonal antibody (Canakinumab Anti-inflammatory Thrombosis Outcome Study) (Ridker et al., 2017). IL-1b was targeted because of its multiple roles in the development of atherosclerotic plaques and in pro-coagulant activity. CANTOS enrolled 10,061 CVD patients of mean age 61 by a prior history of myocardial infarction and elevation of blood CRP  2 m/L. This level of blood CRP is considered a clinical risk indicator of CVD and is higher than most middle-aged individuals of the unusually healthy group represented in the Long Life Family Study (Fig. 4). Patients were given placebo or three different doses of canakinumab in a double-blind randomized format. After 48 months, the higher doses of canakinumab decreased CVD events and mortality by up to 15% (Table 3). Lung cancer was also decreased. Unexpectedly and alarmingly, mortality from infections was nearly doubled. I suggest the increased mortality from infections is a direct consequence of impairments of innate immunity caused by canakinumab. Besides its clinical target of lowering plasma IL-1b, canakinumab also lowered blood CRP by 50%, IL-6 by 40%, and fibrinogen by  15% (Fig. 5). The pathway to lower CRP may include the CRP gene promoter, in which acute phase response elements can respond indirectly to IL-1b and IL-6, through mechanisms involving protein kinases A and C (Ganter et al., 1989). The increased mortality from infection by lowering three acute phase responses (CRP, IL-1b, IL-6) raises red flags for potential infections in future immunotherapy drug trials. Because CRP enhances phagocytosis of gram-negative bacteria, we must ask if lower plasma CRP favored gram-negative pneumonias, which are becoming increasingly antibiotic resistant.

Fig. 5 Canakinumab lowers innate immune proteins (CANTOS study) (Ridker, 2016). Similar decreases of CRP and IL-6 are in the full report (Ridker et al. 2017).

Nutrition, Inflammation, and Infection in the Genomics of Lifespan Table 2

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Arterial atheromas and brain senile plaques shared inflammatory changes

Cells macrophages (CD68) mast cells (CD117) Proteins Amyloid b-peptide (Ab),40–42 amino acids Serum amyloid P (SAP) C-reactive protein (CRP) Complement: C3, C5b-9, clusterin (apoJ) Cytokines IL-1, IL-6, TNFa

Atheroma

Senile plaque

þþþ (foam cells) þþ

þþ (microglia) þþ

þ Ab40 (platelet) þþ þþ þ þþ

þþþ Ab40, 42 þþ þ þ þþ

From Finch, C. E. (2018). Global air pollution in aging and disease: reading smoke signals. San Diego: Academic Press (Chapter 3).

Table 3

CANTOS study: clinical endpoints of immunotherapy to lower plasma IL-1b Incidence rate/100 persons/years

Myocardial infarct Myocardial infarct & stroke, or death from any cause Fatal cancer Fatal infection or sepsis

Placebo

Combined doses

Hazard ratio

2.43 5.56 % from Placebo 0.64 0.18

2.06 (P ¼ 0.03) 4.93 (P ¼ 0.02)

0.84 (0.73–0.97) 0.89 (0.81–0.97)

0.45 (P ¼ 0.02) 0.31 (P ¼ 0.02)

30% þ172%

Hazard ratio, 95% confidence intervals. From Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., et al. 2017. Anti-inflammatory therapy with Canakinumab for atherosclerotic disease. The New England Journal of Medicine 377: 1119–1131.

Besides canakumab for IL-1b, many other monoclonal antibodies (mAbs) are directed at immune targets in this rapidly expanding therapeutic field. For AD, mAbs are targeting the amyloid b-peptide (Ab) found as fibrillary aggregates in senile plaques (Table 2) and as neurotoxic oligomeric forms (oAb) that my lab discovered in collaboration with William Kline and Grant Krafft (Oda et al., 1995; Cline et al., 2018). Another function of Ab peptides has recently emerged: they are produced in response to pathogenic infections and appear to be an ancient molecule of innate immunity in vertebrates. In herpes simplex virus (HSV) infections of mouse brains, injected HSV was bound by oAb, causing rapid focal entrapment (Eimer et al., 2018). Because several mABs have shown

Table 4

Recent trials of MedDiet and Nordic diet Mediterranean diet

Healthy Nordic diet

Beverages Meat Fish

Wine with meals, optional White meat Fish & other seafood,  3 serving/week

alcohol 4 tsp/day; virgin preferred Tree nuts and peanuts, 3 serving/week Bread, pasta, potatoes, rice

Low fat Rapeseed, sunflower, soyabean oils

Plant

Fresh fruit  3 serving/day Vegetables 2 serving/day Commercial baked goods Sugared drinks Red meat and processed fatty meats Vegetable oils and spread fats

discouraged

Whole grain, >50% barley, oat, rye; unpolished rice; low salt, no added sugar; polyunsaturated fatty acids > saturated Vegetables 175 g/day Sugared drinks Red meat and processed fatty meats trans-Fats

MedDiet (Estruch et al. 2018); Healthy Nordic Diet (Uusitupa et al. 2013; Leder et al. 2016).

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efficacy in removing brain Ab in Phase I trials, the prospective phase II and III trial for anti-amyloid immunotherapy should consider potential lowered resistance to viral infections that are common in elderly. Given the importance of innate immune mechanisms and inflammation to CVD and possibly to AD, we had assumed that the highly infectious environment of humans before the 20th Century would have cause accelerated vascular disease in association with their shorter adult life expectancies (Finch and Crimmins, 2004; Crimmins and Finch, 2006). This premise is being revised. As a model for pre-industrial populations, we studied the Tsimane Amerindians, indigenous to lowland Bolivia, where infections have been the main cause of mortality across all ages (Gurven et al., 2007). Plasma CRP and IL-6 tend to be elevated at levels that would be considered clinical risk factors for CVD, due to their frequent acute infections, endemic tuberculosis, and chronic parasitic infections (Vasunilashorn et al., 2010; Blackwell et al., 2016). [Tsimane were mentioned above for showing cognitive benefits to ApoE4 carriers incurring episodes of parasitemia.] Nonetheless, CVD is rare and coronary artery calcification is below age norms lagging by about 20 years behind North America and Western Europe (Kaplan et al., 2017). The exceptionally low levels of CVD and late stage coronary atherosclerosis are being studied for possible gene variants that may be protective. ApoE4, a CVD risk factor discussed above, is present within the global range, but not exceptionally low (Vasunilashorn et al., 2011). However, my colleagues and I think the low CVD can be accounted for by the Tsimane life style of diet, work load, to which I would add the metabolic demands of pathogen-driven infections. Despite having frequent elevations of CRP and other acute phase inflammatory risk factors for CVD, Tsimane do not have two other CVD risk factors: their blood LDL-cholesterol and hemoglobin A1c are very low (Vasunilashorn et al., 2010). These low values reflect the relentless demands of their daily work. Proving sufficient food for their large families requires clearing forests for planting rice and other vegetables, and hunting for the increasingly scarce small animals, in relentless heat and humidity. Their diet is low in fat, salt, and sugar, consistent with low average BMIs. Together the physical demands and sparse diets may suffice to explain the low level of coronary atherosclerosis by lowering blood lipids and glucose, nutrients that drive atherosclerosis in our world. Parasitic worm infections may also be antiatherogenic (Gurven et al., 2018). The Tsimane give a rare opportunity to track health transitions from pre-industrial to modern life style and inflammatory pattern. They are benefiting from greater access to medical care given by the Bolivian government and the Tsimane anthropology and cardiology team. However, as their access to cash increases from day wages, some are eating fatty foods available in nearby towns, where they are also exposed to new sterile-inflammogens from air pollution and motor traffic in nearby towns. As body fat loads increase, they are also exposed to more inflammatory cytokines because of the venous output of fat depots, as noted above. Already obesity, elevated blood lipids, and more coronary artery calcification is emerging in the younger generation.

Nutritional Approaches to Aging Lab studies of mice strongly support benefits of intake of low calories and fat to slowed aging in the brain and arteries (Morgan et al., 2007). In mice carrying AD transgenes, deposits of amyloid are attenuated by caloric restriction, shown by my lab (Patel et al., 2005), or by extra virgin olive oil (Qosa et al., 2015). Returning to the industrial world, recent dietary trials show promising benefits to CVD and AD, discussed in recent meta-analyses (Hersi et al., 2017). However, few studies have rigorously shown diet interventions on later age mortality (Martínez-González et al., 2017). In seeking examples of rigorous recent studies, I found few studies with > 1000 subjects and randomized control design that are normative for drug testing (Box 3). Moreover, few studies included individual records for second hand smoking exposure in home or work place, or diaries for incidental use of nutrients and medications, purchased over-the-counter. We cannot apply lab model standards to assess diet benefits to CVD and AD in populations with major differences in diet and life-style. The examples below begin with comparisons of Mediterranean and Nordic diets. For several decades, Mediterranean diets (“MedDiet”) have been associated with lower total mortality and CVD. Data is mainly from observational studies (Willett et al., 1995; Trichopoulou et al., 2003; Martínez-González et al., 2017) and a few clinical trials (Estruch et al., 2018). MedDiets are epitomized by high intake of fish and shellfish; fruits, legumes, and vegetables; and, low intake of red meat, saturated fats, and processed foods, especially those rich in sugar. Total fat intake may be high from olive oil, up to 30%–45% total calories. Lower CVD risk is attributed to the enrichment of anti-oxidants and anti-inflammatory components, with the low glycemic index. The MedDiet discussions have expanded to consider a Healthy Nordic diet (Table 4). Few studies of MedDiets have enrolled the large numbers of subjects typical of FDA Phase III and IV drug trials (Box 3). A welcome exception is PREDIMED (Prevención con Dieta Mediterránea) trial (Estruch et al., 2018). Starting in 2003, PREDIMED enrolled 7447 Spanish participants aged 55–80 years who had high risk for CVD, but were symptom free (Table 5). Three diets were compared: a baseline ‘MedDiet’ plus extra-virgin olive oil (EVOO) or MedDiet plus mixed nuts, for comparison with “lowfat” control diet. Energy intake (food and wine consumed) was not restricted and physical activity was not promoted. Medications were allowed and were balanced across the groups at entry (see footnote, Table 5). Unfortunately, after the completed study was published in 2013, it was recognized that randomization was not consistent in two of the 11 study sites, and the study was recalled. Fortunately, re-analysis still supported the main conclusions after further adjustments to correct the protocol deviation (Estruch et al., 2018). After 5 years, both MedDiet groups had about 30% fewer acute myocardial infarcts than controls and 50% fewer strokes by my calculation. Despite the decrease of ischemic events in heart and brain on MedDiets, CVD mortality and total mortality were lower only in the EVOO þ MedDiet The impact of MedDiet þ EVOO on total mortality was twofold smaller ( 19%) than for ischemic events (38%, calculated from Table 5). Alcohol consumption shows a similar pattern, benefiting cardiac ischemic events, but not mortality, discussed below. Further concerns are the > 50% drop-out of subjects by the end of the study and the neglect of cancer, which was not mentioned, despite its being the 2nd ranked cause of mortality after age 40.

Nutrition, Inflammation, and Infection in the Genomics of Lifespan Table 5

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PREDIMED trial Findings

End point

MedDiet þ EVOO

MedDiet þ nuts

Low fat control diet

Person years follow-up (# of subjects enrolled vs. completed) Acute myocardial infarcts, 5 years risk Stroke, 5 years risk Deaths, CVD, 5 years risk Deaths, all cause, 5 years risk

11,852 years (2543 vs. 1310)

10,365 years (2454 vs.1031)

9763 years (2450 vs. 946)

1.4 (1.0–2.1) 1.7 (11.3–2.4) 1.0 (0.6–1.5) 4.4 (3.6–5.4)

1.6 (1.1–2.3) 1.5 (1.1–2.3) 1.4 (0.9–2.1) 5.4 (4.4–6.6)

2.1 (1.5–2.9) 3.0 (2.3–3.9) 1.6 (1.1–2.3) 5.4 (4.4–6.7)

PREDIMED trial (Prevencio´n con Dieta Mediterra´nea); subjects: 7% European; 60% never smoked. CVD risks included elevated HDL, hypertension, obesity, smoking, or family history of premature CVD. Medications included ACE inhibitors (ca. 49%), anti-platelet therapy (20%), diuretics (ca. 20%), hypoglycemic agents (29%), and statins (ca. 40%) (Estruch et al. 2018).

For Nordic diets, no randomized control studies are available. The most rigorous data may be from the observational German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe), with 3327 elderly enlisted for 10 years. The only finding was less AD for men who drank red wine (hazard risk HR 0.82), but women showed the opposite association (HR, 1.15). The incidence of AD did not differ between diet groups, for intake of seafood, fruits, vegetables, or olive oil. Uniquely among diet AD studies, AgeCoDe included ApoE alleles. The AD risk was higher for ApoE4 carriers who drank white wine. However, there were gender differences: men ate more red meat and sausages, and women more fruits and vegetables. Conclusions for type of wine and AD risk are highly tentative in my view because of major gaps in data. AgeCoDe did not show data for blood cholesterol by diet group; about 50% had hypertension; and medications were not considered, unlike PREDIMED. Comorbidities were represented by a general index (CCI) that represented some common aging-related diseases: CVD and other heart conditions, chronic kidney and liver disease, but cancer is not mentioned. Caveats stated, this study points to potential interactions of ApoE with alcohol consumption in AD risk. ApoE alleles were not included in observational studies associating alcohol consumption with lower AD risk (Hersi et al., 2017). Alcohol lowered the risk of stroke in a cohort from the Framingham Heart Study, but without ApoE4 interaction (Djoussé et al., 2009). The small sample size (40 Ss aged 65 þ) leaves the question open. Diet studies generally recommend moderate consumption of alcohol of 1–3 units per day (one unit is 10 cc. of pure ethanol, equivalent to half-a glass of wine containing 12% alcohol). Many studies have shown a “J-shaped” mortality curve, with mortality reduction for 1–3 units per day. However, the most recent Global Burden of Diseases Study (GBD 2016 Alcohol Collaborators, 2018) concluded there is “no safe level of alcohol consumption”, based on data from 694 studies of 28 million people, worldwide. While CVD may be reduced by modest drinking, this benefit is offset by higher cancer risk: globally, 27% of cancer deaths in women and 19% in men were alcohol-linked. The FINGEN study of ApoE allele interactions with fish-oil supplements is exemplary for its design with randomized doubleblind cross-over (Caslake et al., 2008). This cardio-healthy normolipidemic sample excluded users of n 3 fatty acid supplements or medications that influence lipid metabolism; however, smoking history was not included. The placebo was compared with two doses of fish oil after 8 weeks, separated by 12 week washout intervals. ApoE4 carriers responded more than E3, with E4 men showing greater decreases in plasma triglycerides. These findings support the larger associations of apoE4 as a proatherogenic risk factor, but add complexity to understanding the relation to CVD risk by the greater decreases of plasma TG in E4 carriers. The recent LIPGENE dietary intervention study for the Metabolic Syndrome (MetS) identified ApoE allele effects for specific plasma fatty acids (Fallaize et al., 2017). MetS is a clinical cluster associated with CVD risk identified by one or more markers: hypertension, insulin-resistance, abdominal obesity, lower HDL-cholesterol and elevated triglycerides. Eight European centers, recruited 442 MetS patients of mean age 54, randomized into four isoenergetic diets with different levels of saturated and unsaturated fats and complex carbohydrates. After 12 weeks, the ApoE4 carriers were distinguished by stronger association of insulin-resistance with Table 6

NIH-AARP diet and health study

Mortality risk reduction by quintile of fish intake, top vs. bottom Total mortality Mortality attributed to Alzheimer’s disease cancer CVD infections

Men, mean (CI)

Women, mean (CI)

9% (6–11%)

8% (5–12%)

24% (5–39%) 6% (1–10% 10% (6–15%) 7% (NS)

38% (20–52%) 2% (NS) 10% (3–17%) 11% (NS)

NS, not significant; CI, 95% confidence intervals. The ethnicity of AARP memberships is biased to European origins (c. 90%). From Zhang, Y., Zhuang, P., He, W., Chen, J. N., Wang, W.Q., et al. 2018a. Association of fish and long-chain omega-3 fatty acids intakes with total and causespecific mortality: Prospective analysis of 421 309 individuals. Journal of Internal Medicine [Epub ahead of print];Zhang, C., Wang, Y., Wang, D., Zhang, J., Zhang, F. 2018b. NSAID exposure and risk of Alzheimer’s disease: An updated meta-analysis from cohort studies. Frontiers in Aging Neuroscience 10:83.

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elevated plasma levels of palmitic acid (C16:0), a saturated fatty acid. ApoE genotype is being considered to optimize individualize dietary intervention for the MetS. Connection of diet to inflammation are indicated in several studies, presented in the order of subject numbers. In the Women’s Health Study, high-level alcohol consumption was associated with CRP elevations (11,815 women who never used postmenopausal hormones) (Levitan et al., 2005). The PREDIMED trial (Table 5) associated plasma IL-6 and TNFa with olive oil, in a substudy of with 1139 high elderly CVD risk subjects. Those receiving olive oil supplements (EVOO) had inverse associations of urinary polyphenols with plasma (Medina-Remón et al., 2017). The anti-inflammatory association with urinary polyphenols is attributed to ingestion of unrefined EEVO which has higher polyphenol content than many cheaper olive oils, from which polyphenols are removed during refinement. A meta-analysis of cross-sectional studies concluded that vegetarians had slightly higher plasma IL-6 but slightly lower plasma CRP, all within the normal range (Haghighatdoost et al., 2017). Analysis was limited by small subject numbers of < 200 in the few studies that maintained diets for at least 2 years, and lacked statistical power to consider age, gender, or diet composition. Another promising MedDiet study is the European Project on Nutrition in Elderly People (NU-AGE, NCT01754012), coordinated by Claudio Franceschi since 2012. NU-AGE includes 1279 relatively healthy, aged 65–79 years, from five European centers, randomly allocated as controls on habitual diets. For comparison, the “intervention group” received individualized MedDiet advice supplemented with vitamin D. Preliminary findings indicate benefits to cognition and inflammatory status. Genotype interactions with diet-associated differences in aging patterns are being analyzed. Lastly, I note the just published NIH-AARP Diet and Health Study, which reported benefits of dietary fish and long-chain n 3 fatty acids to CVD mortality (Table 6)(Zhang et al., 2018a, b). This prospective study followed mortality of 421,309 members of the American Association of Retired Persons (AARP), aged 50–71 at entry for 16 years, and may be the largest and longest observational study of diet ever reported. Dietary fish ( 8 oz. per week) and omega-3 fatty acid supplements (DHE þ EPA of 250 mg/ day) strongly benefited mortality (Table 4). Total mortality was lowered by 8%–9% in both diet groups. CVD deaths were lowered by 10% in both men and women, slightly bettering the total mortality impact. Infection-attributed death did not differ by diet group. AD appeared to benefit threefold more than the other causes of mortality. The mortality assignments are from the National Death Index Plus, classified by ICD-9 and ICD-10. The designation of “AD as cause of death” does not meet current criteria for clinical AD diagnosis and the size of the benefit seems overly large. Further analysis must include data on AD incidence and duration by diet. ApoE alleles are not available for the AARP study, but are included in other ongoing studies based on national samples.

Conclusions Observational studies in nutritional epidemiology are challenged by the high inter-correlation of diet components; moreover, social and behavioral interactions challenge quantification and harmonization between studies (Ioannidis, 2018). The transferability of potential MedDiet benefits to other populations is unclear because of cultural life-style differences, for example in consumption of popular processed foods for snacks and meals. All nutritional studies are subject to uncontrolled (and uncontrollable) use of overthe-counter medications and diet supplements. Moreover, during any study extending more than a year, changes in prescribed medications are likely, particularly in middle-aged and elderly groups. Most important, we have few large-scale, long-term randomized control trials (RCT). Even PREDIMED, despite its original design, does not meet criteria as an RCT. Despite the benefits of extravirgin olive oil to CVD events, survival was not improved.

Gene-Environment Interactions Are Emerging as Important in Population Differences in Lifespan ApoE4 gives a compelling example of a common gene variant with widely varying prevalence that interacts with inflammation at multiple levels, from diet to infection. 1. Studies of drugs and diet must include alleles of ApoE and other metabolic genes that show GxE interactions. 2. MedDiets show more consistent benefits to healthy aging than any anti-inflammatory drug except aspirin. 3. Future analyses of diet and longevity genes must include the gut biome, which has major influence on ingestion of fats, as well as polyphenols and other non-nutrient chemicals. 4. Future lifespan increases may be challenged by increases of infection from the manipulation of inflammatory processes that are critical for host defense. 5. I concur with Joshi et al. (2017): “There appears to be no single genetic elixir of long life.”

Acknowledgments My lab is grateful for support by the NIA and Cure Alzheimer’s Fund. I appreciate comments by Jean-Marie Robinne, Marja Jylhä, Christian Pike, Todd Morgan, and John Wise.

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Further Reading Adamsson, V., Reumark, A., Cederholm, T., Vessby, B., Risérus, U., Johansson, G., 2012. What is a healthy Nordic diet? Foods and nutrients in the NORDIET study. Food & Nutrition Research 56. Austad, S.N., Finch, C.E., 2017. Human life history evolution: New perspectives on body and brain growth. In: Tibayrenc, M., Ayala, F.J. (Eds.), On human nature: Evolution, diversity, psychology, ethics, politics and religion. Academic Press, London, pp. 221–234. Chouinard-Watkins, R., Conway, V., Minihane, A.M., Jackson, K.G., Lovegrove, J.A., Plourde, M., 2015. Interaction between BMI and APOE genotype is associated with changes in the plasma long-chain-PUFA response to a fish-oil supplement in healthy participants. The American Journal of Clinical Nutrition 102, 505–513. Global BMI Mortality Collaboration, Di Angelantonio, E., ShN, B., Wormser, D., Gao, P., et al., 2016. Body-mass index and all-cause mortality: Individual-participant-data metaanalysis of 239 prospective studies in four continents. Lancet 388 (10046), 776–786. Liao, C.Y., Rikke, B.A., Johnson, T.E., Gelfond, J.A., Diaz, V., Nelson, J.F., 2011. Fat maintenance is a predictor of the murine lifespan response to dietary restriction. Aging Cell 10, 29–39. Mitter, S.S., Oriá, R.B., Kvalsund, M.P., Pamplona, P., Joventino, E.S., et al., 2012. Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from Northeast Brazil. Clinics (São Paulo, Brazil) 67, 11–18. Sebastiani, P., Thyagarajan, B., Sun, F., Honig, L.S., Schupf, N., et al., 2016. Age and Sex Distributions of Age-Related Biomarker Values in Healthy Older Adults from the Long Life Family Study. J Am Geriatr Soc. 64, e189–e194. Swindell, W.R., List, E.O., Berryman, D.E., Kopchick, J.J., 2018. Transcriptional profiling identifies strain-specific effects of caloric restriction and opposite responses in human and mouse white adipose tissue. Aging (Albany NY) 10, 701–746. Theendakara, V., Peters-Libeu, C.A., Bredesen, D.E., Rao, R.V., 2018. Transcriptional effects of ApoE4: Relevance to Alzheimer’s disease. Molecular Neurobiology 55, 5243–5254.

Obstructive Nephropathy Periklis Dousdampanis and Konstantina Trigka, Hemodialysis Unit Kyanos Stavros Patras, Patras, Greece Ioannis Stefanidis, University of Thessaly, Larissa, Greece © 2020 Elsevier Inc. All rights reserved.

Introduction Etiology Clinical Manifestations Complications of Obstructive Uropathy Acute Kidney Injury Hypertension Urinary Tract Infection Polycythemia Hyperkalemic Hyperchloremic Acidosis Pathologic Changes of Obstructive Nephropathy Pathophysiology of Obstructive Nephropathy Hemodynamic Effects Tubular Alterations Functional Changes Sodium reabsorption Urinary concentration Acidification Postobstructive diuresis Electrolyte disturbances Chronic Effects on Renal Function Fibrosis The role of oxidative stress Potential Therapeutic Strategies References Further Reading

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Abbreviations (tPA) Tissue-type plasminogen activator ACE-inhibitors Angiotensin-converting-enzyme inhibitors ADH Antidiuretic hormone AKI Acute kidney injury Ang II Angiotensin II ANP Atrial natriuretic peptide AQP-2 Aquoporin-2 AQP-3 Aquoporin-3 AQP-4 Aquoporin-4 ARBs Angiotensin II receptor blockers BMP-7 Bone morphogenic protein-7 BUO Bilateral ureteral obstruction CB2R Cannabinoid receptor 2 CDKs Cyclin-dependent kinases CKD Chronic kidney disease ECF Extracellular fluid EMT Epithelial-mesenchymal transition ESRD End stage renal disease FXa Activated factor GFR Glomerular filtration rate HIPK2 Homeodomain-interacting protein kinase 2

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i NOS Inducible nitric-oxide synthase ICAM-1 Intercellular adhesion molecule 1 IL-1 Interleukin 1 JAK/STAT Janus kinase JNK Jun N-terminal kinases MCP-1 Monocyte chemotatic protein-1 NADPH Nicotinamide adenine dinucleotide phosphate oxidase NFK-b Nuclear factor-k b NKCC2 Naþ Kþ 2Cl contrasporter NO Nitrous oxide ON Obstructive nephropathy OU Obstructive uropathy PAI-1 Plasminogen-activator inhibitor-1 PGE2 Prostaglandin E2 PPARa Peroxisome proliferator-activated receptor-a RANTES Regulated on Activation normal T cell Expressed and Secreted RAS-system Renin–angiotensin system RBF Renal blood flow ROS Reactive oxygen species SOD Superoxide dismutase TGF-b1 Transforming growth factor -b1 TNF-a Tumor necrosis a TXA-2 Tromboxane A-2 UT-A1 Urea transporters-A1 UT-A3 Urea transporters-A3 UT-B Urea receptor B UTI Urinary tract infection UUO Unilateral ureteral obstruction VCAM-1 Vascular cell adhesion molecule 1 VDR Vitamin D receptor

Introduction Obstructive uropathy (OU) is a common clinical condition in the elderly, particularly in men who frequently suffer from benign prostate hyperplasia and from prostate cancer. It refers to either structural and/or functional abnormalities of the urinary tract that obstruct urine flow. Obstructive nephropathy (ON) refers to renal injury and damage of the renal parenchyma that results from this impaired urine flow. The clinical manifestation of OU varies in the elderly, ranging from an asymptomatic clinical condition to a severe acute kidney injury needing dialysis. Hydronephrosis, defined as a distension of renal pelvis and the calyces, is an indicative hallmark of OU. In the elderly (> 64 years), the incidence of hydronephrosis is higher than in younger age (5.1% vs. 3.1%) especially in elderly males (6.2% in men and 2.9% in women) (Klahr, 1999). If inadequately treated (or if it remains untreated), OU results in ON. ON may lead to chronic kidney disease and may progress to end-stage renal disease (ESRD). Prolonged obstruction (for more than 6 weeks) leads to hydronephrosis and a significant loss of functional kidney parenchyma of the obstructed kidney. However, renal function may be also altered even by a short-term obstruction (Klahr, 1999). To note, 57.4% of patients with ESRD due to UN are older than 64 years and 73.8% are males (Klahr, 1999). In the elderly, ON is a very important factor influencing morbidity and mortality and a major cause of ESRD. Treatment strategies of ON consist, apart from reversing obstruction, of selective targeting on molecular mechanisms implicated in apoptosis, inflammation, and renal fibrosis. In this context, the following overview of ON helps unravel key pathogenic processes and new potential therapeutic interventions in CKD progression.

Etiology Prostate disease including hyperplasia or cancer, retroperitoneal, colic or pelvic neoplasms and lithiasis are the primary causes of OU in the elderly (Lameire et al., 2005). There are two classifications of OU. The first is based on topography and includes two

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major categories: intrinsic and extrinsic (Tseng and Stoller, 2009; O΄ Boyle and Porter, 1999). The second is based on disease etiology and contains mainly four categories: inflammatory, neoplastic, inherited, and miscellaneous causes (Tseng and Stoller, 2009). Intrinsic causes of OU can be intraluminal or intramural. Intraluminal causes are either intrarenal or extrarenal. Intrarenal causes include uric acid nephropathy and multiple myeloma (deposition of Bence-Jones protein in the renal tubular lumen). Nephrolithiasis and blood clots are common extrarenal causes of intraluminal obstruction. Elderly patients are predisposed to develop nephrolithiasis due to hyperuricemia and metabolic acidosis. In addition, both the increased use of vitamin supplementation and the recommendation for animal origin proteins (meat) in this population may alter their metabolic profile resulting in an increased susceptibility for nephrolithiasis. Usually vitamin D and calcium are prescribed in the elderly with osteoporosis and/or in patients with nutritional deficiency. However, the coadministration of vitamin D and calcium supplements enhances oxalate stone formation (Letavernier and Daudon, 2018). Intramural causes may be functional or anatomical. Functional causes include: Neurogenic bladder and bladder neck dysfunction. Malignancies, infections, and postradiation strictures are anatomical causes of intramural obstruction (Tseng and Stoller, 2009). Extrinsic causes of OU can be genital, gastrointestinal, vascular or retroperitoneal. Benign prostatic hyperplasia and prostate cancer are the most common extrinsic causes of obstructive nephropathy in elderly men, whereas uterus prolapse and cervix tumors are the most frequent causes in women (Tseng and Stoller, 2009). Malignancies of the gastrointestinal system and aneurysms are additional extrinsic causes of obstruction. Finally, retroperitoneal fibrosis, surgical complications, malignancies, and hematomas are several less common extrinsic causes of OU in the elderly (Tseng and Stoller, 2009).

Clinical Manifestations Symptoms and signs of OU/ON are usually not specific and depend largely on the extension (partial or complete), the duration (acute or chronic) and the site of the obstruction. In addition, the clinical presentation depends on whether the obstruction is unilateral or bilateral. Given that the clinical presentation depends on the degree of the obstruction, partial or/and unilateral obstructions can cause oliguria whereas bilateral obstruction results in AKI with anuria (Klahr, 2000). Often, elderly patients remain asymptomatic even in severe obstruction if it occurs gradually and is chronic. To note, elderly patients with impaired cognitive function may lose the ability to describe their symptoms making the diagnosis of OU more difficult, resulting in treatment delay and permanent kidney damage. Pain and discomfort of the flank, suprapubic or groin region are indicative of OU (complete bilateral or complete unilateral). The pain indicates an acute or rapidly developing obstruction of the urinary tract; it is of increased intensity radiating to the groin, the testicles or the labia (Klahr, 2000). The presence of intermittent episodes of dysuria, stranguria and hematuria also suggests urinary obstruction. Polyuria can be seen in the cases of incomplete or intermittent urinary obstruction due to the defect of urine concentration and in the postobstructive diuresis. Urinary tract infection is a common complication of urinary obstruction; usually, obstruction of the lower urinary tract is the main cause of repeated or refractory urinary infections. Thus, elderly patients with recurrent UTI should be investigated for ureteral obstruction. Emphasis must be given in the extrarenal manifestations of urinary obstruction due to the different underlying processes including retroperitoneal fibrosis. Other symptoms are urinary hesitancy, incontinence, feeling of incomplete emptying of the bladder and alternating episodes of enhanced and diminished urinary output. Gross hematuria is indicative of obstruction usually due to stones. Of note, hematuria is combined with pain. Proteinuria may present due to renal tubular and interstitium dysfunction and it is not massive. Given the high incidence of proteinuria due to hypertension or/and to diabetes in elderly patients, tubular proteinuria of OU should be distinguished from glomerular proteinuria in the elderly.

Complications of Obstructive Uropathy Acute Kidney Injury As mentioned above, bilateral obstruction or complete obstruction of a solitary kidney lead to AKI (Klahr, 2000). AKI is the rapid loss of renal function occurring over hours or days. The risk of AKI in the elderly is high, due to the several anatomic and physiological changes of the aging kidney. Post renal AKI or obstructive AKI is very common in the elderly. Prostate processes (benign hypertrophy/carcinoma), retroperitoneal adenopathy, malignancies, and neurogenic bladder are the most common causes of obstructive AKI in men, whereas pelvic and retroperitoneal carcinomas in the women. Nephrolithiasis and calculi are common causes of post renal AKI in the elderly. In post renal AKI, anuria or oligoanuria suggests complete obstruction, whereas flank or abdominal pain with or without suprapubic fullness may also present. To note, elderly patients with partial obstruction may remain asymptomatic, and usually they report macroscopic hematuria, hesitancy, urgency and nocturia. Urine outflow varies from oliguria to polyuria. Given that these symptoms are not specific for postrenal AKI, the aged patients are being undervalued, which delays the diagnosis. Laboratory findings are nonspecific and they do not differ

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from the other types of AKI. Obstruction of the urinary tract should be considered in elderly patients with uremia and no previous history of CKD or cardiovascular disease with relatively benign urine sediment (absence of hematuria of kidney origin and massive proteinuria).

Hypertension Hypertension is common in acute or chronic obstruction and concomitant ON (Garrett et al., 1970). The pathogenesis of hypertension in ON is multifactorial. Volume overload with increased extracellular fluid volume, decreased sodium excretion and increased sodium absorption with an activation of the renin-angiotensin system are implicated in the pathogenesis of hypertension. In bilateral obstruction it seems that hypertension is due to water and sodium retention (Klahr, 1999; Garrett et al., 1970). In support of this, the use of diuretics leads also to blood pressure control, suggesting that hypertension is volume-dependent. Interestingly, the concentration of rennin in renal and peripheral venous is normal in patients with bilateral obstruction. On the contrary, there is evidence that hypertension in patients with unilateral obstruction is renin-dependent (Nemoy et al., 1973). Data from animal studies with unilateral ureteral obstruction indicate that hypertension in this clinical condition is renindependent (Nemoy et al., 1973). In support of this, high renin blood levels have been reported both in the renal and peripheral veins. Furthermore, in chronic unilateral ureteral obstruction the venous levels of renin are normal suggesting that the pathogenesis of hypertension in OU is more complex. It should be emphasized that relief of obstruction reverses the high blood pressure. Hypertension may also contribute to renal fibrosis which characterizes ON. In addition, hypertension is a common finding in the elderly partially due to structural and functional changes of the aged kidney. Arterial stiffness, neurohormonal, and autonomic dysregulation are implicated in the pathogenesis (Sun, 2015). In this regard, OU may aggravate persistent hypertension due to aging and in return may aggravate ON and develop CKD.

Urinary Tract Infection Mechanical obstruction of the urinary tract, predominantly at the level of the ureterovesical junction, blocks the urine outflow which predisposes to urinary tract infection (Santoro and Kaye, 1978). In addition, older adults have an increased risk of urinary tract infections due to diabetes, age-associated changes in immune function and several neurological diseases including Alzheimer’s and Parkinson’s disease. Factors that predispose to UTIs in the elderly are the high postvoid residual urine volume in the bladder that enables bacterial growth and some alterations of the urinary tract epithelial cells especially in the glycoprotein composition of the bladder epithelium that facilitate bacterial adhesion. The most common organism responsible for UTI is Escherichia coli. To note, the obstruction of the upper urinary tract usually is not complicated with an infection.

Polycythemia An increased production of erythropoietin leading to an increase in hemoglobin levels has been reported for patients with OU. Jaworski and Wolan (1963) reported a case of erythrocytosis in a patient with unilateral hydronephrosis. In support of this, data from animal studies with unilateral ureteral obstruction reported increased levels of erythropoietin.

Hyperkalemic Hyperchloremic Acidosis Hyperkalemic hyperchloremic acidosis due to renal tubular acidosis type IV has been reported in patients with unilateral obstruction. Interestingly, the unilateral ureteral obstruction in animal models leads to a defect of urine acidification (Klahr, 1999).

Pathologic Changes of Obstructive Nephropathy Anatomical changes: Macroscopically, the obstructive kidney appears oedematous with an initial increase of volume and weight because of the accumulation of tissue fluid. If the obstruction remains, the kidney becomes atrophic. As atrophic changes become more marked, a decrease of the parenchymal mass occurs. The ureter dilates and increases its diameter due to the mechanical obstruction (hydronephrosis). If the mechanical obstruction remains unrelieved, the ureter develops smooth muscle hypertrophy. Microscopically, the findings of ON consist of a marked nonspecific tubulointerstitial nephritis with glomerular and/or vascular changes. The changes of tubulus consist of atrophy, thickness of the basement membrane, absence of segment differentiation and the presence of hyaline casts. Both the cortex and the medulla of the obstructed kidney are involved equally (Truong and Mai, 2015). In addition, Tamm–Horsfall protein may be present either in the lumen of the tubulus or/and in the interstitium. Normal or hypertrophic tubuli may also be present. The interstitium presents fibrosis and diffuse inflammation (Truong and Mai, 2015). These alterations can be observed with light microscopy in the first 28 days after the OU and may be irreversible if the obstruction remains unrelieved. Interestingly, these alterations are particularly marked around the capsule of Bowman. It should be noted that changes of the basement membrane can be observed with light microscopy after 30 h.

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The infiltrate predominantly is composed by small lymphocytes. Lymphoid aggregates may be present indicating neolymphoid formation resulting from the activation of the innate immune system. The glomerular alterations are mild in comparison with the changes of the tubulus and the interstitium, supporting that ON is predominantly a type of tubulointerstitial nephritis and not glomerulopathy. The glomeruli give the impression that they are “crowded” due to the disruption of the tubuli and the interstitium architecture (Truong and Mai, 2015). Glomerulus in ON can be either (a) normal, (b) hypertrophic (compensatory hypertrophy), (c) small in size, collapsed, with mild thickening of glomerular capillaries suggesting the “obstructive” effect on the glomeruli and (d) with global sclerosis with subcapsular fibrosis indicating chronic ischemic alterations (Truong and Mai, 2015). Initially, the arterial blood vessels are normal but later they can display medial thickening and fibrosis of the intima indicating intrarenal or/and systemic hypertension rather than a direct effect of the renal obstruction on the vasculature. Urothelial reactive atypia, fibrosis of the lamina and thickening of the muscularis are the predominant changes of the pyelocaliceal system (Truong and Mai, 2015). It should be emphasized that structural changes including the glomeruli, tubulus, interstitium, and vasculature have also been reported in the aged kidney. More specifically, glomeruloscerosis, tubular atrophy and fibrosis of the interstitium and arteriosclerosis are the major aging-related changes of the aged kidney. In addition, changes due to diabetes or/and hypertension could coexist in elderly patients with ON. Thus, in this case the histological diagnosis of ON may be difficult for the pathologists.

Pathophysiology of Obstructive Nephropathy The pathophysiology of ON has been studied in both humans and in animal models with partial or complete renal obstruction. To note, data from animal models can not apply directly to human disease. For example there are major differences in the duration of time following obstruction, which is necessary for renal changes to become irreversible. The acute renal effects and kidney damage of OU, result from hemodynamic changes in renal blood flow and GFR as well as in tubular function. The pathophysiology in unilateral ureteral obstruction (UUO) and in bilateral ureteral obstruction (BUO) differs and they are therefore discussed separately.

Hemodynamic Effects Regarding UUO, a triphasic series of changes occur in renal physiology over a period of 18 h that are protective to the obstructive kidney but have inverse effects on the contralateral kidney. In the first phase, there is an increase in intraluminal hydrostatic pressure (to 50–70 mm Hg) (O΄ Boyle and Porter, 1999). GFR remains stable by a simultaneous elevation of the renal blood flow (RBF) and glomerular capillary pressure due to the dilatation of the afferent arteriolar mediated by the prostaglandin E2 (PGE2), nitrous oxide (NO), and ecosanoids. Administration of PGE2 and NO inhibitors attenuate the increase of RBF and GFR (Wilson, 1980). In the second phase (90 min to 5 h), the elevation of the hydrostatic pressure of the ureter persists whereas the GFR and RBF are decreased. The initial phase of vasodilatation of the afferent arteriolar is succeeded by the vasoconstriction of the efferent and afferent arteriolar due to activation of RAS, resulting in a decrease in GFR. In this phase, administration of angiotensinconverting-enzyme inhibitors (ACE) ameliorates GFR. In addition, activation of tromboxane 2 and endothelin decrease the glomerular blood flow further (Wilson, 1980). The last phase (5–18 h) is characterized by a decrease in hydrostatic pressure of the ureter and by a marked decrease of RBF and GFR due to preglomerular vasoconstriction. Most of the permanent damage of renal parenchyma resulting in ON occurs in this phase. The recovery of renal function depends on the overall duration and the severity of the obstruction. A complete obstruction for 4 h is able to cause a decrease in GFR of more than 50% (O΄ Boyle and Porter, 1999). The main difference between UUO and BUO is the persistent vasoconstriction of the afferent glomerular arteriole that occurs in BUO. The hydrostatic pressure of the ureter remains high over 24 h from the initial obstruction whereas in UUO the hydrostatic pressure begins to fall after 6 h. Several vasoactive substances are responsible for the dilatation of the afferent arterioles and the vasoconstriction of the efferent arterioles. It is likely that these substances are activated and accumulate in the setting of BUO but not in UUO (Wilson, 1980). Volume overload induces the production of atrial natriuretic peptide (ANP) (Klahr and Purkerson, 1994) resulting in increased diuresis. PGE2 and NO are also present in BUO and they enhance the vasoactive action of ANP leading to increased dieresis and GFR (Sutherland, 2013). Interestingly, inhibition of angiotensinogen II and TXA-2 decreases postobstructive diuresis.

Tubular Alterations Tubular dysfunction including decreased Naþ reabsorption, impairment of urinary concentration, acid–base alterations and electrolytes homeostasis occurs in UN/ON (Sutherland, 2013). In addition, a marked loss of tubular function has been reported also for the aged kidney suggesting that all these alterations of the tubular function in ON may be more intense in the elderly.

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Functional Changes Sodium reabsorption A downregulation of all types of Naþ has been reported in obstructed kidney. In the proximal tubule a decreased activity of the apical Naþ/Hþ exchanger (NHE3) has been reported. Similarly, in the loop of Henle a marked reduction of the Naþ Kþ ATPase has been observed. A decreased activity of the apical Naþ Kþ 2Cl cotransporter (NKCC2) of the thick ascending limb has also been reported. The causes of the decreased activity of Naþ transporters reported in ON are still poorly understood (Sutherland, 2013). Diminished GFR decreases the amount of filtrate and Naþ in the lumen. It could be assumed that decreased Naþ presentation in the tubular cells may downregulate both its receptor and its transporters (Sutherland, 2013). Moreover, the reduced luminal presentation of Naþ decreases the electrochemical gradient. In addition, decreased presentation of Naþ in the medullary thick ascending limb cells causes a loss of ouabain-sensitive ATPase. Notably, ischemia contributes to decreased Naþ reabsorption.

Urinary concentration A defect of urinary concentration occurs in obstructed kidney. With the decrease of GFR, a decreased amount of Naþ is available to the medullar interstitium for the maintenance of the osmolar gradient. As mentioned before, there is a loss of NKCC2 and Naþ Kþ ATPase transporters and a decreased Naþ reabsorption. Thus, Naþ does not move from the tubular lumen into the medullary interstitium. This process is critical in order to create and maintain the osmolar gradient. In addition, the solutes necessary to maintain the osmolar gradient are excreted. Furthermore, in the collecting duct a decreased activity of antidiuretic hormone (ADH) due to the decreased AQP-2 in the apical membrane has been reported. This is a post-cAMP defect. More specifically, a decreased transcription of AQP-2 m RNA in combination with an inadequate phosphorylation of AQP-2 has been observed. A decreased of the aquoporines (AQP-3 and AQP-4) of the basolateral membrane has been also noted (Sutherland, 2013). Another important process that increases the medullary interstitial osmolar gradient is the urea recycling. This process is altered in OU. Both urea transporter UT-A1 and the UT-A3 receptors are responsible for urea permeability in the collecting duct tubules. Additionally, the reabsorption of urea by the vasa recta is under the control of ADH. Interestingly, the UT-B receptors stimulate urea reabsorption. In OU, a decreased expression of the urea transporters UT-A1, UT-A3, UT-B has been noted (Sutherland, 2013). Therefore, the defect of urea transportation resulting in a disruption of the urea recycling is the underlying process of the reduction of the maximal concentrating effect of the osmolar gradient.

Acidification A defect on urinary acidification has been reported both in the obstructed kidney and in the elderly. A distal (type 1) renal tubular acidosis (RTA) is the underlying process. Defects of Naþ channels in combination with the loss of Naþ reabsorption of distal tubule and a failure of distal Hþ and Kþ secretion are implicated in the pathogenesis of acidosis and hyperkalemia (Sutherland, 2013). Decreased expression of the Hþ/ATPase in the collecting ducts contributes to metabolic acidosis.

Postobstructive diuresis Postobstructive diuresis occurs in patients with prolonged BUO (Wilson, 1980). The rate of diuresis depends on the volume overload, the urea concentration and the electrolyte disturbances (Wilson, 1980). A decreased osmotic gradient (responsible for the urine concentration) of the tubules due to the decreased reabsorption capacity of Naþ and to the downregulation of Naþ transporters is responsible for postobstructive diuresis. In addition, the downregulation and the decreased activity of the aquoporins of the distal tubules promote aquaresis. Finally, an increased release of ANP due volume overload (increased preload) also enhances postobstructive diuresis (Sutherland, 2013). Fluid administration is the initial treatment of postobstructive diuresis. Administration of intravenous fluids depends on the rate of postobstructive diuresis and the clinical condition of the elderly patients. Moreover, the volume status, the electrolytes, the serum and urine osmolality, the renal and cardiac function should be taken into consideration. PGE2 levels are increased due to COX-2 production mediated by the obstruction. In return, COX-2 inhibition decreases the loss of NKCC2 and NAþ Kþ-ATPase activity indicating an indirect impairment effect of PGE-2 on Naþ reabsorption (Sutherland, 2013). Naþ reabsorption is different between BUO and UUO due to volume expansion. In UUO, the synergic effect of ANP release and the loss of aldosterone further decrease the Naþ reabsorption. In addition, ANP blocs renin release leading to a decrease of angiotensin II synthesis. The net effect is the increased diuresis and natriuresis.

Electrolyte disturbances The excretion of Kþ diminishes after the relief of a 24 h UUO. The decreased sodium delivery in combination with the decreased tubular flow rate in the distal nephron contributes to decreased Kþ excretion (Wilson, 1980). A defect of the secretory mechanism of Kþ in the distal nephron contributes to hyperkalemia in UUO. In contrast, in postobstructive diuresis an increase in Kþ excretion and hypokaliemia has been reported. In UUO, the diminished filtered load of phosphate contributes to decreased phosphate excretion. Increased phosphate reabsorption may occur in the proximal tubule similar to Naþ and water in this nephron segment (Sutherland, 2013). After relief of BUO, an increase of phosphate excretion with concomitant phosphaturia has been noted (Wilson, 1980).

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Chronic Effects on Renal Function Fibrosis Long-term ureteral obstruction leads to tubulointerstitial fibrosis. It should be emphasized that all the activating pathways leading to fibrosis in the obstructed kidney are similar to the other process diseases characterized by renal fibrosis. The evolution of kidney damage/injury in ON, shares many features with the aging kidney. An excess accumulation of extracellular matrix due to increased protein synthesis leads to fibrosis followed by glomerular and vascular sclerosis. As mentioned before, the glomerular and vascular alterations are mild in comparison to those of the tubules and interstitium; nevertheless, studies with mice showed that in adult animals with UUO, the development of significant proteinuria aggravates the glomerular injury. In this regard, it could be assumed that in ON of the aged mice the glomerular lesions including glomeruloscerosis are more prominent compared to younger mice. Falke et al. (2016) observed an age-dependent conversion of kidney response to kidney damage in favor of tubular atrophy. In particular, aged mice with UUO develop higher levels of tubular atrophy than interstitial fibrosis. According to this study, this altered renal response to kidney injury of the aged mice occurs before half of the life span of these animals, before the loss of Klotho and an increase in the expression of TGF-b that characterize the aging kidney. The renal cellular response to UUO is complex. An increased accumulation of interstitial matrix leads to peritubular capillary obliteration, tubular atrophy and fibrosis with progressive kidney insufficiency. However, there is an alternative scenario suggesting that renal inflammation causes glomerular and tubular damage of some nephrons, that, in turn, cause damage to the remaining nephrons; accordingly, fibrosis of the interstitium is a secondary manifestation of ON (Chevalier et al., 2009). The three main pathways implicated in the development of interstitial fibrosis in ON after UUO are: (a) interstitial infiltration of macrophages (4 h after the onset of UUO), (b) increased production of cytokines that trigger tubular apoptosis, proliferation and activation of the fibroblasts and (c) death of tubular cells via apoptosis or necrosis, resulting in the formation of atubular glomeruli, tubular atrophy and epithelial–mesenchymal transition (EMT) (Chevalier et al., 2009). Hypoxia contributes to early onset of fibrosis by hypoxia-inducible factor 1 (HIF-1)-dependent gene expression of several profibrotic mediators, including tissue-type plasminogen activator (Tpa) and connective tissue growth factor (Kabei et al., 2018). Pro-inflammatory cytokines, mainly TNF-a and IL-1, play a crucial role in the recruitment of macrophages and leucocytes (Grande et al., 2010). Interestingly, paricalcitol decreases the infiltration of T cells, macrophages and the chemokine RANTES in the obstructed kidney, accompanied by a decrease in TNF-a and IL-1 expression (Tan et al., 2009). The tubulointerstitial infiltration of leukocytes is an early and prominent event in the development of UUO. After leukocyte recruitment, an increased expression of chemokines and their receptors (such as CC chemokines and CCR1, CCR2, CCR5 receptors), adhesion molecules including osteopontin, selectines, integrines, vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) have been noted (Grande et al., 2010). Prolonged UUO activates the RAS system, the production of reactive oxygen species (ROS) and the transcription factor NF-kB. The end result is the interstitial infiltration by macrophages, tubular apoptosis and interstitial fibrosis. Activated macrophages express NF-kB that mediates pro-apoptotic signaling that leads to renal tubular cell apoptosis. NF-kB also mediates the overexpression of inducible nitric-oxide synthase (iNOS), a characteristic feature of the increased inflammation state in the obstructed kidney (Grande et al., 2010). Overexpression of monocyte chemotatic protein-1 (MCP-1) by tubular cells promotes the trafficking of monocyte (chemotaxis) to the interstitium of the obstructed kidney (Grande et al., 2010). In addition, angiotensin II (Ang II) produced by activated macrophages, induces the production of NF-kB which causes the recruitment of more macrophages and the production of ROS, resulting in aggravation of tubular injury (Grande et al., 2010). In addition to the proliferation of the fibroblasts, tubular epithelial cells acquire characteristics of mesenchymal cells and invade the space of the interstitium, where they produce extracellular matrix. Endothelial cells can also undergo a similar process to the endothelial-mesenchymal transition or die of apoptosis, leading to capillary loss and finally to ischemia and hypoxia. Pericytes and infiltrating hematopoietic stem cells differentiate into fibroblasts which, under the stimulus of TGF-b1, differentiate further into myofibroblasts that are the main contributors of the production and accumulation of extracellular matrix in the renal interstitium. A decrease in the degradation of the extracellular matrix mediated by plasminogen-activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t PA) contributes further to renal fibrosis (Grande et al., 2010). It should be emphasized that TGF-b1 suppresses the expression of Klotho aggravating thus interstitial fibrosis. More specifically, Klotho inhibits the activation of myofibroblasts by depression of Wnt/b-Catenin signaling. Klotho is also an important antiaging hormone (Mencke et al., 2017; Li and Wang, 2018). In this respect, Klotho is a link between the aging kidney and the ON in the elderly (Li and Wang, 2018).

The role of oxidative stress Oxidative stress has been implicated both in aging kidney and the pathogenesis of ON. Thus, oxidative stress may amplify the renal injury of ON in the elderly. Several markers of oxidative stress are elevated in UUO. In this regard, increased carboxymethyl-lysine levels in interstitium indicate an elevated oxidative stress in UUO (Schaier et al., 2003). Concomitantly, the expression of heme oxygenase-1 (a marker of oxidative stress) is elevated in the obstructed kidney (Schaier et al., 2003).

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KIDNEY INJURY

OBSTRUCTIVE NEPHROPATHY Inflammation-apoptosis- fibrosis

CHRONIC KIDNEY DISEASE

END STAGE RENAL DISEASE Fig. 1

Natural history of obstructive nephropathy.

Oxidative stress activates NF-kB and may induce an inflammation state. ROS are increased in long-term obstructed kidney (Heidland et al., 2001). Superoxide anion and hydrogen peroxide are increased in OU. In addition, in OU an increased NADPH oxidase activity has been reported. An increased production of Ang II, trafficking of activated phagocytes in the interstitium and increased levels of medium-weight molecules induce the increase of oxidative stress after UUO (Grande et al., 2010). Increased products of lipid peroxidation and advanced glycation end-products contributing to renal damage have been noted in the obstructed kidney. Interestingly, the levels of several antioxidant enzymes that prevent the oxidative damage are decreased in UO. Furthermore, a decrease activity of several antioxidant enzymes including superoxide dismutase (SOD), catalase and glutathione peroxidase indicates an increase oxidative stress in UUO (Schaier et al., 2003). It is worth noting that TGF-b activates the myofibroblasts via the smad3 signaling. This process is mediated by the activation of NADPH oxidase (Bondi et al., 2010) Fig. 1.

Potential Therapeutic Strategies A multitude of effective antifibrotic drugs have been tested in animal models, with one caveat: In most of these studies, the animals used were young and healthy, whereas elderly patients with ON have often comorbidities including diabetes, heart failure and persistent alterations on kidney structure and function. Relief of the obstruction arrests kidney injury and fibrosis but cannot reverse kidney injury. Thus, therapeutic strategies are needed to reverse or prevent the kidney injury in OU. The end point of all the studies investigating potential therapeutic targets and strategies is fibrosis. To note, a minority of the agents tested are truly antifibrotic. Drugs acting on profibrotic factors including growth factors such as TGF-b, have a true antifibrotic action, whereas several agents may interfere with several different pathways of fibrosis signaling or may act on inflammation, apoptosis and oxidative stress. Despite the large number of potential antifibrotic treatment targets tested in animal models, translation into the clinical setting is poor. There is a pause of data regarding several antifibrotic strategies in the elderly. RAS-system and Ang II play a crucial role in the physiopathogenesis of ON. This role can be direct by acting on inflammation, apoptosis and fibrosis or it can be indirect by inducing several pro-inflammatory cytokines or growth factors including TGF-b. The beneficial effects of the drugs of the RAS-system, including ARBs (valsartan, irbesartan, candesartan) (Chang et al., 2016; Liu et al., 2007; Wamsley-Davis et al., 2004), ACE-inhibitors (enalapril) (Wang et al., 2009) or direct rennin inhibitors such as aliskiren (Choi et al., 2011), on renal fibrosis have been established. Recently, Chang et al. (2016), reported that the coinhibition of AT II and endothelin-1 receptors has a beneficial effect on renal fibrosis in UUO. Of note, drugs acting on the RAS-system have an additional favorable effect on the progression of CKD, the regulation of blood pressure. A synergic effect of aliskiren in combination with ARBs has been reported (Wu et al., 2010). Eplerone and spironolactone acting on aldosterone may also prevent interstitial fibrosis by inhibiting inflammation and oxidative stress (Chen et al., 2013; Trachtman et al., 2004). Paricalcitol, a vitamin D receptor (VDR) activator, seems to have a beneficial effect on fibrosis. The renoprotective effect of VDR on renal fibrosis observed in ON is due at least in part to attenuation of RAS-system. Interestingly, a synergic effect for aliskiren and paricalcitol on renal fibrosis mediated by the attenuation of intrarenal RAS-system has been reported (Chung et al., 2017).

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The antifibrotic role of bone morphogenic protein 7 (BMP-7), a protein of the TGF super family that reduces the production of extracellular matrix formation, is well established. BMP-7 and its receptor (activine-like kinase 3, Alk3), are promising therapeutic targets (Ucero et al., 2014). Targeting of Smad-dependent pathway could be considered an alternative strategy (Ucero et al., 2014). Targeting of several proteins implicated in the deposition/degradation turnover of extracellular matrix including serine proteases of the plasminogen-plasmin axis have been successfully tested in adult animal models with ON (Ucero et al., 2014). Another successful treatment option is to target inflammation, fibrosis or/and apoptosis by pharmacological inhibition of CCR2, CCR1 and kinin B receptor, by CRR antibody neutralization (Ucero et al., 2014). Targeting of several kinases, including JAK/STAT janus kinase (Ucero et al., 2014), Jun N-terminal kinases (JNK) (Sanz et al., 2016), cyclin-dependent kinases (CDKs) and homeodomain-interacting protein kinase 2 (HIPK2), has been suggested as an alternative approach (Ucero et al., 2014). Other therapeutic approaches include targeting of the activation of peroxisome proliferator-activated receptor-a (PPARa), which is implicated in the pathogenesis of kidney injury in ON, and of NF-kB, TNF-a and the TNF-a receptors that are mainly implicated in kidney injury in OU (Ucero et al., 2014). Renal nervous stimulation is implicated in the early phase of activation of profibrotic signaling. Renal denervation seems to arrest both inflammation and fibrogenesis (Ucero et al., 2014). Genetic targeting of the TNF-like weak inducer of apoptosis (TWEAK) and the use of neutralizing anti-TWEAK antibodies may prevent kidney tubular damage, inflammation, and fibrosis (Sanz et al., 2016). Interestingly, the activation of cannabinoid receptor 2 (CB2R) reduces the state of the inflammation in OU. Activation of CB2R with an agonist may arrest the fibrotic process (Tang et al., 2018). Some attention must be given to antidiabetic drugs with potential antifibrotic action. Glipizide (Yang et al., 2017) a type of solfynurea, GLP-1 analogs (Li et al., 2018), metformin (De Broe et al., 2018), and sodium glucose co transporter 2 (SGLT-2) (Abbas et al., 2018) have been successfully used in animal models with UUO. A similar protective role for dipeptidyl peptidase IV inhibitor has been reported (Uchida et al., 2017). Pioglitazone (thiazolidinedione class) in combination with candesartan have an addictive effect on renal fibrosis (Higashi et al., 2010). Given that the prevalence of type 2 diabetes in the elderly is high, these drugs may exert a synergic effect on elderly patients with diabetes and ON. Additionally, a beneficial effect of statins in combination with erythropoietin or alone on kidney injury has been reported (Acikgoz et al., 2014). Recently, it was reported that the activated factor (FXa) acting on protease-activated receptors induces inflammation and is implicated in the pathogenesis of fibrosis. Edoxaban, a new anticoagulant, is a FXa inhibitor which exerts a beneficial effect by inhibiting tubulointerstitial fibrosis (Horinouchi et al., 2018). There is clinical evidence that drugs for hyperuricemia and gout widely used in geriatric patients, like febuxostat and colchicine seem to have a protective role in ON (Cao et al., 2015; Solak et al., 2017). Gasotransmitters that are produced endogenously can permeate cell membranes and mediate several physiological responses. There is increasing evidence that NO, CO, and hydrogen sulfate may ameliorate fibrosis, apoptosis, and inflammation (Lin et al., 2018).

References Abbas, N.A.T., El Salem, A., Awad, M.M., 2018. Empagliflozin, SGLT2 inhibitor, attenuates renal fibrosis in rats exposed to unilateral ureteric obstruction: Potential role of klotho expression. Naunyn-Schmiedeberg’s Archives of Pharmacology 391 (12), 1347–1360. https://doi.org/10.1007/s00210-018-1544-y. Epub ahead of print. Acikgoz, Y., Can, B., Bek, K., et al., 2014. The effect of simvastatin and erythropoietin on renal fibrosis in rats with unilateral ureteral obstruction. Renal Failure 36, 252–257. Bondi, C.D., Manickam, N., Lee, D.Y., et al., 2010. NAD(P)H oxidase mediates TGF-beta1-induced activation of kidney myofibroblasts. Journal of the American Society of Nephrology 21, 93–102. Cao, J., Li, Y., Peng, Y., Zhang, Y., et al., 2015. Febuxostat prevents renal interstitial fibrosis by the activation of BMP-7 Signaling and inhibition of USAG-1 expression in rats. American Journal of Nephrology 42, 369–378. Chang, Y.K., Choi, H., Jeong, J.Y., et al., 2016. Co-inhibition of angiotensin II receptor and Endothelin-1 attenuates renal injury in unilateral ureteral obstructed mice. Kidney & Blood Pressure Research 41, 450–459. Chen, H., Sun, F., Zhong, X., et al., 2013. Eplerenone-mediated aldosterone blockade prevents renal fibrosis by reducing renal inflammation, interstitial cell proliferation and oxidative stress. Kidney & Blood Pressure Research 37, 557–566. Chevalier, R.L., Forbes, M.S., Thornhill, B.A., 2009. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney International 75, 1145–1152. Choi, D.E., Jeong, J.Y., Lim, B.J., et al., 2011. Aliskiren ameliorates renal inflammation and fibrosis induced by unilateral ureteral obstruction in mice. The Journal of Urology 186, 694–701. Chung, S., Kim, S., Kim, M., et al., 2017. Treatment combining aliskiren with paricalcitol is effective against progressive renal tubulointerstitial fibrosis via dual blockade of intrarenal renin. PLoS One 12, e0181757. De Broe, M.E., Kajbaf, F., Lalau, J.D., 2018. Renoprotective effects of metformin. Nephron 138, 261–274. Falke, L.L., Kinashi, H., Dendooven, A., et al., 2016. Age-dependent shifts in renal response to injury relate to altered BMP6/CTGF expression and signaling. American Journal of Physiology. Renal Physiology 31, F926–F934. Garrett, J., Polse, S.L., Morrow, J.W., 1970. Ureteral obstruction and hypertension. The American Journal of Medicine 49, 271–273. Grande, M.T., Pérez-Barriocanal, F., López-Novoa, J.M., 2010. Role of inflammation in túbulo-interstitial damage associated to obstructive nephropathy. Journal of Inflammation 22, 7–19. Heidland, A., Sebekova, K., Schinzel, R., 2001. Advanced glycation end products and the progressive course of renal disease. American Journal of Kidney Diseases 38 (4 Suppl 1), S100–S106. Higashi, K., Oda, T., Kushiyama, T., et al., 2010. Additive antifibrotic effects of pioglitazone and candesartan on experimental renal fibrosis in mice. Nephrology (Carlton) 15, 327–335.

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Horinouchi, Y., Ikeda, Y., Fukushima, K., et al., 2018. Renoprotective effects of a factor Xa inhibitor: Fusion of basic research and a database analysis. Scientific Reports 8, 10858. Jaworski, Z.F., Wolan, C.T., 1963. Hydronephrosis and polychthemia. A case of erythrocytosis relieved by decompression of unilateral hydronephrosis and cured by nephrectomy. The American Journal of Medicine 34, 523–534. Kabei, K., Tateishi, Y., Nozaki, M., et al., 2018. Role of hypoxia-inducible factor-1 in the development of renal fibrosis in mouse obstructed kidney: Special references to HIF-1 dependent gene expression of profibrogenic molecules. Journal of Pharmacological Sciences 136, 31–38. Klahr, S., 1999. The geriatric patient with obstructive uropathy. Geriatric Nephrology and Urology 9, 101–107. Klahr, S., 2000. Obstructive nephropathy. Internal Medicine 39, 355–361. Klahr, S., Purkerson, M.L., 1994. The pathopysiology of obstructive nephropathy: The role of vasoactive comprounds in the hemodynamic and structural abnormalities of the obstructed kidney. American Journal of Kidney Diseases 23, 219–223. Lameire, N., Van Biesen, W., Vanholder, R., 2005. Acute renal failure. Lancet 365, 417–430. Letavernier, E., Daudon, M., 2018. Vitamin D, Hypercalciuria and kidney stones. Nutrients 10, 366. Li, Z., Wang, Z., 2018. Aging kidney and aging-related disease. Advances in Experimental Medicine and Biology 1086, 169–187. Li, Y.K., Ma, D.X., Wang, Z.M., et al., 2018. The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis. Pharmacological Research 131, 102–111. Lin, S., Juriasingani, S., Sener, A., 2018. Is hydrogen sulfide a potential novel therapy to prevent renal damage during ureteral obstruction? Nitric Oxide 73, 15–21. Liu, B.C., Xia, H.L., Wu, J.N., et al., 2007. Influence of irbesartan on expression of ILK and its relationship with epithelial-mesenchymal transition in mice with unilateral ureteral obstruction. Acta Pharmacologica Sinica 28, 1810–1818. Mencke, R., Olauson, H., Hillebrands, J.L., 2017. Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies. Advanced Drug Delivery Reviews 121, 85–100. Nemoy, N.J., Fichman, M.P., Sellers, A., 1973. Unilateral ureteral obstruction. A caue of reversible high renin content hypertension. JAMA 225, 512–513. Santoro, J., Kaye, D., 1978. Recurrent urinary tract infections. Pathogenesis and management. The Medical Clinics of North America 62, 1005–1020. Sanz, A.B., Ruiz-Andres, O., Sanchez-Niño, M.D., et al., 2016. Out of the TWEAKlight: Elucidating the role of Fn14 and TWEAK in acute kidney injury. Seminars in Nephrology 36, 189–198. Schaier, M., Jocks, T., Grone, H.J., Ritz, E., Wagner, J., 2003. Retinoid agonist isotretinoin ameliorates obstructive renal injury. The Journal of Urology 170, 1398–1402. Solak, Y., Siriopol, D., Yildiz, A., et al., 2017. Colchicine in renal medicine: New virtues of an ancient friend. Blood Purification 43, 125–135. Sun, Z., 2015. Aging, arterial stiffness and hypertension. Hypertension 65, 252–256. Sutherland, R.W., 2013. Obstructive uropathy. In: National Kidney Foundation primer on kidney diseases E-book, 6th edn. Elsevier, pp. 397–404. Tan, X., He, W., Liu, Y., 2009. Combination therapy with paricalcitol and trandolapril reduces renal fibrosis in obstructive nephropathy. Kidney International 76, 1248–1257. Tang, M., Cao, X., Zhang, K., et al., 2018. Celastrol alleviates renal fibrosis by upregulating cannabinoid receptor 2 expression. Cell Death & Disease 9, 601. Trachtman, H., Weiser, A.C., Valderrama, E., et al., 2004. Prevention of renal fibrosis by spironolactone in mice with complete unilateral ureteral obstruction. The Journal of Urology 172, 1590–1594. Truong, L., Mai, K., 2015. Obstructive nephropathy: What the surgical pathologist should know. Pathology Case Reviews 20, 250–255. Tseng, T.Y., Stoller, M.L., 2009. Obstructive uropathy. Clinics in Geriatric Medicine 25, 437–443. Ucero, A.C., Benito-Martin, A., Izquierdo, M.C., et al., 2014. Unilateral ureteral obstruction: Beyond obstruction. International Urology and Nephrology 46, 765–776. Uchida, T., Oda, T., Matsubara, H., et al., 2017. Renoprotective effects of a dipeptidyl peptidase 4 inhibitor in a mouse model of progressive renal fibrosis. Renal Failure 39, 340–349. Wamsley-Davis, A., Padda, R., Truong, L.D., et al., 2004. AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: Preservation of kidney tissue mass using candesartan. American Journal of Physiology. Renal Physiology 287, F474–F480. Wang, L., Ning, W., Tao, L., Wang, L., Peng, Z., 2009. Dynamic observation of enalapril on the expression of TGF-beta1, CTGF, Smad7 and alpha-SMA in rats with unilateral ureteral obstruction. Zhong Nan Da Xue Xue Bao. Yi Xue Ban 34, 252–258. Wilson, D.R., 1980. Pathophysiology of obstructive nephropathy. Kidney International 18, 281–292. Wu, W.P., Chang, C.H., Chiu, Y.T., et al., 2010. A reduction of unilateral ureteral obstruction-induced renal fibrosis by a therapy combining valsartan with aliskiren. American Journal of Physiology. Renal Physiology 299, F929–F941. Yang, G., Zeng, G., Wu, J.P., et al., 2017. Glipizide blocks renal interstitial fibrosis by inhibiting AKT signaling pathway. European Review for Medical and Pharmacological Sciences 21, 867–872. O΄ Boyle, P., Porter, T., 1999. Obstructive nephropathy: Causes and management. European Urology 5, 36–42 (Curric Urol. 5, 1–11).

Further Reading Ucero, A.C., Gonçalves, S., Benito-Martin, A., et al., 2010. Obstructive renal injury: From fluid mechanics to molecular cell biology. Open Access OptionsdThe Journal of Urology 2, 41–55.

Oral Care Joanna Zarzecka, Jagiellonian University Medical College, Krakow, Poland ska-Pawelec, Jagiellonian University Medical College, Krakow, Poland; and Ludwik Rydygier’s Specialistic Graz_ yna Wyszyn Hospital, Krakow, Poland Jan Zapała, Jagiellonian University Medical College, Krakow, Poland; and Ludwik Rydygier’s Specialistic Hospital, Krakow, Poland Tomasz Kaczmarzyk and Małgorzata Pihut, Jagiellonian University Medical College, Krakow, Poland Janusz Czekaj, Long-term health care center in Cracow, Krakow, Poland Justyna Hajto-Bryk, Karolina Babiuch, and Maciej Lesko´w, Jagiellonian University Medical College, Krakow, Poland © 2020 Elsevier Inc. All rights reserved.

Saliva Function and Secretion Age-Related Conditions Etiology of Dry Mouth Sjögren Syndrome A Clinical Picture of Dry Mouth Diagnosis, Prevention, and Treatment Noncarious Lesions and Toothwear Caries Lesions Oral Mucosa Age-Related Changes of the Oral Mucosa Oral Manifestations of Systemic Diseases Gastrointestinal diseases Hematologic disorders Immune-based diseases Drug-Induced Oral Adverse Effects Oral Potentially Malignant Disorders Periodontium Age-Related Changes in Periodontium Periodontal Disease in the Elderly Periodontal Disease as a Risk for Systemic Disease Oral Cancer in the Elderly Epidemiology Etiology Clinical Manifestations of OSCC Differential Diagnosis Diagnosis and Staging of the Primary OSCC Management of OSCC in the Elderly: Basic Principles Prosthetic Treatment of Geriatric Patients Partial Removable Dentures Complete Dentures Implant Restoration Dental Stomatitis Hygiene of Dentures Temporomandibular Joint Dysfunction and Neuromuscular Disorder Pain Conditions Dental Pain Conditions Nondental Chronic Pain Conditions References

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Demographic, epidemiological, and social changes are exceeding the adaptive capacity of the current healthcare systems. The lack of a comprehensive, coordinated, and balanced approach to the health of older adults is evident. Inadequate medical care leads to negative health, social, and economic impacts. Investment in reframing healthcare systems, education regarding healthy and active aging, and development of integrated care focused on the elderly are expected to result in benefits and returns in the future, including better health and well-being for older people, who will then make greater contributions to society, and the reduction of healthcare expenditures (World Health Organisation, 2015).

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Age is the single greatest risk factor in many diseases, including oral-cavity disorders (An et al., 2018). The cellular and molecular hallmarks of aging defined by geroscientists include epigenetic alterations, genomic instability, telomere attrition, mitochondrial dysfunction, loss of proteostasis, cellular senescence, stem cell exhaustion, altered intercellular communication, and deregulated nutrient sensing. Age-related oral diseases share molecular links with the hallmarks of aging (Fig. 1) (An et al., 2018). Clinically, the health problems of aging populations are usually the result of noncommunicable chronic conditions (World Health Organisation, 2015). Local inflammation (“inflammaging”), dysregulation of microbiomes, and stem cell dysfunction likely contribute to declining oral health (An et al., 2018). Many of these conditions can be prevented or delayed; others should be detected early and monitored to protect patients’ high intrinsic capacity and functional ability to age in a healthy manner (World Health Organisation, 2015). As the health of the oral cavity is a component of general health, the dentist should be part of an interprofessional team. This partnership may yield many benefits. Poor oral health can impair the functions of the oral cavity, including difficulty in chewing, leading to an impaired formation of food boli and problems in swallowing, resulting in poor nutrition; it can also promote mouth breathing and can significantly restrict communication and social participation for older adults. Oral microbiome dysbiosis contributes not only to the development of oral diseases but also contributes or may contribute to whole-body disorders. Lu Gao et al. in their review of last trials shows (Gao et al., 2018): - gastrointestinal system diseases: inflammatory bowel disease (IBD): ulcerative colitis (UC), Crohn’s disease (CD) other gastrointestinal system diseases: liver cirrhosis, and pancreatic cancer, - nervous system diseases: Alzheimer disease (AD), - endocrine system disease: diabetes, adverse pregnancy outcomes (APOs), obesity, polycystic ovary syndrome (PCOs),

sis teosta f pro o ss Lo

Cellular sere sce nc e

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n on ati nic mu Altered intercellular com

Rare diseases

Orofacial pain • Altered intercellular communication

Perodontal disease • Altered intercellular communication • Epigenic regulation • Cellular senescence D

er eg ula ted nu trie nt

ce ll e xh au sti on

Oral complications of systemic diseases • Sjogren’s syndrome - altered proteostasis; altered cellular communication; loss of proteostasis • Chronic graft-versus-host-disease - genomic instability

Epig enetic alterations

Ge no mi ci ns ta bi

Head and neck cancers • Genomic instability • Telomere attrition • Cellular senescence • Epigenetic alterations

n itio ttr ea er om

Te l

y lit

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Fig. 1 Molecular links shared by the hallmarks of aging and age-related oral diseases Based on An, J.Y., Darveau, R. and Kaeberlein, M. M. (2018). Oral health in geroscience: Animal models and the aging oral cavity, GeroScience 40(1), 1–10.

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- immune system diseases: rheumatoid arthritis and shift in the oral microbiome with HIV infection, - atherosclerosis. As the patients attend more frequently physicians than dentists the first have higher possibility of early diagnosis of poor oral conditions. The experts recommend reframing medical care systems and creating a new framework for multiprofessional partnerships, beginning with primary care (Fig. 2) (Hummel et al., 2015; Kossioni et al., 2018). Patients should be partners in their own health care. The importance of prevention, education, development of oral-health selfcare practices, and motivation of patients and their families is emphasized (Hummel et al., 2015). Repetition of health practices, which are easily incorporated into daily routines, can become automatic and can be maintained even in the face of advancing cognitive decline (Friedman, 2014). Kossioni et al., of the European Geriatric Medicine Society Task and Force Group (EUGMS T&F) and European College of Gerodontology, promote the incorporation of oral cavity examination into routine assessment of general health as best practice for general practitioners and specialists. A screening examination of the oral cavity is a simple procedure and, as a routine, can contribute to improvements in therapy and further monitoring. One example of validated, reliable, and comprehensive screening for oral health is the Oral Health Assessment Tool (OHAT), used primarily by caregivers in residential-care facilities (Table 1). An extraoral light source, as opposed to any intraoral light sources or specific dental equipment, is sufficient to perform this kind of screening (Chalmers et al., 2005). This tool is a modification of the former Kayser-Jones Brief Oral Health Status Examination (BOHSE) (Kayser-Jones et al., 1995), the first published comprehensive OHAT for use by caregivers for residents in residential-care facilities, especially for residents with moderate-tosevere dementia (Chalmers et al., 2005). OHAT consists of eight categories. Saliva is a dynamic liquid environment regulating all functions of the oral cavity. Morphological categories comprise lips, tongue, gums, tissues, and natural teeth. Oral cleanliness influences the development of plaquerelated diseases (caries, gingivitis, periodontitis). Dentures recreate conditions enabling proper biting and chewing of food, food bolus formation, pronunciation, and aesthetic appearance. Dental pain is a subjective symptom of developing pathologies. Any score of 1 (¼ changes) or 2 (¼ unhealthy) requires referral to a dentist.

Partnering to expand prevention Primary care Dental care Population health management and reporting toolsa

Quality improvement methodology

Medication list management

Care coordination

Management of chronic diseases

a

Restorative treatment of caries Prevention Risk Assessment Dietary Counseling Oral Hygiene Training Smoking Cessation Fluoride Varnish Fluoride Supplementation Antibiotic Rinses Screening for Oral Diseases

Dental X-rays Endodontics Dental sealants

Orthdontics

Periodic cleaning

Crowns and implants

Mouth guards

Deep scaling and root planing for periodontal disease

Including structured EHR data and diagnostic codes, diseasa registries, and other tools

Fig. 2 Partnering to expand prevention. Modified from Hummel, J., Phillips, K., Holt, B. and Hayes, C. (2015). Oral health: An essential component of primary care. Seattle, WA: Qualis Health.

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Oral Health Assessment Tool (OHAT) for dental screening.

Resident

Completed by Date ScoresdYou can circle individual words as well as giving a score in each category (*if 1 or 2 scored for any category please organize for a dentist to examine the resident) Category 0 ¼ Healthy 1 ¼ Changes* 2 ¼ Unhealthy * Category scores Lips Smooth, pink, moist Dry, chapped, or red at corners Swelling or lump, white/red/ulcerated patch; bleeding/ulcerated at corners Tongue Normal, moist, roughness, pink Patchy, fissured, red, coated Patch that is red and/or white, ulcerated, swollen Gums and Pink, moist, smooth, no bleeding Dry, shiny, rough, red, swollen, one Swollen, bleeding, ulcers, white/red tissues ulcer/sore spot under dentures patches, generalized redness under dentures Saliva Moist tissues, watery, and free-flowing Dry, sticky tissues, little saliva present, Tissues parched and red, very little/no saliva resident thinks they have a dry mouth saliva present, saliva is thick, resident thinks they have a dry mouth Natural teeth No decayed or broken teeth/roots 1–3 decayed or broken teeth/roots or 4þ decayed or broken teeth/roots, or yes/no very worn-down teeth very worn down teeth, or fewer than 4 teeth Dentures yes/ No broken areas or teeth, dentures 1 broken area/tooth or dentures only More than 1 broken area/tooth, denture no regularly worn, and named worn for 1–2 h daily, or dentures not missing or not worn, loose and needs named, or loose denture adhesive, or not named Oral Clean, and no food particles or tartar in Food particles/tartar/plaque in 1–2 areas Food particles/tartar/plaque in most cleanliness mouth or dentures of the mouth or on small area of areas of the mouth or on most of dentures or halitosis (bad breath) dentures or severe halitosis (bad breath) Dental pain No behavioral, verbal, or physical signs Are verbal &/or behavioral signs of pain Are physical pain signs (swelling of of dental pain such as pulling at face, chewing lips, cheek or gum, broken teeth, ulcers), as not eating, aggression well as verbal &/or behavioral signs (pulling at face, not eating, aggression) , Organize for resident to have a dental examination by a dentist TOTAL , Resident and/or family/guardian refuses dental treatment SCORE , Complete Oral Health Plan and start oral hygiene care interventions for resident , Review this resident’s oral health again on Date: __/__/____ Modified from Kayser-Jones, J., Bird, W.F., Paul, S.M., Long, L. and Schell, E.S. (1995). An instrument to assess the oral health status of nursing home residents. Gerontologist 35(6), 814–24 by Chalmers, J., King, P., Spencer, A.,Wright, F. and K. Carter. (2005). The oral health assessment tooldValidity and reliability. Australian Dental Journal 50(3), 191–9.

Saliva Function and Secretion The role of saliva in the oral cavity cannot be overestimated. Speaking, chewing, swallowing, tasting, and digestion are all severely affected when the production of saliva is impaired. The antimicrobial, remineralizing, and buffering properties of saliva protect the balance of the oral cavity (Gonsalves et al., 2008). Saliva as a whole (mixed) is the secretion of three pairs of large salivary glands (90% of total secretion) and numerous minor glands (up to 10%). The parotid glands produce enzyme-rich serous saliva, the submandibular glands produce mixed, mucin-rich saliva, and the sublingual glands produce mucous saliva. The small glands, scattered throughout the oral mucosa, with the exception of the anterior part of the hard palate and the gums, excrete mixed saliva. Pure mucous saliva is produced by small salivary glands located in the region of the soft palate.

Age-Related Conditions Age-related structural changes affect all salivary glands, which nevertheless retain their secretory capacity. In healthy adults, no symptoms of dry mouth are observed (Friedman, 2014). At the same time, oral dryness is among the most characteristic symptoms in the elderly. Its overall prevalence in this group is 12%–28%, but it rises to 40%–60% in institutionalized individuals (Kossioni and Dontas, 2007). Thomson emphasizes the need for adequate definitions of the terms describing this problem. Xerostomia, a symptom, is a subjective feeling; its diagnosis requires asking the patient directly about the complaint of dry mouth. Salivary-gland hypofunction (SGH), as a symptom, can be diagnosed objectively using a salivary-flow measurement (Thomson, 2015). The prevalence of xerostomia in noninstitutionalized older people is 12%–39%; for SGH, 17%–47%. Furthermore, the conditions are not necessarily concurrent (Thomson, 2005).

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Impairment of saliva secretion in elderly patients results from complex conditions. Conditions such as cancer, cardiovascular disease, and neurodegeneration are related to the aging itself (Niccoli and Partridge, 2012). There is also a strong positive correlation between age and the prevalence of multiple chronic disorders. According to Cassell et al., the mean number of morbidities in a group of patients aged 65–74 was 2.06%; in a group aged 75–85, 2.97%; and in a group older than 85, 3.65% (Cassell et al., 2018). Increasing numbers of physical disorders contribute to the development of mentalhealth disorders, particularly depression (Cassell et al., 2018; Barnett et al., 2012). Multimorbidity is related to the prescription of multiple medications. The main complications related to polypharmacy include: adverse drug reactions and interactions, exposure to potentially inappropriate medications, underprescription of recommended drugs, medication errors, poor compliance, cognitive and functional decline, occurrence of geriatric syndromes (e.g., delirium, malnutrition), additional institutionalization, higher mortality, and greater costs of treatment (Mannucci et al., 2014).

Etiology of Dry Mouth General systemic states that contribute to the presence of dry mouth (both xerostomia and SGH) include the following (Mortazavi et al., 2014):

• • • • • • • • • • • • • •

diabetes, types 1 and 2, systemic lupus erythematosus (SLE), viral infections (e.g., HIV, HCV, EBV, CMV, HTLV-1), autoimmune thyroid disease, end-stage renal disease, graft-versus-host disease, primary biliary cirrhosis, ectodermal dysplasia: hypoplasia/aplasia of salivary glands, lymphocytic infiltration, parenchymal destruction, and fibrosis within salivary-gland tissue, sarcoidosis, rheumatoid arthritis (RA), hemochromatosis, Parkinson disease, tuberculosis, amyloidosis.

Medications associated with oral dryness are called xerogenic. This group involves drugs that reduce salivary flow, alter the threshold for dry mouth perception, or both (Thomson, 2015). Commonly reported xerogenic drugs include anticholinergics, antihistamines, tricyclic antidepressants, diuretics, antihypertensives, antispasmodics, antiparkinson medications, antiarrhythmics, anxiolytics, NSAIDs, antiarthritics, and antineoplastics (Gonsalves et al., 2008; Thomson, 2005). A special etiologic factor in dry mouth is radiotherapy in the head and neck region as a part of cancer therapy (Gonsalves et al., 2008). Local factors include mouth breathing, sometimes caused by muscle hypotonia. Some researchers also emphasize the role of the cumulative effect of an unhealthy lifestyle and environmental exposure to harmful factors (e.g., tobacco) (Niccoli and Partridge, 2012).

Sjögren Syndrome One characteristic state that contributes to salivary function impairment is a chronic inflammatory autoimmune disease known as Sjögren syndrome. The primary type of this syndrome (pSS) is a local disorder related to the salivary and lacrimal glands, with symptoms including dry eyes and a dry mouth. The secondary type (sSS) develops in the course of other autoimmune diseases, for example, SLE (15%–36%), RA (20%–32%), or systemic sclerosis (11%–24%), as well as, less frequently, multiple sclerosis, autoimmune hepatitis, and thyroiditis. Signs and symptoms of sSS may involve various organs and thus present a diverse clinical picture. Dryness may be the first manifestation of the underlying disease (Stefanski et al., 2017). A diagnosis of pSS requires oncological alertness. In about 5% of patients with pSS, malignant non-Hodgkin lymphoma (NHL) of the B-cell lineage occurs. Because of the increased risk of developing NHL, patients require systematic monitoring and further diagnostic investigation (Stefanski et al., 2017; Nishishinya et al., 2015).

A Clinical Picture of Dry Mouth Impaired production of saliva significantly influences patients’ well-being. Patients experience difficulties when talking, chewing dry foods, and swallowing. Their sense of taste is altered, and the oral mucosa is thinner and more prone to damage. The rate of oral selfcleaning is reduced, contributing to greater prevalence and intensity of caries compared to populations without hyposalivation. Other symptoms include burning mouth syndrome (BMS), oral pain, and halitosis. Patients often have problems with the use of dentures (reduced adhesion, discomfort) (Fig. 3E). Candida infections also occur with greater frequency. In terms of oral health, quality of life is significantly reduced (Kossioni and Dontas, 2007).

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Fig. 3 (A) Sublingual area in a 70-year-old female with hyposalivation: dry mucosa of dull appearance, no saliva present (left) in comparison to the physiologic clinical picture in an 81-year-old female (right). (B) A 70-year-old female with SGH: dry, chapped lower lip. (C) A 70-year-old female with SGH: dry, fissured, red, depapillated tongue. (D) A 70-year-old female with SGH: dry, sticky tissues, no saliva present. (E) A 70-year-old female with SGH: poor adhesion of dentures.

Diagnosis, Prevention, and Treatment The following xerostomia inventory may be useful for primary-care providers in diagnosing this problem (Table 2) (Thomson, 2015). To manage dry mouth effectively, identification of the main cause is essential (Mortazavi et al., 2014). A multidisciplinary team approach to patient health and care is required (Kossioni and Dontas, 2007; Mannucci et al., 2014). Treatment of oral dryness includes regular review of the patient’s medication list and regimen, prescription of less xerogenic drugs where possible, and the use of salivary stimulants and substitutes. The patient should be given dietary advice, and liquid intake should be monitored (Kossioni and Dontas, 2007). The use of air humidifiers may also be beneficial (Friedman, 2014). Regular dental visits are aimed at reducing the number of dryness episodes.

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Table 2

The available versions of the xerostomia inventory. Original version

Item content

Response options Possible score range

• • • • • • • • • • •

I sip liquids to aid in swallowing food My mouth feels dry when eating a meal I get up at night to drink My mouth feels dry I have difficulty in eating dry foods I suck sweets or cough lollies to relieve dry mouth I have difficulties swallowing certain foods The skin of my face feels dry My eyes feel dry My lips feel dry The inside of my nose feels dry “Never” (scoring 1), “Hardly ever” (2), “Occasionally” (3), “Frequently” (4), or “Always” (5) 11 (no xerostomia) to 55 (most severe xerostomia)

Short-form version

•

My mouth feels dry when eating a meal

• •

My mouth feels dry I have difficulty in eating dry foods

• •

I have difficulties swallowing certain foods My lips feel dry “Never” (scoring 1), “Occasionally” (2), “Often” (3) 5 (no xerostomia) to 15 (most severe xerostomia)

Data from Thomson, W.M. (2015). Dry mouth and older people, Australian Dental Journal 60(S1), 54–63.

Noncarious Lesions and Toothwear With age, changes in the shape of the teeth are observed, resulting mostly from causes other than caries, such as contemporary diet, wear, habits, chronic diseases, parafunctions, and individual susceptibility. The percentage of organic components in dental hard tissues decreases, whereas that of inorganic components increases. With age, dental pulp undergoes senescence; the number of cell elements decreases, the number and density of collagen fibers increases, and pulp vascularization and innervation are reduced. Deposition of dentine, along with the gradual obliteration of dentinal tubules, is visible; consequently, the teeth become more brittle and prone to fracture. There are four basic types of wear: 1. Attrition: Caused by contact between teeth; observed typically on occlusal and approximal surfaces. Loss of teeth contributes to occlusal overload of residual dentition, and wear progresses more rapidly. A typical clinical sign of attrition is shortening of the crowns (“short crowns”) (Figs. 4 and 5) (Burke and McKenna, 2011). At advanced stages, attrition may cause severe functional, aesthetic, and biological complications. 2. Abrasion: Caused by the interaction of teeth and foreign bodies; most often caused by improper hygienic procedures or by habits (Burke and McKenna, 2011) such as pipe smoking. 3. Abfraction: The etiologic factor is occlusal overload, causing frequent tensions in the cervical region. 4. Erosion: Chemical dissolution of minerals connected with the action of acids and chelating agents included in dietary products (e.g., citric acid) or internal disorders (e.g., gastroesophageal reflux disease, or GERD). The localization of an erosive lesion depends on the relevant etiology. Erosion of the labial surfaces of the upper front teeth, premolars, and lower canines is caused

Fig. 4 Attrition in a 87-year-old female: the most advanced process is visible in the central region of lower dental arch, where occlusal contact occurs (yellowish dentine surrounded by brighter enamel).

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Fig. 5 Attrition in a 61-year-old male: worn-down teeth, with significantly changed shapes, reduced heights of the crowns, and exposed dentine (brownish spots surrounded by brighter enamel).

Fig. 6 Erosion on the labial surface of the upper teeth in a 67-year-old male: a shallow, wide cavity in the cervical region, with exposed dentine in its central part (yellowish spot), cervical region of lower premolars affected with abrasion (wedge-shaped cavities).

by extrinsic acids (foodstuffs, occupational exposure), erosion of the lingual surfaces of upper teeth, and the occlusal surfaces of all teeth by intrinsic acids (GERD, alcoholism, other gastrointestinal disorders). Reflux may be the consequence of taking certain medications. Long-term medication and polypharmacy raise the risk of dental erosive complications. Medications that may cause gastrointestinal symptoms related to gastric acid withdrawal include cardiac glycosides, opiate analgesics, anticancer agents, nonsteroidal antiinflammatory drugs, diuretics, and alcohol. Antihistamines, antidepressants, and antihypertensive drugs also have important impacts (Pontefract, 2002). Clinically, in the course of the erosive process, convex areas of teeth are flattened and shallow concavities occur (Fig. 6). On occlusal surfaces, cusps become rounded or cupped, and the edges of existing restorations may protrude above the surface of the tooth. In severe cases, tooth morphology disappears. Shortening of the tooth crown can lead to functional and aesthetic problems (muscle, TMJ) (Pontefract, 2002). Prevention of erosion includes dietary and hygienic instructions. A patient’s list of medications should be reassessed. General disease should be treated. Restorative dental treatment is indicated in cases of functional or aesthetic impairment. (Pontefract, 2002).

Caries Lesions Dental caries (coronal and root) is a disease associated with modern civilization and lifestyle changes. This condition, associated with the negative effects of life brought on by a highly developed civilization, is widespread. Changes in lifestyle have tended to eliminate natural environmental factors favoring the maintenance of health. Caries is a contagious disease consisting of the mineral dissolution of inorganic components followed by the decomposition of the organic matrix of enamel, dentin, and root cementum. Root cementum and dentin, as they are less mineralized, are more susceptible to cavitation than enamel. Untreated caries leads to the involvement of dental pulp and periapical tissues, the development of acute or chronic conditions, and, finally, loose teeth. All of these consequences can be avoided by early detection.

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Fig. 7 Cavitated and active root caries, visible gingival recessions, gingivitis, and dental plaque in a 74-year-old male (visible Lichen planus of buccal mucosa).

Etiological factors for development of caries include the presence of acidogenic and acidophilic bacteria, consumption of fermentable carbohydrates, long-term acidification of the oral cavity, and histological and morphological structures of teeth that favor the formation and stagnation of dental plaque. The literature points out that chronic illness, poor-quality diet, impaired salivary function, the use of xerogenic medication, problems with manual dexterity, the need for caregiver assistance, impaired cognitive ability, and the declining use of dentalcare services contributes to the risk of caries (Friedman, 2014). The polymicrobial microbiome forms a biofilm that forms an especially well-organized structure in plaque stagnation sites, developing a special pattern in the oral cavity. Within the highest category of risk of caries development are the cementumenamel junction; exposed hard tissues of roots, fossae, and grooves of crowns; surfaces between teeth under contact points, under overhangs of fillings, and prosthetic reconstructions; and parts of teeth adjacent to removable partial dentures (Carrilho, 2017). Monosaccharides (simple sugars) and disaccharides, known as nonmilk extrinsic sugars, serve as substrates for cariogenic bacteria. These fermentable carbohydrates are present in food in a free form or added as flavor boosters. Snack foods, seepage from sweet drinks, and foods with a sticky consistency prolong acidification and demineralization times in the oral cavity. Protective salivary remineralization is not effective in such conditions; thus, caries develop. Root caries lesions (RCLs) are predominant in older adults as a consequence of the apical migration of the gingival margin and exposure of the hard tissue of roots to the environment of the oral cavity. RCLs may be primary or secondary, cavitated or noncavitated, active or inactive. A general decline in functional ability may be an early sign of subsequent deterioration of oral cavity status as reflected in the development of root caries (Friedman). Institutionalized or frail elders are characterized by a greater prevalence of root caries than those living independently. Root caries is a major cause of tooth loss in older adults. Tooth loss and edentulism lead to deterioration in all functions of the oral cavity and have the most significant impact on quality of life in terms of oral health (Friedman, 2014; Carrilho, 2017) (Fig. 7). Efforts should be made to protect tooth integrity; accordingly, in addition to conventional preventive therapies, new approaches aimed at protecting teeth from caries continue to emerge. The conventional, twice-a-day use of highly concentrated fluoride toothpaste (5000 ppm) during brushing, combined with a professional fluoride application, is the most evident choice for the prevention and controlling of root caries. Attempts are made to modify the composition and structure of the dental pellicle to enhance the remineralization and to inhibit bacterial adhesion. Another emerging strategy is the biomodification of dentin (Carrilho, 2017). Minimal invasive management of cavitated root caries is recommended. The options from remineralization and arresting shallow and broad lesions to mechanical and chemomechanical root caries management are taken into consideration. The material of choice for the restoration of a lost shape are glass ionomer cements (GIC), but for saliva-deficient elders, a highly polished resin composite with enamel/dentin adhesive or resin-modified GIC adhesive systems would be the preferable option (Carrilho, 2017).

Oral Mucosa Age-Related Changes of the Oral Mucosa With increasing age, the oral mucosa reveals diminution in thickness of the epithelium as well as loss of elastic fibers and disorganization of collagen bundles in the connective tissue. The epithelial cells enlarge but flatten, and the thickness of keratin layer increases; however, the epithelial cell proliferation rate is not altered by age. In the elderly, a decline in resilience of the oral mucosa accompanied by reduction in microvascularity increases susceptibility to infection and trauma as well as impaired wound healing (Lamster et al., 2016). The rise in incidence of systemic diseases and the use of multiple medications may result, in turn, in a wide variety of mucosal lesions (see the text that follows).

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Oral Manifestations of Systemic Diseases Gastrointestinal diseases The oral cavity is an entry into the gastrointestinal tract and is often involved in conditions that affect the digestive system. Gastroesophageal reflux may lead to burning sensations, halitosis (bad breath), as well as mucosal and dental erosions (Marx and Stern, 2012; Odell, 2017). Some inflammatory bowel diseases, particularly Crohn’s disease and ulcerative colitis, may also affect oral mucosa. Crohn’s disease has its second peak incidence in the sixth and seventh decades of life and may involve the development of noncaseating granulomas, specifically within lips and buccal mucosa, producing the characteristic cobblestone appearance. Linear ulcers with hyperplastic folds of inflamed mucosa along their margins can be present along the buccal sulci, and the gingiva may show an erythematous nodular gingivitis with hyperplastic tags (Odell, 2017). In the course of ulcerative colitis, oral lesions are rare. Both ulcerative colitis and Crohn’s disease are sometimes associated with characteristic pustular eruptions of the oral mucosa, defined as pyostomatitis vegetans, which may be a specific marker of a silent form of inflammatory bowel disease (Odell, 2017). In turn, petechiae and yellowing of the oral mucosa, excessive gingival bleeding after minor trauma, and oral lichenoid reaction may be manifestations of liver disease.

Hematologic disorders The incidence of the hematologic disease progressively increases with age. About 70% of cases of leukemia occur in individuals over the age of 60, with the most common type of leukemia in the elderly being acute myeloid leukemia. Typical oral signs are gingival swelling (caused by infiltration with leukemic cells) and mucosal ulcerations. Purplish mucosal patches and prolonged bleeding after surgery (resulting from thrombocytopenia) as well as delayed healing (caused by lack of normal white cells) should also raise suspicion of acute leukemia. In chronic leukemias, oral manifestations are relatively uncommon and mild (Odell, 2017). Anemia is another very common hematologic condition in older individuals. It is the most frequent cause of glossitis with characteristic erythematous surface of the tongue resulting from atrophy of the epithelium, which becomes thin and loses its filiform papillae. Accordingly, a fiery red, smooth and sore tongue always requires careful hematological investigation (hemoglobin indices, serum iron, folate levels). Other important signs of anemia in the oral cavity include: angular stomatitis, recurrent aphthae and infections, particularly candidosis (Odell, 2017).

Immune-based diseases There are some diseases precipitated by an actual disturbance in immune function, which, in turn, usually provokes an inflammatory response. Mucous membrane pemphigoid is one from a group of B-cell-mediated autoimmune diseases that characteristically forms vesicles and bullae on skin and mucous membranes. It is a disease of older adults (typically in the seventh decade), and females are predisposed. The first sign may be a reddened and burning attached gingiva (desquamative gingivitis), followed by a diffuse series of vesicles, ulcers, and erythematous areas involving palatal, buccal, or labial mucosa. Similarly, pemphigus vulgaris results in multiple bullae that quickly progress into large, shallow ulcerations. It occurs, however, more often in younger patients than does mucosal pemphigoid and is usually more symptomatic (Marx and Stern, 2012).

Drug-Induced Oral Adverse Effects Systemic drug treatment may produce untoward oral reactions. The most common side effect is a dry-mouth syndrome, which may be caused by various drugs, including antihypertensives (diuretics), sympathomimetic drugs (pseudoephedrine, bronchodilators, drugs suppressing appetite) and antimuscarinic drugs (atropine, tricyclic antidepressants, selective serotinine-reuptake inhibitors, antihistaminic drugs, and neuroleptics). Often, oral lichenoid reactions may occur. These lesions are indistinguishable from oral lichen planus (OLP) (see the “Oral Potentially Malignant Disorders” section), both clinically and histologically. Lichenoid reactions, apart from amalgam contact reaction and graft-versus-host disease, may be induced by beta-blockers, ACE inhibitors, lithium, antimalarials, methyldopa, and some NSAIDs. These lesions are more prone to malignant transformation than OLP. In turn, gingival hyperplasia may follow a long-term medication regimen with the antiepileptic drug phenytoin, immunosuppressant ciclosporin, and calcium channel blockers (e.g., nifedipine). The overgrowth involves interdental papillae, which become bulbous and may cover the teeth. Other postmedication oral reactions are rare but may have tumultuous clinical course. These include hypersensitivity reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, as well as oral lesions in the course of depression of marrow function (caused by antibacterials, analgesics, phenothiazines, and antithyroid agents) or depression of cell-mediated immunity (in the course of immunosuppressive therapy).

Oral Potentially Malignant Disorders Most oral cancers are squamous cell carcinomas (SCCs). They usually develop in clinically normal mucosa. However, some oral disorders may indicate an increased risk of developing oral SCC in the future. According to the WHO, they are designated as

522 Table 3

• • • • • • • •

Oral Care Oral potentially malignant disorders.

Leukoplakia Erythroplakia Palatal lesions in reverse smokers Oral submucous fibrosis Actinic keratosis Lichen planus Discoid lupus erythematosus Hereditary disorders (dyskeratosis congenita, epidermolysis bullosa)

Modified from Warnakulasuriya, S., Johnson, N.W. and Van Der Waal I. (2007). Nomenclature and classification of potentially malignant disorders of the oral mucosa, Journal of Oral Pathology & Medicine 36(10), 575–80.

Fig. 8

Leukoplakia in a 67-year-old male smoker. White, thin and leathery plaque with superficial cracks localized on the buccal mucosa.

oral potentially malignant disorders (OPMDs). OPMDs include a variety of heterogeneous lesions and conditions (Table 3) (Warnakulasuriya et al., 2007). Leukoplakia is the most common OPMD. Its estimated average prevalence is 2% worldwide. Leukoplakia is defined as “white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer” (Fig. 8). It usually occurs in male smokers in their fifth to seventh decade of life. Leukoplakia, which is a purely clinical designation, has no characteristic microscopic picture, hence the term should not be used by the pathologist. The diagnosis requires the exclusion of several other lesions (lichen planus, lichenoid reaction, frictional keratosis, traumatic or chemical injury, nicotine stomatitis, pseudomembranous candidiasis (thrush), hairy leukoplakia, leukoedema, and white sponge naevus) (Warnakulasuriya et al., 2007). Leukoplakia is clinically classified as homogeneousduniform in appearance, usually thin and leathery with occasional superficial cracksdor as a nonhomogeneous typedspeckled (mixed, white-red patch), nodular with polypoid excrescences or verrucous (cauliflower-like, white or gray appearance) (Kuriakose, 2017). The overall malignant transformation rate for leukoplakia is estimated at 5% (Kuriakose, 2017). Some factors increase the risk of its malignant transformation (Table 4) (Odell, 2017; Van der Waal, 2009). Importantly, the histological presence of epithelial dysplasia is the single most significant predictor of malignant transformation (Kuriakose, 2017).

Table 4

• • • • • • • • • •

Risk factors that increase the malignant potential of oral leukoplakia.

Advanced age Female gender Leukoplakia in nonsmokers (idiopathic leukoplakia) Location on the lateral or dorsal part of the tongue, floor of the mouth, and retromolar region Large lesion Nonhomogeneous type Long duration of lesion Enlargement or change in character of preexisting lesion Presence of Candida albicans Presence of epithelial dysplasia

Based on Odell, E.W. (2017). Cawson’s essentials of oral pathology and oral medicine (9th edn.), Elsevier Ltd.; Van der Waal, I. (2009). Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management, Oral Oncology 45(4–5), 317–23.

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Fig. 9 Lichen planus in a 65-year-old female. A lacy network of white striae on the buccal mucosa. The lesions are usually distributed symmetrically. Clinical diagnosis was confirmed by histopathology.

Proliferative verrucous leukoplakia (PVL)da distinct type of leukoplakiadoccurs usually in female nonsmokers older than 60. It is defined as multifocal white plaques persistent for years that increase in size and thickness, progressing from flat to a verrucoid and exophytic surface. The malignant transformation rate for PVL is high (about 70%) (Kuriakose, 2017). OLP is a chronic inflammatory disease of unclear etiology that affects 1%–2% of the world population. The reported malignant transformation of OLP is less than 1%. Clinical presentation is variable, ranging from a lacy network, usually located on the buccal mucosa (Wickham’s striae), and white plaques to atrophic areas and ulcers (Fig. 9). Histopathological confirmation of the clinical diagnosis is mandatory. Typical histopathological features of OLP include: well-defined, bandlike, mainly lymphocytic infiltrate restricted to the superficial connective tissue and liquefaction degeneration of the basal layers (Kuriakose, 2017). Erythroplakia is a rare lesion; however, it bears the highest risk of malignant transformation among all OPMDs. It is defined as a “fiery red patch that cannot be characterized clinically or pathologically as any other definable disease.” Alcohol consumption and tobacco smoking or chewing are listed as risk factors. In the Western world, erythroplakia is encountered particularly in the elderly (the sixth to seventh decades of life), but in India it occurs in younger patients. Clinical examination and histopathological evaluation are crucial to exclude various mimickers, including desquamative gingivitis, discoid lupus, atrophic lichen planus, erythematous candidiasis, and other inflammatory/infectious conditions (Kuriakose, 2017). Oral submucous fibrosis (OSF) is associated with chewing areca nut products. It is a quite common disorder in the Indian subcontinent, but not elsewhere. Initially, burning sensations and scattered small vesicles develop, followed by fibrosis and the loss of vascularity, which leads to extreme pallor of the affected areas (especially buccal mucosa, soft palate, or inner aspects of the lips). The fibrosis starts immediately below the epithelium but extends to deeper tissues. Involvement of the muscles of mastication frequently occurs, leading to a limitation in mouth opening. At this stage, the epithelium appears smooth, thin, and atrophic (Odell, 2017). Approximately 7%–13% of OSFs will progress to SCC (Kuriakose, 2017). OPMDs constitute a very heterogeneous group of lesions, and correct diagnosis may be difficult, especially for an inexperienced clinician. For that reason, every patient with any red or white lesion in the mouth should be referred to a specialist. It may turn out to be innocuous, but it must be assessed for the possibility of future carcinomatous change. All patients with a diagnosis of OPMD should be followed up on a regular basis for the rest of their lives.

Periodontium Age-Related Changes in Periodontium The periodontium provides the support necessary to maintain teeth in function. It comprises gingiva, alveolar bone, periodontal ligament, and root cementum. With healthy aging, the periodontal tissues are depleted but still functional (Lamster et al., 2016). In the course of life, the metabolic activity of the periodontium gradually reduces (Newman et al., 2015) because of the general decline in cellular responsiveness. The number of cellular elements decreases with age. The gingival connective tissue gets coarser and denser while the periodontal surface of the bone and the insertion of collagen fibers becomes more irregular. The junctional epithelium slowly migrates apically with consequent gingival recession (usually less than 3 mm). The thickness of the periodontal ligament is frequently diminished because of the reduction in the force applied by masticatory muscles over time. The lifelong apposition of dental cementum reduces the periodontal gap, as seen on periodical radiographs of older individuals (Newman et al., 2015). Although there is some increase in the crown-to-root ratio, the teeth retain their physiologic mobility, and probing depths should not exceed 4 mm (Lamster et al., 2016) (Fig. 10). Deviations from this standard can be considered pathologic.

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Fig. 10 Periodontium in an 89-year-old female. Coral pink, dense, and firm gums with small gingival recessions resulting from physiological apical migration of the junctional epithelium.

Table 5

Risk elements for periodontal disease.

Risk factors: • Smoking • Diabetes mellitus • Periopathogens Risk determinants: • Genetic factors • Age • Gender • Socioeconomic status • Stress Risk indicators: • HIV/AIDS • Osteoporosis Risk markers: • Previous history of periodontal disease • Bleeding on probing Modified from Newman, M.G., Takei, H.H., Klokkevold, P.R. and Carranza, F.A. (2015). Carranza’s clinical periodontology (12th edn.), Elsevier Sounders.

Periodontal Disease in the Elderly While gingivitis and aggressive forms of periodontitis are mostly seen in children and young adults, chronic periodontitis is a disease of adults and seniors. Periodontitis is an inflammatory disease of supporting tissues of teeth caused by specific microorganisms from plaque biofilm that forms around the teeth (Newman et al., 2015). Chronic inflammation results in the continuous release of cytokines, prostaglandins, bacterial toxins, and many other destructive enzymes from inflammatory cells. This process leads to the formation of periodontal pockets and the progressive destruction of connective tissue and alveolar bone. Susceptibility to periodontitis varies greatly between individuals (Hamaker et al., 2012; Van Dyke and Sheilesh, 2005). Elements that may influence the risk for periodontal disease are listed in Table 5. The prevalence of chronic periodontitis increases steadily between 30 and 80 years of age. In the United States, only 20%–30% of the population over 65 years of age are free of periodontitis (Eke et al., 2016). Risk factors for periodontal disease are similar in the elderly as in younger individuals (Lamster et al., 2016). The prevalence of periodontitis increases with age probably not because of the age-related increase in susceptibility to periodontal disease, but rather as a result of the cumulative effects of disease risk factors over a lifetime, that is, deposits of plaque/calculus and risk of developing contributing conditions such as diabetes mellitus (Eke et al., 2016). Clinical manifestations of inflammation, such as changes in color, contour, and consistency of gingiva, bleeding on probing, as well as pathological mobility and migration of teeth are alarming signs indicating periodontal disease (Fig. 11). Typical changes can be observed on panoramic radiograph (Fig. 12). However, other pathological conditions, particularly malignancy (primary intraosseous carcinoma, oral SCC, or leukemia) and Langerhans cell histiocytosis should be always excluded (Fig. 13).

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Fig. 11 Periodontitis in a 69-year-old male. Deposits of dental plaque and calculus, bright red marginal gingiva, pathological migrations of the teeth, and gingival recessions due to periodontal disease.

Fig. 12

Panoramic radiograph of a 66-year-old female with periodontitis. Generalized horizontal bone loss with localized vertical components.

Untreated periodontitis inevitably leads to tooth loss. Since the oral health quality of life decreases with the number of lost teeth, it is crucial to diagnose periodontal disease at an early stage and to introduce therapy that can prevent future tooth loss.

Periodontal Disease as a Risk for Systemic Disease There is a strong evidence that periodontitis may influence a variety of systemic diseases, including cardiovascular disease, diabetes mellitus, neurodegenerative diseases (Alzheimer disease and dementia), and others (e.g., rheumatoid arthritis and cancer) (Scannapieco and Cantos, 2016). Aspiration of oropharyngeal (including periodontal) bacteria can also cause some respiratory diseases, such as pneumonia and chronic obstructive pulmonary disease (Nagpal et al., 2015). In view of these factors, the patient should be referred to the periodontist immediately whenever a suspicion of any of the mentioned diseases occurs.

Oral Cancer in the Elderly Epidemiology SCC comprises 90% of all cancers of the oral mucosa. Undifferentiated carcinoma and cancers arising from small salivary glands of the oral cavity account for the remaining 10%. The incidence of oral SCC (OSCC), in comparison with all other malignant tumors, reaches 2.08%, whereas the mortality rate is 1.69%. Most OSCCs are diagnosed in patients after 50 years of age and about 25% of OSCCs are in patients older than 70 years. Specifically, an increased incidence of OSCC and a higher proportion of females are observed in this group of patients (Gugic and Strojan, 2013).

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Fig. 13 Computed tomography with 3D reconstruction of a 71-year-old male with squamous cell carcinoma of the lower gingiva mimicking periodontits.

Etiology Tobacco and alcohol abuse, poor oral hygiene, oral potentially malignant disorders (see OPMDs), chronic ulcerations of oral mucosa, malnutrition, immunosuppression, and previous radiotherapy are well known risk factors of OSCC. The human papilloma virus is not a significant risk factor of OSCC in the elderly (Datema et al., 2010; Peters et al., 2014). However, age alone is considered a significant factor. Some OSCC risk factors increase the incidence of other cancers, such as larynx, lung, or esophagus cancers. Lifestyle-related habits and severe comorbidities, which, especially in elderly patients, influence the choice of therapy.

Clinical Manifestations of OSCC Predominant locations of primary OSCC are the tongue and the floor of the mouth, followed by the retromolar trigone and the buccal mucosa. The typical ulcerative lesion has an irregular border with induration of surrounding soft tissues. A cauliflower-like appearance is characteristic for exophytic growth, whereas the induration of soft tissues is common in endophytic tumors. Circumscribed induration, infiltration, or fissure are clinical features of the early stages of OSCC (Fig. 14), while covered by keratin, extensive, pinkishwhite ulcerations with bleeding surfaces are encountered in advanced cases (Fig. 15). Otalgia, odynophagia, dysphagia, trismus, halitosis, restricted mobility of the tongue, impaired speech, pathological mobility of the group of teeth, pathological fracture of edentulous mandible, and enlarged cervical lymph nodes indicate advanced OSCC (Fig. 16). Metastases to the regional lymph nodes in the elderly with primary OSCC occur less frequently and in later stages of the disease than in younger patients.

Differential Diagnosis OSCC ulcerations should be differentiated with other tumors, for example, cancers of minor salivary glands, which are usually covered by intact oral mucosa. NHL in the oral cavity, often localized in the tongue or buccal area, also present themselves as tumors covered by mucosa. MALT (mucosa-associated lymphoid tissue) lymphomas occur in the palate and present themselves as surface lesions. Primary malignant melanoma of the oral mucosa, usually with characteristic pigmentation, is more common in the elderly than in patients younger than 70 years. Apart from primary lesions, metastatic tumors from other primaries such as breast, prostate, stomach, kidney cancers, or unknown primaries might be encountered in the oral cavity.

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Fig. 14

Endophytic SCC of the tongue in a 74-year-old female.

Fig. 15

Advanced SCC of the lower gingiva in a 78-year-old female.

Fig. 16

Advanced SCC of the floor of the mouth with infiltration of the lower gingiva in a 68-year-old male.

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Fig. 17

Venous malformation of the buccal mucosa with visible leukoplakia in a 75-year-old male.

Also, other nononcologic pathologies should be excluded, especially in older patients. In medication-related osteonecrosis of the jaw (MRONJ), ulcerations of the oral mucosa with exposed bone appear in elderly patients treated with bisphosphonates, monoclonal antibodies, or angiogenesis inhibitors for osteoporosis, during hormonal treatment of prostate cancer or in cases of breast, digestive tract, and kidney tumors (Ascani et al., 2014). A similar manifestation is characteristic for osteoradionecrosis (ORN) of the jaws in elderly patients who underwent radiotherapy in the past. Venous malformations observed in oral mucosa in an older population might be misdiagnosed as malignant melanoma (Fig. 17).

Diagnosis and Staging of the Primary OSCC Advancement of the primary OSCC is based on the TNM classification introduced by Union Internationale Contre le Cancer and the American Joint Committee on Cancer (UICC/AJCC), modified in 2010, which enables staging of the disease: 0 –IV (Edge and Compton, 2010). Proper staging of OSCC is vital for the choice of a proper treatment modality. Clinical examination of the oral cavity and cervical lymph nodes is followed by biopsy of the tumor. Imaging of the primary focus comprises a CT/MRI of the head and an assessment of lymph nodes by CT/MRI of the neck. Distant metastases are excluded or confirmed by chest CT, abdomen USG/CT, and in advanced cases by PETCT (NCCN guidelines: Head and Neck Cancers, version 1.2018) (NCCN, 2018).

Management of OSCC in the Elderly: Basic Principles Elderly patients with OSCC, in a good general health condition, might receive standard treatment with curative intent, which comprises either surgery or radiotherapy in the early stages of advancement or surgery followed by postoperative radiotherapy and rarely chemoradiotherapy, in advanced stages (Hamaker et al., 2012). Reconstructive procedures should be simple so as not to extend the time of anesthesia and to start rehabilitation as soon as possible (Figs. 18 and 19). Good performance status of the older patient is crucial and should be meticulously evaluated by a Comprehensive Geriatric Assessment (Weir et al., 2012).

Fig. 18

SCC of the floor of the mouth in a 72-year-old male.

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Fig. 19

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The same patient after neck dissection and tumor excision. Reconstruction of the floor of the mouth by a split-thickness skin graft.

Prosthetic Treatment of Geriatric Patients Preserved original teeth or the use of correctly made prosthodontics restorations (fixed and removable), as well as the absence of caries, periodontal tissues, and mucous membrane desease protect an aesthetic appearance and influence the quality of interpersonal contacts and the course of social life. It is important to motivate patients to restore missing teeth, even with a slightly shortened arch (inclusive of premolars) (Friedman, 2014; Aneja et al., 2016). The main goal of prosthetic treatment is the reconstruction of missing teeth and/or crowns that have been damaged for various reasons (pathological abrasion, noncarious-origin cavity). The decision about the type of prosthesis depends on many factors, such as: the number of residual teeth, their clinical condition, the degree of atrophy of the alveolar processes, oral hygiene, and general heath. The medicines used in the group of geriatric patients have an impact on the conditions of the prosthetic treatment, for example, reduced salivation impairs retention of denture baseplate (Friedman, 2014; Budtz-Jørgensen, 1999).

Partial Removable Dentures Partial dentures are used for partially missing dentition, which are more extensive than the use of bridges. Correctly made dentures should meet a number of clinical requirements, such as appropriate height of the occlusion, correct course of the occlusal surface of the artificial dentition, correct relation of the mandible to the maxilla, and proper range of the prosthesis baseplates. The reduced occlusal height may be caused not only by its incorrect determination during clinical procedures, but also by too-long use of prostheses by patients, resulting in excessive artificial tooth wear. Clinical evaluation of prostheses performed by a physician should include the stage of intraoral verification. Artificial teeth should imitate the shape of natural teeth (Fig. 20A). Shortened and deformed artificial teeth, can suggest that they are used a longer time than the recommended 5 years (Fig. 20B). (Friedman, 2014; Budtz-Jørgensen, 1999).

Fig. 20

(A) Proper shape of the artificial teeth in the denture. (B) Excessive wear of chewing surfaces of artificial teeth in an acrylic prosthesis.

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Fig. 21

Incorrect placement of the teeth due to a lack of dentition in the opposite arch in a 69-year-old male.

Fig. 22

Angular cheilitis of the mouth (Cheilitis angularis) in a 40-year-old male.

Missing teeth should be supplemented, and it’s optional to include the first molars. In the case of fixed dentures, we can accept the slightly reduced dental arch. A simple introduction track is to facilitate the use of a denture for the patients with poor manual dexterity. Often, a patient with partially missing teeth or pathological tooth wear requires some preparatory procedures before application of removable appliances (Fig. 21). The reduced occlusal height may result in the occurrence of angular cheilitisdcheilitis angularis. It is an infection with fungal and staphylococcus-streptococcal dominance. The development of this disease is favored by facial skin deprivation, hygienic neglect, muscle flaccidity, reduced short-circuit height of prostheses, significant dry mouth, or salivation in the corners of the mouth (Fig. 22) (Friedman, 2014; AlZarea, 2017).

Complete Dentures There are many causes of tooth loss: dental caries, periodontal disease, hypoplasia, congenitally missing teeth, traumatic injuries, or tooth fracture. Total loss of teeth results in significant changes in the stomatognatic system, such as changing the profile of the face (facial appearance) (Fig. 23), uneven atrophy of the alveolar processes (Fig. 24), pathological ethereality of mastication muscles, and changes in the temporomandibular joints (Budtz-Jørgensen, 1999). Among the elderly patients, the problems of adaptation to complete dentures are much more pronounced than in younger ages. Age-related resorption of the alveolar processes and changes in soft tissues are not conducive to good fixation of appliances on the prosthetic substructure of tissue (Fig. 25A and B), and the exposed chin bite or sharp mylohyoid ridges in the mandible can cause pain. The success of treatment with complete dentures depends on the general health condition, anatomical shape of alveolar processes (degree of bone loss), amount and composition of saliva, and properly made dentures. In the case of poor retention of dentures, the stability can be improved with relining (in the laboratory) or denture glue. Excessive use of the zinc-containing denture adhesives can cause copper deficiency myelopathy, sensory and motor neuropathies, anemia, and bone marrow depression (Friedman, 2014; Budtz-Jørgensen, 1999; Kulkarni and Pawar, 2017).

Implant Restoration In this group of patients, it is important to exclude contraindications to the use of implants due to the significant burden of general diseases, and the prognosis to comply with impeccable dentures and oral hygiene, which is not easy in geriatric patients, for example

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Fig. 23

Changing the profile of the face edentulous an 83-year-old female,

Fig. 24

Uneven atrophy of the alveolar process in a 67-year-old female.

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due to eyesight problems, dexterity, and coordination of the hands (e.g., rheumatoid arthritis) (Friedman, 2014; Budtz-Jørgensen, 1999; El Osta et al., 2017). Implants can be used in combination with the fixed dentures (abutment of bridges) (Fig. 26A–C) or reconstruction of individual teeth and movable ones (in the form of over denture). Especially when implants are used, rigorous compliance with oral hygiene is required (Friedman, 2014; El Osta et al., 2017).

Dental Stomatitis Lack of good fastener for removable appliances often becomes the cause of significant chronic mucosal injuries and promotes the development of prosthetic stomatitis (stomatitis prothetica), that is, inflammation of the oral cavity in the place of contact of the mucous membrane with the prosthesis plate (about 40% of patients using removable restorations). They may take the form of atrophic or proliferative. Local reasons for inflammation include fungal infections (most commonly Candida albicans, Candida tropicalis, and Torulopsis glabrata), which develop favorable conditions of elevated temperature and increased atmospheric pressure under the plate of the appliance, lack of regular cleansing the rest of food, residues through 24-h use of dentures and hygienic neglect; the acrylate plate

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Fig. 25

(A) Radiological picture of a young patient with full dentition. (B) Significant atrophy of the alveolar bone of the mandible.

Fig. 26 (A) Schema of implants in combination with the fixed denture. (B) Implants in combination with the fixed denture in the mouth. (C) Bridge placed in the mouth.

creates favorable conditions for the accumulation and development of the pathogens. It can be a significant reservoir of pathogenic organisms and can contribute to the formation of lower respiratory tract infections by aspiration of the prosthetic plaque pathogens through the nasopharynx mucosa during swallowing. It has already been proven that cytokines and interleukins released during microflora infection of the plaque in the mouth can be transported to the lungs, where they stimulate inflammatory processes (Friedman, 2014; Budtz-Jørgensen, 1999).

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Fig. 27

Decubitus in the mouth caused by denture in an 83-year-old male.

Fig. 28

Granuloma fissuratum in the vestibule of the oral cavity in a 70-year-old.

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Often an additional factor contributing to the development of fungal flora in the oral cavity may be an improperly made prosthesis, with a rough mucosal surface, causing microtrauma of the mucous membrane (Fig. 27), which significantly facilitates the penetration of pathogens into the mucosal surface. In addition, incorrect occlusion of the dentures, chemical trauma (residual monomer in acrylic base), or changes in the mucous membrane that arise with age may affect the exacerbation of the local condition. The systemic factors favoring the development of prosthetic stomatitis include: nutritional deficiencies, lack of vitamins, immunological disorders, general diseases (diabetes, uremia, anemia, kidney disease, cancer, endocrinopathies), drugs such as antibiotics, corticosteroids, cytostatics, and radiotherapy (Friedman, 2014; Budtz-Jørgensen, 1999). A special form of changes associated with the use of prostheses is granuloma fissuratum, taking the form of an additional fold of the mucous membrane in the vestibule of the oral cavity, resulting from chronic trauma of the periphery of the denture plate (Fig. 28) (Friedman, 2014).

Hygiene of Dentures The unfavorable influence of the prosthesis plaque on the development of pathological changes in the oral cavity obliges patients to frequently and thoroughly clean their own teeth and dentures (Fig. 29). Unfortunately, this is not an easy task for the elderly. They should be informed about the necessity of not using dentures during the night and keeping them in a dry environment. Cleaned dentures should periodically be placed in a dish with a disinfectant solution. The most recommended method of cleaning dentures after each meal is to use a soft brush and mild soaps in the form of pastes and powders, especially when patients use adhesive paste (Friedman, 2014; Martín-Ares et al., 2016).

Temporomandibular Joint Dysfunction and Neuromuscular Disorder Temporomandibular joint disorders include dysfunction of the masticatory muscles of the stomatognathic system, temporomandibular joints, and the surrounding structures. They are often associated with abnormal conditions of occlusion. Functional disorders do not include all desease associated with musculoskeletal organs, like inflammatory, degenerative arthritis, and cancer lesions of the

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Fig. 29

Denture plaque due to wrong hygiene of prosthesis in an 81-year-old female.

muscles (multiple sclerosis, tetany, dermatomyositis). They are often the result of the muscle undergoing prolonged and excessive work and nonphysiological loads occurring in the stomatognathic system (Friedman, 2014; Budtz-Jørgensen, 1999; Okeson, 2012). The pain form of the disease is manifested by spontaneous pain in the preaural region, accompanied by pain or tenderness of mastication muscle (raising the jaw). The cause of this problem is a long-term overload of soft tissue causally associated with excessive muscle tension, which sometimes even persists for years (Okeson, 2012). In groups of elderly patients, temporomandibular joint dysfunctions are rare, but physiological changes in the form of loss of flexibility of the joint capsule or joint ligaments might be the cause of habitual joint subluxation. The lack of teeth in the areas of occlusal support or improperly made prostheses are the main causes of dysfunction. Also, neuromuscular disorders for which the origin is mostly genetic can deteriorate by muscle aging (limpness of muscles) or missing teeth, and they are manifested by problems with the use of dentures, lack of tongue coordination, or dysphagia. Physiotherapy and rehabilitation is very important in this group of patients (Friedman, 2014). Treatment of functional disorders involves the use of occlusal splints (acrylic or vacuum-pressed polyethylene foil) and supportive physiotherapy (laser, ultrasound, or manual therapy) (Okeson, 2012).

Pain Conditions Dental Pain Conditions Dental pathology (caries, noncarious lesions, pulpopathia) in the elderly is often of chronic course and does not exhibit symptoms. In the elderly, usually chronic, asymptomatic pulp inflammation, or periapical inflammation is present. Pain occurs only in the case of exacerbation. Its course is nontypical, nonlocalized, and dull. Thus, the pulp state assessment is often difficult to establish and differentiate. The patient should be referred to a dentist for proper diagnosis. The treatment method selection is strongly determined by the patient’s general health.

Nondental Chronic Pain Conditions Aside from the dental inflammatory process, orofacial pain may occasionally stem from disturbances of the central and peripheral nervous system. This is termed neuropathic pain, and it is more prevalent in the elderly. It may arise from nerve trauma associated with pressure, deafferentation, or amputation (neurovascular conflict, neoplasia, trauma, maxillofacial surgery, or root canal therapy), infection (e.g., postherpetic neuralgia, immunodeficiency), or metabolic disease (e.g., diabetic neuralgia) (Max, 2001). Occasionally, it may also be idiopathic (of unknown cause). The most common neuropathic pain is trigeminal neuralgia, characterized by very severe episodes of sudden, shocklike, lancinating unilateral pain typically confined to the area innervated by the second and third division of the trigeminal nerve. It lasts for few seconds to minutes with remissions lasting for days to years. Characteristically, attacks of pain are evoked by innocuous tactile stimuli (e.g., light touch, washing, shaving, brushing teeth, chewing, or talking) and may be accompanied by involuntary spasms of the facial muscles (Feller et al., 2017). Bilateral neuralgical pain may be associated with multiple sclerosis or expanding cranial tumors, but this presentation is more common in younger individuals, usually under 40. Infrequently, neuropathic pain (intense burning sensations, allodynia, and hyperalgesia) may follow mucocutaneous eruptions in the course of herpes zoster (postherpetic neuralgia). In turn, BMS is a rare, but very persistent pain condition typically affecting postmenopausal females in the form of intraoral burning sensations of the anterior two-thirds of the tongue, palate, and other oral sites. It is more common in patients with Parkinson disease. Atypical facial pain is a type of chronic pain that has no objective signs, negative results with all tests, no obvious

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cause, and responds poorly to attempted treatments. Both BMS and atypical facial pain may be secondary to somatoform pain disorder. An evaluation of the patient’s mental state is essential, as depression or psychological overlay is frequent, especially in elderly females (Quail, 2005).

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An instrument to assess the oral health status of nursing home residents. Gerontologist 35 (6), 814–824. Kossioni, A.E., Dontas, A.S., 2007. The stomatognathic system in the elderly. Useful information for the medical practitioner. Clinical Interventions in Aging 2 (4), 591–597. Kossioni, A.E., Hajto-Bryk, J., Maggi, S., McKenna, G., Petrovic, M., Roller-Wirnsberger, R.E., et al., 2018. An Expert Opinion from the European College of Gerodontology and the European Geriatric Medicine Society: European Policy Recommendations on Oral Health in Older Adults. Journal of the American Geriatrics Society 66 (3), 609–613. Kulkarni, R.S., Pawar, R.S., 2017. Fabrication of complete dentures in three visits using existing prosthesisdA simplified technique for geriatric patients. Special Care in Dentistry 37 (2), 99–101. Kuriakose, M.A., 2017. Contemporary oral oncology: Biology, epidemiology, etiology, and prevention. Springer International Publishing, Switzerland. Lamster, I.B., Asadourian, L., Del Carmen, T., Friedman, P.K., 2016. The aging mouth: Differentiating normal aging from disease. Periodontology 2000 72 (1), 96–107. Mannucci, P.M., Nobili, A., Tettamanti, M., Pasina, L., et al., 2014. Multimorbidity and polypharmacy in the elderly: Lessons from REPOSI. Internal and Emergency Medicine 9 (7), 723–734. Martín-Ares, M., Barona-Dorado, C., Guisado-Moya, B., Martínez-Rodríguez, N., Cortés-Bretón-Brinkmann, J., Martínez-González, J.M., 2016. Prosthetic hygiene and functional efficacy in completely edentulous patients: Satisfaction and quality of life during a 5-year follow-up. Clinical Oral Implants Research 27 (12), 1500–1505. Marx, R.E., Stern, D., 2012. Oral and maxillofacial pathology: A rationale for diagnosis and treatment, 2nd edn. Quintessence Pub. Co. Max, M., 2001. Management of neuropathic pain. In: Lund, J.P., Lavigne, G.J., Dubner, R., Sessle, B.J. (Eds.), Orofacial paindFrom basic science to clinical management. Quintessens Publishing Co, Carol Stream, Illinois. Mortazavi, H., Baharvand, M., Movahhedian, A., Mohammadi, M., Khodadoustan, A., 2014. Xerostomia due to systemic disease: A review of 20 conditions and mechanisms. Annals of Medical and Health Sciences Research 4 (4), 503–510. Nagpal, R., Yamashiro, Y., Izumi, Y., 2015. The two-way association of periodontal infection with systemic disorders: An overview. Mediators of Inflammation 2015, 793898. NCCN, 2018. NCCN guidelines: Head and Neck Cancers. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed 17 July 18). Newman, M.G., Takei, H.H., Klokkevold, P.R., Carranza, F.A., 2015. Carranza’s clinical periodontology, 12th edn. Elsevier Sounders. Niccoli, T., Partridge, L., 2012. Ageing as a risk factor for disease. Current Biology 22 (17), R741–R752. Nishishinya, M.B., Pereda, C.A., Muñoz-Fernández, S., Pego-Reigosa, J.M., Rúa-Figueroa, I., Andreu, J.L., et al., 2015. Identification of lymphoma predictors in patients with primary Sjögren’s syndrome: A systematic literature review and meta-analysis. Rheumatology International 35 (1), 17–26. Odell, E.W., 2017. Cawson’s essentials of oral pathology and oral medicine, 9th edn. Elsevier Ltd. Okeson, J.P., 2012. Management of temporomandibular disorders and occlusion, 7th edn. Elsevier, St. Louis, MO. Peters, T.T.A., van Dijk, B.A.C., Roodenburg, J.L.N., van der Laan, B.F.A.M., Halmos, G.B., 2014. Relation between age, comorbidity, and complications in patients undergoing major surgery for head and neck cancer. Annals of Surgical Oncology 21 (3), 963–970. Pontefract, H.A., 2002. Erosive toothwear in the elderly population. Gerodontology 19 (1), 5–16. Quail, G., 2005. Atypical facial paindA diagnostic challenge. Australian Family Physician 34 (8), 641–645. Scannapieco, F.A., Cantos, A., 2016. Oral inflammation and infection, and chronic medical diseases: Implications for the elderly. 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Thomson, W.M., 2005. Issues in the epidemiological investigation of dry mouth. Gerodontology 22 (2), 65–76. Thomson, W.M., 2015. Dry mouth and older people. Australian Dental Journal 60 (S1), 54–63. Van der Waal, I., 2009. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncology 45 (4–5), 317–323. Van Dyke, T.E., Sheilesh, D., 2005. Risk factors for periodontitis. Journal of the International Academy of Periodontology 7 (1), 3–7. Warnakulasuriya, S., Johnson, N.W., Van Der Waal, I., 2007. Nomenclature and classification of potentially malignant disorders of the oral mucosa. Journal of Oral Pathology & Medicine 36 (10), 575–580. Weir, A., Ganti, A.K., deShazo, M., Samant, S., Hurria, A., 2012. Management of squamous cell carcinoma of the head and neck in the elderly: Review and recommendations. Journal of Geriatric Oncology 3 (3), 265–272. World Health Organisation, 2015. World Report on Ageing and Health [Internet]. WHO, Geneva. http://apps.who.int/iris/bitstream/10665/186463/1/9789240694811_eng.pdf.

Osteosarcopenia: The Modern Geriatric Giant J Zanker, SL Brennan-Olsen, and G Duque, Department of Medicine-Western Health, The University of Melbourne, St Albans, VIC, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St Albans, VIC, Australia © 2020 Elsevier Inc. All rights reserved.

Introduction Epidemiology Osteosarcopenia Osteopenia/Osteoporosis Sarcopenia Pathophysiology Assessment Presentation of Osteosarcopenia Secondary Causes of Osteosarcopenia History Falls Screening and Case-Finding Physical Assessments Investigations Bone Mineral Density (BMD) and Muscle Mass Risk Calculation Management Non-pharmacological Dietary calcium Vitamin D Physical activity Dietary protein and protein supplementation Pharmacological Osteoporosis Therapy duration and sequence Models of care Future Directions Conclusion References Further Reading Relevant Websites

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Introduction A major development in the biological and medical aspects of geroscience is the evolution of osteosarcopenia: a condition that represents the concomitant presence of two diseases: osteopenia/osteoporosis and sarcopenia. Osteosarcopenia, and its component diseases increases in prevalence with aging. As the global population ages, the number of older adults living with osteosarcopenia will increase. The consequences of osteosarcopenia for individuals (such as falls, fractures, decreased quality of life, institutionalization and increased morbidity and mortality) and society (health care costs) present a great public health challenge. However, given osteosarcopenia is potentially preventable and treatable, the increasing prevalence of osteosarcopenia provides great opportunities to reduce fragmentation of care between two very inter-related diseases, to close the gap between diagnosis and treatment, and to improve knowledge on the best management for individuals with this condition. Here, we address the epidemiological, pathophysiological and management aspects of osteosarcopenia.

Epidemiology The epidemiology of osteosarcopenia will be first described, followed by osteoporosis/osteopenia and sarcopenia separately.

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Osteosarcopenia Osteosarcopenia is where individuals experience a combination of sarcopenia and osteopenia or osteoporosis (Hirschfeld et al., 2017); thus, where individuals experience a synchronic loss of bone mineral density (BMD T score
 1 SD) and muscle mass, strength and function, the condition should be termed osteosarcopenia (Hirschfeld et al., 2017). Negative outcomes of osteosarcopenia are increases in falls, fractures, dependence, frailty, institutionalization, and mortality (Hirschfeld et al., 2017; Huo et al., 2015a; Hassan and Duque, 2017). The prevalence of osteosarcopenia varies depending on the populations studied and definition applied. Whether osteopenia should be included prevalence estimates of osteosarcopenia remains a contentious point (Hirschfeld et al., 2017). Osteosarcopenia is more prevalent among high-risk persons (those who fall or have fractured) (27.2%–40.0%) than average community dwelling older adults (10.4–28%) (Huo et al., 2015a; Wang et al., 2015; Drey et al., 2016; Yoo et al., 2016). Including osteopenia in the definition of osteosarcopenia increases the prevalence of osteosarcopenia and similarly predicts negative adverse outcomes. Prevalence estimates from recent studies on osteosarcopenia are detailed in Table 1.

Osteopenia/Osteoporosis Osteopenia and osteoporosis are well-described as conditions characterized by reduced density and quality of bone, which leads to brittle and weak bones, and a subsequent increase in fracture risk, particularly of the hip, spine and wrist (Osteoporosis Australia, 2013; International Osteoporosis Foundation, 2015; Watts et al., 2010). Using the World Health Organization guidelines, osteopenia is define as a BMD
 1 SD below the young healthy adult reference population and osteoporosis is defined either by the presence of a minimal trauma fracture, or according to measures of BMD ascertained from dual-energy x-ray absorptiometry (DXA), whereby a T-score at the hip and/or lumbar spine is identified as being at or below 2.5 SD below the young healthy adult reference population (World Health Organization, 1994). Commonly referred to as a ‘silent disease,’ osteopenia/osteoporosis is asymptomatic until a fracture occurs (Watts et al., 2013). Approximately 200 million people are living with osteoporosis worldwide, and osteoporosis/osteopenia account for over 9 million fractures per year (Kanis and WHO Scientific Group, 2008). Data suggests that one in three women and one in five men aged 50 years or older will experience an osteoporotic fracture (International Osteoporosis Foundation, 2015; International Osteoporosis Foundation, 2007), with one fracture estimated to occur every 3 sec (Watts et al., 2013). Following a hip fracture, 10–20% of people will require long-term nursing care, and one if five people will die in the first 12 months post-hip fracture (Katsoulis et al., 2017; Haentjens et al., 2010). Worldwide, osteoporotic fractures account for 0.83% of the global burden of non-communicable diseases (NCDs) (Johnell and Kanis, 2006); while Disability Adjusted Life Years (DALYs) attributable to low BMD increased from > 3million in 1990 to > 5million in 2010 (Sanchez-Riera et al., 2014).

Sarcopenia Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength or function (Cruz-Jentoft et al., 2019). Sarcopenia should not be confused with frailty, which has been defined as cumulative deficits in multiple physiological systems, which may involve the presence of sarcopenia. Diagnostic criteria for sarcopenia include usual gait speed, grip strength, and measures approximating skeletal muscle mass; however, there is no current internationally accepted consensus definition (Scott et al., 2011; Reijnierse et al., 2015). Various methodologies are used to assess the domains of sarcopenia: muscle mass (or lean mass in common clinical practice), muscle strength, and physical performance (Cruz-Jentoft et al., 2019). Lean mass can be assessed by DXA and bioelectrical impedance analysis (BIA). Muscle mass can be approximated by computed tomography and magnetic resonance imaging. Anthropometric measurement of the calf circumference has been used as an approximation of muscle mass. Measurement of muscle strength can be determined by handgrip strength, knee flexion and extension, and peak expiratory flow. Physical performance can be measured by timed up and go test, gait speed, short physical performance battery, and stair climb power test (Cruz-Jentoft et al., 2019). After the age of 40 years, muscle mass begins to decline by 1–2% per year (McLean and Kiel, 2015), and accelerates after the age of 65 years. Between the age of 40 and 80 years, muscle mass is estimated to decline by between 30 and 50%, while the loss of

Table 1

Prevalence of osteosarcopenia.

Reference

Year

Country

Participants

Definition

Prevalence

Huo et al. (2015a)

2015

Australia

Sarcopenia and osteoporosis/osteopenia

37.0%

Wang et al. (2015)

2015

China

Sarcopenia and osteoporosis

Drey et al. (2016) Yoo et al. (2016)

2016 2018

Germany Korea

Community-dwelling older adults attending a falls and fracture clinic Community dwelling older adults (recruited from community) Prefrail community-dwelling older adults Older adults with hip fracture

10.4% in men, 15.1% in women 28.0% 27.2%

Sarcopenia and osteoporosis/osteopenia Sarcopenia and osteoporosis

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functional capacity associated with the loss of muscle mass amounts to approximately 3% for each year beyond the age of 60 years (Denison et al., 2015). Although dependent on the definition applied, the prevalence of sarcopenia has been estimated to be as high as 33% in community-dwelling older adults (Bijlsma et al., 2013). Sarcopenia results in a loss of independence and quality of life, an increased trajectory toward frailty and disability, greater risk of falls and fall-related injuries, and earlier mortality (Hirschfeld et al., 2017). Listed in the International Classification of Diseases, 10th Revision in 2016, the ‘newness’ of sarcopenia means that the disease has, to date, received little attention in clinical practice, and is only beginning to appear in medical curricula. In this context those at greatest risk of sarcopenia are severely under-diagnosed and under-treated. It is imperative that the loss of lean mass attributable to sarcopenia not be merely considered as a ‘normal’ part of aging, rather as a musculoskeletal condition that is amenable to intervention.

Pathophysiology Bone and muscle are connected anatomically, metabolically and chemically (Hirschfeld et al., 2017). The maintenance of bone and muscle structure and function requires a balance of formation and resorption, synthesis and degradation (Boirie, 2009). An imbalance of this process of tissue gain and loss can result in osteopenia, osteoporosis, or sarcopenia. The closeness of the relationship between bone and muscle are observed in the synchronicity of changes in their mass. Increases in bone mass are associated with increases in muscle mass, and a similar association is observed with decreases in bone and muscle mass (Demontiero et al., 2014). Osteopenia/osteoporosis and sarcopenia are associated with aging but also share numerous pathophysiological mechanisms and risk factors. These shared pathways are comprised of genetic, endocrine, lifestyle and exogenous factors. Particular genetic polymorphisms have been identified as having a relationship with bone and muscle loss. These include genetic polymorphisms of GLYAT, myocyte enhancer factor 2C (MEF-2C), proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a), a-actinin 3, myostatin, and methyltransferase-like 21C (METTL21C) (Karasik and Kiel, 2008). While numerous endocrinological causes of osteoporosis and sarcopenia are recognized, the key contributing conditions include diabetes, abnormal thyroid function and deficiencies of androgens, vitamin D, normocalcemic hyper PTH (Suriyaarachchi et al., 2018), growth hormone and insulin-like growth factor-1 (IGF-1) (Kawao and Kaji, 2015). The main contributing lifestyle factors include malnutrition, obesity and tobacco smoking. While multiple pharmaceutical agents have been implicated in bone or muscle loss, the most common and extensively researched are the glucocorticoid family (Kawao and Kaji, 2015). As the body ages, fat infiltrates muscle and bone. This process was formerly thought to be an age-related phenomenon and its pathophysiological implications were under-recognized. Lipotoxicity is the process by which body fat secretes inflammatory cytokines that have a negative impact on the growth and function of surrounding and distant tissues (Maugeri et al., 1998). The inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) and free fatty acids (mostly palmitic acid) have been associated with lipotoxicity (Tagliaferri et al., 2015; Singh et al., 2018). Patients with sarcopenia or osteoporosis have high circulating blood levels of IL-6 and TNF-a (Demontiero et al., 2014), a process which underlies the putative inflammatory mechanism of osteosarcopenia. However, the ways in which the effects of these fatty acids and inflammatory cytokines can be mitigated is poorly understood. The shared risk factors for loss of bone and muscle mass account for only part of the pathophysiological process of osteosarcopenia. Bone and muscle, known as the musculoskeletal unit, interact anatomically and physically. Mechanical stressors on this unit are osteogenic and confer protection from bone loss. In addition, mechanical stress and tension is a necessary component of muscle protein synthesis. Yet there is increasing evidence that bone and muscle, with fat as an intermediary, interact biochemically (Kawao and Kaji, 2015). These interactions are via the paracrine and endocrine pathways. Factors and chemokines involved in this communication system include osteocalcin, vascular endothelial growth factor (VEGF), IGF-1, osteoglycan, irisin, osteonectin, myostatin, fibroblast growth factor-2, IL-6 and IL-15 (Tagliaferri et al., 2015). Research is being undertaken on a number of these factors for therapeutic purposes and uncertainties remain as to the exact role of each factor involved in the pathophysiological process. Myostatin is a transforming growth factor of particular focus of research into the treatment of sarcopenia. Myostatin is expressed primarily in skeletal muscle and has a downregulating effect on myoblast proliferation (Kaji, 2014). Myostatin may also have a negative effect on osteogenesis (Kaji, 2014). Clinical trials have demonstrated that in those with myostatin gene deficiency, or in those receiving the systemic myostatin decoy receptor (ACVR2B-Fc), skeletal muscle hypertrophy and BMD increases (Becker et al., 2015). Myostatin, in addition to the other factors described, will be targets of future research into osteosarcopenia and its treatment. The complex interplay of factors involved in the pathophysiological process of osteosarcopenia is best depicted schematically in Fig. 1.

Assessment The diagnosis of osteosarcopenia requires a comprehensive assessment comprising a thorough medical, risk factor identification, physical examination, functional assessments and targeted investigations. The application of accepted definitions (for osteopenia/osteoporosis and sarcopenia) is required to make the diagnosis and formulate a management plan. A challenge with diagnosis remains the absence of an international consensus on the operational definition of both sarcopenia and osteosarcopenia. The most commonly cited consensus definitions for sarcopenia are listed in Table 2.

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Fig. 1 The pathophysiology of Osteosarcopenia. GH/IGF-I, growth hormone/insulin-like growth factor-I; FGF2, fibroblast growth factor 2; FAM5C, family with sequence similarity 5, member, C; IL, interleukin; MMP2, matrix metalloproteinase-2; MGF, mechanogrowth factor; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor. Adapted from Hirschfeld, H.P., Kinsella, R., Duque, G. (2017). Osteosarcopenia: Where bone, muscle, and fat collide. Osteoporosis International 28(10), 2781–2790.

The term osteosarcopenia has been used interchangeably with sarco-osteoporosis in recent years. Both osteosarcopenia and sarco-osteoporosis are largely accepted as the presence of osteoporosis and sarcopenia in older adults (Huo et al., 2015a). However, some researchers have defined osteosarcopenia as the presence of sarcopenia and osteopenia (Wang et al., 2015), whether the concept should include osteopenia is a subject of debate. Nevertheless, for the interest of this review, we define osteosarcopenia in accordance with recent literature by Huo et al, as osteoporosis/osteopenia and sarcopenia in older adults (Huo et al., 2015a). In Fig. 2 we present a conceptual algorithm outlining the approach to individuals presenting with possible osteosarcopenia. A detailed description of the approach to osteoporosis, osteopenia and sarcopenia as individual disease entities can be found elsewhere in this work.

Presentation of Osteosarcopenia Older adults with osteosarcopenia may present with falls, fractures, loss of function or independence, or with other health complications for which the link between osteosarcopenia and their presenting issues may not be immediately obvious to treating clinicians. Clinicians should apply a vigilant, case-finding approach for those suspected of living with osteosarcopenia. Furthermore, osteosarcopenia should be considered in all adults who undergo a comprehensive geriatric assessment (Zanker and Duque, 2019). A recent study of a high-risk community dwelling older adults found those with osteosarcopenia were older, more likely to be women, at high risk of depression and malnutrition, have a low body mass index, impaired mobility and comorbid disease than those without osteosarcopenia, or those with sarcopenia or osteopenia/osteoporosis alone (Huo et al., 2015a).

Secondary Causes of Osteosarcopenia Any approach to an assessment of an older adult at risk of osteosarcopenia should consider the possible underlying (secondary) causes of the condition. Given the shared pathophysiological mechanisms of osteoporosis/osteopenia and sarcopenia, there may be significant overlap in the secondary causes of osteosarcopenia as illustrated in Table 3.

History The history and physical examination are integral components of assessing an individual for osteosarcopenia (Zanker and Duque, 2019). The information gathered by the history and physical examination should be combined with targeted investigations to assist

Osteosarcopenia: The Modern Geriatric Giant Table 2

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Different operational definitions of sarcopenia.

Component

Cut-points

Revised European Working Group on Sarcopenia in Older People (Cruz-Jentoft et al., 2019) Low muscle quantity ASM adjusted for height (m2) using whole-body DXA Men: 20 s 2 ¼ Able to complete 4 steps without aids but with supervision 1 ¼ Able to complete >2 steps and requires minimal assistance 0 ¼ Requires assistance to keep from falling/unable to try 4 ¼ Able to place foot tandem position independently and hold 30 s 3 ¼ Able to place foot ahead independently and hold 30 s 2 ¼ Able to take small step independently and hold 30 s 1 ¼ Requires assistance to step but can hold 15 s 0 ¼ Loses balance while stepping or standing 4 ¼ Able to lift leg independently and hold for > 10 s 3 ¼ Able to lift leg independently and hold for 5–10 s 2 ¼ Able to lift leg independently and hold for
3 s 1 ¼ Attempts to lift leg, unable to hold for 3 s but remains standing independently 0 ¼ Unable to attempt or requires assist to prevent from falling

Cut-points Individuals performing the BBS can achieve a total score of 56 points. A score < 45 may indicate greater risk of falls (Berg et al., 1992). Scoring ranges also indicate mobility deficits as follows: independent (score 41–56), walking with assistance (score 21– 40) and wheelchair bound (score 0–20) (Berg et al., 1992). While this assessment tool is comprehensive, a limitation includes the large change in score which can result in a change in mobility category. When performing repeated measures, the minimum detectable change is 4 points (Donoghue et al., 2009).

Short physical performance battery (SPPB) Initially developed in the 1990s, the SPPB is a measure which comprises 5 tests in total, assessing an individual’s balance, gait and lower limb strength (Guralnik et al., 1994). It is scored out of 12 and has been used in numerous trials as a marker of lower limb function and can be completed in 5 min. The scoring sheet for the SPPB can be found in Table 3. Setup The SPPB does not require any specialist equipment, and can be performed with a stopwatch, chair and clear space for gait speed measurement. Performance The SPPB begins with balance assessments progressing from a feet together stand to semi tandem and full tandem stand. This is followed by the assessment for gait speed (previously described) and the five times sit to stand test (5STS). To perform the five times sit to stand test, individuals begin in a seated position and are instructed to independently (without use of chair arms) stand from the chair and sit 5 times as quickly as possible. Cut-points With regards to cut-points for the SPPB, several have been proposed, with a score  6 associated with a threefold higher rate of falls compared to those who scored
10 (Veronese et al., 2014). Additionally, items which showed the greatest associations for falls were gait speed (in women) and the 5STS (in men). Meanwhile, a change in score of 0.5 points has been enough to signify a small but clinically significant change (Perera et al., 2006). Given the SPPB is scored in increments of 1 point, this has also been used as a marker for a substantial meaningful change.

Postural InstabilitydBalance, Posture and Gait Table 3

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Scoring sheet for the Short Physical Performance Battery (SPPB).

Patient Short Physical Performance Battery Feet Together Stand (s) Semi Tandem (s) Tandem (s)

Gait Speed (best out of 3 trials)

5 Sit to Stand (5STS) X1? , Yes , No Time: __________ SPPB Score

Date , No attempt (0) , 10 s (1) , No attempt (0) , 10 s (1) , No attempt (0) , 10 s (2) Speed (m/s): ______________ , Unable to perform (0) , 0.83 m s 1 (4) Aid (if any): , Unable />60 s (0) , >16.7 s (1) , 13.7–16.69 s (2) , 11.2–13.69 s (3) , 1/3 of any food offered. Eats 2 servings or less of protein (meat or dairy products) per day. Takes fluids poorly. Does not take a liquid dietary supplement. OR is NPO and/or maintained on clear liquids or IV’s for >5 days

Friction and shear

1. Problem: Requires moderate to maximum assistance in moving. Complete lifting without sliding against sheets is impossible. Frequently slides down in bed or chair, requiring frequent repositioning with maximum assistance. Spasticity, contractures or agitation lead to almost constant friction

Total Score: Initials:

2. Very limited: Responds only to painful stimuli. Cannot communicate discomfort except by moaning or restlessness. OR has a sensory impairment which limits the ability to feel pain or discomfort over 1/2 of body 2. Very moist: Skin is often, but not always, moist. Linen must be changed at least once a shift 2. Chairfast: Ability to walk severely limited or non-existent. Cannot bear weight and/or must be assisted into chair or wheelchair 2. Very limited: Makes occasional slight changes in body or extremity position but unable to make frequent or significant changes independently 2. Probably Inadequate: Rarely eats a complete meal and generally eats only about 1/2 of any food offered. Protein intake includes only three servings of meat or dairy products per day. Occasionally will take a dietary supplement. OR receives less than optimum amount of liquid diet or tube feeding 2. Potential problem: Moves feebly or requires minimum assistance. During a move skin probably slides to some extent against sheets, chair, restraints, or other devices. Maintains relatively good position in chair or bed most of the time but occasionally slides down

3. Slightly limited: Responds to verbal commands, but cannot always communicate discomfort or need to be turned. OR has some sensory impairment which limits ability to feel pain or discomfort in 1 or 2 extremities

4. No impairment: Responds to verbal commands, has no sensory deficit which would limit ability to feel or voice pain or discomfort

3. Occasionally moist: Skin is occasionally moist, requiring an extra linen change approximately once a day

4. Rarely moist: Skin is usually dry, linen only requires changing at routne intervals

3. Walks Occasionally: Walks occasionally during day, but for very short distances, with or without assistance. Spends majority of each shift in bed or chair 3. Slightly limited: Makes frequent though slight changes in body or extremity position independently

4. Walks Frequently: Walks outside the room at least twice a day and inside room at least once every 2 h during waking hours

3. Adequate: Eats over half of most meals. Eats a total of four servings of protein (meat, dairy products) each day. Occasionally will refuse a meal, but will usually take a supplement if offered. OR is on a tube feeding or TPN regimen which probably meets most of nutritional needs 3. No Apparent Problem: Moves in bed and in chair independently and has sufficient muscle strength to lift up completely during move. Maintains good position in bed or chair at all times

Note: Patients with a total score of 16 or less are considered to be at risk of developing pressure ulcers.(15 or 16 ¼ mild risk. 13 or 14 ¼ moderate risk. 12 or less ¼ high risk).

4. No limitations: Makes major and frequent changes in position without assistance 4. Excellent: Eats most of every meal. Never refuses a meal. Usually eats a total of four or more servings of meat and dairy products. Occasionally eats between meals. Does not require supplementation

Pressure Injury

Date of assessment/reassessment (day/month/year)

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ISitting position may be given for eating, reading, etc. but it should not last more than a few hours in this position. Pillows should be placed under the heels for sitting people and should be placed between the knees in the patient lying side. All nurses and medical personnel should know general principles about changing position for elderly patients. These general principles include the equal distribution of body weight, the exposure of body parts to as little pressure as possible, the control of whether therapeutic instruments prevent circulation, and if necessary, changing the position of these instruments.

Nutrition It is important to have a balanced diet due to being as both thin and overweight pose a risk for pressure injury. There is a strong relationship between protein-energy malnutrition and pressure injury development. The stress-response factor should be taken into consideration when calculating the calorie requirement of a patient with pressure injury. It is necessary to take 30–35 kcal/ kg/day calorie and 1.25–1.5 g/kg/day protein to provide positive nitrogen balance in patients at risk of malnutrition (van Anholt et al., 2010; Yatabe et al., 2013; Mino et al., 2001). There is no clear evidence of the efficacy of specific nutritional therapies in the prevention or treatment of pressure injury (Langer and Fink, 2014). If vitamin C and zinc deficiency are present, the wound can improve with nutritional support (DeFranzo et al., 2001). However, sufficient fluid intake should be provided by the patient (Posthauer et al., 2015). Patient’s nutrition should be organized considering the risk factors for the development of pressure injury.

Body and Skin Care IThe purpose of skin care is to provide skin integrity and to protect from dry skin, wetness, friction, and contact with hard surfaces. Dry skin should be moistened with moisturizing creams. The wet skin should not be wiped. It should be dried by buffering soft materials such as towels. If the patient is using the underpad, skin protective barrier creams can be used by consulting the doctor because of exposure to wetness and contact with feces. Skin care products containing alcohol should not be used. Areas where pressure injuries are common like the tailbone, hip protrusions and heels should be checked regularly. The skin should be protected from friction. Bed linen should be clean, dry and ironed. A wrinkle or fold on the bed lining will facilitate wound formation. The bed should be checked regularly, and foreign objects (napkins, paper towels, food items and small medical supplies) should be removed. Dirty clothes should be replaced promptly. It should not be forgotten that catheter can make pressure to the skin in patients who have the urinary catheter. Patients should be washed at least two times a week with mild soap and warm water. It should be avoided from fabrics that increase the perspiration such as nylon and synthetic and clothes that is narrow, zippered and buttoned. Cotton, breathable, absorbent garments should be preferred. Feet and nail care should be performed periodically. Family members responsible for elderly care should be trained on all these issues.

Support Surfaces It is intended to reduce the pressure between the surface and the tissue using the support surface and special bearings in order to keep the pressure under capillary closure pressure. The systems used for this are; 1. Materials placed on the bed: They are used directly on the bed. 2. Therapeutic beds: These systems include mattresses. They are usually solid, polyurethane foam, air static mattress, Alternating Pressure Mattress (electric is required; it is noisy and pierceable), gel pad, water mattress (changing position of patients is difficult.). 3. Pressure Relieving Support Surfaces: They are separate materials that are used instead of the hospital bedstead. While most therapeutic beds and materials placed on the bed are pressure reducing, special bed systems are pressure remover. All of the pressure reducing systems are examined in two subcategories as dynamic and static. In dynamic systems, an energy source is needed to change the pressure points; whereas in static systems the pressure is distributed over a large area and energy source is not necessary. Vanderwee et al. have shown that there is no difference between static and dynamic support surfaces in the prevention of pressure ulcers (Oguz and Olgun, 1998). Anderson et al. have evaluated standard beds in addition to static and dynamic support surfaces. Although they did not find the difference between static and dynamic support surfaces, they found that the risk was significantly reduced compared to standard beds (Pinar and Oguz, 1998). While there is evidence that support surfaces can prevent and treat pressure ulcers, there is no conclusive evidence of which support surface is more effective than others. It is important to note that no support surface system can take the place of a good nursing service in the prevention of pressure injuries (National Pressure Ulcer Advisory Panel Support Surface Standards Initiative, 2013).

Pain Management The damage can be quite painful. Local factors that may be associated with pain, such as ischemia, infections or surrounding tissue damage, should be examined. The initial and follow-up pain assessment should be done using a pain scale. Detection of the type

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and severity of the pain may lead to appropriate treatment. Pain may appear intermittently as during debridement, or cyclic as during changing of the wound dressing, or persistent. While oral non-opioid medications are used for mild pain, opioid agents may be needed for moderatedsevere pain. The benefits of topical local anesthetics such as lidocaine have been demonstrated in small studies. However, these treatments provide short-term relief, and they should not be used for pain management primarily. Systemic treatment of pain is required in patients with deep ulcer. Wound cleaning and wound closure techniques should be reevaluated if they cause severe pain. Particularly pain control should be performed prior to debridement and replacement of the wound cover. Intensive debridement should be performed under surgical conditions (Moore and Cowman, 2014). Training of the patient and his/her relatives: Patient, relatives of the patient and hospital personnel should be trained on causes and prevention of pressure injury. The cost of training is much lower than the cost of wound treatment (Qaseem et al., 2015a).

Treatment of Pressure Injury Pressure injuries require proper wound care. These are debridement, wound cleansing, and closure of the wound. Necrotic tissue may need to be debrided for wound healing. “Sharp debridement” requires a bistoury and scissors, and dead tissue is removed. Mechanical debridement is the removal of dead tissue by mechanical force. In this process, wet-dry dressing, washing with highpressure liquid and irrigation are performed. Living tissues can be removed from the body because of that this method is nonselective. Enzymatic debridement is performed using enzymes that break down fibrin and collagen in the necrotic tissue. Enzymatic ointments are expensive. In otolithic debridement, the necrotic tissue is slowly removed using the wound’s own enzymes (Bellingeri et al., 2016). Wound cleaning should be done with sterile water or saline. Antiseptic solutions should be avoided because they harm healthy tissue (Bellingeri et al., 2016). In a recently published single-blind randomized controlled trial, when compared to the wound dressing with propyl betaine-polyhexanide solution, propyl betaine-polyhexanide solution reduced inflammation and accelerated wound healing (Gist et al., 2009). Wound closure is done with wound care products.

Wound Care Products It is aimed to provide the optimal wound environment by wound dressings to prevent external contamination and to provide wound healing. There are different options depending on the nature of the wound and its characteristics. The aim of the wound care products is to provide fluid balance in the ulcer tissue.

Wound Care Products Which Increase Moisture Transparent films Film covers have adhesive or non-adhesive forms. It is made of polyurethane or synthetic polymers. It is often used to cover intravenous catheter sites. Sometimes it is used to heal or protect the wounds which have partial thickness. They can not absorb intense moist, they can not be used primarily in treatment of exudate wounds. The best usages are superficial, non-exudative wounds or late phase of wound healing (Mouës et al., 2011).

Hydrocolloids Hydrocolloids have a hydrocolloid gel made of carboxymethylcellulose (CMS) in combination with pectin. The inner adhesive layer which contacts with the wound is positioned between the foam or film layer on the outer layer. When wound becomes exudate, hydrocolloid gel absorbs moist. As the hydrocolloid absorbs moisture, it becomes more water permeable. This feature improves the passage of moisture and treats wound exudate. The hydrogel-covered wound bed is useful in autolytic debridement. Once these wound covers are removed, they leave a gel-like substance. Since this condition may confuse with the infection, it is necessary to clean and evaluate the wound after the wound cover is removed. It is changed every 2–7 days if necessary. It is useful for venous ulcers, pressure ulcers, diabetic foot ulcers. Using this is relatively contraindicated in the case of arterial insufficiency, vasculitis and infection (Brett, 2006).

Hydrogel They are semi-occlusive and are formed by cross-linking of hydrophilic polymers. Because they are semi-occlusive, they provide otolithic debridement by drying mild exudates. It is useful in burn patients. It should not be used in ischemic ulcers. It should be changed every 24–72 h. Wound therapy gels are either isotonic or hypertonic. They are used as secondary dressings (Brett, 2006).

Moisture Retention Products Calcium alginate dressings They are made from water algae and contain calcium alginate polysaccharides. They work according to the sodium-calcium exchange between the wound exudate and the wound dressing. The sodium-alginate gel forms and thus absorbs the moist and treats

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the exudative-infected wound. Calcium ions are effective in the coagulation pathway. Thus, such cover may be used for bloody exudative wounds. Alginates containing mannuronic acid form a partially soluble soft gel with solutions containing sodium ions such as wound exudate. Alginates with guluronic acid at high concentration maintain their integrity and structure during the gelling process. Alginates are useful for moderate to severe exudate wounds. The use of topical antibiotics or systemic antimicrobial agents may reduce wound exudation (Brett, 2006).

Foam dressings Foam dressings have hydrocellular polyurethane center with absorbent porous formed with a semi-occlusive outer layer. Foam dressings consist of different outer layers with different moisture vapor transmission rates. They permit rapid evaporation of the moist due to having a vapor transmission rate. This feature makes these dressings useful in exudative wounds. Foam dressings may not be sticky or sticky. It may show various shapes and absorbent properties. They have different flexibility and density ratings. Many of these can be shaped to fit any size and depth of injury. The detection of the wound without removing the covering is possible because of the opacity feature of dressings (Brett, 2006).

Hydrofiber dressings Hydrofiber dressings have the high concentration of absorbent sodium CMS. They are suitable for moderate to severe exudates. Because they are non-adherent, a secondary dressing is required to keep them in place. Hydrofiber dressings are useful in the treatment of chronic venous ulcers, which are drains. Both foam and hydrofiber dressings have wear times of up to 1 week.

Compound dressings Composite dressings consist of multiple layers with varying absorbent properties. They are used as a secondary dressing to exudation control for foams, alginates, and hydrofibers.

Synthetic skin grafts It was developed to prevent morbidity associated with full thickness skin grafts and to reduce the time required for wound healing. Synthetic skin grafts have been shown to increase the likelihood of recovery of venous ulcers when compared to known wound dressings (Brett, 2006).

Infections of Pressure Injuries Bacteria are found on all skin surfaces. Primer defense is provided by intact skin texture, and if there is a loss of this tissue, bacteria will be placed on the wound surface. Infection will also occur when the bacteria damage the body. If the scar tissue is not healing in 2 weeks, if there is a fragile granulation tissue, if there is bad smell, temperature increase around the ulcer, development of local infection is possible. The risk of incfection increases with diabetes, protein-energy malnutrition, autoimmune disease, immunosuppression, and hypoxia. Any erythema or induration around the ulcer, incipient or increase of pain and temperature, existence of crepitation or color change on the ulcereous tissue, fever, malaise are indicator for acute infection. Delirium, confusion or anorexia could be refer acute infection especially in elderly population. Infection should be considered if the ulcer does not heal in 14 days. Culture should be obtained by deep aspiration and biopsy to protect from contaminating culture. If there are > 105 colonies in the material, treatment should be started. Infections are usually polymicrobial. Antibiotics which effective on gram-positive, gram-negative microorganisms, and anaerobic bacteria are needed. (Table 5).

Vacuum-Asissted Closure (VAC) VAC or negative pressure therapy is used for diabetic foot ulcers, pressure ulcers, traumatic wounds, surgical wounds. The mechanism of action is unknown, but it has effects on creating a moist environment, reducing edema, reducing wound size, and stimulating angiogenesis (Mouës et al., 2004). A prospective study compared VAC with conventional wound treatment showed that wound healing were faster and wound size significantly reduced with VAC therapy (Eskes et al., 2013).

Hyperbaric Oxygen Therapy Hyperbaric oxygen therapy (HBOT) is defined as the use of 100% oxygen therapy at 1 atm pressure. In this way, the oxygen saturation is increased by the increase of the oxyhemoglobin on the blood (Eskes et al., 2013). Hyperoxia accelerates wound healing by increasing growth factors and nitric oxide and by releasing endothelial progenitor cells (Goldstein, 2013). HBOT is used for chronic wounds, acute wounds, diabetic foot ulcers. The use of HBOT is limited in terms of cost and difficulty in reaching treatment units.

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Antibiotherapy of pressure Ulcer

Antibiotherapy Monotherapy Cefoxitin Ceftizoxime Cefotetan Piperacillin-Tazobactam Meropenem Combination therapy Clindamycin Ciprofloxacin Metronidazole Ciprofloxacin MRSA infection (þ) Vancomycin Quinupristin/dalfopristin Linezolid

Dosage 1–2 g IV or IM every 6–8 h 1–2 g IV every 8–12 h 1–2 g IV or IM every 12–24 h 3,1 g IV every 4–6 h 0,5–1 g IV every 6–8 h 450–600 mg IV every 6–8 h or 450 p.o. 4  1 200–400 mg IV every 12 h or 500 mg p.o. 2  1 500 mg IV every 6–8 h or 500 mg p.o. 3  1 200–400 mg IV every 12 h or 500 mg p.o. 2  1 0,5 g IV every 6–8 h 7,5 mg/kg IV every 8–12 h 600 mg IV every 12 h

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BMJ 332 (7539), 472–475. National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance (NPUAP/EPUAP/PPPIA), 2014. In: Haesler, E. (Ed.), Prevention and Treatment of Pressure Ulcers: Quick Reference Guide. Cambridge Media, Osborne Park, Western Australia. Barry, M., Nugent, L., 2015. Pressure ulcer prevention in frail older people. Nursing Standard 30 (16), 50–58. Bergstrom, N., Braden, B.J., Laguzza, A., Holman, V., 1987. The Braden scale for predicting pressure sore risk. Nursing Research 36 (4), 205–210. Sardo, P.M.G., Guedes, J.A.D., Alvarelhão, J.J.M., Machado, P.A.P., Melo, E.M.O.P., 2018. Pressure ulcer incidene and Braden subscales: Retrospective cohort analysis in general wards of a Portuguese hospital. Journal of Tissue Viability 27 (2), 95–100. Oguz, S., Olgun, N., 1998. Predicting pressure sore risk with the Braden Scale and determining the effectiveness of predetermined nursing prevention of pressure sores (in Turkish). Hemsirelik Forumu 1 (3), 131–135. Pinar, R., Oguz, S., 1998. The reliability and validity of Norton and Braden pressure ulcer assessment scales for the same group of bedridden patients. In: VI. National-International Participation Nursing Congress BookDamla Press, Ankara, Turkey, pp. 172–175. Qaseem, A., Mir, T.P., Starkey, M., Denberg, T.D., 2015a. Clinical guidelines Committee of the American College of Physicians.Risk assessment and prevention of pressure ulcers: A clinical practice guideline from the American College of Physicians. Annals of Internal Medicine 162 (5), 359–369. Qaseem, A., Humphrey, L.L., Forciea, M.A., Starkey, M., Denberg, T.D., 2015b. Clinical Guidelines Committee of the American College of Physicians. Treatment of pressure ulcers: A clinical practice guideline from the American College of Physicians. Annals of Internal Medicine 162 (5), 370–379. Pacific, P.A.N., 2014. Prevention and treatment of pressure ulcers: Quick reference Guide. Cambridge Media, Perth, Western Australia. van Anholt, R.D., Sobotka, L., Meijer, E.P., et al., 2010. Specific nutritional support accelerates pressure ulcer healing and reduces wound care intensityin non-malnourished patients. Nutrition 26 (9), 867–872. Yatabe, M.S., Taguchi, F., Ishida, I., et al., 2013. Mini nutritional assessment as a useful method of predicting the development of pressure ulcers in elderly inpatients. Journal of the American Geriatrics Society 61 (10), 1698–1704. Mino, Y., Morimoto, S., Okaishi, K., et al., 2001. Risk factors for pressure ulcers in bedridden elderly subjects: Importance of turning over in bed and serum albumin level. Geriatrics and Gerontology International 1, 38–44. Langer, G., Fink, A., 2014. Nutritional interventions for preventing and treating pressure ulcers. Cochrane Database of Systematic Reviews 12 (6), CD003216. DeFranzo, A.J., Argenta, L.C., Marks, M.W., et al., 2001. The use of vacuum-assisted closure therapy for the treatment of lower-extremity wounds with exposed bone. Plastic and Reconstructive Surgery 108 (5), 1184–1191. Posthauer, M.E., Banks, M., Dorner, B., Schols, J.M., 2015. The role of nutrition for pressure ulcer management: National pressure ulcer advisory panel, European pressure ulcer advisory panel, and pan pacific pressure injury alliance white paper. Advances in Skin & Wound Care 28 (4), 175–188 quiz 189-90. National Pressure Ulcer Advisory Panel Support Surface Standards Initiative (2013) Terms and definitions related to support surfaces. www.npuap.org/NPUAP_S3I_TD.pdf (Accessed on April 07, 2013). Moore, Z.E., Cowman, S., 2014. Risk assessment tools for the prevention of pressure ulcers. Cochrane Database of Systematic Reviews 2, CD006471.

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Bellingeri, A., Falciani, F., Traspedini, P., et al., 2016. Effect of a wound cleansing solution on wound bed preparation and inflammation in chronic wounds: A single-blind RCT. Journal of Wound Care 25 (3), 160,160,162-6,168. Gist, S., Tio-Matos, I., Falzgraf, S., Cameron, S., Beebe, M., 2009. Wound care in the geriatric client. Clinical Interventions in Aging 4, 269–287. Mouës, C.M., Heule, F., Hovius, S.E., 2011. A review of topical negative pressure therapy in wound healing: Sufficient evidence? American Journal of Surgery 201 (4), 544–556. Brett, D.W., 2006. A review of moisture-control dressings in wound care. Journal of Wound, Ostomy, and Continence Nursing 33 (6 Suppl), 53–58. Mouës, C.M., Vos, M.C., van den Bemd, G.J., Stijnen, T., Hovius, S.E., 2004. Bacterial load in relation to vacuum-assisted closure wound therapy: A prospective randomized trial. Wound Repair and Regeneration 12 (1), 11–17. Eskes, A., Vermeulen, H., Lucas, C., Ubbink, D.T., 2013. Hyperbaric oxygen therapy for treating acute surgical and traumatic wounds. Cochrane Database of Systematic Reviews 12, CD008059. Goldstein, L.J., 2013. Hyperbaric oxygen for chronic wounds. Dermatologic Therapy 26 (3), 207–214.

Further Reading Levenson, S.M., Geever, E.F., Crowley, L.V., et al., 1965. Healing of rat skin wounds. Annals of Surgery 161, 293–308. European Pressure Ulcer Advisory Panel and National Pressure Ulcer Advisory Panel, 2009. Prevention and Treatment of Pressure Ulcers: Quick reference Guide. National Pressure Ulcer Asdvisory Panel, Washington DC.

Proteasome Modulation: A Way to Delay Aging? Niki Chondrogianni, National Hellenic Research Foundation, Institute of Chemical Biology, Athens, Greece Mary A Vasilopoulou, National Hellenic Research Foundation, Institute of Chemical Biology, Athens, Greece; and Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece Marianna Kapetanou and Efstathios S Gonos, National Hellenic Research Foundation, Institute of Chemical Biology, Athens, Greece © 2020 Elsevier Inc. All rights reserved.

Proteasome 26S Proteasome 20S core particle 19S regulatory particle Proteasome and Aging Cellular Senescence Mammalian Systems Low Eukaryotes Saccharomyces cerevisiae Caenorhabditis elegans Drosophila melanogaster Homo sapiens Proteasome Activation Genetic Manipulation Genetic activation through overexpression of proteasome subunits Transcriptional activators Conformational Activators Post-Translational Modifications Other Types of Activation Conclusions Acknowledgments References Further Reading

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Proteasome Cells are a continuous working machine that generates proteins to fulfill their diverse functions. Some of these proteins are damaged, abnormal, or have to be removed after completing their functions. Thus, cells need to have a mechanism to maintain protein homeostasis and keep the balance between synthesis and elimination of proteins, a process called protein turnover. The ubiquitin-proteasome system (UPS) is one of the main systems that mediates this process (Rousseau and Bertolotti, 2018). The proteasome plays a pivotal role in various cellular processes, including cell cycle, cell differentiation, DNA repair and apoptosis, among others (Carrard et al., 2002). It comprises up to 5% of the total cellular proteins, albeit its concentration differs among different cell types (Raynes et al., 2016). It is located in the cytoplasm and nucleus or in the endoplasmic reticulum where it degrades membrane-bound polypeptides (Raynes et al., 2016; Gu and Enenkel, 2014). Proteasome-mediated protein degradation leads to shorter peptides, most of which are between 2 and 10 residues in size. Then, they are further broken down by other proteases into amino acids, thereby resulting in amino acid recycling (Rousseau and Bertolotti, 2018; Collins and Goldberg, 2017).

26S Proteasome The 26S proteasome is a 2,5 MDa enzymatic complex with multiple catalytic subunits. It consists of the 20S proteasome or core particle (CP) and one or two 19S regulatory particles (RPs) (Rousseau and Bertolotti, 2018). Attachment of the RP to one side of CP forms the 26S proteasome. When two RPs cap both sides of CP, it is referred to as 30S proteasome (Gu and Enenkel, 2014). Nevertheless, both proteasome configurations are frequently mentioned as the 26S proteasome complex. To specifically recognize the target-proteins, the 26S proteasome can degrade proteins that either have loosely folded regions or have been ubiquitinated (Collins and Goldberg, 2017). Ubiquitination is a three-step ATP-dependent process which is catalyzed by three ubiquitin ligases; E1, E2, and E3. Initially, ubiquitin is activated by the E1 ubiquitin-activating enzyme. Subsequently, ubiquitin is transferred to an E2 ubiquitin-conjugating enzyme that together with an E3 ubiquitin-ligase enzyme lead to the attachment of ubiquitin to the protein that will be degraded. This process is repeated to form a poly-ubiquitin chain. The standard form of ubiquitination consists

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Fig. 1 The Ubiquitin-Proteasome System (UPS). Four ubiquitin molecules (Ub) tag the target protein in a three-step ATP-dependent process involving the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin-ligase enzyme (E3). The ubiquitinated protein is recognized, unfolded and deubiquitinated by the 19S regulatory particle (19S RP). The deubiquitinating enzymes (DUBs) remove the poly-ubiquitin chain and the released ubiquitin molecules are used for another ubiquitination cycle. Then, the unfolded protein is degraded by the 20S core particle (20S CP), which possesses the proteolytic activities of the proteasome. The tetra-ubiquitination that is needed for protein degradation is the standard form of ubiquitination, but there are also others, such as mono-ubiquitination and/or multiple mono-ubiquitinations.

of four ubiquitin moieties (tetra-ubiquitination), but lately, several others, such as mono-ubiquitination and/or multiple monoubiquitinations have also been revealed (Livneh et al., 2017). After the attachment of the ubiquitinated protein to the 19S RP, poly-ubiquitin chains are removed by the deubiquitinating enzymes (DUBs; Rpn11, USP14, and UCH37). Then, the targetprotein is driven to the proteolytic core of the 20S proteasome. The ubiquitin molecules are then free to participate in another ubiquitination cycle (Fig. 1) (Rousseau and Bertolotti, 2018; Njomen and Tepe, 2019).

20S core particle The 20S core particle is a 700 kDa barrel-shaped structure composed of seven different a and b subunits arranged in four rings. These 28 protein subunits create the a1–7b1–7b1–7a1–7 configuration. The two outer a-rings serve as the proteasome gate allowing substrates to enter the proteolytic chamber. The two inner b-rings possess the proteolytic activities of the proteasome, which are attributed to three b subunits, namely b1, b2, and b5 that are known as the catalytic centers of caspase-like (C-L) or peptidylglutamyl-peptide hydrolyzing (PGPH) activity, trypsin-like activity (T-L) and chymotrypsin-like activity (CT-L), respectively. Unlike the 26S proteasome, which mostly degrades proteins in a ubiquitin-dependent manner, the 20S proteasome has been suggested not to require the existence of ubiquitin molecules for proteolysis (i.e., proteolysis of oxidized proteins) (Rousseau and Bertolotti, 2018; Raynes et al., 2016; Budenholzer et al., 2017). Three additional proteasome isoforms have been mentioned, namely the immunoproteasome, the thymoproteasome and the testis-specific proteasome. The immunoproteasome or i20S differs from the standard proteasome in three b subunits; b1, b2, and b5 subunits are replaced by b1i (proteasome subunit beta type 9, PSMB9), b2i (PSMB10), and b5i (PSMB8) subunits, respectively. The immunoproteasome shows elevated CT-L and T-L activity, and its primary role is the assistance in antigen presentation on major histocompatibility complex (MHC) class I molecules (Rousseau and Bertolotti, 2018; Budenholzer et al., 2017; Papaevgeniou and Chondrogianni, 2016). The thymoproteasome has been identified in cortical thymic epithelial cells, being responsible for the positive selection of CD8þ T cells. It contains b1i, b2i, and the thymus-specific b5t subunit (Rousseau and Bertolotti, 2018; Kniepert

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Table 1

Human genes that encode the 20S and 19S proteasome subunits.

20S core particle a subunits

Gene

Chromosomal location

b subunits

Gene

Chromosomal location

a1 a2 a3 a4 a5 a6 a7

PSMA6 PSMA2 PSMA4 PSMA7 PSMA5 PSMA1 PSMA3

14q13.2 7p14.1 15q25.1 20q13.33 1p13.3 11p15.2 14q23.1

b1 b2 b3 b4 b5 b6 b7 b1i b2i b5i b5t

PSMB6 PSMB7 PSMB3 PSMB2 PSMB5 PSMB1 PSMB4 PSMB9 PSMB10 PSMB8 PSMB11

17p13.2 9q33.3 17q12 1p34.3 14q11.2 6q27 1q21.3 6p21.32 16q22.1 6p21.32 14q11.2

19S regulatory particle Base subunits

Gene

Chromosomal location

Lid subunits

Gene

Chromosomal location

Rpt1 Rpt2 Rpt3 Rpt4 Rpt5 Rpt6 Rpn1 Rpn2 Rpn10 Rpn13

PSMC2 PSMC1 PSMC4 PSMC6 PSMC3 PSMC5 PSMD2 PSMD1 PSMD4 ADRM1

7q22.1 14q32.11 19q13.2 14q22.1 11p11.2 17q23.3 3q27.1 2q37.1 1q21.3 20q13.33

Rpn3 Rpn5 Rpn6 Rpn7 Rpn8 Rpn9 Rpn11 Rpn12 Sem1

PSMD3 PSMD12 PSMD11 PSMD6 PSMD7 PSMD13 PSMD14 PSMD8 SEM1

17q21.1 17q24.2 17q11.2 3p14.1 16q23.1 11p15.5 2q24.2 19q13.2 7q21.3

The proteasome subunits b1i, b2i and b5i are the subunits that differentiate the immunoproteasome from the other forms and the b5t is the thymus-specific proteasome subunit. Data accessible from: Gene [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004d[cited 2019 Jul 01]. Available from: https://www.ncbi.nlm.nih.gov/gene/ and Online Mendelian Inheritance in Man, OMIMÒ. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), 2019. World Wide Web URL: https://omim.org/.

and Groettrup, 2014). Lastly, in the testis-specific proteasome, the a4 subunit has been replaced by the a4s subunit. This proteasome isoform has been firstly described in Drosophila melanogaster in the mid-1990s while recently it was also identified in mammals (Rousseau and Bertolotti, 2018; Kniepert and Groettrup, 2014).

19S regulatory particle The 19S regulatory particle (RP), also called PA700, is the proteasome’s supervisor of the 20S gate opening, recognition of the substrate target-protein, deubiquitination, unfolding and translocation into the narrow 20S core (Rousseau and Bertolotti, 2018; Njomen and Tepe, 2019). RP is a 1 MDa protein complex that consists of two subcomplexes, the base and the lid. The base is comprised of six AAA-ATPase subunits, RP triple-A protein 1 (Rpt1)dRpt6, which are arranged in an Rpt1-2-6-3-4-5 ring conformation (Njomen and Tepe, 2019; Budenholzer et al., 2017; Chondrogianni et al., 2015a). It also contains four non-ATPase subunits, named as RP non-ATPase 1 (Rpn1), Rpn2, Rpn10, and Rpn13. The six AAAATPase subunits are responsible for gate opening, substrate target-protein unfolding and translocation into the proteolytic core (Budenholzer et al., 2017; Papaevgeniou and Chondrogianni, 2016). Rpn1 and Rpn2 are the two biggest proteasome subunits that participate in the unfolding and the entry of the substrate into the core proteasome. Furthermore, these two subunits facilitate the joining of the remaining subunits to form the RP (Budenholzer et al., 2017; Papaevgeniou and Chondrogianni, 2016). Rpn1 also functions as a ubiquitin receptor (Collins and Goldberg, 2017). Rpn10 and Rpn13 are the intrinsic ubiquitin receptors that can recognize and bind to the polyubiquitinated proteins (Collins and Goldberg, 2017; Budenholzer et al., 2017). Nine non-ATPase subunits (Rpn3, 5-9, 11, 12, Sem1) give rise to the regulatory particle’s lid (Gu and Enenkel, 2014). The lid is the bridge between the 20S core and the 19S regulatory particle. Until recently, Rpn10 and Rpn13 were thought to be the essential subunits that connect the base and the lid. However, latest data demonstrate that this association relies on the subunits Rpn3, Rpn7, Rpn8 and Rpn11 (from the lid) and Rpt3–Rpt6 and Rpn2 subunits (from the base) (Rousseau and Bertolotti, 2018; Njomen and Tepe, 2019). Table 1 summarizes the proteasome subunits along with the human genes encoding them.

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Proteasome and Aging Cellular Senescence With age, cells accumulate damaged proteins bearing oxidative modifications, such as carbonylation and glycation as well as misfolded, cross-linked, and aggregated proteins. This imbalance in proteostasis equilibrium that appears in cells across time is related to the impairment of the proteasome machinery. Human senescent fibroblasts exhibit downregulation of b-catalytic subunits expression along with a decline in all three proteasome activities (Chondrogianni et al., 2003), while partial proteasome inhibition in normal young fibroblasts triggers an irreversible p53-dependent premature senescence (Chondrogianni et al., 2008). Recently, the age-related decline in proteasome expression and activity, in conjunction with the age-related alterations in the assembly of the proteasomal complexes, has been associated with senescence of human mesenchymal stem cells (hMSCs) and the subsequent loss of their stemness (Kapetanou et al., 2017). In contrast, the immortal human embryonic stem cells (hESCs), which can proliferate continuously in the absence of senescence, are characterized by high proteasome activity that has been correlated with increased expression levels of the Rpn6 proteasome subunit (Saez and Vilchez, 2014). Moreover, the damaged proteins that accumulate with age clog up the proteasome and further hinder its proteolytic activity (Grune et al., 2004). Notably, human senescent fibroblasts do not exhibit a significant decrease in their nuclear proteasome activity, but they become unable to induce the proteasome in the nucleus under stress conditions (Bakondi et al., 2011).

Mammalian Systems In line with the in vitro studies, an age-related impairment of proteasome function has been revealed in several mammalian tissues. Specifically, proteasome activity declines during aging in bovine lens, adipose, liver, lung, heart, kidney, spinal cord, hippocampus, cerebral cortex and muscle tissues of rodents, potentially contributing to the overall loss of homeostasis in aged tissues (Chondrogianni et al., 2014a; Saez and Vilchez, 2014). Interestingly, a transgenic mouse with low proteasomal CT-L activity provided in vivo evidence that impaired proteasomal activity accelerates aging, aggravates the accumulation of damaged proteins and stimulates the progression of age-related metabolic disorders, such as hepatic steatosis and obesity (Tomaru et al., 2012). Accordingly, several studies in mammals support that sustained proteasome activity promotes longevity. For instance, the naked mole rat, which is by far the longest living rodent, is characterized by high 20S and 26S proteasome activities (Chondrogianni et al., 2014a; Saez and Vilchez, 2014).

Low Eukaryotes Saccharomyces cerevisiae Saccharomyces cerevisiae (S. cerevisiae) is an extensively studied model organism in the aging field. The two methods of measuring aging in the budding yeast are the replicative and the chronological senescence/lifespan. The replicative lifespan is the number of divisions performed by a single mother cell to produce daughter cells. On the other hand, chronological lifespan or stationary phase is the period during which a yeast cell can survive in a non-dividing state (Papaevgeniou and Chondrogianni, 2016; Chondrogianni et al., 2015a). The stationary phase model of aging in S. cerevisiae is a frequent model for studying cellular aging. Many studies have highlighted the correlation between the proteasome and the replicative lifespan and have shown that proteasome dysfunction leads to accelerated aging. Enhancement of proteasome capacity increases cellular viability and there is evidence that this beneficial effect is due to the maintenance of protein homeostasis (Andersson et al., 2013; Kruegel et al., 2011). Studies from Chen and colleagues showed that UMP1, an essential factor that regulates the 20S proteasome assembly, is necessary for cell viability in the stationary phase. Deletion of UMP1 gene reduces the survival of cells and rapidly increases the levels of oxidized proteins. In contrast, overexpression of UMP1 improves lifespan and increases CT-L proteasome activity, while the levels of oxidized proteins are reduced (Chen et al., 2006).

Caenorhabditis elegans Caenorhabditis elegans (C. elegans) is a eukaryotic soil nematode. It is the model organism that has been studied the most in aging and age-related diseases mainly due its short lifespan and its fully characterized genotype (Papaevgeniou and Chondrogianni, 2016; Chondrogianni et al., 2015a). Proteome analysis in C. elegans has revealed that proteome balance is disturbed during aging and this imbalance leads to extensive protein aggregation and toxicity. Under these conditions, proteasome subunits are upregulated as an attempt to cope with the increasing proteotoxicity and oxidative stress caused by aging. However, the effort of the proteasome to maintain protein turnover leads to the collapse of the UPS (Dhondt et al., 2017; Walther et al., 2015). Research using a photoconvertible reporter for the UPS has revealed that the activity of the proteasome is already decreased in 7-day-old worms and this impairment is manifested in a cell-specific manner (Papaevgeniou and Chondrogianni, 2016). Lastly, overexpression of rpn-6 or pbs-5 (ortholog of b5) proteasome subunits leads to an extension in lifespan and an increase in nematode healthspan. Knockdown of these proteasome subunits reduces the lifespan of the animals and accelerates aging, highlighting the crucial role of the proteasome in the progression of the phenomenon (Chondrogianni et al., 2015b; Vilchez et al., 2012).

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Drosophila melanogaster Drosophila melanogaster (D. melanogaster), also known as the fruit fly, is another model organism for aging studies. Research by Vernace et al. supports disturbance of proteasome assembly and activity upon aging. More specifically, the comparison between young and old flies shows that in young flies the 26S proteasome is the dominant form, while in older flies it is the 20S complex. Despite that, both age groups have a reduction in ATP levels (Vernace et al., 2007). Results from a recent study using female flies also claimed a correlation between impairment of protein homeostasis and increasing aging, as proteasome subunits were downregulated (Brown et al., 2018). Furthermore, overexpression of b5 proteasome subunit during adulthood increases CT-L activity and extends lifespan (Nguyen et al., 2019a). Finally, proteasome function has been shown to decline in somatic tissues of the fly, whereas it was preserved in gonads and eggs maybe as a mechanism to secure an effective reproduction of healthy offspring (Tsakiri et al., 2013).

Homo sapiens Many studies have been conducted in tissues from human donors to elucidate how the proteasome behaves during the progression of aging. A decline in proteasome function and activity has been revealed in several human tissues such as lens, epidermis, lymphocytes, and muscle upon aging progression (Papaevgeniou and Chondrogianni, 2016; Chondrogianni et al., 2015a). In contrast, Bellavista et al. support that the three proteolytic activities of the proteasome remain unaltered in the liver of young and old donors. They also stated that there are small differences in proteasome subunit composition, probably due to the cellular effort to maintain protein turnover (Bellavista et al., 2014). Contrary to normal aging and the studies mentioned above, centenarians display different results. Centenarians are considered as paradigms of successful aging with lessening of age-related diseases and maintenance of good mental shape despite their very old age. Fibroblast cultures from healthy centenarians have revealed that their proteasomes maintain their function with their activities being similar to those found in cultures from young donors (Chondrogianni et al., 2000).

Proteasome Activation Collapse of proteostasis is a hallmark of aging and is profoundly related to a progressive decline of the respective defense systems. As such, proteasome activation can promote and rescue the age-related deterioration of proteostasis, providing beneficial effects in cellular and organismal lifespan. The enhancement of proteasome function has been successful until now through: (a) genetic manipulation (either through overexpression of proteasome subunits or through manipulation of transcription factors that regulate the expression of proteasome subunits), (b) compounds that promote conformational changes of the proteasome and (c) activating post-translational modifications. Finally, there are also some other types of activation that will be described below.

Genetic Manipulation Genetic activation through overexpression of proteasome subunits The first attempts to genetically induce proteasome function were performed in lymphoblasts and HeLa cells. These studies revealed that overexpression of the catalytic immunosubunit b1i results in the increase of T-L activity, while overexpression of the catalytic immunosubunit b5i enhances both CT-L and T-L activities. Remarkably, overexpression of b5 catalytic subunit in WI-38/T and IMR90 human fibroblast cell lines induces the expression of several proteasome subunits and enhances proteasome assembly and activity. Proteasome activation not only renders the cells resistant to oxidative stress but also delays senescence of human primary fibroblasts. Similarly, overexpression of b5 subunit in human lens epithelial cells results in upregulation of proteasome subunit expression, enhances proteasome activity, improves clearance of carbonylated proteins, and protects cells from oxidative stress. An ex vivo study in dermal fibroblasts derived from elderly donors also suggests that restoration of normal levels of proteasome subunits via lentiviral transfection with vectors expressing b5 or b6 subunits rescues the decrease in proteasome activity and alleviates the manifestation of aging biomarkers (Chondrogianni et al., 2015a). Interestingly, a recent study has highlighted the pivotal role of the proteasome in stemness. Specifically, the activation of the proteasome and the elimination of the age-related deterioration of its function, through overexpression of b5 subunit, not only doubles cellular lifespan but also improves the expression of the core pluripotency factors and enhance the differentiation capability of both young and senescent hMSCs (Kapetanou et al., 2017). In addition, proteasome activation via pbs-5 overexpression in C. elegans extends organismal lifespan and decelerates the progression of protein aggregation-related pathologies, such as Alzheimer’s disease (Chondrogianni et al., 2015b). Recently, researchers revealed that in D. melanogaster adult-only overexpression of b5 subunit increases CT-L activity, enhances the clearance of ubiquitinated or aggregated proteins and improves longevity (Nguyen et al., 2019b). A different effective approach to genetically enhance proteasome function targets on improving proteasome assembly. Ectopic expression of Rpn11 subunit in flies inhibits the age-related decline in the 26S proteasome activity and elongates lifespan (Saez and Vilchez, 2014). Recent studies have also demonstrated that overexpression of Rpn6 proteasome subunit in C. elegans (Vilchez et al., 2012) or D. melanogaster (Tain et al., 2017) is sufficient to enhance proteasome activity and extend the lifespan of these model organisms. Furthermore, overexpression of the chaperone involved in proteasome assembly, namely POMP, increases proteasome function and confers oxidative stress resistance in human fibroblasts (Chondrogianni and Gonos, 2007). In S. cerevisiae, overexpression of UMP1 (ortholog of POMP) leads to upregulation of proteasome activity and promotes longevity and viability during oxidative stress (Chondrogianni et al., 2014a; Chen et al., 2006). Similarly, overexpression of PA28 increases the proteolytic function of

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the proteasome in mice, ultimately protecting them against cardiac proteinopathy and myocardial ischemia/reperfusion (Li et al., 2011). Finally, a different innovative approach to enhance proteasome function is the opening of its gate. The convergent N-terminals of a-subunits block the entrance of substrates in the catalytic core of 20S proteasomes. Remarkably, expression of engineered a3 forms with an N-terminal deletion generates intact, hyperactive proteasomes, able to rapidly degrade toxic protein aggregates (Choi et al., 2016).

Transcriptional activators Studies in model organisms have revealed that the genes encoding the crucial proteasome subunits are under strict transcriptional control (Dohmen et al., 2007). RPN4, nuclear factor (erythroid-derived 2)-like 1 (Nrf1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heat shock factor 1 (HSF-1) and forkhead box protein O (FOXO) are important transcription factors that have been correlated with the expression of proteasome subunits. RPN4 is a 60 kDa yeast protein which contains a C2H2-type zinc finger motif and two acidic domains (Dohmen et al., 2007). It binds to specific elements that are present in the promoters of almost all genes encoding proteasome subunits (Budenholzer et al., 2017; Dohmen et al., 2007). These elements are known as PACE (Proteasome-Associated Control Element) and are essential for the expression of proteasome genes as well as genes that are related to other UPS components (Budenholzer et al., 2017; Dohmen et al., 2007). The induction of proteasome genes through RPN4 depends on the cells need for increased levels of functional proteasomes (such as during proteotoxic stress), while cells lacking RPN4 demonstrate a reduction of the proteasome activity (Dohmen et al., 2007). In yeast, the ablation of UBR2 and MUB1, two factors that participate in the ubiquitination and degradation of RPN4, increases the levels of RPN4, which subsequently lead to increased levels of the 20S and 26S proteasomes, replicative lifespan extension, and resistance to proteotoxic stress (Kruegel et al., 2011). The transcription factors Nrf1 and Nrf2 belong to the Cap’n’Collar transcription factor family with a basic leucine zipper domain. They both recognize a cis-acting DNA element, namely Antioxidant Response Element (ARE), which is found in the promoter regions of their target genes (Rousseau and Bertolotti, 2018; Papaevgeniou and Chondrogianni, 2016). Nrf1 controls the induction of proteasome genes in response to proteasome inhibition, whereas Nrf2 regulates the transcription of many components of the UPS, mainly upon oxidative stress (Budenholzer et al., 2017). It is also worth noting that Nrf2 regulates several enzymes that are part of the cellular antioxidant and detoxification systems, such as glutathione S-transferases, g-glutamylcysteine ligases, heme oxygenase-1 and NADPH quinone oxidoreductase. Microarray analysis has revealed that 20 genes of the proteasome and ubiquitination machinery are under the control of Nrf2 (Pajares et al., 2017). Thus, many studies have been conducted to identify compounds that could increase proteasome activity through Nrf2 activation. These compounds are summarized in Table 2. Two natural antioxidants isolated from cruciferous vegetables, 3H-1,2-dithiole-3-thione (D3T) and sulforaphane, increase the expression of proteasome subunits and enhance proteasome activity through Nrf2 induction (Njomen and Tepe, 2019; Chondrogianni et al., 2014a; Liu et al., 2014; Santin-Marquez et al., 2019). Quercetin is a flavonoid present in fruits and vegetables, known for its antioxidant activity and its ability to activate Nrf2, leading to increased CT-L activity and extended cellular lifespan of HFL-1 human embryonic fibroblasts. Moreover, treatment of senescent fibroblasts with quercetin leads to their rejuvenation (Chondrogianni et al., 2010). Hederagenin and 18a-glycyrrhetinic acid (18a-GA) are two triterpenoids that activate the proteasome in an Nrf2-dependent manner and extend the cellular lifespan of human primary fibroblasts. Moreover, treatment of terminally senescent cells with 18a-GA upregulates proteasome expression and increases CT-L activity, pinpointing the potential of this compound to stimulate the proteasome even in the late passage cells (Kapeta et al., 2010). Likewise, 18a-GA stimulates proteasome function and prolongs lifespan in C. elegans; both are driven by SKN-1 (ortholog of Nrf2) induction (Papaevgeniou et al., 2016). Ginkgo biloba leaf extract (EGb 761) is a compound with strong antioxidant activity (Liu et al., 2007; Stark and Behl, 2014). Treatment of HEK293 cells with EGb 761 increases the CT-L activity and upregulates the transcript levels of the proteasome genes PSMB5, PSMB6, and PSMB7 (Stark and Behl, 2014). In another study, the Ginkgo biloba extract activates Nrf2 by stimulating its translocation to the nucleus (Liu et al., 2007). These results demonstrate that the positive effects of Gingko biloba on proteasome are possibly due to its ability to activate Nrf2 (Liu et al., 2007; Stark and Behl, 2014). Curcumin is the orange pigment extract of turmeric, the root of Curcuma longa. It is a compound that has been reported to activate the proteasome by elevating CT-L activity in human epidermal keratinocytes (Chondrogianni et al., 2014a). Liao and coworkers also revealed that curcumin extends the lifespan in C. elegans and this effect is dependent on SKN-1 (Liao et al., 2011). Moreover, ASC-JM17, a curcumin analog, induces the expression of Nrf1 and Nrf2, which in turn upregulate the expression of proteasome subunits and antioxidant enzymes, thereby increasing proteasome activity (Bott et al., 2016). Furthermore, Nrf2 activation induced by tert-butylhydroquinone (t-BHQ) or sulforaphane enhances proteasome activity in hESCs and iPS-IMR90 cells, postponing differentiation, while favoring self-renewal (Njomen and Tepe, 2019; Chondrogianni et al., 2015a). Finally, tiliroside, one of the richest flavonoid glycosides derived from the fruits of Platanus orientalis, increases proteasome activity and the expression levels of proteasome subunits in D. melanogaster that further prolongs lifespan and improves the healthspan of the flies. Similarly, tiliroside enhances CT-L activity and delays cellular senescence in IMR90 cells (Chatzigeorgiou et al., 2017). These beneficial effects are probably due to the ability of tiliroside to activate, among others, Nrf2 (Chatzigeorgiou et al., 2017; Velagapudi et al., 2018). Two additional transcription factors, FOXO and HSF-1, are implicated in the aging progression. HSF-1 is the master regulator of the heat-shock response, which mediates the expression of several molecular chaperones responsible for protein folding (Bott et al., 2016). FOXO is part of the Insulin/IGF-1 signaling (IIS) pathway and has a crucial role in longevity as it regulates an array of genes that are associated with longevity, cellular stress response, metabolism and antimicrobial defense (Chondrogianni et al., 2015a,

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Table 2

Compounds that induce proteasome expression and activity via Nrf2 activation.

Compound

Structure

Mechanism of action

References

Sulforaphane

[ Nrf2 expression Nrf2 activation

Njomen and Tepe (2019), Chondrogianni et al. (2014a), Liu et al. (2014), and Santin-Marquez et al. (2019)

D3T

Nrf2 activation

Njomen and Tepe (2019) and Chondrogianni et al. (2014a)

Quercetin

[ Nrf2 expression [ Nrf2 protein levels Nrf2 activation

Chondrogianni et al. (2010)

Hederagenin

Nrf2 activation

Kapeta et al. (2010)

18a-glycyrrhetinic acid (18a-GA)

[ Nrf2 expression [ Nrf2 protein levels Nrf2 activation

Kapeta et al. (2010) and Papaevgeniou et al. (2016)

Gingko biloba extract Curcumin

Nrf2 activation Nrf2 activation

Liu et al. (2007) and Stark and Behl (2014) Chondrogianni et al. (2014a) and Liao et al. (2011)

ASC-JM17

[ Nrf1 and Nrf2 Bott et al. (2016) expression Nrf1 and Nrf2 activation

tert-butylhydroquinone (tBHQ)

Nrf2 activation

Njomen and Tepe (2019) and Chondrogianni et al. (2015a)

Tiliroside

[ Nrf2 protein levels Nrf2 activation

Chatzigeorgiou et al. (2017) and Velagapudi et al. (2018)

2014a). In a recent study, we have shown that an increase in proteasome content and function, through overexpression of pbs-5 proteasome subunit in C. elegans, extends lifespan and confers oxidative stress resistance (Chondrogianni et al., 2015b). Nevertheless, this proteasome enhancement is abolished in DAF-16/FOXO, SKN-1/Nrf2 and HSF-1 mutant animals overexpressing pbs-5

Proteasome Modulation: A Way to Delay Aging?

99

subunit. These results indicate that there is a correlation between DAF-16/FOXO, SKN-1/Nrf2, and HSF-1 transcription factors and proteasome activation, highlighting the complexity between the signaling pathways that mediate the cellular homeostasis and proteostasis (Chondrogianni et al., 2015b).

Conformational Activators The proteasome exists in a closed form with its two outer a-rings sealing its proteolytic core. The a-rings, which are the proteasome’s gates, control the entrance of the candidate protein for degradation. Research toward the discovery of proteasome activators has revealed natural and synthetic compounds that stimulate the proteasome function. Some of these compounds have been identified to enhance proteasome activity through conformational changes by inducing the opening of the a-gated channel of the 20S CP. Compounds with this potential are summarized in Table 3. Sodium dodecyl sulfate (SDS) has been described as an in vitro activator of the 20S proteasome by increasing all three proteasome activities (Njomen and Tepe, 2019; Chondrogianni et al., 2014a; Huang and Chen, 2009). Proteasome activation has also been succeeded by fatty acids, such as oleic, linoleic and linolenic acids that favor the gate opening by denaturation of the 20S proteasome, similarly to SDS (Njomen and Tepe, 2019; Chondrogianni et al., 2014a,b; Huang and Chen, 2009). The lipid extract of microalgae Phaeodactylum tricornutum enhances all three proteasome activities in vitro and protects human keratinocytes by decreasing the level of oxidized proteins before and after exposure to UV-A and UV-B irradiation (Chondrogianni et al., 2015a, 2014a,b). Oleuropein is another compound that interacts with the 20S proteasome and increases its three proteolytic activities in vitro. Oleuropein is the main phenolic constituent of Olea europaea leaf extract, olive oil and olives. Studies in human embryonic fibroblast cells treated with oleuropein decipher its anti-aging properties as the cells exhibit a 15% increase in lifespan and a delay in cellular senescence (Katsiki et al., 2007). A similar stimulatory effect has been identified in bee pollen; a widely used anti-aging food supplement. Bee pollen, rich in flavonoids and phenolic acids, increases CT-L proteasome activity in HFL-1 human embryonic fibroblasts and serves as a free radical scavenger (Graikou et al., 2011). Betulinic acid is another positive modulator of the proteasome as it increases CT-L proteasome activity. In contrast, it does not affect T-L activity, while C-L activity is only slightly increased (Chondrogianni et al., 2014b). Betulinic acid has been extensively modified to further enhance its action, but the production of its derivatives led to the opposite results (Njomen and Tepe, 2019; Huang and Chen, 2009). Moreover, a synthetic peptide called Proteasome Activating Peptide-1 (PAP1) enhances CT-L activity in vitro and cell culture; this result is due to the ability of PAP1 to open the 20S proteasome gate (Dal Vechio et al., 2014). More recent studies have identified new proteasome activators, which serve as proteasome agonists by either interacting allosterically with the proteasome or inducing the opening of its active chamber. Compounds such as chlorpromazine, imidazoline TCH-165, MK-886, AM-404, and ursolic acid have been also characterized as novel 20S proteasome stimulators (Njomen and Tepe, 2019).

Post-Translational Modifications Recent discoveries have provided compelling evidence that proteasome activity is also modulated by post-translational modifications. The human 26S proteasome has 455 known phosphorylation sites and undergoes dynamic and reversible phosphorylation in response to several physiopathological conditions (Guo et al., 2017). A rise in intracellular cAMP is involved in a wide array of signaling pathways and leads to the activation of protein kinase A (PKA). Even though the biological significance of proteasome phosphorylation remains largely unknown, data are demonstrating that phosphorylation of Rpn6 by PKA positively regulates the 20S proteasome assembly and activity (Guo et al., 2017). Fasting or treatment with rolipram, glucagon, epinephrine, vasopressin or forskolin stimulates Rpn6 phosphorylation and the 26S proteasomes capacity to degrade ubiquitinated proteins and peptides (VerPlank et al., 2019; Lokireddy et al., 2015). Rpn6 phosphorylation is sufficient to induce proteasome activity and eliminate the accumulation of misfolded or abnormal proteins, including tau, which in turn mitigates cognitive failure in a mouse model of Alzheimer’s disease. In support, the overexpression of a phosphomimetic Rpn6 mutant enhances proteasome activity, whereas the expression of a phosphodead mutant represses proteasome function. The cGMP-dependent kinase, Protein Kinase G (PKG), also phosphorylates and activates the 26S proteasome. It has been suggested that the PKG-mediated phosphorylation occurs at the catalytic b5 subunit or the 19S ATPase subunit Rpt6. The overexpression of PKG and treatment with sildenafil or pilocarpine, that increase the intracellular cGMP levels and activate PKG, stimulate proteasome function and highlight the potential of PKG activators to combat proteotoxic diseases. In addition, proteasomes during S, G2 and M phase contain phosphorylated Rpt3 and have a higher capacity to degrade ubiquitinated proteins and short peptides, possibly to facilitate the rapid elimination of cell cycle progression inhibitors. On the other hand, the phosphorylation of proteasome subunits by various members of the Mitogen-Activated Protein Kinase (MAPK) family reduces the 26S proteasome activity and protein breakdown. Interestingly, siRNA-mediated knockdown of endogenous ASK1 or MKK6 that are upstream activators of p38 MAPK or knockdown and chemical inhibition of MK2, a kinase that acts downstream of p38 MAPK, enhances proteasome activity (Lokireddy et al., 2015; VerPlank and Goldberg, 2017). Thus, understanding the mechanisms and effects of proteasome phosphorylation will offer new possibilities for clinical proteasome-based regimens.

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Table 3

Compounds that serve as stimulators or gate openers of the proteasome.

Compound

Structure

Mechanism of action

References

SDS

Gate opener [ CT-L, T-L, and C-L activity

Njomen and Tepe (2019), Chondrogianni et al. (2014a), and Huang and Chen (2009)

Fatty acids

Gate openers [ CT-L, T-L, and C-L activity

Njomen and Tepe (2019), Chondrogianni et al. (2015a, 2014a,b), and Huang and Chen (2009)

Oleuropein

[ CT-L, T-L, and C-L activity

Katsiki et al. (2007)

Bee pollen (flavonoids)

[ CT-L activity

Graikou et al. (2011)

Betulinic acid

[ CT-L activity

Njomen and Tepe (2019), Huang and Chen (2009), and Chondrogianni et al. (2014b)

Proteasome Activating Peptide-1 (PAP1) Chlorpromazine

[ CT-L activity

Dal Vechio et al. (2014)

[ CT-L activity

Njomen and Tepe (2019)

TCH-165

Gate opener

Njomen and Tepe (2019)

MK-886

20S proteasome stimulator Njomen and Tepe (2019) (agonist)

AM-404

20S proteasome stimulator Njomen and Tepe (2019) (agonist)

Ursolic acid

20S proteasome stimulator Njomen and Tepe (2019)

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Fig. 2 Mechanisms of proteasome activation. (A) Genetic activation of the proteasome can be achieved following overexpression of the b5 or Rpn6 subunits that increases 26S assembly and activity or by the expression of N-terminal truncated a3 subunits that generate open-gated, hyperactive proteasomes. (B) Transcription-mediated upregulation of proteasome subunits expression. Nrf2 is the most prominent example of an inducible transcription factor that regulates the expression of proteasome subunits. Nrf2 normally resides in the cytosol in a complex with Keap1 that prevents it from entering the nucleus. The disturbance of the Nrf2-Keap1 complex by compounds leads to the release of Nrf2, which enters the nucleus and induces the transcription of proteasome genes through binding to Antioxidant Responsive Elements (AREs) in their promoter regions. (C) Proteasome induction by (i) stimulators that allosterically interact with the proteasome and enhance its catalytic activities and (ii) gate-openers that facilitate the access of the substrate to the catalytic core. (D) Phosphorylation of the proteasome complex by PKA or PKG in response to high cAMP or cGMP levels respectively enhances proteasome activity and/or assembly.

Other Types of Activation Finally, other types of proteasome activation include: (A) Calorie restriction, the most well-established strategy to increase mammalian lifespan counteracts the age-related decline in proteasome activity in several tissues, including heart, liver, skeletal muscle and brain (Chondrogianni et al., 2015a). (B) The silencing or small molecule inhibition of deubiquitinases, such as USP14 and UCH37 that trim ubiquitin chains and thereby inhibit the proteasome-mediated degradation of ubiquitinated proteins, increases the elimination of proteasome substrates including tau and oxidized proteins (Lokireddy et al., 2015). (C) Neuronal depolarization is another factor that can alter proteasome function and localization. In hippocampal neurons, calcium influx triggers the translocation of the 26S proteasomes from the dendrites into the spines. This translocation causes a localized boost of protein degradation, decreasing the levels of ubiquitinated proteins in the spines. In addition to promoting proteasome activity, the rise in cellular calcium levels also stimulates protein ubiquitination, possibly by inducing E3 ligases that are dependent on calcium or calmodulin (Lokireddy et al., 2015). The depolarization of neurons with bicuculline, a GABA

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receptor antagonist, enhances proteasome activity and both the ubiquitin-dependent and independent degradation of proteasome substrates. (D) Finally, pyrazolones are enhancers of proteasome activity with lifespan extending and neuroprotective properties in an ALS transgenic mouse model (Njomen and Tepe, 2019). However, the mechanism of their action on proteasome function remains unknown.

Conclusions The proteasome is a multicatalytic enzyme complex that precisely surveils the protein quality control systems and orchestrates crucial cellular functions. Studies have revealed that there is a causal role of the proteasome in the progression of aging. Decreased levels of proteasome content and function lead to the accelerated progression of aging, while upregulation of several proteasome subunits or enhancement of its proteolytic activities can extend the lifespan of various model organisms and mammalian cells. These observations highlight that the proteasome system is a highly conserved longevity pathway among the organisms. Due to its involvement in diverse cellular processes and its important implication in aging and age-related diseases, many efforts have been performed toward proteasome activation as a potential therapeutic strategy. Overexpression of proteasome subunits, activation of transcription factors that induce the expression of proteasome genes, post-translational modifications and natural or synthetically derived compounds which can stimulate proteasome function, are some of the means that have successfully modulated the UPS upon aging progression (Fig. 2). Despite all these exciting findings there is still a lack of studies that investigate the correlation between the impairment of proteostasis and aging, especially in humans. Thus, a future perspective should focus on further research to elucidate the beneficial effect of proteasome activation in the pursuit of longevity. As proteasome dysfunction is considered a hallmark of aging, proteasome activation is a promising approach for both lifespan and healthspan improvement.

Acknowledgments Part of the research presented here from our lab has been co-financed by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation under the call RESEARCHdCREATEdINNOVATE (project codes: T1EDK-00353 and T1EDK-01610 to NC and T1EDK-05165 to ESG). NC and ESG lab is also co-financed under the Action “Action for the Strategic Development on the Research and Technological Sector” (project STHENOS-b, MIS 5002398).

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Further Reading Chondrogianni, N., Gonos, E.S., 2012. Structure and function of the ubiquitin-proteasome system: Modulation of components. Progress in Molecular Biology and Translational Science 109, 41–74. Chondrogianni, N., Gonos, E.S., 2008. Proteasome activation as a novel antiaging strategy. IUBMB Life 60, 651–655.

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Chondrogianni, N., Gonos, E.S., 2005. Proteasome dysfunction in mammalian aging: Steps and factors involved. Experimental Gerontology 40, 931–938. Gonos, E.S., Chondrogianni, N., Djordjevic, A.M., 2019. Where ageing goes nowadays: Mechanisms, pathways, biomarkers and anti-ageing strategies. Mechanisms of Ageing and Development 177, 1–3. Kaushik, S., Cuervo, A.M., 2015. Proteostasis and aging. Nature Medicine 21, 1406–1415. Kenyon, C., 2005. The plasticity of aging: Insights from long-lived mutants. Cell 120, 449–460. Lopez-Otin, C., Blasco, M.A., Partridge, L., Serrano, M., Kroemer, G., 2013. The hallmarks of aging. Cell 153, 792–806. Opattova, A., Cente, M., Novak, M., Filipcik, P., 2015. The ubiquitin proteasome system as a potential therapeutic target for treatment of neurodegenerative diseases. General Physiology and Biophysics 34, 337–352. Papaevgeniou, N., Chondrogianni, N., 2019. Anti-aging and anti-aggregation properties of polyphenolic compounds in C. elegans. Current Pharmaceutical Design 24, 2107–2120. Papaevgeniou, N., Chondrogianni, N., 2014. The ubiquitin proteasome system in Caenorhabditis elegans and its regulation. Redox Biology 2, 333–347. Wedel, S., Manola, M., Cavinato, M., Trougakos, I.P., Jansen-Durr, P., 2018. Targeting protein quality control mechanisms by natural products to promote healthy ageing. Molecules 23 pii: E1219.

Psoriatic Arthritis: A Current Vision Rube´n Queiro, Andre´s Lorenzo, and Estefanı´a Pardo, Hospital Universitario Central de Asturias, Oviedo, Spain Juan D Can˜ete, Arthritis Unit, Hospital Clinic, Barcelona, Spain © 2020 Elsevier Inc. All rights reserved.

Introduction Etiology and Pathogenesis Environmental Factors Clinical Characteristics Peripheral Arthritis Axial Arthritis or Spondylitis Enthesitis Bone Involvement Extra-Skeletal Manifestations Complementary Studies Diagnosis, Early Recognition and Differential Diagnosis The Age Factor in Psoriatic Disease Disease Evaluation and Outcome Disease Management and Treatment Conventional Synthetics Disease Modifying Anti-Rheumatic Drugs Biological Therapies Targeted Synthetic Disease Modifying Anti-Rheumatic Drugs Treatment Recommendations and Tight Control Strategies Unmet Needs References Further Reading

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Introduction Psoriasis and psoriatic arthritis (PsA) are relatively common entities in the general population. Psoriasis is a chronic, immunemediated disorder of the skin with a worldwide prevalence ranging 2–3%. Although rarely life threatening, it is associated with increased morbidity, mortality, and reduced quality of life. Its clinical course is characterized by variable disease severity and periods of remissions and flares. Individuals who develop psoriasis before the age of 40 (type I psoriasis) tend to have more severe disease that is familial in nature compared to those who develop psoriasis after the age of 40 (type II psoriasis). In either case, it is characterized by hyperproliferation of the epidermis, incomplete differentiation of keratinocytes, and an inflammatory infiltration of the epidermis and papillary dermis. Psoriasis most typically occurs on the trunk, limbs, scalp, elbows, knees, or in the body folds. Psoriasis can also affect the nails, resulting in yellowish discolouration, pitting, ridges, and onycholysis, characterized by detachment of the nail from the nail bed. Although the most common form of psoriasis is the plaque form, the disease can adopt various appearances, including life threatening forms such as psoriatic erythroderma (Nestle et al., 2009). Psoriasis is the result of complex interactions, both genetic and epigenetic, that facilitate the development of immunological abnormalities modulated by certain environmental factors, partially known, that finally give rise to the varied clinical picture of this condition. Thanks to this pathogenic knowledge, it has been possible to develop different therapeutic targets (inhibitors of TNFa, inhibitors of IL-23 signaling, and IL-17A inhibitors) that constitute the current basis of treatment for moderate-severe forms of the disease (Conrad and Gilliet, 2018). Although a cutaneous-articular condition reminiscent of PsA was already recognized by French dermatologists throughout the 19th century, the modern concept of PsA is relatively new. It was not until 1964 that a specific form of arthritis that develops in psoriasis patients, was recognized by the American Rheumatism Association (currently, American College of Rheumatology) as a clinical entity distinct from rheumatoid arthritis due to its distinctive clinical characteristics and lack of association with rheumatoid factor (Espinoza, 2018). Of the various associated features of psoriasis, PsA is the most common, with an estimated prevalence ranging from 6% to 42% among psoriasis patients. Considering that the prevalence of psoriasis is around 2–3% worldwide, and that almost one third of psoriasis patients develop PsA, it can be extrapolated that the prevalence of PsA is around 0.5–1% in the general population (Ritchlin et al., 2017; Alinaghi et al., 2018). Psoriatic arthritis belongs to a family of conditions known as spondyloarthritis, which include ankylosing spondylitis (AS), reactive arthritis, inflammatory bowel disease-associated arthritis, a juvenile form, and undifferentiated spondyloarthritis (Ritchlin et al., 2017). Psoriatic arthritis usually has two peaks of incidence, one between 30 and 40 years, and another, after 50 years (Ritchlin et al., 2017; Alinaghi et al., 2018). Some studies indicate that the incidence of the disease has grown since the 70s of the last

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century, although the reasons for this are unknown (Wilson et al., 2009). Most cases develop after psoriasis onset (in 70% of cases), but can appear concomitantly with psoriasis in 15% of cases or before psoriasis in the remaining 15% of cases (Ritchlin et al., 2017). The disease is characterized by varying degrees of axial and peripheral arthritis, to which are added distinctive features such as dactylitis (sausage digit), enthesitis (inflammation of the sites where ligaments and tendons attach to the bone) and arthritis of the distal interphalangeal joints (Ritchlin et al., 2017). This phenotypic variability was recognized by Moll and Wright who described the five classic patterns of the disease (Moll and Wright, 1973): -

Asymmetric oligoarthritis Symmetric polyarthritis Predominant distal interphalangeal joint arthritis Spondylitis (axial disease) Arthritis mutilans

In many patients, it is not uncommon for these different patterns to overlap with each other over time (Ritchlin et al., 2017). Although PsA affects men and women equally, men are more likely to develop spondylitis and severe radiographic damage in peripheral joints compared to women (Eder et al., 2013). These differences are partly explained by the differential distribution of certain genes (especially HLA-B27) between men and women with PsA (Queiro et al., 2016). Psoriatic arthritis is a chronic, progressive disease. Few patients (< 20%) achieve clinical remission, however this lasts for 2.6 years on average and relapses are common (Ritchlin et al., 2017). It is now apparent that PsA is more severe than previously thought, and can lead to progressive joint damage and disability, as well as increased mortality (Ritchlin et al., 2017). The progressive nature of PsA is evident from an increased frequency of patients with greater than or equal to 5 damaged joints at follow-up over 5 years (Ritchlin et al., 2017). While PsA patients experience similar causes of death compared to the general population, they may have higher mortality risk compared to the general population (Gladman, 2008). Patients with severe disease, defined by higher disease activity and higher number of damaged joints, are prone to this increased mortality (Gladman, 2008). Moreover, PsA patients have an increased risk of other comorbidities such as cardiovascular disease, type 2 diabetes, neurologic conditions, gastrointestinal disorders, and liver disease, and demonstrate a reduced quality of life and physical function compared to the general population (Ritchlin et al., 2017; Patel et al., 2018). There have been a plethora of classification criteria for PsA. There has been a virtually linear evolution of proposed classification criteria for PsA since the earliest concept of the disease proposed by Moll and Wright in 1973 (Moll and Wright, 1973; Raychaudhuri et al., 2017). Since 2006, the most used criteria for the classification and diagnosis of the disease are the CASPAR criteria (Taylor et al., 2006) (Table 1). These criteria have a high sensitivity and specificity and their usefulness has been contrasted in different clinical scenarios (Raychaudhuri et al., 2017).

Etiology and Pathogenesis Psoriatic arthritis is the result of complex interactions between elements of genetic/epigenetic predisposition, together with environmental and immunological factors. The way in which these interactions occur is only partially known (Ritchlin et al., 2017). Table 1

The CASPAR criteria.

Inflammatory articular disease (joint, spine, or entheseal) plus Three or more points from the following 1. Evidence of psoriasis (one of a, b, c)

2. Psoriatic nail dystrophy 3. A negative test for rheumatoid factor 4. Dactylitis (one of a, b) 5. Radiological evidence of juxta-articular new bone formation

a. Current psoriasisa: Psoriatic skin or scalp disease present today as judged by a rheumatologist or dermatologist b. Personal history of psoriasis: A history of psoriasis that may be obtained from patient, family doctor, dermatologist, rheumatologist or other qualified health-care provider c. Family history of psoriasis: A history of psoriasis in a first or second degree relative according to patient report Typical psoriatic nail dystrophy including onycholysis, pitting and hyperkeratosis observed on current physical examination By any method except latex but preferably by ELISA or nephelometry, according to the local laboratory reference range a. Current: Swelling of an entire digit b. History: A history of dactylitis recorded by a rheumatologist Ill-defined ossification near joint margins (but excluding osteophyte formation) on plain X rays of hand or foot

Specificity 0.987, Sensitivity 0.914. a Current psoriasis scores 2 whereas all other items score 1. Adapted from Taylor W, Gladman D, Helliwell P, et al; CASPAR Study Group. Classification criteria for psoriatic arthritis: Development of new criteria from a large international study. Arthritis and Rheumatism 2006; 54(8): 2665–73.

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Genetic factors are evident from the high prevalence of PsA among first-degree relatives of PsA probands, and a recurrence risk ratio of 30–35. The PsA concordance rate for monozygotic twins is higher compared to that of dizygotic twin. Like psoriasis, both dominant and recessive inheritance, as well as an excessive paternal transmission pattern, has been proposed for PsA but it is clear that neither apply, thus PsA has also been considered a multifactorial polygenetic disease (Ritchlin et al., 2017; Rahman and Elder, 2005). Genetic linkage analysis has been used to investigate the genetics of psoriasis. The psoriasis susceptibility loci that have been mapped using linkage methods include: PSORiasis Susceptibility locus (PSORS)1 on 6p21.3, PSORS2 on 17q, PSORS3 on 4q, PSORS4 on 1q21, PSORS5 on 3q21, PSORS6 on 19p, PSORS7 on 1p, PSORS8 on 16q, PSORS9 on 4q, and PSORS10 on 18p11. By far the strongest association is with a locus within the MHC on chromosome 6p21 (PSORS1). Additional putative psoriasis candidate loci have been reported on 16q and 20p. The loci on 6p and 17q have been replicated with independent linkage studies and a meta-analysis of previous studies has found an increased allele sharing for 16q. With regard to PsA, however, only one genome-wide linkage scan has been conducted. This study identified a locus on 16q close to the PSORS8 locus identified for psoriasis, but only when conditioned on paternal inheritance (Rahman and Elder, 2005). The familial aggregation of psoriatic disease supports the strong contribution of genetic factors for disease susceptibility. However, for complex diseases candidate-gene association studies yield more information than linkage studies. Association studies suggest that the strongest genetic contribution to psoriasis and PsA susceptibility is the MHC loci and particularly HLA-class I genes (Ritchlin et al., 2017; Chandran, 2013). The HLA class I region on chromosome 6 encompasses multi-allelic genes that encode highly polymorphic proteins that play an important role in self/non-self immune recognition. The HLA genes polymorphisms are determined largely by differences in amino acids in the binding pockets of the HLA molecules which influence the repertoire of peptides presented to the immune cells by these molecules. The association between HLA class I genes and psoriasis and PsA was first reported in the 1970s and has been confirmed in numerous candidate-gene and genome-wide association studies (GWAS) (Queiro et al., 2016; Chandran, 2013). It is estimated that these genes are responsible for approximately one-third of the entire genetic contribution to psoriatic disease (Chandran, 2013). Several HLA alleles have been associated with disease susceptibility as well as with different phenotypic features of psoriasis and PsA (FitzGerald et al., 2015). While psoriasis has been associated with HLA-C alleles, it appears that HLA-B alleles contribute to PsA disease susceptibility (Chandran, 2013; FitzGerald et al., 2015). Among these HLA alleles, HLA-C*06 is the major genetic determinant of psoriasis, and is detected in more than half of the patients with psoriasis. It is associated with familial psoriasis, earlier onset, and more severe skin disease (type I psoriasis) (Nestle et al., 2009; Chandran, 2013). The prevalence of HLA-C*06 is also elevated in PsA patients, however, significantly less prevalent than in psoriasis patients which suggests genetic heterogeneity of the two conditions (FitzGerald et al., 2015). The HLA region is a highly genetic and polymorphic density region, involved in the genesis of several autoimmune diseases. Within the HLA-B genes, the one that has been most consistently associated with the risk of PsA is HLA-B27, although with lower penetrance than that described in AS (Queiro et al., 2016; Chandran, 2013; FitzGerald et al., 2015). Other HLA-B alleles have also been associated with PsA risk (B*38, B*39, B*08) (Chandran, 2013; FitzGerald et al., 2015). More refined studies have linked the risk conferred by these alleles to a glutamine in position 45 (Okada et al., 2014). This polymorphic region has been detected in HLA-B*27, B*38, and B*39. This Glu-45 position is located in the antigenic recognition pocket, which underscores the pathogenic importance of processing and presentation of antigens in PsA (Okada et al., 2014). Very recently, it has been shown that the greatest genetic effect that differentiates the risk of PsA from that of psoriasis is located at position 97 of HLA-B, where asparagine (OR 2.46) or serine (OR 1.45) increase the risk of PsA respect to psoriasis (Bowes et al., 2017). Asp-97 is also a risk factor for AS (Cortes et al., 2015), although with greater genetic weight (OR 16.51) than PsA (OR 2.46). On the other hand, Ser-97 is only associated with PsA (OR 1.45), being protective for AS (OR 0.86) (Bowes et al., 2017). Currently, the markers used in candidate-gene association studies are called SNPs (single nucleotide polymorphisms) and it is possible to analyze millions of these SNPs in a single moment with genotyping technologies by microarrays. Thanks to these GWAS technologies and their corresponding meta-analysis, numerous genes with genome-wide significance have been identified in psoriasis and PsA, which are basically incorporated into three fundamental networks (David et al., 2018): - Genes involved in the maintenance of the cutaneous barrier function (only important for the risk of skin disease). - Genes that control innate immune responses mediated by NF-kB and interferon signaling (relevant in both cutaneous and joint disease). - Genes that control adaptive immune responses that involves CD8 lymphocytes and Th17 signaling (relevant in both cutaneous and joint disease). Although recent GWAS studies have identified > 60 risk loci of psoriatic disease, almost 50% of the heritability of the disease remains unknown, and most of the genes identified so far have a small weight in the genetic etiology of the disease. This “lost” heritability can be attributed, among others, to common variants that have a very small weight in risk, copy number variants, epigenetic or epistatic interactions, or lack of power of current detection tools (David et al., 2018). The traditional pathogenic model linking psoriasis and PsA suggested that both diseases are autoimmune in origin and result from defects in the adaptive immune system. In this model, a shared autoantigen expressed in both the skin and joints or cartilage elicits chronic autoreactive T cell-driven inflammation, with dysregulation occurring in the primary or secondary lymphoid organs. Histological evidence of CD8 þ T cell populations in both inflamed skin and synovium of PsA patients supports this mechanism, as does the strong association of both psoriasis and PsA with variants of HLA Class I genes HLA-C and HLA-B, respectively, which both function in antigen presentation. However, the problem of this model is that synovial T cells do not exhibit auto-reactivity, and no self-antigen has ever been identified (Ritchlin et al., 2017; FitzGerald et al., 2015).

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As a result, an alternative model of PsA has been proposed, which instead of dysregulation occurring in the primary or secondary lymphoid organs, places the entheses (anatomical sites where ligaments and tendons insert into bones) as the starting point of inflammation (McGonagle et al., 2015). This model can be divided into several stages. In the initiation phase, biomechanical strain, entheseal microtrauma or dysregulated tissue homeostasis attracts inflammatory cells to the adjacent synovium and bone marrow, because the enthesis itself is relatively resistant to vascular and immune cell invasion. These inflammatory cells are basically innate immune cells that are activated without the need for prior antigen recognition. It is assumed that these cells reside in the entheses, although it cannot be ruled out that they migrate from the gut (McGonagle et al., 2015; Ciccia et al., 2016; Schett et al., 2017). The entheseal theory was given a remarkable boost when Sherlock through a murine model of continuous release of IL-23 (injection of IL-23 DNA microspheres), in the context of a collagen-induced arthritis, proved that enthesitis was the starting point of a disease reminiscent of human spondyloarthritis (Sherlock et al., 2012). This author was able to verify that entheseal cells that responded to IL-23 were CD3 þ CD4-CD8- IL-23R þ ROR-gt þ T lymphoid cells, which produced important amounts of IL-17 and 22, suggesting a central role of innate immune cells in disease pathogenesis. Studies are beginning to be published in humans where the source of IL-23 appears to be type 3 innate immune cells (ILC-3) and gd T cells (Schett et al., 2017). These innate immune cells are capable of producing proinflammatory cytokines such as TNFa, IL-17A, and IL-22, among others. In the amplification stage it is believed that IL-23 is capable of generating a feedback loop on cells expressing the receptor for this cytokine, giving rise to Th17 responses in neighboring lymphoid organs. IL-17 and Th17 levels have been found to correlate with systemic disease activity. Activated T cells likely contribute to the enhanced production of cytokines in both the synovial fluid and synovial cultures from PsA patients (Ritchlin et al., 2017; McGonagle et al., 2015). These cytokines also include IL-1b, IL-2, IL-10, IFN-a, and TNF-a, which induce proliferation and activation of synovial and epidermal fibroblasts, leading to the fibrosis reported in patients with longstanding PsA (Ritchlin et al., 2017; Barnas and Ritchlin, 2015). Several other innate immune lymphocytes also participate in inflammation in the amplification phase, including natural killer (NK) cells and gd T cells (Barnas and Ritchlin, 2015). Both NK and NK-T cells have been desc00ribed in increased numbers in psoriatic plaques and in synovial tissues from PsA patients (Barnas and Ritchlin, 2015). TNFa is also produced by different cell types in the synovium, such as monocyte-macrophage lineages (Barnas and Ritchlin, 2015). Compared to RA histopathology, less hypertrophy of the synovial lining and a lower infiltration of fibroblast-like synoviocytes and macrophages are observed in PsA. Another striking feature of PsA histology is neoangiogenesis with more marked vessels, more tortuous and denser than in RA, even since the onset of the disease (Ritchlin et al., 2017; Barnas and Ritchlin, 2015) (Fig. 1). The phenomenon of lymphoneogenesis has been described in about 40% of patients with PsA (Cañete et al., 2007). This histopathology consisting of increased vascularity, as well as infiltration by neutrophils and CD68 macrophage lineages, is common to other spondyloarthritis (Barnas and Ritchlin, 2015) (Fig. 2). In contrast to psoriasis, in which the effecter phase results in no permanent damage to the skin, permanent joint damage can occur in PsA through loss of cartilage and bone erosion (Paine and Ritchlin, 2018). Interestingly, the opposite process of new bone formation can also occur in PsA, as evidenced by the presence of enthesophytes and syndesmophytes that can lead to ankylosis (Paine and Ritchlin, 2018). The role of innate and adaptive immune mechanisms involved in the processes of joint destruction and new bone formation are not well known. Cartilage loss during inflammation is associated with upregulation of various tissue destructive enzymes such as the matrix metalloproteinases (MMPs) and ADAMTS protease, which are regulated by IL-1 and TNFa. Osteoclasts, which break down calcified bone, might be involved. These cells differentiate from monocytic osteoclast precursors (OCPs) upon exposure to monocyte colony stimulating factor (M-CSF) and receptor activator of NF-kB ligand (RANKL).

Fig. 1

Arthroscopic view of PsA. Characteristic tortuous neoangiogenesis. Courtesy of Prof. Cañete (Hospital Clinic. Barcelona. Spain).

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Fig. 2 Abundance of CD68 þ macrophages in the synovial lining of PsA. Macrophages correlate with disease activity and joint erosions. In addition, its reduction during treatment is associated with treatment success. Immunohistochemical staining with anti-CD68. Courtesy of Prof. Cañete (Hospital Clinic. Barcelona. Spain).

RANKL is produced by chondrocytes and Th17 cells under inflammatory conditions, and binds to its receptor RANK, which is expressed on the surface of OCPs. OCPs have been found in increased numbers in the circulation and synovial lining of PsA patients compared to healthy controls (Paine and Ritchlin, 2018). In PsA, it has been proposed that monocytes activated by TNFa migrate to the synovium, where they are exposed to M-CSF and RANKL, differentiate into OCPs, and promote osteolysis and bone resorption (Paine and Ritchlin, 2018). Less is known about the mechanisms of new bone formation in PsA patients, although it has been shown that TNFa and IL-1 can upregulate bone and cartilage anabolic cytokines like bone morphogenetic protein as well as antagonists of the Wnt pathway, an important signaling pathway in the regulation of bone metabolism (Paine and Ritchlin, 2018). It has been suggested that IL-22 (produced by entheseal ILC3 cells) could contribute to new bone formation in PsA by driving the proliferation, migration and osteogenic differentiation of mesenchymal stem cells in an inflammation-dependent context (Schett et al., 2017; Paine and Ritchlin, 2018). The current view of the etiopathogenesis of PsA maintains that the initial inflammatory events of the disease occur in the entheses due to the intervention of cytokines (TNFa, IL17, IL22) produced by innate immune cells (ILC3, gd T cells) residing in these anatomical areas, but with a second step that occurs in neighboring lymphoid tissues and that involves cells of adaptive immunity (Th17), which exert a positive feedback on the former (McGonagle et al., 2015; Schett et al., 2017) (Fig. 3). An alternative theory, and complementary at the same time, is that which holds that there is a gut-joint axis, where primary events occur in the gut lamina propria with the activation of certain immune cells that would then be translocated to subchondral bone, joints and entheses (Ciccia et al., 2016). Many patients with psoriasis and PsA associate subclinical intestinal inflammation. In these populations, a decrease in bacterial diversity has been demonstrated due to the lower abundance of several taxa (Caminer et al., 2017). Thus, it was found that Coprococcus was inversely associated with psoriasis with or without arthritis, whereas a decrease in the relative abundance of Ruminococcus and Akkermansia was characteristic of PsA (Caminer et al., 2017). This is of particular interest since Ruminococcus is also reduced in the microbiome of patients with inflammatory bowel disease (IBD) (Caminer et al., 2017). On the other hand, the decrease in the abundance of Akkermansia in PsA contrasts with that in juvenile idiopathic arthritis (JIA), which indicates that different microbes can also promote the etiology of these diseases (Caminer et al., 2017). In PsA and IBD there is also a relative decrease of another positive commensal such as Alistipes. Many of these microorganisms play a role in the degradation of mucus and produce short chain fatty acids that influence homeostasis of the intestine. Therefore the decrease in the presence of some species with respect to others may alter the intestinal permeability, which in certain predisposing genetic background (HLAB27), could generate immune responses in the lamina propria (Caminer et al., 2017). Studies in HLA-B27 transgenic rats indicate that intestinal inflammation and deterioration of the epithelial barrier function occur at the same time. Thus, the development of gut epithelial barrier dysfunction, dysbiosis and inflammation in the lamina propria may be closely linked temporally and spatially (Lin et al., 2014). The effects of HLA-B27 on gut microbiota and dysbiosis in spondyloarthritis are highly dependent on the host genetic background and/or environment, despite convergence of dysregulated immune pathways. This implicates an ecological model of dysbiosis, with the effects of multiple microbes contributing to the aberrant immune response, rather than a single or small number of microbes driving pathogenesis (Gill et al., 2018). It is possible that HLA-B27 individuals have cellular stress responses (autophagy, unfolded protein response) in a subset of inflammatory cells. This could lead to a disruption of the epithelial barrier, a local inflammatory response, or both, culminating with the loss of barrier function and the loss of oral tolerance (Gill et al., 2018; Asquith et al., 2014). It is conceivable that the increased translocation of microbial products may favor the development of certain immune populations that subsequently migrate to peripheral tissues. In

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Fig. 3 The current view of the etiopathogenesis of PsA. (1) The enthesis is a functional organ predisposed to damage, either by microtraumas or by the activation of an intestinal-enthesis axis, favored by a predisposing genetic background (HLA-B27). Activated enthesis resident cells (or that reach the enthesis through the gut-enthesis axis), release proinflammatory cytokines that can generate reparative inflammatory responses, or in appropriate contexts, activate adaptive immunity responses in neighboring lymph node. (2) A second step occurs in regional lymph nodes, where dendritic cells (DC) in an MHC-I restriction context can present antigens to cytotoxic Th17 cells (Tc17). (3) These cells, in turn, through the secretion of IL17, generate a greater recruitment of inflammatory cells towards the enthesis, where by action of IL23 a positive feedback loop is closed.

addition, since microbial products can induce peripheral inflammation themselves (curdlan/SKG model, endotoxin-induced uveitis), translocated microbial products may contribute to the inflammatory cascade in extra-intestinal sites, such as uvea, entheses and joints (Asquith et al., 2014; Speca and Dubuquoy, 2017). Unlike what occurs in AS, in the gut of patients with PsA, Paneth cells are characterized by the expression of IL-9 and not IL-23. IL-9 is a cytokine initially purified and characterized as a growth factor for T and mast cells that affects the function of the intestinal barrier and prevents the healing of mucous wounds in vivo. Interestingly, in the intestine of PsA, Paneth cells not only express IL-9R, but its stimulation on epithelial cells increases the expression of antimicrobial peptides (a-defensin 5) and cytokines (IL-23, IL-9), suggesting the possibility of a functional autocrine loop involving IL-9/IL-9R (Ciccia et al., 2016). Therefore, Paneth cells seem to play a fundamental role in the regulation of innate intestinal immunity, presumably in response to altered microbiota in patients with SpA and PsA. The subclinical gut inflammation of patients with AS and PsA is characterized by a clear Th17, Th22, and Th9 polarization. Unlike AS, in PsA there is an up-regulation of intestinal IL-9, mainly expressed by Th9 cells and high endothelial venules. A Th9 expansion has been demonstrated in the intestinal inflammation of ulcerative colitis and the significant expansion that is observed of these cells in the gut of patients with PsA may indicate a role for these cells in psoriatic bowel inflammation. Th9 are also expanded in the peripheral blood and synovial tissues of PsA, where there is an overexpression of the a4b7 integrin indicating the intestinal origin of these synovial cells (joint-gut axis). These findings may suggest a different immune polarization in the gut in AS (Th17) vs. PsA (Th9) (Ciccia et al., 2016).

Environmental Factors It has been known for decades that certain environmental factors are linked to the appearance or exacerbation of psoriasis and/or PsA. Guttate psoriasis is usually preceded by tonsillar infections caused by Streptococci, and human immunodeficiency virus (HIV) has been associated with severe exacerbations of psoriasis and PsA, thus highlighting the role of CD8 T lymphocytes in the pathogenesis (Ogdie and Gelfand, 2015). Although the literature describes many inductors of PsA, most recent evidences point to three key elements in the determinism of the disease: trauma, smoking, and obesity (Ogdie and Gelfand, 2015). Some series collect a traumatic antecedent in up to 15% of early PsA cases (Ogdie and Gelfand, 2015). In a recent observation, a Hazard Ratio (HR) of 1.32 for PsA was established after physical trauma. When analyzing HR by type of trauma, only bone (HR: 1.46) and joint (HR: 1.50)

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traumas were associated with the risk of PsA (Thorarensen et al., 2017). This connection is in line with the hypothesis of mechanical stress on the entheso-synovial organ proposed by McGonagle as the conductive element of the earliest stages of the disease (McGonagle et al., 2015). Both obesity and smoking have been linked to an increased risk of PsA, and this association is clearly dose-dependent (Ogdie and Gelfand, 2015). This implies that subjects with psoriasis who smoke more and for longer have a much higher risk of developing PsA and the same applies for overweight and obesity (Ogdie and Gelfand, 2015). In any case, the age at which individuals are exposed to these risk factors is important (Queiro et al., 2014). The harmful effect of smoking as risk factor appears early in the disease course, and this risk remains for a long time, even when this habit has been abandoned (Alonso et al., 2016). Obesity is more prevalent among late onset cases (Alonso et al., 2016). It may be argued that since overweight and obesity tend to accompany human aging, this factor gets more etiologic relevance in late disease (Alonso et al., 2016).

Clinical Characteristics In PsA there are varying degrees of axial and peripheral joint manifestations, as well as extra-articular manifestations, which confers a high degree of clinical pleomorphism to this entity (Ritchlin et al., 2017).

Peripheral Arthritis The most common presentation of peripheral PsA is as insidious onset arthritis with nocturnal pain and morning stiffness. In up to a third of cases it can be acute and febrile, forcing a differential diagnosis with septic or microcrystalline arthritis. Two classic patterns are described: an asymmetric oligoarthritis of the lower limbs and a polyarthritis of greater or lesser symmetry -which sometimes resembles RA- but where involvement of the DIP joints with onychopathy is typical (Fig. 4). The symmetric character has been described from 28% to 78%. An axis-type pattern of joint involvement is typical, where all the joints of one (or two) finger or toe are affected, the rest being respected (Fig. 4). Involvement of DIP joints may be the initial manifestation in 5% of cases, but in general it is associated with time to other manifestations of PsA. Almost 5% of the subjects with PsA develop a particularly aggressive form of arthritis with osteolysis of small bones of the hands and feet, known as arthritis mutilans (Fig. 4). Nowadays, the involvement of the DIP joints and the mutilating forms are considered characteristic of PsA rather than independent models of this. Another highly suggestive feature (although not pathognomonic) is the global swelling of a finger or toe, which is what is known as dactylitis or sausage digit (Fig. 4). For some authors, dactylitis is a marker of aggressiveness and poor prognosis (Ritchlin et al., 2017).

Axial Arthritis or Spondylitis Between 40% and 50% of patients with PsA have radiological signs of sacroiliac joint (SIJ) involvement, and up to 20% have axial radiological signs of disease without apparent symptoms. Symmetric SIJ involvement is linked to HLA-B27 while asymmetric one has been recently associated to HLA-B*08. Axial disease is more common in men than in women. Probably, because of its more

Fig. 4 Typical features of PsA. There is a greater involvement of the middle finger of the hand (ray- or axis pattern). The nail involvement is patent on all the fingers. There is global swelling of the middle finger (dactylitis or sausage digit). The third finger appears shortened with respect to the other fingers due to osteolysis of the phalanges (arthritis mutilans).

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asymmetrical radiological character and the presence of syndesmophytes that are more separated from the spine, psoriatic spondylitis has been associated with less functional impairment than classical AS. It is also classically accepted a less painful character in comparison with AS. Isolated axial forms are rare (10%) and most commonly they coexist with varying degrees of peripheral involvement (Ritchlin et al., 2017).

Enthesitis The inflammation of the bone anchoring sites of tendons, capsules and ligaments is known as enthesitis and is a common feature of spondyloarthritis, including PsA. Enthesitis has a high discriminant value for the distinction between these conditions and other chronic arthropathies. Clinical enthesitis is described in 30–50% of cases of PsA, but it is likely that the ultrasound prevalence of this manifestation is even greater. The most affected entheses in PsA are those of the Achilles tendon, those of the knee and those of the pelvic ring. In some studies this manifestation has been described predominantly in patients with axial involvement. The presence of Doppler signal in the ultrasonography of the entheses of psoriatic subjects has been linked to the future development of PsA (Ritchlin et al., 2017).

Bone Involvement Bone disease in PsA manifests in the form of the so-called SAPHO syndrome (Kahn, 1993). This is the acronym of synovitis, acne, pustulosis, hyperostosis and osteitis. The usual picture is palmoplantar pustulosis linked to inflammatory manifestations in the rib cage (sternoclavicular joints and sternal manubrium). Less frequently is associated with acneiform lesions and hidradenitis suppurativa. In children, the usual presentation of SAPHO is in the form of chronic recurrent multifocal osteomyelitis (Kahn, 1993). This syndrome is not related to HLA-B27 (Kahn, 1993). Psoriatic onychopachydermoperiostitis (POPP) syndrome characterizes a clinical variant of PsA (Fournié et al., 1989). Both great toes are generally affected presenting with nail changes, painful swelling of the soft tissue close to the distal phalanx as well as specific radiologic changes such as periosteal reaction and bone erosions of the distal phalanges. Joint involvement is characteristically absent.

Extra-Skeletal Manifestations These are shared manifestations with the rest of spondyloarthritis (such as anterior uveitis), although in PsA, a uveitis with a greater tendency to bilaterality, chronicity and affectation of the posterior pole has been also described. Other manifestations as lymphedema, amyloidosis, osteoporosis, aortic root involvement, gut inflammation, etc. are also described (Ritchlin et al., 2017). The high prevalence of traditional cardiovascular risk factors and metabolic abnormalities contributes to the high cardiovascular burden in patients with psoriasis and PsA. The presence of systemic inflammation in combination with metabolic abnormalities may act in a synergistic manner to increase cardiovascular risk in these patients (Ritchlin et al., 2017).

Complementary Studies There are no diagnostic tests for PsA. In general, as in the rest of spondyloarthritis, there is no good correlation between acute phase reactants (erythrocyte sedimentation rate and C-reactive protein -CRP-) and disease activity (Ritchlin et al., 2017). Determinations of autoantibodies (rheumatoid factor, antinuclear antibodies, anti-citrullinated protein antibodies) are usually negative. Synovial fluid characteristics are unspecific. Some serum biomarkers can help distinguish subjects with PsA versus psoriasis alone; this is the case of ultrasensitive CRP, osteoprotegerin, MMP-3 and the CPII/C2C ratio (Chandran and Scher, 2014). The combination of ITGb5, M2BP, and CRP level differentiates PsA from psoriasis, and performs better than CRP level alone (Cretu et al., 2018). Innate lymphoid cells (ILC) have a high potency for cytokine production independent of specific antigenic stimulation. Imbalance of ILC subsets may influence cytokine production in humans and hence be associated with the development of inflammatory diseases. Very recently, a Receiver-Operating Characteristic (ROC) curve was used to test the performance of the ILC2/3 ratio as marker of remission in PsA and to find the best cutoff level for ILC2/3 ratio in differentiating between remission and disease activity. ILC2/3 ratio at the cutoff of 0.57 exhibited highest sensitivity (92.9%) and 84.7% specificity in identifying remission (Soare et al., 2018). Radiological findings in the peripheral skeleton in PsA are characterized by little or no juxta articular osteoporosis, erosive and osteoproliferative images near to the joint limits, pencil-cup or diffuse osteolysis, ankylosis, resorption of phalangeal tufts and periostitis (Fig. 5). It is typical the coexistence, in the same digital axis, of lesions in different evolutionary degrees. In the axial skeleton, asymmetric sacroiliitis and thick, irregular syndesmophytes located far from the spinal column (parasyndesmophytes) are typical (Poggenborg et al., 2015) (Fig. 6). Occasionally, advanced destructive changes in the cervical spine are also seen, with scarce involvement of the lumbar and sacroiliac region (Poggenborg et al., 2015). Erosive vertebral disc lesions and facet joint involvement are less frequent than in AS (Poggenborg et al., 2015). Sonographic changes of the entheses are common to those of other spondyloarthritis, except perhaps for the higher prevalence of subclinical changes in psoriasis (Poggenborg et al., 2015) (Fig. 7). In general, MRI is the technique that provides more information on axial skeletal lesions, but its use is being extended to better assess joint and entheses at peripheral sites (Poggenborg et al., 2015).

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Fig. 5 Typical radiographic appearance of psoriatic arthritis. Marked osteolysis of the phalanges of the 2nd and 5th fingers that appear shortened with respect to the other fingers. Ankylosis of the DIP joint of the 2nd finger. Cup deformity at the base of the proximal phalanx of the 1st finger. The image on the right shows the typical bone proliferation and erosions adjacent to the joint margins (in this case, a DIP joint. This type of image corresponds to the radiological definition of the CASPAR criteria). Courtesy of the Spanish Society of Rheumatology slide collection.

Fig. 6

Parasyndesmophyte (arrow).

Diagnosis, Early Recognition and Differential Diagnosis The majority of cases of PsA are diagnosed in patients who have been suffering psoriasis for many years. The average time between the onset of psoriasis and the onset of arthritis is about 10 years (Ritchlin et al., 2017). This, together with the clinical characteristics mentioned above, makes the diagnosis of this form of arthropathy not particularly complicated. However, 15% of subjects have clinical-radiological features suggestive of PsA without psoriasis (Ritchlin et al., 2017). In other cases the only manifestation is an enthesitis, or the patient present with rheumatoid factor positivity, so the classic criteria of Moll and Wright (1973) are not operational in these cases. Since 2006, the CASPAR criteria are available, which served to obviate these situations and to correctly label a case as PsA (Taylor et al., 2006).

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Fig. 7 Ultrasonographic enthesitis of the quadriceps tendon of the knee (longitudinal view). The box image shows a thickened, hypoechoic enthesis with power Doppler activity.

Some characteristic of psoriasis can help predicting which patients will develop arthritis. Psoriasis features associated with a higher risk of PsA were scalp lesions (HR 3.89), nail dystrophy (HR 2.93) and intergluteal/perianal lesions (HR 2.35) (Ogdie and Gelfand, 2015). Nail lesions are very common and help distinguish between patients who have PsA and those who have RA, and between patients with psoriasis who have arthritis and those who do not have arthritis. In fact, nail dystrophy occurs in approximately 40–45% of patients with psoriasis uncomplicated by arthritis, and approximately 87% of those having PsA (Ogdie and Gelfand, 2015). Diagnosis of PsA may sometimes offer difficulties, even for expert clinicians in this field, and therefore it is necessary to establish solid strategies for an early recognition of this potentially disabling disease. In that sense, a multidisciplinary management between dermatologists and rheumatologists, as well as with other specialists, is highly recommended (Queiro and Coto, 2017). One of the strategies for early recognition of PsA has been the development of different screening questionnaires, applicable both in dermatology and general medicine clinics (Raychaudhuri et al., 2017). Most of these instruments have had an adequate capacity to distinguish patients with and without PsA (Table 2). However, the high sensitivity and specificity achieved by these tools in the original studies has not been corroborated in subsequent studies (Queiro and Coto, 2017).

Table 2

Screening questionnaires for psoriatic arthritis.

Tool

Setting

Items

Cut-off

Sensitivity (%)

Specificity (%)

PASE

Dermatology/rheumatology clinics

15

47 44

24–82 76–78

50–73 40–76

ToPAS/ToPAS2

Dermatology, rheumatology and family medicine clinics

12/12

8 8

41–87 96

55–93 99

PEST

Primary care clinics

5

3

28–92

45–78

PASQ/ePASQ

Dermatology/rheumatology clinics

10/8

7 7

67–93 88–98

75 75

EARP

Dermatology clinics

10

3

79–85

35–92

PASE, Psoriatic Arthritis Screening and Evaluation; ToPAS: Toronto Psoriatic Arthritis Screen; ToPAS2, Toronto Psoriatic Arthritis Screen version 2; PEST, Psoriasis Epidemiology Screening Tool; PASQ, Psoriasis and Arthritis Screening Questionnaire; ePASQ, e-version Psoriasis and Arthritis Screening Questionnaire; EARP, Early Arthritis for Psoriatic Patients. Adapted from Raychaudhuri SP, Wilken R, Sukhov AC, Raychaudhuri SK, Maverakis E. Management of psoriatic arthritis: Early diagnosis, monitoring of disease severity and cutting edge therapies. Journal of Autoimmunity 2017; 76: 21–37.

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The differential diagnosis of PsA includes other causes of polyarthritis such as RA, SLE, vasculitis, sarcoidosis, etc. The monooligoarticular forms demand a differential diagnosis with infectious or microcrystalline arthritis (Ritchlin et al., 2017).

The Age Factor in Psoriatic Disease Psoriasis has been classified according to age of onset. Early onset psoriasis (also referred to as type I) has onset before the age of 40 years, with peak onset at 16–22 years of age, and comprises 70% of all psoriasis cases. Late-onset psoriasis, also termed type II psoriasis, shows onset at or after age 40 years, with a peak age of onset between 57 and 60 years (Queiro et al., 2014). Although these forms of psoriasis cannot be distinguished on clinical or histopathological grounds, a distinct pattern of HLA association has been reported. Hence, with early onset psoriasis, which also displays a strong family history, a strong association with class I HLA alleles, and specifically HLA-C*06, is observed. In contrast, type II psoriasis is more sporadic and rarely familial, and its genetic background is unclear (Queiro et al., 2014). Currently there is no consensus on what we mean by early onset PsA compared with what might be considered late-onset disease. To address this issue, most researchers have determined two potential cut-offs, one at 40 years (as in psoriasis) and the other at 60 years (as in RA) (Queiro et al., 2014). The spondyloarthritis complex, includes definite entities (such as PsA) as well as undifferentiated forms. Each of these may have a late onset. Late-onset undifferentiated spondyloarthritis appears to be relatively more common than late-onset AS. Its clinical spectrum seems to be as broad as that observed in young and middle-aged adults, with the exception of distal inflammatory swelling with pitting edema (more frequently seen in late-onset cases) (Queiro et al., 2014). It is interesting to note that, as in psoriasis, the risk effect attributable to HLA-C*06 declines with increasing age in patients with PsA and the strongest association is observed in subjects with age of onset < 30 years, so it has been postulated that this age limit is suitable for distinguishing between type I and type II psoriasis in PsA (Queiro et al., 2014). By using this age limit, a study found that PsA patients with early onset psoriasis more frequently showed longer psoriasis-arthritis latency, a positive family history of disease, severe psoriasis, clinical enthesitis and oligoarthritis (Queiro et al., 2014). Therefore, dividing the PsA according to an age limit of 30–40 years seems to be an appropriate descriptor from a clinical and genetic standpoint. It is possible that, as occurs in psoriasis, where the age of onset below or above 40 years marks phenotypic characteristics that depend on the presence of HLA-C*06, likewise in PsA the presence of HLA-B27 may act not only as an etiological factor, but also as a modulator of phenotypic expression. Thus patients with PsA and disease onset before 40 years of age tend to have higher familial aggregation, bilateral SI, B27 positivity, uveitis, isolated axial pattern and enthesitis compared with those with disease onset after this age limit (Queiro et al., 2016). PsA frequently begins in the elderly. Punzi et al. have prospectively evaluated the presenting manifestations and the 2 year outcome of 66 consecutive patients with PsA, 16 of whom with elderly onset (> 60 years) and 50 with younger onset. The elderly group had a significant higher number of active joints, foot erosions and levels of serum CRP and synovial IL1b and IL6 than younger patients. After 2 years, the progression rate of the joint damage and the CRP level were higher in older patients than in younger ones (Punzi et al., 1999). More recently, Kobak et al. followed-up a total of 180 patients diagnosed with PsA according to CASPAR criteria. The patients with initial symptoms starting after age 65 were accepted as elderly-onset PsA (EOPsA). Nineteen (10.5%) of 180 patients were diagnosed as EOPsA, and 161 (89.5%) patients were evaluated as young-onset PsA (YOPsA). Higher rates of fatigue, pain scores, comorbid diseases, and acute phase reactants elevation were detected in EOPsA patients comparing to YOPsA (Kobak et al., 2017). Alonso et al. found that patients with psoriasis starting after 40 years had a higher risk for diabetes development, while those with arthritis onset above this age limit were more prone to hypertension. These findings suggest that both phenotypes (skin and joint) of psoriatic disease were associated with a differential cardiovascular risk profile. This author also found obesity more commonly among late onset cases (Alonso et al., 2016). The question, therefore, is why late-onset cases appear to have a more aggressive course with higher inflammatory markers than younger-onset PsA cases. As discussed before, obesity is not only a risk factor for the disease, but it is more prevalent in cases of late onset (Ogdie and Gelfand, 2015; Alonso et al., 2016). Obesity is linked to chronic inflammation through several mechanisms, including the dysregulation of autophagy, whereas fasting has anti-inflammatory effects, similar to the effect of exercise, and may downregulate inflammatory biomarkers (Rea et al., 2018). There is also a connection between obesity and intestinal dysbiosis. There is, therefore, considerable interest in the role of the intestinal microbiota and health and the so-called immune-relevant microbiome, with important correlations between inflammation and neurodegenerative disease, bacterial b-hydroxybutyrate metabolites, and the role of vagal stimulation (Rea et al., 2018). However the role of this immune-relevant microbiome in PsA is unknown. Another potential explanation for the greater severity of late-onset PsA could be found in the concept of inflammaging (Rea et al., 2018). Aging is characterized by a low-grade chronic pro-inflammatory state, called inflammaging, which is a significant risk factor for morbidity and mortality of older individuals as it is implicated in the pathogenesis of several disabling diseases of the elderly, such as type-2 diabetes mellitus, osteoporosis, Alzheimer’s disease, RA, and coronary heart disease (Rea et al., 2018). Circulating inflammatory mediators such as cytokines and acute phase proteins, e.g., CRP and mannose-binding lectin (MBL), are markers of this low-grade inflammatory status. Increasing evidence shows that many signaling pathways are activated in a stress-type-dependent fashion, and all appear to converge with nuclear factor (NF)-kB signaling, which is a central controller of the immune response, and inflammatory cascade. With increasing age, immune homeostasis loosens, NF-kB signaling becomes less tightly controlled or is more readily triggered, cytokine dysregulation occurs, and a pro-inflammatory phenotype predominates that underpins most major age-related diseases from atherosclerosis to cancer, and aging itself (Rea et al., 2018). Thus, for example, in the synovial tissue of RA

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factors secreted by senescent cells, including highly activated T cells, macrophages, NK cells, plasma cells, promote chronic inflammation, responsible for determining the outcome of the local inflammatory process (Rea et al., 2018). Fibroblast-like synoviocytes express several molecules that can function as co-stimulatory receptors for senescent CD4 þ T cells, thereby providing fertile ground for the activation of these inflammatory T cells in the synovium (Rea et al., 2018). In any case, the way in which this inflammaging process affects patients with late onset PsA is unknown to date.

Disease Evaluation and Outcome Psoriatic arthritis is an entity affecting entheses, axial and peripheral joints, skin and nails. All these domains must be evaluated to obtain the degree or intensity with which the disease affects these patients. It is also necessary to know to what extent these domains respond to the prescribed treatments. In recent years there has been a considerable effort to achieve accurate, reproducible and sensitive to change tools, reflecting disease activity as well as the global impact of the disease on the health of patients (Ritchlin et al., 2017). About 20% of patients with PsA develop severe and destructive forms of arthritis. Thus, 55% of subjects with  10 years of follow-up have  5 deformed joints. In series of early PsA, it is described that 47% present erosive disease within the first 2 years of follow-up. < 10% of patients with PsA have prolonged drug-free remissions and no progression of radiographic damage (Ritchlin et al., 2017). Some studies point to an over-mortality of PsA over the general population, which is usually related to the degree of disability and inflammation at baseline visits (Ritchlin et al., 2017; Gladman, 2008). Finally, it should be remembered that subjects with PsA have an excess of cardiovascular morbidity and mortality related both with classic cardiovascular risk factors, and others more linked to the inflammatory load of the disease (Ritchlin et al., 2017).

Disease Management and Treatment The first step in the correct management of the disease is to establish strategies for the early recognition of the disease, as well as to evaluate the presence of the so-called factors of poor prognosis (Ritchlin et al., 2017). It has been established that a diagnostic delay > 6 months is associated with greater structural damage, worse physical function, and a lower probability of therapeutic success, even with biological therapies (Ritchlin et al., 2017). On the other hand, two of the risk factors of the disease, such as tobacco, and especially obesity, are associated with poorer responses and lower retention rates of biologic therapies (Ritchlin et al., 2017; Ogdie and Gelfand, 2015). Therefore, both factors must be adequately addressed (Ritchlin et al., 2017; Ogdie and Gelfand, 2015). Some cases of PsA can be easily managed with conventional anti-inflammatory medications, physiotherapeutic aid, or even, with intra or periarticular injections of glucocorticoids (GC). In some cases, low doses of systemic GC can also be useful. However, given that the aim of treatment for these patients is remission or low disease activity, in most cases, PsA requires another type of therapeutic approach. This essentially refers to the use of so-called disease modifying anti-rheumatic drugs (DMARDs), which currently include conventional synthetics (cs), specific target (st), and biological therapies (Van den Bosch and Coates, 2018; Gossec et al., 2016).

Conventional Synthetics Disease Modifying Anti-Rheumatic Drugs The most commonly used csDMARDs in PsA are methotrexate, leflunomide, and sulfasalazine. In general, these drugs are used for the treatment of peripheral arthritis but their antipsoriatic action is modest at best (better with MTX than with the other two drugs). They have not shown efficacy to treat axial arthritis and neither seem to inhibit the progression of radiological damage. Their utility to treat enthesitis or dactylitis is controversial. These drugs are used as first-line agents after the failure of the most basic treatment measures or if there are poor prognostic factors (Van den Bosch and Coates, 2018; Gossec et al., 2016).

Biological Therapies All TNFa antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab) have shown efficacy in all PsA domains, as well as their inhibitory effect on radiological progression in adequate randomized controlled trials. The concomitant use of methotrexate with the monoclonal inhibitors of TNFa (especially infliximab and adalimumab) may prolong the half-life of these agents. In general, they are used when patients do not respond, or are intolerant, to csDMARDs. TNFa antagonists are contraindicated in severe infections, cancer, demyelinating diseases or in advanced congestive heart failure. The screening of tuberculosis is mandatory before starting this type of drugs (Van den Bosch and Coates, 2018; Gossec et al., 2016). Ustekinumab is a fully human IgG1 monoclonal antibody that binds with high affinity to the shared p40 subunit of human IL12 and IL-23, inhibiting their binding to the IL-12Rb1 receptor on the surfaces of T cells, NK cells, and antigen presenting cells. Its safety and efficacy have been evaluated in two multicentric, double-blind, placebo-controlled trials (PSUMMIT 1 and PSUMMIT 2). At week 24, there was a significant improvement in ACR 20 in PSUMMIT 1 (UST 90 mg 50%, UST 45 mg 42%, placebo 23%), as well as in PSUMMIT 2 (UST 90 mg 44%, UST 45 mg 44%, placebo 20%) (Van den Bosch and Coates, 2018; Gossec et al., 2016).

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Secukinumab is a high affinity, human immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to and neutralizes interleukin 17A. Interleukin 17 A is postulated to play an important role in the pathogenesis of PsA. Increased levels of interleukin 17A producing cells are found in the circulation, skin and joints of patients with PsA. Its safety and efficacy were evaluated in two RCT (FUTURE I and II). In both studies Secukinumab was better than placebo in all domains of PsA. In FUTURE I it was shown that the drug inhibit the progression of structural damage (Van den Bosch and Coates, 2018; Gossec et al., 2016). This drug is currently approved for the treatment of PsA. Ixekizumab is a humanized IgG4 monoclonal antibody that neutralizes interleukin-17A. Two RCTs (SPIRIT P1 and P2) have demonstrated its efficacy and safety in PsA. The drug adequately covers all domains of PsA, and also, slows the progression of radiographic damage. Ixekizumab has recently received FDA and EMA approval for the treatment of moderate-severe PsA (Van den Bosch and Coates, 2018). Brodalumab, a human anti-IL17R monoclonal antibody, inhibits IL17 receptor thus effectively blocking the activity of IL-17A, IL-17F, IL-17A/F, and IL-17E (also called IL-25). A study that investigated the safety and efficacy of brodalumab in PsA showed that brodalumab treated patients had significant ACR20 and ACR50 but not ACR70 responses. Dactylitis outcome measures and psoriasis also improved (Van den Bosch and Coates, 2018). Brodalumab has not yet been approved for the treatment of PsA. Clazakizumab, an IL-6 monoclonal antibody, and Abatacept, a selective T-cell costimulatory modulator, have shown efficacy in PsA adequate clinical trials, but still have no indication to treat the disease (Van den Bosch and Coates, 2018).

Targeted Synthetic Disease Modifying Anti-Rheumatic Drugs Apremilast is an oral phosphodiesterase 4 inhibitor indicated for the treatment of psoriasis and PsA. It has been assessed in a number of phase III clinical trials in PsA (PALACE trials). The drug has shown superiority over placebo on several PsA domains, although ACR responses (around 40% of patients reach ACR20 at week 16) are lower than those achieved by biological agents (around 60%) in PsA. Apremilast was well tolerated and demonstrated an acceptable safety profile. Enthesitis was shown to improve in patients on the 30 mg but not 20 mg dose arm. Statistically significant improvement in dactylitis could not be demonstrated (Van den Bosch and Coates, 2018; Gossec et al., 2016). Tofacitinib is a novel, oral janus kinase (JAK) inhibitor with proven efficacy in RA. Tofacitinib efficacy was demonstrated in PsA by the OPAL Broaden and OPAL Beyond phase III studies, and received FDA and EMA approval. Both tofacitinib 5 or 10 mg twice a day were superior to placebo for ACR 20 improvement criteria response at 3 months and showed significant improvement of skin, enthesitis and dactylitis (Van den Bosch and Coates, 2018).

Treatment Recommendations and Tight Control Strategies PsA is a heterogeneous disease where choosing the appropriate drug may be difficult since some drugs may not benefit all the active domains. In view of the heterogeneity of the disease process, different drugs are used for different phenotypes. EULAR recommendations define broad domains, mainly predominant peripheral arthritis, predominant axial disease, enthesitis or dactylitis or predominant skin disease (with a recommendation to refer to a dermatologist), whereas GRAPPA defines six domainsdskin, nails, peripheral arthritis, axial arthritis, enthesitis and dactylitis- and gives six flow charts for an approach to treatment (Gossec et al., 2016). Both types of recommendations emphasize the need to monitor and manage, in a multidisciplinary manner, the comorbidities that accompany PsA. For example, it has been demonstrated that regardless of the type of diet, a successful weight loss of  5% is associated with a higher rate of achievement of MDA in overweight/obese patients with PsA who start treatment with TNFa inhibitors (Van den Bosch and Coates, 2018; Gossec et al., 2016). In summary, these and other recommendations suggest the following treatment steps. Patients who have predominant peripheral arthritis need to be commenced on early csDMARDs, in order to achieve remission or a state of minimal disease activity (MDA). Should this not be achieved with csDMARDs, biologic therapy will need to be introduced. NSAIDs are generally first-line for axial disease. Inadequate response to NSAIDs will require the introduction of biologic therapy. Enthesitis and dactylitis are generally difficult to treat. Apremilast and biologic therapy are indicated for severe enthesitis or dactylitis. The holistic management of a patient with PsA always includes assessment of the skin and nails, even by the rheumatologist in collaboration with a dermatologist (Van den Bosch and Coates, 2018; Gossec et al., 2016). It is important to identify and address the factors of poor prognosis, even with intensive treatment schemes such as the treat to target (T2T) strategy. The TICOPA (TIght COntrol of Psoriatic Arthritis) study was the first trial to evaluate tight control in PsA with MDA as the target for treatment and showed that patients who were treated according to a T2T strategy (monthly escalation of therapy until MDA was achieved) had better articular and skin outcomes (ACR20, 50, 70, and PASI 75) as well as improvements in multiple patient reported outcomes, compared to usual care (Coates et al., 2015).

Unmet Needs Whilst there have been advances in understanding the pathogenic mechanisms of the disease which have resulted in targeted therapies, there is still the need for further studies as some patients fail or are intolerant of current therapies. Better identification of early disease and knowledge of prognostic markers would enable clinicians to initiate appropriate therapy with the expectation that early

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aggressive treatment will minimize joint damage progression. Improved knowledge of the condition would also enable clinicians to better tailor specific treatment strategies for each of the various clinical domains in psoriatic arthritis (Mahmood et al., 2018). There is also a need to transfer the information obtained from RCTs with new molecules to real-life scenarios, since the patients usually included in the RCTs do not correspond to those routinely seen in rheumatology clinics. It is also necessary to standardize the way of measuring the results of these real-life studies (Mahmood et al., 2018). The recent introduction of biosimilar drugs in the pharmacopeia of the disease supposes a cheapening of the treatments and the possibility of offering these drugs to a larger number of patients. However, there are important evidence gaps around the safety of switching between biologics and their biosimilars. Sufficiently powered and appropriately statistically analyzed clinical trials and pharmacovigilance studies, with long-term follow-ups and multiple switches, are needed to support decision-making around biosimilar switching (Mahmood et al., 2018).

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Gladman, D.D., 2008. Mortality in psoriatic arthritis. Clinical and Experimental Rheumatology 26 (5 Suppl 51), S62–S65. Gossec, L., Coates, L.C., de Wit, M., Kavanaugh, A., Ramiro, S., Mease, P.J., et al., 2016. Management of psoriatic arthritis in 2016: A comparison of EULAR and GRAPPA recommendations. Nature Reviews Rheumatology 12 (12), 743–750. Kahn, M.F., 1993. Psoriatic arthritis and synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome. Current Opinion in Rheumatology 5 (4), 428–435. Kobak, S., Yildiz, F., Karaarslan, A., Semiz, H., Orman, M., 2017. Characteristics of Turkish patients with elderly onset psoriatic arthritis: A retrospective cohort study. Medicine (Baltimore) 96 (33), e7833. Lin, P., Bach, M., Asquith, M., et al., 2014. HLA-B27 and human b2-microglobulin affect the gut microbiota of transgenic rats. PLoS One 9 (8), e105684. Mahmood, F., Coates, L.C., Helliwell, P.S., 2018. Current concepts and unmet needs in psoriatic arthritis. Clinical Rheumatology 37 (2), 297–305. McGonagle, D., Aydin, S.Z., Gül, A., Mahr, A., Direskeneli, H., 2015. ‘MHC-I-opathy’-unified concept for spondyloarthritis and Behçet disease. Nature Reviews Rheumatology 11 (12), 731–740. Moll, J.M., Wright, V., 1973. Psoriatic arthritis. Seminars in Arthritis and Rheumatism 3 (1), 55–78. Nestle, F.O., Kaplan, D.H., Barker, J., 2009. Psoriasis. The New England Journal of Medicine 361 (5), 496–509. Ogdie, A., Gelfand, J.M., 2015. Clinical risk factors for the development of psoriatic arthritis among patients with psoriasis: A review of available evidence. Current Rheumatology Reports 17 (10), 64. Okada, Y., Han, B., Tsoi, L.C., et al., 2014. Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. American Journal of Human Genetics 95 (2), 162–172. Paine, A., Ritchlin, C., 2018. Altered bone remodeling in psoriatic disease: New insights and future directions. Calcified Tissue International 102 (5), 559–574. Patel, P., Rosen, C.F., Chandran, V., Ye, Y.J., Gladman, D.D., 2018. Addressing comorbidities in psoriatic disease. Rheumatology International 38 (2), 219–227. Poggenborg, R.P., Østergaard, M., Terslev, L., 2015. Imaging in psoriatic arthritis. Rheumatic Diseases Clinics of North America 41 (4), 593–613. Punzi, L., Pianon, M., Rossini, P., Schiavon, F., Gambari, P.F., 1999. Clinical and laboratory manifestations of elderly onset psoriatic arthritis: A comparison with younger onset disease. Annals of the Rheumatic Diseases 58 (4), 226–229. Queiro, R., Coto, P., 2017. Multidisciplinary care for psoriatic disease: Where we are and where we need to go. Rheumatology (Oxford) 56 (11), 1829–1831. Queiro, R., Tejón, P., Alonso, S., Coto, P., 2014. Age at disease onset: A key factor for understanding psoriatic disease. Rheumatology (Oxford) 53 (7), 1178–1185.

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Queiro, R., Morante, I., Cabezas, I., Acasuso, B., 2016. HLA-B27 and psoriatic disease: A modern view of an old relationship. Rheumatology (Oxford) 55 (2), 221–229. Rahman, P., Elder, J.T., 2005. Genetic epidemiology of psoriasis and psoriatic arthritis. Annals of the Rheumatic Diseases 64 (Suppl 2), ii37–9. Raychaudhuri, S.P., Wilken, R., Sukhov, A.C., Raychaudhuri, S.K., Maverakis, E., 2017. Management of psoriatic arthritis: Early diagnosis, monitoring of disease severity and cutting edge therapies. Journal of Autoimmunity 76, 21–37. Rea, I.M., Gibson, D.S., McGilligan, V., et al., 2018. Age and age-related diseases: Role of inflammation triggers and cytokines. Frontiers in Immunology 9, 586. Ritchlin, C.T., Colbert, R.A., Gladman, D.D., 2017. Psoriatic arthritis. The New England Journal of Medicine 376 (10), 957–970. Schett, G., Lories, R.J., D’Agostino, M.A., Elewaut, D., Kirkham, B., Soriano, E.R., McGonagle, D., 2017. Enthesitis: From pathophysiology to treatment. Nature Reviews Rheumatology 13 (12), 731–741. Sherlock, J.P., Joyce-Shaikh, B., Turner, S.P., et al., 2012. IL-23 induces spondyloarthropathy by acting on ROR-gt þ CD3 þ CD4-CD8-entheseal resident T cells. Nature Medicine 18 (7), 1069–1076. Soare, A., Weber, S., Maul, L., et al., 2018. Cutting edge: Homeostasis of innate lymphoid cells is imbalanced in psoriatic arthritis. Journal of Immunology 200 (4), 1249–1254. Speca, S., Dubuquoy, L., 2017. Chronic bowel inflammation and inflammatory joint disease: Pathophysiology. Joint, Bone, Spine 84 (4), 417–420. Taylor, W., Gladman, D., Helliwell, P., et al., CASPAR Study Group, 2006. Classification criteria for psoriatic arthritis: Development of new criteria from a large international study. Arthritis and Rheumatism 54 (8), 2665–2673. Thorarensen, S.M., Lu, N., Ogdie, A., et al., 2017. Physical trauma recorded in primary care is associated with the onset of psoriatic arthritis among patients with psoriasis. Annals of the Rheumatic Diseases 76 (3), 521–525. Van den Bosch, F., Coates, L., 2018. Clinical management of psoriatic arthritis. Lancet 391 (10136), 2285–2294. Wilson, F.C., Icen, M., Crowson, C.S., et al., 2009. Time trends in epidemiology and characteristics of psoriatic arthritis over 3 decades: A population-based study. The Journal of Rheumatology 36 (2), 361–367.

Further Reading 1. Bilal, J., Riaz, I.B., Kamal, M.U., Elyan, M., Sudano, D., Khan, M.A., 2018. A systematic review and meta-analysis of efficacy and safety of novel interleukin inhibitors in the management of psoriatic arthritis. Journal of Clinical Rheumatology 24 (1), 6–13. 2. Coates, L.C., Conaghan, P.G., D’Agostino, M.A., et al., 2018. Remission in psoriatic arthritis-where are we now. Rheumatology (Oxford) 57 (8), 1321–1331. 3. Coates, L.C., FitzGerald, O., Merola, J.F., et al., 2018. Group for Research and Assessment of psoriasis and psoriatic arthritis/outcome measures in rheumatology consensusbased recommendations and research agenda for use of composite measures and treatment targets in psoriatic arthritis. Arthritis & Rhematology 70 (3), 345–355. 4. Chimenti, M.S., Perricone, C., Novelli, L., et al., 2018. Interaction between microbiome and host genetics in psoriatic arthritis. Autoimmunity Reviews 17 (3), 276–283. 5. D’Angiolella, L.S., Cortesi, P.A., Lafranconi, A., et al., 2018. Cost and cost effectiveness of treatments for psoriatic arthritis: A systematic literature review. PharmacoEconomics 36 (5), 567–589. 6. Elalouf, O., Chandran, V., 2018. Novel therapeutics in psoriatic arthritis. What is in the pipeline? Current Rheumatology Reports 20 (7), 36. 7. Ford, A.R., Siegel, M., Bagel, J., et al., 2018. Dietary recommendations for adults with psoriasis or psoriatic arthritis from the Medical Board of the National Psoriasis Foundation: A systematic review. JAMA Dermatology 154 (8), 934–950. 8. Gossec, L., McGonagle, D., Korotaeva, T., et al., 2018. Minimal disease activity as a treatment target in psoriatic arthritis: A review of the literature. The Journal of Rheumatology 45 (1), 6–13. 9. Maese, J., Díaz Del Campo, P., Seoane-Mato, D., Guerra, M., Cañete, J.D., 2018. Effectiveness of conventional disease-modifying antirheumatic drugs in psoriatic arthritis: A systematic review. Reumatología Clinica 14 (2), 81–89. 10. Queiro, R., Cañete, J.D., Montilla, C., et al., 2017. MAAPS study group. Minimal disease activity and impact of disease in psoriatic arthritis: A Spanish cross-sectional multicenter study. Arthritis Research & Therapy 19 (1), 72. 11. Smolen, J.S., Schöls, M., Braun, J., et al., 2018. Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. Annals of the Rheumatic Diseases 77 (1), 3–17. 12. Veale, D.J., Fearon, U., 2018. The pathogenesis of psoriatic arthritis. Lancet 391 (10,136), 2273–2284.

Regulation of Metabolism and Longevity , Department of Biochemistry and Cell Biology, University of Rzeszow, Rzeszow, Poland Mateusz Mołon © 2020 Elsevier Inc. All rights reserved.

Introduction The TOR Kinase PathwaydThe Best Understood and Complex Longevity Pathway That Controls Metabolism According to the Available Nutrient Level Regulation of Metabolism by Reducing Calorie Intake Insulin/IGF-1 Pathway Mitochondrion and Free Radicals Theory References

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Glossary Calorie restriction Method to reduces calorie intake without a reduction in essential nutrient, is the most effective dietary intervention known to regulate aging and increase the healthy lifespan. Dietary restriction Limitation of nutrient intake, food intake or food choices by humans or other organisms in experimental and non-experimental situations; nonpharmacological intervention that is known to increase active and healthy lifespan in a variety of species. FOXO Family of transcription factors (proteins) that play important roles in regulating the expression of genes involved in e.g., cell growth and longevity. Insulin/IGF-1 Involved in many functions that are necessary for metabolism, growth, and aging in animal models including mammalians. Klotho An aging-suppressor gene; overexpression of the klotho gene extends the life span. mTOR Mammalian target of rapamycin, coordinates eukaryotic cell growth and metabolism with environmental inputs including nutrients and growth factors. ROS Reactive oxygen species; generated during mitochondrial oxidative metabolism as well as e.g., in cellular response to xenobiotics. Oxidative stress results in macromolecular damage and is implicated in various disease states and aging. Sirtuins Play key role during cell response to a variety of stresses, e.g., oxidative or genotoxic stress and are crucial for cell metabolism; slowing down the aging process. SOD Key enzyme of the organism’s antioxidant barrier.

Introduction The answer to the question “Why do we age?” is far from easy. It is worth underlining that the mechanisms of evolution make it impossible to control the maximum duration of life within species. Over 4 billion years of evolution have shaped the life on Earth in such a way that organisms are able to cope with environmental changes as well as destructive changes in their bodies for the period necessary for reproduction. This is to ensure evolutionary survival of the species. Due to differences in the average and maximum lifespans of individuals across different species, it is important to note that while the process of aging is genetically controlled, it is not a programmed process sensu stricto. In fact, genetic control, or the lack of appropriate repair systems, has a significant impact on the rate of accumulation of damaged cellular macromolecules, such as nucleic acids, proteins or lipids. Aging and longevity are results of a number of processes. They may be conditioned by thousands of genes and, as recent studies show, epigenetic factors. In addition, in many cases longevity is determined by different variants of completely different genes or accidental somatic mutations affecting activation of various genes that trigger adaptation mechanisms. It is now known that there is no single gene that would be responsible for aging and longevity. However, in the genome we can find longevity assurance genes, which are responsible for the overall homeostasis of the body, including DNA repair (Calabrese et al., 2011). Therefore, it seems reasonable to look for mechanisms responsible for longevity at the cellular and molecular levels. In addition, it is important to locate new connections between signaling pathways that affect overall systemic metabolic reactions. In this article I place particular emphasis on the strongly conserved basic evolutionary signaling paths responsible for the longevity of various groups of organisms, including humans. I focus mainly on those longevity pathways that sense nutrient availability and that are in fact strongly correlated with cellular energetic.

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The TOR Kinase PathwaydThe Best Understood and Complex Longevity Pathway That Controls Metabolism According to the Available Nutrient Level Cellular metabolism is regulated by many pathways including the TOR kinase (mammalian mTOR), a key component of the molecular nutrient sensor pathway that plays a crucial role in cellular longevity and aging. The TOR (target of rapamycin) gene encodes serine/threonine kinase, which plays a key role in the regulation of cell metabolism, proliferation, growth and aging in all experimental models such as budding yeast, nematode, fruit fly and mammals. The TOR kinase is activated by nutrients (availability of glucose or amino acids) as well as growth factors, e.g., IGF-1 or insulin. Activation of TOR kinase in various groups of organisms may occur through various mechanisms. This is due to the fact that, for example, the insulin/IGF-1 pathway does not occur in yeast. The target of rapamycin kinase acts as a molecular signaling center controlling cellular growth, cell cycle, ribosome biogenesis, protein synthesis, and degradation. TOR is present in two structurally and functionally different complexes: TORC1 (TOR Complex 1) and TORC2 (TOR Complex 2). The target of rapamycin proteins were first identified in Saccharomyces cerevisiae through mutants that confer resistance to growth inhibition induced by rapamycin (Kunz et al., 1993). It has been demonstrated that TORC1 is tether to lysosomal membranes where it regulates cellular metabolic processes, such as protein biosynthesis and autophagy, in response to amino acids or growth factors (Takahara and Maeda, 2013). In contrast, mTORC2 is involved in cell survival, apoptosis, and proliferation. Interestingly, Zinzalla et al. have shown that active mTORC2 is physically associated with ribosomes (Zinzalla et al., 2011). These observations suggest that ribosomes activate mTORC2 directly and ensure that TORC2 is active only in growing cells. The mTOR pathway is extremely intriguing. A disorder in certain signaling pathways involving the TOR kinase may lead to carcinogenesis or diseases such as Alzheimer’s disease. On the other hand, inhibition of mTOR activity by pharmacological or genetic means has been shown to extend lifespan or healthspan in many experimental systems, e.g., the Saccharomyces cerevisiae yeast, Caenorhabditis elegans nematode, Drosophila melanogaster fruit fly, mice and dogs (Molon et al., 2015; Vellai et al., 2003). Cellular stress, including energy decline, hypoxia and DNA damage, acts in part through the expression of TSC1 and TSC2 genes to inhibit mTORC1. TSC1/2 (tuberous sclerosis-1 and 2) complex is important in at least several upstream signals that impact mTORC1 activity. These complex is activated by adenosine monophosphate-activated protein kinase (AMPK) and inhibited by protein kinase B (Akt/PKB), the ribosomal S6 kinase (S6K1) that directly phosphorylates and inactivates TSC1/2 (Roux et al., 2004). AMPK has an undisputable effect on life extension. It acts as energy level sensor and regulates mTORC1 activity. AMPK responds to low levels of AMP; therefore, overexpression of AMPK extends lifespan in Caenorhabditis elegans (Greer et al., 2007). AMPK regulates longevity by FOXO complex activation and down-regulates the mTORC1 kinase activity indirectly by phosphorylating the serine sites on TSC2 (Inoki et al., 2003). Pharmacological activation of AMPK through the use of drugs for diabetics, for example metformin, leads to increase in the lifespan of mice (Martin-Montalvo et al., 2013). It is also worth noting that metformin treatment can increase lifespan by AMPK activity and by inhibition of mTORC1 independently of AMPK (Ben Sahra et al., 2011). As a nutrient sensor mTOR kinase is also engaged in pathways mediating lifespan extension in dietary restriction (Greer et al., 2007). It seems that determining contribution of individual nutritional components and their effect on dietary restrictions may be of crucial importance. Interestingly, it has been shown that calorie restriction and protein restriction have positive effects on lifespan. As shown by Mair et al. (2005), protein restriction in fruit fly plays a more significant role in lifespan extension than mere caloric restriction. It is also possible that individual amino acids, mainly arginine, leucine, tryptophan and methionine, may have crucial roles in controlling the activity of lifespan modulating signaling pathways partially via mTOR pathway. It seems that methionine has a key role in protein restriction because of its importance in protein synthesis and Met-tRNA wellestablished essentiality as the targeted start codon (AUG) for nearly all proteins. The biological aging process in higher eukaryotes, including humans, is strongly associated with a progressive decline of adaptive capacity and significant increase in the occurrence of diseases strongly related with age, such as cancer, cardiovascular and neurodegenerative diseases. The data shows that methionine restriction is linked to a slower rate of aging in all experimental models of aging, including human cells. As it has already been shown, methionine restriction has a number of beneficial effects, including decreases in body weight, plasma IGF-I levels, ROS production and oxidative stress. It is highly probable that these relevant effects of protein/dietary restriction are due to the decrease in the general rate of metabolism and energy intake. Why do humans not use methionine restriction? The answer is simple. Generally, sulfur amino acids are important for growth. Furthermore, sulfur amino acids are found in all foods containing proteins; therefore avoiding them is not an easy task. Hence, restricting the amount of e.g., methionine available in the diet slows down that growth by significantly decreasing translation efficiency. Such a stunted growth of body mass is certainly a bottleneck to progress in human beings. On the other hand, this translation disorder leads to increase in the healthspan and lifespan of experimental animals that are smaller than animals without the dietary restriction. Interestingly enough, the only limitation for the application of this approach is slow growth as no other serious side effects of the diet have been observed. In cells, there are continuous biochemical processes that result in the production of metabolites, some of which may be harmful. As shown previously, lifespan may be modulated not only by amino acids restriction but also by amino acid metabolites. Khayati et al. (2017) has recently shown that the methionine metabolite homocysteine can regulate mTORC1 activity. In humans, homocysteine is formed as a result of demethylation of the methionine amino acid derived from the protein consumed. Due accumulation of this metabolite in the blood causes hyperhomocysteinemia which is an important risk factor for ischemic stroke and Alzheimer’s disease. A recent comprehensive review of sulfur amino acid, including methionine restriction, has shown that this approach increased lifespan without the need to use caloric restriction (Dong et al., 2018).

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mTOR signaling may regulate proteostasis through regulation of protein translation by the eIF4E kinase, as well as through regulation of proteasome, a complex involved in the degradation of proteins in the ubiquitination pathway. Protein synthesis is a tightly regulated process involving multiple steps. Numerous studies have established that general protein synthesis rates decline with age in a variety of organisms (Partridge and Gems, 2002). TOR kinase also regulates eIF4E, an important eukaryotic mRNA translation initiation factor. Tavernarakis (2007) showed that elimination of eIF4E function in somatic cells reduces protein synthesis and extends lifespan in the nematode Caenorhabditis elegans. What is more, depletion of eIF4E in the soma extends lifespan via a mechanism independent of the insulin/IGF pathway that modulates aging in diverse species. This suggests that regulation of genes involved in protein synthesis is vital for achievement of longevity. TOR signaling also affects transcriptional control of the proteasome via DAF-16/FOXO. It has been shown that this transcription factor increases expression of rpn-6, encoding a subunit of the 19S proteasome, in germline-deficient Caenorhabditis elegans (Vilchez et al., 2012). Is the pharmacological reduction of TOR signaling really beneficial to organisms? The use of experimental models has shown a positive effect on longevity. However, as shown by Lamming et al. pharmacological inhibition of mTOR in higher eukaryotes, including humans, is associated with side effects such as immunosuppression, the current medical use for rapamycin in organ transplant patients, and insulin insensitivity (Lamming et al., 2012). Therefore, it seems that immunosuppression may be a serious factor limiting the use of the TOR pathway in promoting longevity in future. It seems that more understanding of mTORC1-specific nutrient-sensing pathways is needed to preventing age-related diseases. mTOR kinase can also modulate life expectancy by affecting autophagy. Autophagy is a process of degradation of macromolecular components of the cytoplasm, especially proteins with a long half-life and whole organelles. The process of autophagy is responsible for maintaining intracellular homeostasis and allows survival of cells under stressful conditions. Autophagy also plays a role in the pathogenesis of many diseases, including cancer. In cancer cells autophagy may play a double role as a process involved in the survival or death of a cell. As has been shown, autophagy alone is not sufficient for lifespan extension, but requires the activity of DAF-16/FOXO (Hansen et al., 2008), which engages programs that protect macromolecules due to ROS detoxification. Autophagy is strictly regulated by mTORC1 activity dependent on the nutritional status and lysosomal function. Both are regulated by the transcription factor EB (TFEB), which demonstrates central importance of autophagy in the regulation of cellular metabolism and is strongly evolutionarily conserved as a transcription factor for adaptive responses to starvation. Autophagy was first shown to be required for rapamycin-induced, TOR-mediated increase for extension of yeast chronological lifespan (Alvers et al., 2009). Interestingly, rapamycin failed to increase lifespan when two genes were mutated, namely atg1 and atg7, which are essential for autophagy and crucial for autophagosome formation and longevity. The mechanism through which mTOR decreases the rate of cellular and organismal aging is still unclear, but indirect signaling paths are well known. It seems that in the future amino acid metabolites can play significant role in human healthspan and lifespan progression. For a deeper understanding of the mechanism of action of mTOR kinase I recommend referring to a review study (Antikainen et al., 2017).

Regulation of Metabolism by Reducing Calorie Intake Already in the 1930s, it was shown that rodents’ lifespans can be significantly prolonged by subjecting these animals to caloric restriction (McCay et al., 1975). Caloric restriction (CR) is the limitation of the supply of calories in food while maintaining the fullness of food. The positive effect of caloric restriction has been demonstrated in all experimental systems, from yeasts to mice. However, it is difficult to determine clearly the impact of caloric restriction on humans. This is mainly due to the reduced calorie supply for a long time, which is a discomfort for the human body. There are residual data that confirm the positive effect of CR on the quality of life by improving the parameters of the cardiovascular system. Unfortunately, we cannot say much about the impact of CR on the lifespan in humans. There is a controversial debate whether calorie restriction increases lifespan in primates. Eric Le Bourg shows quite opposing results: one study conducted on macaques did not report a lifespan increase while one study in the mouse lemur and another study in macaques showed a lifespan increase (Le Bourg, 2018). It is worth noting the differences between the animals that were taken into account during the experiment. The mouse lemur (Microcebus murinus) has a mean lifespan of only 6 years and is able to reproduce three times a year usually giving birth to two offspring. On the other hand, the macaque (Macaca mulatta) is a long-lived species of a large size and long gestation period. The studies from non-human primates showed not so much that calorie restriction may increase lifespan but rather that ad libitum feeding can decrease lifespan. Eric Le Bourg concludes that no beneficial effect of calorie restriction on lifespan can be expected in normal-weight or lean people, but that overweight and/or obese people could benefit to some extent from a decrease in excessive food intake. However, a most recent study has found that calorie restriction can slow down human metabolism. The data shown by Redman et al. raise hopes that a lowcalorie diet or calorie restriction mimics could prolong healthspan and probably extend lifespan (Redman et al., 2018). The study was part of the multi-center trial called CALERIEdComprehensive Assessment of Long term Effects of Reducing Intake of Energy. All the other clinical measurements were in line with the reduced metabolic rate, and indicated a decrease in damage due to aging. Overall, Redman concludes that metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging. This is a demanding way to achieve longevity or reduce signs of aging. But understanding the molecular mechanism of how restriction of calories increases lifespan will allow us to find easier ways to slow down aging in the future.

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It has been demonstrated by the use of model organisms that CR has a positive effect on the average and maximum life expectancy, and the effect depends on the duration of the restriction. So far, at least a few hypotheses have been formulated to explain the mechanism of action of CR. The most popular ones explain the positive effect of CR using the mitochondrial theory of aging, or the free radical theory. The reduction of food intake leads to a reduction in the intensity of biological oxidation processes in the mitochondria, which slows down the rate of production of free radicals and significantly reduces the rate of accumulation of oxidatively damaged macromolecules, including DNA and proteins. On the other hand, attempts were made to explain the positive impact of CR through the accelerated rate of aerobic respiration, which is accompanied by the formation of ROS and which activates mechanisms of antioxidant defense. External supplementation or increase in the intracellular level of antioxidants might seem to prolong life. However, many data show that in the case of various groups of organisms, the supply of antioxidants yields results that are difficult to be generalized in a non-ambiguous way. This is most often due to the homeostasis and adaptive abilities of the organism. In other words, the intake of exogenous antioxidants results in reduced production of endogenous antioxidants. For years, attention has focused on the relationship between CR and longevity enzymesdsirtuins. Silent Information Regulator (SIR) proteins belong to NADþ-dependent deacetylases, enzymes that catalyze the deacetylation reaction. Attention was drawn to sirtuins began when it was discovered that limiting the supply of calories resulted in increasing sirtuin activity. It has also been observed that the aging process in model organisms is not delayed when sirtuins encoding genes are deleted, whereas overexpression of sirtuin significantly extends lifespan. Significant effect of some polyphenols has also been shown, for example resveratrol, which activates sirtuins similarly to a low-calorie diet (Howitz et al., 2003). In human organism, seven genes encoding sirtuin (SIRT1-7) have been known. The products of these genes are located in the cell nucleus (Sirt1, Sirt6, Sirt7), in the cytoplasm (Sirt3, Sirt4, Sirt5) and in the mitochondrion (Sirt3). Activation of sirtuin occurs as a result of energy deficiencies that arise from calorie restriction or during exercise. One of the better known human sirtuins is SIRT1, which is very similar to the yeast Sir2 and acts as a transcription regulator due deacetylation activity. Then an excess of NADþ arises, which is a cofactor of sirtuin. Recently, SIRT3 activity has been also intensely investigated. Activation of SIRT3 affects the electron transport chain and the prevention of mitophagy. As previous studies have shown, two variants of SIRT3 are related to the achievement of longevity in humans; interestingly enough, there are also variants of this gene that contribute to the occurrence of metabolic syndrome (Kincaid and Bossy-Wetzel, 2013). SIRT6 is another sirtuin that raises high hopes in terms of delaying aging and maintaining good fitness. More recent studies in mice have uncovered key roles of SIRT6 in promoting healthspan. The data show that SIRT6-deficient mice have shorter lifespans and phenotypes associated with aging, cancer, and metabolic disorders. As has been shown by Schwer et al. mice with tissue specific inactivation of SIRT6 in the brain had low growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels, similar to whole body SIRT6 knockout mice (Schwer et al., 2010). Conversely, increased levels of SIRT6 in mice may protect them against metabolic pathologies associated with diet-induced obesity. To this day, a lot of controversy have arisen about sirtuins and their protective actions. This is due to the fact that not all studies confirm the positive effect of these proteins. It is worth noting that for many years scientists have been looking for supplements that could increase activity of sirtuins, including polyphenolic compounds such as resveratrol. Resveratrol as well as caloric restriction were shown to extend lifespan in some model organisms and may possibly delay onset of aging-related diseases in humans. Pallauf et al. conclude that in mouse models, resveratrol did not act as CR mimetics; furthermore, resveratrol supplementation does not always extend lifespan of animal models or improve health status of humans (Pallauf et al., 2019). Resveratrol may only exert its putative health effects under certain circumstances. Therefore, reasonable caution should be warranted when promoting resveratrol as a caloric restriction mimetic. Although resveratrol has been demonstrated to slow down the rate of aging of yeast, nematode and fruit fly, a general mechanism of action can hardly be formulated as not all of the studies have confirmed that phenomenon (Le Couteur et al., 2012).

Insulin/IGF-1 Pathway An important route of response to food is the insulin/IGF-1 pathway. The proteins involved in insulin/IGF-1 signaling are highly conserved evolutionarily and are characterized by high homology in most of the experimental systems tested for nematode up to mammals. This path plays an important role in controlling growth and development or maintaining homeostasis. While the receptors for both insulin and insulin-like growth factors are structurally similar, their effects vary. IGF-1 is essential for normal growth and development, while insulin is involved in the regulation of metabolism. IGF-1 is produced by several cell types (mainly hepatocytes) in response to growth factor release from the anterior pituitary. IGF-1 has been shown to trigger the same intracellular signaling pathways stimulated by insulin. In invertebrate animals such as nematodes and insects insulin and IGF-1 use a common receptor which, when inactivated, significantly extends life. In mammals, IGF-1 uses a different receptor, the mutation of which leads to prolonged life as observed in mice. Interestingly, the life of mice is also increased due to a mutation in the growth hormone signaling pathway that stimulates the secretion of IGF-1. Studies carried out on mouse mutants with insulin receptor dysfunction confirm these reports. Many data suggest a significant effect of that signaling pathway in dietary restriction on life expectancy. This is evidenced by studies in which impact of diet restriction was not reported when the pathway was blocked. On the other hand, dietary restriction have impact on nematodes in the situation of DAF-1 gene disruption, which is an IGF1R orthologue (insulin-like growth factor 1 receptor). This shows

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that the longevity resulting from dietary restriction in C. elegans is independent of the insulin pathway. As it turns out, activation of some pathways may also be dependent on the evolutionary level of the organism. It should be noted that activation of the insulin/IGF-1 pathway leads to phosphorylation of the FOXO transcription factor. Studies have revealed that FOXO transcription factors are important determinants in aging and longevity and are the most important transcriptional effectors of the insulin/IGF-1 pathway. FOXO proteins represent a subfamily of transcription factors evolutionary conserved from worms to mammals that act as key regulators of longevity. Invertebrates have only one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. At least few mechanisms of how FOXO proteins promote longevity have been suggested. Webb and Brunet have recently shown the role of FOXOs as pro-longevity factors through the maintenance of protein homeostasis (Webb and Brunet, 2014). It has been shown that FOXO factors are involved in the regulation of genes responsible for two key mechanisms of intracellular clearance: autophagy and the ubiquitin-proteasome system. In general, defects in autophagy have been associated with premature aging and age-related disorders. Additionally, a significant function of FOXO proteins is their role in cellular responses to oxidative stress. Accumulation of damage macromolecules, e.g., DNA, proteins and lipids caused by reactive oxygen species was postulated to be the main factor responsible for aging; therefore, it has been suggested that FOXO factors influence aging and age-related diseases by increasing the antioxidant capacity of cells. FOXOs regulate the expression of the key antioxidation enzymes MnSOD (manganese superoxide dismutase) and catalase, which play an important role in detoxification of superoxide radical anion or hydrogen peroxide. The phosphorylated form of the protein remains in the cytosol and as a transcription factor does not function in the activation of gene expression. The FOXO transcription factor is transported to the cell nucleus under the nutrition deficiency condition or during the disturbance of FOXO regulatory protein production. This leads to a lack of phosphorylation, and FOXO activates a number of genes involved in metabolism or protection against stress. FOXO has a crucial role in the cell as it activates the genes responsible for ROS detoxification, cell cycle arrest, apoptosis, substrate metabolism, protein turnover and cell survival. FOXO proteins are expressed across multiple tissues of the body but their expression level, function, and targets are tissue specific. Genetic variants of FOXO are associated with unique longevity in worms, flies, and mammals. Interestingly, this group includes the FOXO3 protein. FOXO3 is a key transcription factor in the control of skeletal muscle protein turnover and a central effector of the main regulator of protein synthesis and degradation in the muscledAkt/PKB in the PI3K signaling pathway. In anabolic conditions, Akt phosphorylates FOXO3 and suppresses its transcriptional activity (Goodman, 2014). As has been shown by Flachsbart et al. a variant of FOXO3 is associated with longevity in humans (Flachsbart et al., 2009). It is found in most centenarians across a variety of ethnic groups around the world. The current study shows that FOXO3A genotype is strongly associated with human longevity in the Caucasian and Asian populations (Wilicox et al., 2008). In mammalian tissue, FOXO proteins reduce mTORC1 activity, thereby activating protein kinase B (Akt) that plays a key role in multiple cellular processes such as transcription, apoptosis, glucose metabolism, and cell proliferation. Thus, FOXO proteins may play an intricate role in balancing Akt and mTORC1 activities in response to changing metabolic conditions. FOXO indirectly regulates the aging process by regulating the concentration of these two key proteins. Due to the strongly preserved evolution of the insulin/IGF-1 pathway mechanism, it seems reasonable to claim that it is of great importance in the regulation of lifespan. In humans, lack of sensitivity to growth hormone caused by a mutation in its receptor or low levels of IGF-1 in the blood lead to dwarfism. As has been shown in many studies, the growth hormone contributes to longevity not only in humans, but also in mice. The best examples are the Ames and Snell lines of mice that do not produce growth hormone, are dwarf and live on average 50% longer than wild-type mice. These mice, however, suffered from infertility. On the other hand, excessive production of growth hormone in people with gigantism may contribute to cardiovascular disease, diabetes or cancer, which can significantly increase the risk of death. It is worth mentioning that in mammals, unlike in lower animals such as insects or nematodes, there is no simple mechanism to prolong life by regulating the insulin/IGF-1 path, and the complete blockage of this pathway may have a negative influence on the lifespan and healthspan. Therefore, in humans other factors are also likely to play crucial roles in regulating longevity. An interesting example of the regulation of the IGF-1 insulin pathway is Klotho protein expression. The Klotho gene was first identified in 1997 in transgenic mice in which it was inactivated by this gene. Initially, the KL -/- mouse line was considered useless because the transgenes introduced into the mouse genome did not cause phenotypic changes (Kuroo et al., 1997). As it turned out, after a few weeks mice with an inactivated Klotho gene showed signs of premature aging. Klotho mice (KL -/-) died relatively quickly around 8–9 weeks of age. In contrast, Klotho overexpression is correlated with the increase in the lifespan of mice. In relation to the wild-type mice, the survival time of Klotho overexpressed males increases by approximately 31% and females by approximately 19% (Kurosu and Kuro, 2009). Klotho is involved in the inhibition of the insulin/insulin-like growth factor pathway, thus indirectly affecting the aging delay. Klotho deficient mice exhibit hypoglycemia and high insulin sensitivity, whereas Klotho overexpression has been observed for moderate resistance to insulin and IGF-1. In spite of insulin resistance, these mice show normal blood glucose levels and no incidence of diabetes has been observed. These data were the basis for the claim that the Klotho protein is involved in the suppression of the insulin/IGF-1 pathway (Kuro-o, 2009). The mechanism by which the secreted form of the Klotho protein contributes to the inhibition of the insulin pathway and IGF-1 has not been fully understood. However, it is known that the Klotho function is based on inhibition of receptor autophosphorylation. It is suggested that Klotho protein contributes to the extension of vitality due to two mechanisms that interact with each other: inhibition of IGF-1 signaling and increasing resistance to oxidative stress. Blockade of the insulin/IGF-1 pathway leads to inhibition of Akt kinase activation, which phosphorylates the FOXO transcription factor. The non-phosphorylated factor FOXO is located in the cell nucleus where it acts as a transcription factor, as already mentioned earlier.

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Dietary restriction, which can be read by the organism as a signal of starvation, triggers at least a two-phase metabolic reaction whose main task is to provide energy to cells. In the first phase, as a result of lowering the glucose level, insulin secretion decreases and glucagon secretion increases. In the second phase, the state of balance is reached, and the reduction in glucose increases due to gluconeogenesis. The glucose concentration is set at a lower level than during the ad libitum nutrition, which leads to a decrease in insulin secretion. The consequence of dietary restriction, apart from the described changes at the molecular level, is reduction in the thyroid hormone secretion. This contributes to the reduction in body temperature. It has been shown that lowering the body temperature of mice by 0.5 Celsius increases life expectancy by 15%. In addition, diet restriction reduces the secretion of growth hormone, reduces oxidative stress, lowers blood pressure, increases the concentration of high-density lipoproteins, and reduces the concentration of low-density lipoprotein and triglycerides. The improvement of all these factors has a positive effect on the functioning of the cardiovascular system and prevents the development of age-related diseases. One should be aware that the dietary regime may adversely affect the psycho-physical conditions of humans. Side effects of dietary restrictions include lowering of blood pressure, which can lead to vertigo, syncope and other injuries. In addition, what is important, there may be a reduction in the production of sex hormones, the consequences of which are lower libido, infertility, osteoporosis, or menstrual disorders. The loss of body fat and muscle mass in turn contributes to the generation of lower amounts of heat, which causes a feeling of coldness. As has been shown, the nutritional regime has a positive effect on longevity through the control of complex molecular pathways, but the side effects associated with the use of this method to achieve longevity raise a lot of controversy.

Mitochondrion and Free Radicals Theory In the 1950s, Denham Harman proposed a hypothesis that the main cause of aging of organisms is the reaction of free radicals with macromolecules (Harman, 1956). The free radical theory of aging has long been considered the most relevant and crucial to explain the mechanisms of aging. According to Harman aging of cells would be due to the constant delivery of ROS inside mitochondria throughout life and damaging the mitochondrial DNA. Importantly, mitochondrion is not protected by histones or repairing enzymes such as the nuclear DNA. The mitochondrial DNA damage leads to a vicious cycle of ROS resulting in a decrease in energy production, because damage of mtDNA leads to deficiency of key electron transport enzymes and subsequent ROS generation which destroys macromolecules. Mitochondria are the energetic center of the cell and are present in all types of cells of humans and animals (except red blood cells). They generate cellular energy and produce reactive oxygen species (ROS) that regulate physiological processes. Mitochondria are also involved in the normal mammalian aging process and the control of cell death (Galluzzi et al., 2012). Metaphorically speaking, oxygen has two aspects. On the one hand, it is an essential element for aerobic organisms used for a series of enzymatic reactions, as a result of which organic substances are finally oxidized to carbon dioxide and water with the release of energy necessary to carry out numerous metabolic processes requiring significant energy. On the other hand, oxygen can be a toxic compound because free radicals are formed as by-products of oxygen-based respiration. Despite a lot of data and the fact that the free radical theory is considered a paradigm by a number of scientists, it is now known that there are no clear correlations between oxidative damage and aging, especially in higher organisms, including mammals. Years of research carried out on various model organisms, including yeast, fruit fly, nematode and mouse, aiming at detailed verification of this theory, provided a huge amount of data, both standing in line with the theory as well as presenting strong evidence against it. Currently, this theory is mostly considered to be false. However, we cannot undermine the free radical theory’s contribution to the understanding of a range of mechanisms that can partly contribute to aging. During testing of the free radical theory, many approaches were used. Longevity effects were achieved by regulating metabolism using antioxidant supplementation. Another approach was overexpression of antioxidant enzymes, including superoxide dismutases Cu/ZnSOD and MnSOD and catalase. Indeed, many data confirm that reducing the level of free radicals through supplementation of scavengers of free radicals or overexpression of antioxidant enzymes can extend life. Subsequent studies have shown, however, that these treatments may accelerate aging or have no effect on life expectancy. They also failed to confirm definitively that a long-lived animal has a reduced ROS level. The best example is the Heterocephalus glaber, which leads a very long life as a rodent. Research has shown that this organism lives long despite having elevated levels of ROS (Andziak et al., 2006). The phenomenon of the universal occurrence of superoxide dismutase leads to the question whether SOD is absolutely necessary in animal life and whether its inactivation will shorten the lifespan. Research on the model organism Caenorhabditis elegans, which was completely devoid of SOD activity (deletion of all five SOD genes), showed that these animals have a normal life expectancy despite an increased sensitivity to environmental stress (Van Raamsdonk and Hekimi, 2012). Furthermore, the theory was not confirmed by experiments that consisted in the deletion of glutathione peroxidase four in mice. As we can see, there is a lot of data against the assumptions of the theory. We should not, therefore, treat ROS as the main factor modulating the aging of an organism, but as one of the potential agents that can damage biological macromolecules. In the future, much research is still needed to indicate why we are and what we have to do in order to live long and enjoy health.

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Rehabilitation and Physical Therapy in Older Adults Pushpa Suriyaarachchi, Department of Rehabilitation Medicine, Nepean Hospital, Penrith, NSW, Australia; Musculoskeletal Ageing Research Program, Sydney Medical School Nepean, The University of Sydney, Penrith, NSW, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St Albans, VIC, Australia Laurence Chu, Department of Rehabilitation Medicine, Nepean Hospital, Penrith, NSW, Australia Neeta Menon, Department of Geriatric Medicine, Nepean Hospital, Penrith, NSW, Australia Oddom Demontiero, Department of Geriatric Medicine, Nepean Hospital, Penrith, NSW, Australia; Musculoskeletal Ageing Research Program, Sydney Medical School Nepean, The University of Sydney, Penrith, NSW, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St Albans, VIC, Australia Anuka Parapuram, Royal Rehabilitation Hospital, Ryde, NSW, Australia; and Metro Rehabilitation Private Hospital, Petersham, NSW, Australia Piumali Gunawardene, Department of Geriatric Medicine, Nepean Hospital, Penrith, NSW, Australia; Musculoskeletal Ageing Research Program, Sydney Medical School Nepean, The University of Sydney, Penrith, NSW, Australia; and Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St Albans, VIC, Australia © 2020 Elsevier Inc. All rights reserved.

The Effects of Aging on Physical Functioning Comprehensive Rehabilitation Assessment Multidisciplinary Rehabilitation Team Functional Outcome Measures Exercise Prescription for Older Adults Physical Therapy Programs Strengthening exercises Endurance exercises (aerobic exercises) Balance exercises Flexibility exercises Hydrotherapy Clearance for exercise programs Exercise prescription Lower Limb Orthoses (LLO) Foot Orthoses (FO) Ankle Foot Orthoses (AFO) Novel Models of Care Rehabilitation in the Preoperative Period: Prehabilitation Early Rehabilitation for Hospital Associated Deconditioning Rehabilitation Programs for Falls Prevention Stroke Rehabilitation Stroke Incidence Stroke Impairments and Disabilities Neuroplasticity Stroke Care Review of Treatment Strategies Emerging Research Techniques Specific Stroke Related Problems Secondary prevention Community Reintegration Rehabilitation in Neurodegenerative Disorders Parkinson’s Disease (PD) Physical therapies Speech therapy References Further Reading

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The Effects of Aging on Physical Functioning The pace of population aging around the world is increasing dramatically. By 2050, the world’s population aged 60 years and older is expected to total 2 billion, up from 900 million in 2015 (World health organization, 2015). In low- and middle-income countries, this is the result of reductions in mortality at younger ages, during childhood and childbirth, and from infectious diseases. In high-income countries, this is related to declining mortality among those who are older. This will present a huge challenge for the health systems around the globe. Health systems need to be designed to enhance healthy and active aging, which is preserving the physical and mental capacity to maintain the functional ability to enhance quality of life. The World Health Organization’s (WHO) active aging policy framework in 2002, defined active aging as “the process of optimizing opportunities for health, participation and security to enhance quality of life as people age”. It emphasizes the need for action across multiple sectors and has the goal of ensuring that “older persons remain a resource to their families, communities and economies” (World health organization, 2015). The WHO International Classification of Impairments, Disabilities and Handicaps (ICIDH) in 1980, provides a tool for the classification of consequences of disease and of their implications for the lives of individuals. According to this classification impairment refers to a loss or abnormality at the tissue, organ and body system level. Disability is any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner within the range considered normal and handicap is the disadvantage resulting from impairment and disability (World Health Organization, 1980). The International Classification of Functioning, Disability and Health (2001), provides the most comprehensive model of functioning and disability. Within this model the experience of functioning is not considered as the consequence of a disease but the result of the interaction between a health condition and both personal attributes and environmental influences (contextual factors). The impact of these contextual factors are important, since they can act as facilitators or barriers for functioning (Rauch et al., 2008). There is evidence that mobility disability (defined as the inability to walk quarter of a mile and or to climb a flight of stairs without help), in older persons is a highly dynamic process, characterized by frequent transitions between states of independence and disability. Older age, female sex, and physical frailty are generally associated with greater likelihood of transitioning to states of greater disability and lower likelihood of regaining independent mobility. In addition, episodes of continuous or intermittent disability in mobility almost invariably preceded transitions to death (Gill et al., 2006). Those growing older with long standing, early-onset disabilities (such as polio, multiple sclerosis) said to age with disability. These individuals age faster than their non-disabled peers with more severe onset of health conditions, mobility limitations, perceived symptoms (pain, fatigue) and secondary conditions such as depression (Molton and Jensen, 2010). There are number of different factors which will affect the physical functioning in older adults. A conceptual model has been proposed to explore factors that influence physical function in older adults. The primary variables include physical activity, body composition (fat mass and skeletal muscle mass), muscle capacity (leg strength and leg power), and muscle quality (combining a measure of body composition and muscle capacity). The individual effects of the primary variables must be considered in context of the additional contributing factors chronic health conditions, markers of inflammation, cognition, smoking, social support, sleep, fatigue, depression, and self-efficacy (Brady et al., 2014). Gender of the person also affects each of these factors and contributes to differences in physical function between men and women. Older women tend to have higher amounts of body fat and lower muscle quality, poorer physical function (Brady et al., 2014). Frailty is defined as a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual’s vulnerability for developing increased dependency and/or death (Morley et al., 2013). It has high predictive power for disability in older people and can predict other undesired outcomes in these same populations independent of chronic diseases. These characteristics, in the face of a high prevalence of frailty in older people and its potential reversibility, make frailty an important clinical target to reduce rates of disability in older adults, and become a potentially powerful instrument in daily clinical practice. There are to two main conceptual models: the cumulative deficit approach model by Rockwood et al. and the physical frailty phenotype model by Fried et al. Both models have received empirical validation (Bernabei et al., 2014). The physical frailty phenotype presents substantial overlaps with sarcopenia, “a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death” (Bernabei et al., 2014). Many of the adverse outcomes of frailty are probably mediated by sarcopenia, which may be considered the biological substrate for the development of physical frailty and related negative health outcomes (Bernabei et al., 2014). In terms of pathophysiology, sarcopenia has been associated with accelerated loss of fast motor units, loss and atrophy of type II fibers and adaptive conversion of fiber II into fiber I. The other changes include significant amounts of inter and intra-fiber fat infiltration and high levels circulating inflammatory cytokines (Demontiero et al., 2014). Several different therapeutic strategies have been proposed according to the multifactorial pathogenesis of sarcopenia: physical exercise training, nutritional interventions, and hormonal therapies. Of these interventions, physical exercise and nutritional supplementation reported as having positive benefits (Demontiero et al., 2014; Huo et al., 2015). The Lifestyle Interventions and Independence for Elders (LIFE) Study has reported that a structured moderate-intensity physical activity program consisting of aerobic, strength, flexibility, and balance training significantly reduced the occurrence of major mobility disability (MMD) and enhanced recovery after an occurrence of MMD. In addition, it can assist in reducing the risk of subsequent MMD episodes. Programs that are designed to enhance independent mobility should focus not only on the prevention of mobility disability, but also on the restoration and maintenance of independent mobility (Gill and Guralnik, 2016).

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Comprehensive Rehabilitation Assessment Rehabilitation is a process that seeks to restore a person to his or her highest level of function after illness or injuries and to enable the person to optimize their role in the community. Older persons requiring hospital-based rehabilitation has newly acquired functional decline from acute illness such as stroke, falls, fractures, infection and cardiac failure. These acute problems often compound their existing co-morbidities like diabetes, Parkinson’s disease, dementia, degenerative arthritis, osteoporosis, cardiorespiratory insufficiency or renal impairment. Many older persons live alone or have limited support network that might influence their ability to manage at home in the future. They are at risk of long-term residential care if unable to regain their previous level of function. A comprehensive rehabilitation assessment is required to enable the treating team to identify the functional deficits and to develop goals to help the person to regain any lost function in a reasonable time frame. The assessment needs to determine the medical stability and ensure all co-morbidities are well control to minimize acute events that might interrupt the rehabilitation process. It includes the review of medications as they are at higher risk of adverse events from medications. Functional status needs to be established including current level of cognition, mobility, activities of daily living and communication. Nutritional status should be noted as older persons are prone to suboptimal nutrition from pre-existing health and social problems or from the current illness. Mental health issues like anxiety and depression are common and are often undiagnosed. Their social situation including accommodation, finance, support network are important for care plan. Older adults might have no significant others to assist with decision making or there might be multiple interested parties involved that make planning the future challenging. The situation is more complex if the person has cognitive problems from dementia or other illness. Comprehensive rehabilitation assessment in an older person incorporates comprehensive geriatric assessment (CGA) which offers a multidisciplinary approach to diagnose and manage these complex medical, cognitive, psychosocial, functional needs of the elderly and targeted to manage complex geriatric syndromes. Its benefits vary depending on the different settings of care, availability of resources, appropriate referrals and selection of patients. Most of outpatient comprehensive geriatric assessment programs are targeted to manage patients with complex geriatric syndromes as compared to the inpatient programs, which target patients with specific surgical or medical causes. The rehabilitation therapy services should be delivered in the most appropriate setting. The hospital-based rehabilitation commences in the acute care settings (medical/surgical units, intensive care unit) or in the subacute care settings (inpatient rehabilitation units). There should be adequate continuum of care in the community setting on discharge from hospital, through center-based/home-based outpatient programs or residential care programs. The emphasis will be to optimize the community reintegration with restoration and maintenance of function. Assessing cognition and mood underpins the psychological health domain of the CGA. Both cognitive impairment and depression are associated with increased risk of falling (Fig. 1) and both affect the capacity of individuals to participate in rehabilitation processes. The degree of cognitive deficits overall as well as deficits in specific domain are associated with falls through several mechanisms including gait abnormalities (Table 1). Similarly, several mechanisms may explain the relationship between anxiety and major depression with falls (Fig. 1, Table 2) and indeed the presence of these mood disorders can predict rehabilitation outcome. Nevertheless, with varying severity dementia states and delirium, success with restoration of mobility and functional abilities to improve quality of life is achievable. A meta-analysis has shown that although exercise alone did not infer positive effects on cognition overall, psychological symptoms, and depression, it did improve the ability of people with dementia to perform daily activities (Forbes et al., 2015). However, when physical exercise is combined with cognitive training, positive effects have been seen with activities of daily living, mood and global cognitive function (Law et al., 2014; Karssemeijer et al., 2017). These benefits were seen in older people with and without mild cognitive impairment (MCI) and those with dementia (Law et al., 2014; Karssemeijer

Anxiety Fear of falling Social isolation

Depression Antidepressant SEs

Falls Consequences of falls Fig. 1

Complex interplay and bidirectional relationships between depression and falls.

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Rehabilitation and Physical Therapy in Older Adults Table 1

Cognitive impairment and associated factors predisposing to falls.

Component

Mechanisms/related factors

Cognition

Impaired executive function

• • • •

Gait and balance

Function Demographics Mood Medications Others

increased gait variability in dual-task conditions gait slowing impaired selective attention deficit in process of inhibition Decline in working memory Verbally disruptive and attention-seeking behavior MMSE < 17 Attention and orientation score on ACE–R < 9 Impaired static standing balance Velocity, mean stride length, heel-to heel, base of support variability, and double support time variability Ambulation with mobility aid Dependency in hygiene Increasing age High scores on anxiety and impulsivity Antipsychotics, anxiolytics, hypnotics, sedatives and antidepressants Taking more than four prescription medications Participation in outdoor walks Vision impairment Any fall in the previous year

The risk increases exponentially with increasing number of risk factors present.

Table 2

Depression and underlying mechanisms of falls.

Depression and depression related factors Symptoms Associated cognitive deficits Psychomotor slowing Antidepressant side effects

Insomnia, sleep fragmentation, poor appetite weight loss, nutritional deficiencies including vitamin D, folate and B12 Attention, executive function and processing speed Gait disturbance: walk slowly with a shorter stride length, longer standing phase, and increased gait variability Impaired sensorium, e.g., balance, sedation Electrolyte disturbance including sodium Orthostatic hypotension Anticholinergic Involuntary movements Cardiac rhythm disturbance

et al., 2017). Physical and cognitive strategies incorporated to multicomponent interventions program also improved balance, functional mobility and gait speed in those with MCI (Booth and Hood, 2016). In general, two main approaches to enhance cognition have been described (Table 3). Similar to cognitive impairment, depression and anxiety is prevalent with age. Both conditions, whether primary or secondary to organic causes, are associated with reduced functional abilities and poorer functional outcomes after rehabilitation. A reduced capacity to participate in therapy is one possible explanation but precise mechanisms underlying this effect is unclear. A complex interrelationship between a number of associated factors have been reported (Fig. 3, Table 2). Physical exercise can benefit older patients with depression undergoing rehabilitation as moderate to large reduction in symptoms may be seen. In fact, with mild to moderate depression the effects may be comparable to antidepressant medication and psychotherapy and in severe cases, exercise may be useful as complementary therapy (Knapen et al., 2015). In addition to the severity, significant psychological symptoms such as fatigue and fear of falling (Kendrick et al., 2016) may be reduced when exercise is employed as a component of depression treatment. However, it may be reasonable to individualize patients as some metaanalyses have found no effect of exercise on quality of life, depression severity or cognition (Krogh et al., 2017). Another key component of CGA is optimizing physical health through medication review in conjunction with evaluation of comorbidities. Both medication burden and comorbidities contribute to falls risk. Certain class of medications as well as combinations of medications (Fig. 2) and comorbidities are associated with greater risks (Fig. 3).

Rehabilitation and Physical Therapy in Older Adults Table 3

131

Cognitive training approaches.

Approach

Characteristics

Biopsychosocialdcognitive rehabilitation

Targets people with cognitive deficits Improve daily functioning and the patient’s quality of life Highly individualized application Administered by Health professionals and caregivers. Individual sessions Targets healthy individuals and people with cognitive deficits Indirectly improve user’s quality of life by enhancing cognitive function Used for groups of people with similar characteristics Self-administered Individual and group participation

Cognitivedcognitive training

Both are designed to train specific cognitive processes and are based on theories of neuroplasticity. Cognitive rehabilitation is a holistic biopsychosocial approach that takes into account the person’s emotional, cognitive and social deficits which stem from disease or injury. Cognitive training, also known as cognitive exercise, is defined as a standardized set of exercises which involves repeated practice and increasing levels of difficulty, and taps into specific cognitive functions.

X2 Any psychotropic Benzodiazepines drug Type 1a antiarrhythmic Antipsychotics

X1 Sedatives and hypnotics

Antidepressants Fig. 2

Opioids Antihypertensive agents

NSAIDs Digoxin Diuretics

Tranquilizers

Drug class and falls risk (odds ratio).

X3 Parkinson’s Disease

X1 Gait dysfunction

Depression Rheumatic disease History of stroke Pain

Fig. 3

Cognitive impairment Visual impairment Diabetes

Comorbidities and falls risk (odds ratio).

However, in those undergoing rehabilitation aiming to be mobile and functionally independent, medication reviews serve to not only reduce falls risk but reduce mortality, treat and prevent diseases, relieve symptoms and delay physical and functional decline. Alternatively, in those who are frail, the aim is to alleviate symptoms and maintain function. Key steps to rationalize medication in older patients are outlined in Fig. 4. Although rehabilitation improves function and prevents admission to nursing homes, a discharge home is considered an indicator of successful rehabilitation and quality care. Thus, goal setting becomes essential to achieve a discharge and an outcome that is acceptable to both clinicians and patients. As individuals have unique lifestyle, health status and living environment the goals should be patient centered and achievable. Patient factors need to be considered (Table 4), rehabilitation interventions more targeted to achieve realistic rehabilitation goals and provide adequate support to caregivers to better prepare both patient and caregiver for successful discharge. Setting goals with older patients can be challenging. Although, most clinicians engage patients in goal-setting, the process is often not a part of their daily practice. In rehabilitation, the goal setting needs to be done through close collaboration between the multidisciplinary team and the patient. It is generally agreed that a good goal is specific, measurable, achievable, realistic/relevant and timed (SMART). To improve this process, instruments have been developed to allow clinicians and patients define and agree on achievable goals. In addition, these instruments help structure a more efficient rehabilitation process by providing guidance and motivation for greater compliance with interventions. In geriatric rehabilitation, the most validated tools are the Goal-Attainment Scaling (GAS) (Rockwood, 1994) and the International Classification of Functioning, Disability and Health (ICF) (Rauch et al., 2008) instruments. An example of the process and application of GAS is described in Table 5.

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Medical Assessment Physical examination, Psychosocial and functional history Estimate frailty and life expectancy and prognosis of comorbidities

Determine goals of therapeutics Reduce mortality, treat and prevent diseases, relieve symptoms, delay physical and functional decline OR Relieve symptoms and maintain function as long as possible

Complete medication history including over the counter and complementary

Evaluate medications and correlate with comorbidities For each medication and corresponding condition being treated, assess: • indication - current, evidence for duration of benefit, treatment targets, • Side effects • Interactions

Optimize dosage and simplify regimen for drugs that need to continue Cease drugs with no net benefit and drugs causing adverse events Cease drug most likely associated with adverse events first Wean off drugs that can cause withdrawals such as CNS active agents and corticosteroids

Monitor Compliance Withdrawals Fig. 4

Adverse events Targets achieved

Main steps to rationalizing medications in older patients.

Despite the use of these instruments, some patients may have difficulty formulating appropriate goals other than to “go home” and functional outcomes may not be achieved during the period of inpatient rehabilitation. Home rehabilitation thus provides an opportunity for clinicians to address patient-centered goals over time and in a continuum of settings. As patients are in their own environment rehabilitation processes can be adjusted to patients’ specific daily needs and activities. This way, clinicians can effectively address patients’ long-term goals post-discharge and help patients achieve goals that are important to them once they are home again.

Multidisciplinary Rehabilitation Team Rehabilitation of older persons requires a team approach. No single clinician processes all the necessary knowledge and skills to manage all the medical, functional and psychosocial problems that are common in this population. The team usually consists of the following core members as summarized in Table 6. Other clinicians may be required on a consultation basis depending on the clinical need. Clinical psychologists to provide cognitive based therapy, neuropsychologist to provide detailed assessment and treatment plan for problems related to cognitive functioning. The rehabilitation team usually communicates formally in weekly case conference where patient assessment, treatment strategies, progress and discharge plan are discussed. Team members need to feel free to discuss their findings in a professional environment. This can pose a challenge due to different training backgrounds, experience and personalities. The team usually adopts a function model: Traditional medical model with physician driven decision making including treatment decisions.

Rehabilitation and Physical Therapy in Older Adults Table 4

133

Setting realistic rehabilitation goals require evaluation of a number of factors that can influence a successful discharge home. Initial Assessment for setting goals in rehabilitation

Demographics

Age, gender, ethnicity, marital status, living situation (alone), obesity

Medical

Co-morbidities leading to disability/multi-morbidity. Consider trajectories and life expectancy Cognition incl. types and severity (delirium, dementia) Language deficit (dysphasia) Psychological state (depression, anxiety, mood) Vision impairment Hearing deficits Pain Premorbid basic activities of daily living, physical function Premorbid extended activities of daily living Continence Premorbid, pre-fracture mobility status Falls risk Nutritional state Oral care including dentition Swallowing Social circumstances including home environment and network of support and contacts Estimate of the access to food and financial stressors Caregiver stress Length of stay in acute setting Post op complications Pressure sore

Sensory Function

Nutrition Social

Other factors

These factors are assessed on admission to rehabilitation.

Table 5

Example of Goal Attainment Scaling to set goals for an 80 year old patient admitted into rehabilitation 3 days after hip surgery for a fractured neck of femur. Domain goals

Attainment level

Activities of daily living (ADL)

Mobility

Post discharge care

Much better than expected (þ2) Somewhat better than expected (þ1) Expected level Program goal (0)

Back to premorbid function with no aids 1 in 2 in the 85 þ age group. These rates are doubled in the inpatient setting and is tripled in the long term are setting. In general, of those who fall in 1 year half to two thirds experience a repeat fall in the subsequent year. Major injuries resulting from falls average approximately 6%, 4% and 6% in the community, inpatient and long-term care setting respectively. A number of risk factors predispose the older person to fall in these different settings (Table 8-9). Each risk factor on its own may not greatly increase the risk of falling however the overall risk of falling increases linearly with the number of risk factors, from 8% with none to 80% with four or more combination of risk factors. Some risk factors such as dementia, Parkinson’s disease, and taking > 5 prescribed medications are common in all settings and are independent risk factors. As such, a key goal of rehabilitation in older people is not only to restore function and mobility to maintain a certain quality of life but also to reduce the individual’s falls risk and prevent any future falls. As a single intervention, exercise is the most effective way to reduce falls risk in older fallers living in the community including older adults with cognitive impairment (Chan et al., 2015). It is however important that the correct type of exercise is implemented, as not all types of exercise improve balance to an extent that actually prevents falls (Table 10). Exercise programs that focus on and challenge balance and are of a higher dose have demonstrated larger effects. A meta-analysis by Sherrington et al. (2011) showed that programs which included balance training, contained a higher dose of exercise and did not include walking training had the

138

Rehabilitation and Physical Therapy in Older Adults Table 8

Risk factors for falls reported in epidemiological studies.

Intrinsic risk factors

Demographic Systems

Symptoms/disease

Extrinsic risk factors

Medications

Recent hospitalization Home Footwear

Table 9

Age, gender, race Gait and balance disturbance Reduced strength Vision Cognition ADLS limitation Frailty Fear of falling Dizziness/vertigo Cognitive impairment Anxiety/depression Syncope Diabetes/diabetic foot ulcer Stroke Anemia Alzheimer’s dementia Parkinson’s disease Prostate hypertrophy chronic lung disease/asthma Psychotropics Benzodiazepines Analgesics Digitalis Antihypertensives Poor lighting and objects around the home, such as loose rugs Inappropriate (slippers, fastened shoes, nonslip socks) Shoes with heels >2.5 cm high

Risk factors for falls in inpatient and long-term care setting.

Intrinsic risk factors

Demographic Systems

Symptoms/diseases

Extrinsic risk factors

Hospital/Home environment Medications

Age Gait instability Agitated confusion Need for transfer assistance Previous falls/falls history Cognitive impairment Vertigo Urinary incontinence Sleep disturbance Stroke Carpet flooring Psychotropic medications Sedatives Antidepressants Anticonvulsants Tranquilizers Antihypertensives

greatest effect on reducing falls. Another meta-analysis in fact showed that in healthy older adults, balance training was effective in improving static/dynamic steady-state, proactive, and reactive balance as well as performance in balance test batteries and a number of modalities could be utilized (Lesinski et al., 2015). The effective modalities had the following characteristics: a training period of 11–12 weeks, a frequency of 3 sessions per week, a total number of 36–40 training sessions, a single training session was 31–45 min in duration, and a total duration of 91–120 min of balance training each week. These findings were confirmed in a recent updated meta-analysis by the US Preventive Services Task Force (Grossman et al., 2018), who also emphasized specific modalities and the importance of higher intensity regime (Table 11). Although exercise is effective, different exercise regime and indifferent settings may achieve different falls outcome. Exercise classes containing multiple components (i.e., a combination of two or more categories of exercise) reduce rate of falls and risk of falling in both participants at higher risk of falling (history of falling or one or more risk factors for falls at enrolment) and lower

Rehabilitation and Physical Therapy in Older Adults Table 10

139

Exercises with positive effect on balance ([Y).

Exercise

Timed Up & Go Test

Single leg stance on the floor with eyes open/eyes closed

Gait speed

Berg Balance Scale

Gait, balance co-ordination and functional tasks Strengthening exercise 3D exercise (Tai Chi, Gi Gong, dance, yoga) General physical activity (walking) Computerized balance Vibration Multiple exercise

Y Y Y – ND – Y

–/– [/– [[ –/– ND/ND ND/ND [/[

[ [ – – ND ND –

[ – [ ND ND ND [

“–” indicates no difference between exercise and control group outcomes. No data (ND) available.

Table 11

Findings by the US Preventative Taskforce.

Exercise program and types of training Multifactorial interventions and components

Gait, balance, functional training, resistance training, flexibility, endurance training, Tai Chi, general physical activity. 3 sessions per week for 12 months (duration of exercise interventions ranged from 2 to 42 months) 1. Initial assessment of modifiable risk factors for falls:  A multidisciplinary comprehensive geriatric assessment or  An assessment using a combination of various components, such as balance, gait, vision

Postural blood pressure, medication, environment, cognition, and psychological health.

2. Customized interventions for each patient based on issues identified in the initial assessment. Summary of characteristics of exercise programs effective in reducing falls and characteristics of multifactorial interventions.

Table 12

Single exercise interventions in community. Falls outcome

Exercise program

Rate of falls

Risk of falling

Group exercise: multiple categories of exercise vs. control Individual exercise at home: multiple categories of exercise vs. control Group exercise: Tai Chi vs. control Group and individual exercise: balance training vs. control Group and individual exercise: strength/resistance training vs. control Individual exercise: general physical activity (walking) vs. control Exercise vs. exercise: higher intensity multiple component exercise vs. lower intensity exercise Vitamin D (with or without calcium) vs. control/placebo/calcium

Y Y Y Y – – Y

Y Y Y – – – Y

–

–

“–” indicates no difference between exercise and control group outcomes.

risk (not selected on falls risk at enrolment) (Gillespie et al., 2012). Similarly, home-based exercises containing multiple components were found to reduce rate of falls and risk of falling. However, the components vary and not all are effective (Table 12). In comparison to single interventions, multifactorial interventions have been shown to be effective consistently (Gillespie et al., 2012). However, the overall net benefit of routinely offering multifactorial interventions to prevent falls is small. It is prudent to individualize the approach taken based on the circumstances of prior falls, presence of comorbid medical conditions, and the patient’s values and preferences. Key aspects of the multifactorial interventions as recommended by the US Preventive Services Task Force (Grossman et al., 2018) are described in Table 11. In contrast, the most recent meta-analysis examined multifactorial interventions, where component interventions differ based on individual assessment of risk, and multiple component interventions, where the same component interventions are provided to all people and found that both reduced rate of falls and risk of falling (Hopewell et al., 2018). A summary of the characteristics of these programs are describe in Table 13. Compared to the community setting, evidence in long term care and hospital settings are limited according to the most recent Cochrane meta-analysis (Cameron et al., 2018). In care facilities, the effect of exercise on rate of falls is uncertain and exercise may make little or no difference to the risk of falling. The authors similarly reached the same conclusion for multifactorial interventions. Nevertheless, through physical rehabilitation interventions compared with usual care, activities of daily living (ADL) independence and performance are enhanced or decline less and possibly some positive effects on mood, cognition and fear of falling. Table 14 describes some of the components of interventions that maybe beneficial.

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Rehabilitation and Physical Therapy in Older Adults Table 13

Multiple components and multifactorial interventions in community.

Multifactorial interventions

Rate of falls

Risk of falls

Exercise þ home safety intervention Exercise þ vision assessment Exercise þ home safety þ vision assessment Exercise þ education þ home safety intervention vs. control Exercise þ education þ home safety intervention vs. education Exercise þ education þ home safety intervention þ clinical assessment vs. education Exercise þ education vs. education Exercise þ education þ risk assessment vs. control Exercise þ home safety þ multifactorial assessment and referral vs. multifactorial assessment and referral Exercise þ nutritional supplementation þ vitamin D and calcium vs. Calcium and Vitamin D Exercise þ vitamin D vs. no exercise/no vitamin D Exercise þ cognitive behavioral therapy vs. control Exercise þ “individualized fall prevention advice” vs. control

Y Y Y Y – –

Y Y Y – – –

– – Y

– – ND

–

ND

– – – – – ND ND Y Y Y

– – ND – ND – Y Y ND –

Y

–

Physical training þ education vs. control Home safety þ vision assessment Home safety þ medication review vs. control Education þ free access to geriatric clinic vs. control Centre-based rehabilitation program (exercise þ education) vs. comparable home-based program Multifunctional training þ whole body vibration vs. light physical exercise “Multifaceted podiatry” (customized orthoses, footwear review, foot and ankle exercises, fall prevention education, and “usual podiatry care”) vs. “usual podiatry care” alone Multidisciplinary rehabilitation þ home safety visit vs. multidisciplinary rehabilitation (no home visit)

In hospitals additional physiotherapy may reduce the rate of falls and the risk of falling. Multifactorial interventions may also reduce rate of falls particularly in the subacute setting; however, the effect of these interventions on risk of falling is uncertain. Table 15 describes some interventions that have been studied. In both long-term care and hospital settings, interpretation of the effectiveness of multifactorial interventions is complex because of the variation in components, case mix of the sample, duration and intensity of the intervention, and how the interventions were implemented. Care provided in health care setting and long-term care facilities differ between countries and even when interventions seem ineffective careful consideration of the context is needed. Considerations of cultural and organizational contexts need to be taken into account when applying the results from these studies into practice.

Stroke Rehabilitation Stroke Incidence Fifteen million strokes occur worldwide each year and resulted in 5.8 million death. Stroke incidence in less developed countries exceeded that of developed countries by 20%. It is a leading cause of long-term disability and particularly impacts on poorer countries, while the risk factor management has contributed to improved stroke prevention, the overall stroke rate is rises due to aging (World Health Organization, 2002).

Stroke Impairments and Disabilities Neurological impairments from first ever stroke include: Visual deflect Visual neglect Upper limb sensory deficit Lower limb sensory deficit Upper limb weakness Lower limb weakness

26.1% 19.8% 30.3% 72.4% 77.4% 72.4%

Ataxia Dysphasia Dysarthria Dysphagia Urinary incontinence Cognitive problem

7.23% 44.7% 41.5% 23% 48% 43.9%

Rehabilitation and Physical Therapy in Older Adults Table 14

141

Interventions in care facilities.

Interventions

Rate of falls

Risk of falls

Exercise overall vs. usual care Gait, balance, functional training vs. usual care Whole body vibration vs. usual care Combination of exercise categories vs. usual care 3D (Tai Chi) vs. usual care Exercise vs. exercise Additional gait, balance, functional training Strength/resistance vs. self-training Balance and strength vs. self-training Flexibility (Yoga) vs. ‘staying active’ program 3D (Tai Chi) vs. ‘staying active’ program 3D exercises (“in balance”) vs. functional balance, strength and mobility Flexibility (Yoga) vs. 3D (Tai Chi) Wii balance board vs. Otago balance program Medication review vs. usual care General medication reviews Medication review for hyponatremia Vitamin D vs. no vitamin D supplementation Additional Vitamin D supplementation Multivitamins (including vitamin D3 þ calcium) vs. placebo Education on Vitamin D þ calcium þ osteoporosis medications vs. usual care Vitamin D þ calcium supplementation vs. placebo Environmental interventions vs. usual care Wireless position monitoring patch Social environment vs. usual care Staff education on fracture prevention Guideline implementation program Risk assessment tool vs. nurses’ judgment Dementia care mapping Other single interventions Exercise (Ex) þ cognitive training vs. Ex Lavender patch vs. placebo Sunlight exposure vs. usual Multiple interventions vs. usual care Exercise þ management of urinary incontinence þ fluid therapy Sunlight exposure þ calcium Multifactorial interventions vs. usual care (grouped by level of care) High level nursing care facilities Intermediate level care facilities Mixed level care facilities Multifactorial interventions vs. usual care (grouped by level of cognition) Participants with cognitive impairment Participants with no cognitive impairment or mixed sample

Y Y Y Y ND

Y Y Y ND Y

Y Y Y Y Y Y Y Y

Y Y Y ND ND Y ND ND

Y Y

Y Y

Y Y Y ND

Y Y Y Y

–

ND

– – – –

ND ND – ND

– – –

ND – –

– –

– –

Y Y Y

Y Y Y

Y Y

Y Y

“–” indicates no difference between comparison group outcomes. No data (ND).

Long term disabilities are common after stroke and at 6 months: Dependent in ADL Reduced mobility Assisted mobility

26% 50% 30%

Aphasia Depression Placement

19% 35% 26%

Even 15% of patients with transient ischemia attack and minor stroke was found to be disabled after 90 days as measured by modified Rankin Scale.

Neuroplasticity Stroke recovery is underpinned by neuroplasticity with the injured brain having the potential for neuronal and functional recovery with appropriate trainings. Animals exposed to an enrich environment and challenging activities develop more dendritic

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Rehabilitation and Physical Therapy in Older Adults

Table 15

Interventions in hospitals.

Interventions

Rate of falls Risk of falls

Additional exercises vs. usual physiotherapy Medication review vs. usual care Vitamin D supplements vs. no vitamin D supplements Environmental interventions vs. usual care Carpet flooring vs. vinyl flooring Low-low beds vs. usual care Blue identification bracelet vs. usual care (no bracelet) Bed alarms vs. usual care Social environment vs. control Organizational service model change (fall prevention guideline implementation) Organization service model change (falls prevention, incontinence and ulcer guideline implementation) Organizational service model change (fall prevention toolkit software) Acute care service for elderly patients vs. usual care Post-operative orthogeriatric service after hip fracture Fall prevention tool kit software vs. usual care Behavior advisory service vs. usual care Knowledge/education interventions vs. usual care Educational materials þ health professional follow-up Educational materials only Individualized educational session Educational materials þ health professional follow-up Educational materials only Multifactorial interventions vs. usual care Acute care: risk assessment and up to 6 interventions for high risk patients, plus staff education Acute and subacute care: risk assessment, staff and patient education, drug review, environmental modifications, exercise Subacute: risk assessment and targeted interventions (exercise, educational sessions from OT, hip protectors) Acute and subacute care: risk factor screening and targeted care plan in at-risk patients Subacute care: Multimedia falls education with follow-up for patients plus staff education and feedback

Y – Y

Y – Y

– – – Y

– – – –

– Y Y Y Y ND ND

ND ND ND ND Y – –

Y Y ND ND ND

ND – Y Y Y

– – Y Y Y

– – Y Y –

“–” indicates no difference between comparison group outcomes. No data (ND).

branching and synapses than animals housed in standard environment. Several mechanisms are proposed: (1) Excitatory and inhibitory neurotransmitters (glutamate, NMDA, GABA, noradrenaline, acetylcholine, etc.) can modify cortical synaptic connections and reorganization. (2) Local neurotrophins promote synaptic remodeling and changes in receptor expression and may protect cortical tissue from secondary damage in the acute stage. (3) Astrocytes may also contribute to synaptic plasticity. These plastic changes occur in the cortex, thalamus and brain stem. Neuroplasticity underpins the current rehabilitation approach to increase treatment activities, intensity and specificity and to provide an enrich rehabilitation environment for stroke patients (Johansson, 2000).

Stroke Care Acute stroke management in organized stroke unit has reduced mortality and institutional care at 1 year follow up independent of age, sex, stroke severity or stroke type (Stroke Unit Trialists’ Collaboration, 2007). Stroke rehabilitation should be provided by a multi-disciplinary team that develops and monitor a rehabilitation plan to optimize function and formulate discharge plan and community reintegration. There is no general agreement about the types, intensity, frequency, and duration of therapies offered to stroke patients. Evaluation of sub-acute rehabilitation is difficult from a methodological perspective. Specialized subacute stroke rehabilitation is associated with reduced mortality and combined death/dependency, but not the need for institutionalization or length of hospital stay, when compared to general rehabilitation. Subgroup analysis shows that those with severe strokes experience reduced mortality; those with moderate strokes experience improved functional outcomes; and those with mild stroke do not improve to a greater extent compared with standard care (Teasell et al., 2018).

Review of Treatment Strategies Evaluation of rehabilitation treatment are challenging due to the heterogeneous nature of stroke population, varying extent of impairments, a lack of standardized rehabilitation protocol, difficulty with blinding and the confounding factor of spontaneous recovery over time.

Rehabilitation and Physical Therapy in Older Adults

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Some therapies are shown to be effective and consideration can be given to incorporate them into routine clinical care: Mirror therapy improves upper limb motor impairment and function, activities of daily living and pain. Electromechanical and robot assisted training can improve upper limb strength, function and activities of daily living. Treadmill training with body weight support improves walking speed in the short term and has the most benefit for ambulant stroke patients. Circuit class training can improve walking speed, distance and balance. Cardiovascular training can improve mobility, balance and reduce disability. SSRIs improves dependence, disability, neurological impairment, anxiety and depression after stroke. Table 16 illustrates a selected summary of Cochrane Review (Das Nair et al., 2016; Bowen et al., 2013; Chung et al., 2013; Winter et al., 2011; Corbetta et al., 2015; French et al., 2016; Coupar et al., 2010; Doyle et al., 2010; Langhorne et al., 2018) on some current rehabilitation therapies, many results are inclusive and signpost the need for further high-quality studies to develop evidence-based stroke rehabilitation therapies.

Emerging Research Techniques Patients exposed to additional physical and cognitive challenging activities with increasing complexity showed improved cognitive and functional ability compared to control. The effect remains at 3 months follow up (Khan et al., 2016). Mental practice has produced the same neural and muscular events as physical practice and can be used to increase skill reacquisition in stroke patients. Virtual environment intervention is a low risk modality that has produced a small positive effect for motor relearning] Non-invasive stimulation (repetitive transcranial stimulation (rTMS), transcranial direct current stimulation (tDCS)) may improve motor outcomes and bilateral stimulation may be more effective than unilateral stimulation (Cunningham et al., 2015).

Specific Stroke Related Problems Spasticity is velocity dependent increase in muscle tone. It usually affects flexor muscles in the upper limb and extensor muscles in the lower limb. Spasticity can interfere with functional tasks and can cause pain that affect one’s quality of life. Mild spasticity can be managed by stretching exercise. More severe spasticity that interferes with function should be evaluated for treatment. Oral agents (baclofen, gabapentin, pregabalin) are the first line treatment. More severe focal spasticity can be treated with intramuscular botulinum toxin injection. Spasticity management requires a multidisciplinary approach to ensure treatment goals are clear and achievable.

Secondary prevention Medical risk factors (hypertension, diabetes, hypercholesterolemia atrial fibrillation, carotid stenosis) and life style factors (smoking, alcohol obesity) need to be addressed with education, counseling and medications.

Community Reintegration Most older persons with stroke will make significant functional recovery to return to pre-morbid home environment. Some will require additional support from family or services to stay home safely. The issues of social isolation and carer’s stress need to be monitored. Some elderly has more severe cognitive or physical deficits and will require supported care environment. For post stroke patients, a network of medical care, family and social support are vital to maintain their quality of life.

Rehabilitation in Neurodegenerative Disorders Neurodegenerative disorders are incurable and debilitating conditions that affect the neurons in the human brain resulting in progressive degeneration and death of cells. The most common of these conditions are Parkinson’s disease (PD) and the Parkinson’s plus syndromes, Alzheimer’s disease, Prion disease, motor neuron disease, Huntington’s disease, spinocerebellar Ataxia and spinal muscular atrophy. Each disease has its own rate of progression over time however the outcome is the same with progressive decline resulting in impairments, functional limitations and disabilities that impact on quality of life. Even though the disease course cannot be altered a multidisciplinary team can play an important role to assist individuals with neurodegenerative disease maintain their optimum physical, psychological and social function and independence for a long as possible. Rehabilitation of the patients with dementia pose challenges to most existing rehabilitation facilities and is beyond discussion of this article.

Parkinson’s Disease (PD) PD is multi system neurodegenerative disorder which is characterized by both motor and non-motor symptoms that is a global phenomenon affecting 1% of the population over 55 years old (Hayes et al., 2010).

144

Rehabilitation therapies in stroke rehabilitation.

Treatment

Sample

Conclusion

Notes

References

Cognition strategies to improve memory problem after stroke including use of “drills and practices”, internal or external memory aids, teaching of coping strategies Cognitive strategies to reduce spatial neglect after stroke including structured therapies, computerized therapies, prescription of aids and specific environmental modifications Cognitive rehab strategies to improve executive dysfunction after stroke. This include restorative interventions (self-awareness training, cognitive remediation, problem solving training and verbal feedback) and compensatory interventions (use of written strategies/electronic technology, self instruction techniques and feedback methods including mirror and video feedback) Hand on techniques to improve upper limb motor return and functions

13 studies 514 subjects

Demonstrated short term subjective improvement in memory but no long-term improvement in objective tests, mood, functional abilities, or quality of life

Small no of studies, small sample sizes, poor quality reporting and inconsistent outcome measures

Das Nair et al. (2016)

23 RCT 628 subjects

Poor quality studies with poor randomization, Bowen et al. (2013) inadequate allocation concealment and high risk of bias

13 studies 770 subjects

Effectiveness of cognitive rehab for spatial neglect remains unproven. There is limited evidence of immediate beneficial effect on test of neglect that warrant further studies Insufficient high-quality studies to reach a generalization of effectiveness of cognitive rehab on executive function after stroke

3 RCT 86 subjects

Limited evidence for stretching, passive exercise and mobilization

Use of constraining approaches (CIMT, modified CIMT and forced use) for upper limb function

42 studies 1453 subjects

Repetitive task training (RTT) to improve upper limb and lower limb functions

33 studies 1853 subjects

Simultaneous bilateral upper limb training to improve function

14 studies 421 subjects

Evaluate various sensory interventions including sensory re-education, tactile kinesthetic guiding, repetitive sensory practice, or desensitization to prove function or remediate sensory impairment of upper limbs Very early mobilization (VEM) usually within 48 hours after stroke to improve outcomes (death and disability)

13 studies 467 subjects

Limited improvement in motor impairment and function but not in disability. Result less positive than previous review in 2008 Low- to moderate-quality evidence that repetitive task Need to clarify the definition for repetitive training improves upper and lower limb function for task training and the type and amount of up to 6 months training for future studies Good quality RCT required to compare The technique may be no more (or less) effective than bilateral and unilateral treatment. usual care or other upper limb interventions for upper limb ADL, functional movement and motor impairment outcomes Insufficient evidence to support or refute their Need well designed, better reported studies effectiveness. Some preliminary evidence for mirror therapy, tactile stimulation and intermittent pneumatic compression in sensory rehab.

9 RCT 2958 subjects

Uncertain benefit for VEM. A large study with 2104 subjects (AVERT III 2015) detected risk with death and disability at 3 months.

Small no of studies. Generally small sample sizes and poor quality

Chung et al. (2013)

Unable to conduct meta-analysis due to heterogeneity of studies. Further studies with these 3 techniques are recommended There are quality issues with most studies. Recommends further studies

Winter et al. (2011)

Need further research

Corbetta et al. (2015) French et al. (2016) Coupar et al. (2010)

Doyle et al. (2010)

Langhorne et al. (2018)

Rehabilitation and Physical Therapy in Older Adults

Table 16

Rehabilitation and Physical Therapy in Older Adults

145

These symptoms include impairment of speech, swallowing, gait, function, balance and activities of daily living. Despite optimal medical and surgical management, it remains a challenge to these symptoms in a majority of PD sufferers and have a negative impact on quality of life (Fox et al., 2012). The strongest evidence of efficacy of rehabilitation occurs when delivery of interventions occurs early in the disease. This is when rehabilitation plays a key role in maintaining mobility, balance and endurance and prevents secondary complications from reduced physical activity (Canning, 2013). Due to the complex nature of this disease ideally there should be interdisciplinary collaboration between the multiple health professional involved. Patient centered care is recommended as it is associated with greater wellbeing and physical functioning.

Physical therapies Exercise programs from recent empirical evidence may be an effective way to delay or reverse functional decline as exercise may trigger neuroplasticity related events in the human PD Brain (Goodwin et al., 2008; Hirsch et al., 2016). Early Intensive Multidisciplinary Rehabilitation programs show delay in progression of motor symptoms. There is current supportive evidence for group aerobic exercise, cycle ergometry and treadmill walking. Other physical interventions such as Tai-Chi, Tango dancing, Irish set dancing, muscle strengthening exercises and muscle power training also have supportive evidence (Canning, 2013). Physical Therapy is an integral part of PD treatment focusing on gait and balance retraining and falls prevention. Lee Silverman Voice Treatment (LSVT) BIG is an exercise and self-cue based physical or occupational therapy treatment derived from the speech treatment LSVT LOUD. It encourages patient to move with powerful and large amplitude movements during progressive, high intensity training (Fox et al., 2012). PD Warrior exercise program is based on the principles of neuroplasticity which considers the role of intensity in training and cognitive retraining by dual tasking exercises (https://pdwarroior.com/).

Speech therapy More than 90% of patients with PD patients will have issue with their speech or swallow which on self-reported data from these individuals are associated with inactivity, embarrassment and withdrawal from social situations. LSVT LOUD is a standardized research based intensive speech treatment protocol to improve hypophonia and has evidence of 2-year retention of improved loudness (Fox et al., 2012; Ebersbach et al., 2010). As the disease progresses, swallowing issues become evident and aspiration pneumonia is a leading cause of death. Speech Therapy assessment and intervention is therefore required for these individuals.

References Aruin, A.S., Rao, N., 2010. Ankle-foot orthoses: propreoceptive inputs and balance implications. American Academy of Orthotists and Prosthetists 22, 34–37. Bernabei, R., Martone, A.M., Vetrano, D.L., et al., 2014. Frailty, physical frailty, sarcopenia: A new conceptual model. Studies in Health Technology and Informatics 203, 78–84. Booth, V., Hood, V., Kearney, F., 2016. Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: A systematic review. JBI Database of Systematic Reviews and Implementation Reports 14, 110–135. Bowen, A., Hazelton, C., Pollock, A., Lincoln, N.B., 2013. Cognitive rehabilitation for spatial neglect following stroke. Cochrane Database of Systematic Reviews (7), CD003586. https://doi.org/10.1002/14651858.CD003586.pub3. Brady, A.O., Straight, C.R., Evans, E.M., 2014. Body composition, muscle capacity, and physical function in older adults: An integrated conceptual model. Journal of Aging and Physical Activity 22, 441–452. Cadore, E.L., Pinto, R.S., Bottaro, M., Izquierdo, M., 2014 Jun. Strength and endurance training prescription in healthy and frail elderly. Aging and Disease 5 (3), 183–195. Cameron, I.D., Dyer, S.M., Panagoda, C.E., et al., 2018. Interventions for preventing falls in older people in care facilities and hospitals. Cochrane Database of Systematic Reviews 9, CD005465. https://doi.org/10.1002/14651858.CD005465.pub4. Carli, F., Gillis, C., Scheede-Bergdahl, C., 2017. Promoting a culture of prehabilitation for the surgical cancer patient. Acta Oncologica 56 (2), 128–133. Colleen G. Canning (2013) Rehabilitation in Parkinson’s Diseasedthe challenge to provide early and ongoing, evidence-based, patient-centred care https://www.researchgate.net/ publication/259353071_Rehabilitation_in_Parkinson_disease_-_the_challenge_to_provide_early_and_ongoing_evidence-based_patient-centred_care (accessed on 26.09.2018). Chan, W.C., Yeung, J.W., Wong, C.S., et al., 2015. Efficacy of physical exercise in preventing falls in older adults with cognitive impairment: A systematic review and meta-analysis. Journal of the American Medical Directors Association 16, 149–154. Chung, C.S.Y., Pollock, A., Campbell, T., Durward, B.R., Hagen, S., 2013. Cognitive rehabilitation for executive dysfunction in adults with stroke or other adult non-progressive acquired brain damage. Cochrane Database of Systematic Reviews (4), CD008391. https://doi.org/10.1002/14651858.CD008391.pub2. Cohen, M.E., Marino, R., 2000. The tools of disability outcomes research functional status measures. Archives of Physical Medicine and Rehabilitation 81, 21–29. Corbetta, D., Sirtori, V., Castellini, G., Moja, L., Gatti, R., 2015. Constraint-induced movement therapy for upper extremities in people with stroke. Cochrane Database of Systematic Reviews (10), CD004433. https://doi.org/10.1002/14651858.CD004433.pub3. Coupar, F., Pollock, A., van Wijck, F., Morris, J., Langhorne, P., 2010. Simultaneous bilateral training for improving arm function after stroke. Cochrane Database of Systematic Reviews (4), CD006432. https://doi.org/10.1002/14651858.CD006432.pub2. Cunningham, D.A., Potter-Baker, K.A., Knutson, J.S., Sankarasubramanian, V., Machado, A.G., Plow, E.B., 2015. Tailoring brain stimulation to the nature of rehabilitative therapies in stroke. Physical Medicine and Rehabilitation Clinics of North America 26 (4), 759–774. Das Nair, R., Cogger, H., Worthington, E., Lincoln, N.B., 2016. Cognitive rehabilitation for memory deficits after stroke. Cochrane Database of Systematic Reviews (9), CD002293. https://doi.org/10.1002/14651858.CD002293.pub3. Demontiero, O., Boersma, D., Suriyaarachchi, P., Duque, G., 2014. Clinical outcomes of impaired muscle and bone interaction. Clinical Reviews in Bone and Mineral Metabolism 12, 86–92.

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Doyle, S., Bennett, S., Fasoli, S.E., McKenna, K.T., 2010. Interventions for sensory impairment in the upper limb after stroke. Cochrane Database of Systematic Reviews (6), CD006331. https://doi.org/10.1002/14651858.CD006331.pub2. Ebersbach, G., Ebersbach, A., Elder, D., et al., 2010. Comparing exercise in Parkinson’s diseasedthe Berlin LSVT® BIG study. Movement Disorders 25, 1902–1908. Forbes, D., Forbes, S.C., Blake, C.M., et al., 2015. Exercise programs for people with dementia. Cochrane Database of Systematic Reviews (12), CD006489. https://doi.org/ 10.1002/14651858.CD006489.pub4. Fox C, Ebersbach G, Ramig L and Sapir S (2012) LSVT LOUD and lSVT BIG: Treatment programs for speech and body movement in Parkinson disease. https://www.hindawi.com/ journals/pd/2012/391946/ (accessed on 26.09.2018). Frankel, J.F., Bean, J.F., Frontera, W.R., 2006. Exercise in the elderly: Research and clinical practice. In: Christian, A. (Ed.), Clinics in geriatric medicine, geriatric rehabilitation. Elsevier Inc., Philadelphia, PA. French, B., Thomas, L.H., Coupe, J., McMahon, N.E., Connell, L., Harrison, J., Sutton, C.J., Tishkovskaya, S., Watkins, C.L., 2016. Repetitive task training for improving functional ability after stroke. Cochrane Database of Systematic Reviews (11), CD006073. https://doi.org/10.1002/14651858.CD006073.pub3. Gill, T.M., Guralnik, J.M., Timothy, M., 2016. Effect of structured physical activity on overall burden and transitions between states of major mobility disability in older persons: Secondary analysis of a randomized controlled trial. Annals of Internal Medicine 20, 833–840. Gill, T.M., Allore, H.G., Hardy, S.E., Guo, Z., 2006. The dynamic nature of mobility disability in older persons. Journal of the American Geriatrics Society 54, 248–254. Gillespie, L.D., Robertson, M.C., Gillespie, W.J., et al., 2012. Interventions for preventing falls in older people living in the community. Cochrane Database of Systematic Reviews (9), CD007146. https://doi.org/10.1002/14651858.CD007146.pub3. Goodwin, V.A., Richards, S.H., Taylor, R.S., Campbell, J.L., 2008. The effectiveness of exercise interventions for people with Parkinson’s disease: A systemic review and metaanalysis. Movement Disorders 23, 631–640. Grossman, D.C., Curry, S.J., Owens, D.K., et al., 2018. Interventions to prevent falls in community-dwelling older adults: US preventative services taskforce recommendation statement. Journal of the American Medical Association 319, 1696–1704. Hayes, M.W., Fung, V., et al., 2010. Current concepts in the management of Parkinson disease. The Medical Journal of Australia 192, 144–149. Hirsch, M.A., Iyer, S.S., Sanjak, M., et al., 2016. Exercise-induced neuroplasticity in human Parkinson’s disease: What is the evidence telling us? Parkinsonism & Related Disorders 22, S78–S81. Hopewell, S., Adedire, O., Copsey, B.J., et al., 2018. Multifactorial and multiple component interventions for preventing falls in older people living in the community. Cochrane Database of Systematic Reviews 7, CD012221. https://doi.org/10.1002/14651858.CD012221.pub2. Horak, F.B., 2006. Postural orientation and equilibrium: What do we need to know about neural control of balance to prevent falls? Age and Ageing 35 (Suppl. 2), ii7–ii11. Howe TE, Rochester L, Neil F, Skelton DA and Ballinger C (2011) Exercise for improving balance in older people. Cochrane Database of Systematic Reviews 11. Huo, Y.R., Suriyaarachchi, P., Gomez, F., et al., 2015. Comprehensive nutritional status in sarco-osteoporotic older fallers. The Journal of Nutrition, Health and Aging 19, 474–480. Johansson, B.B., 2000. Brain plasticity and stroke rehabilitation. Stroke 31, 223–230. Karssemeijer, E.G.A., Aaronson, J.A., Bossers, W.J., et al., 2017. Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis. Ageing Research Reviews 40, 75–83. Kendrick, D., Kumar, A., Carpenter, H., et al., 2016. Exercise for reducing fear of falling in older people living in the community: Cochrane systematic review and meta-analysis. Age and Ageing 45 (3), 345–352. Khan, B., Amatya, B., Elmalik, A., et al., 2016. An enriched environmental programme during neurorehabilitation: A randomized controlled trial. Journal of Rehabilitation Medicine 48 (5), 417–425. Knapen, J., Vancampfort, D., Moriën, Y., et al., 2015. Exercise therapy improves both mental and physical health in patients with major depression. Disability and Rehabilitation 37, 1490–1495. Kohler, F., Connolly, C., Sakaria, A., et al., 2013. Can the ICF be used as a rehabilitation outcome measure? A study looking at the inter- and intra-rater reliability of ICF categories derived from an ADL assessment tool. Journal of Rehabilitation Medicine 45, 881–887. Krogh, J., Hjorthøj, C., Speyer, H., et al., 2017. Exercise for patients with major depression: A systematic review with meta-analysis and trial sequential analysis. BMJ Open 7, e014820. https://doi.org/10.1136/bmjopen-2016-014820. Langhorne, P., Collier, J.M., Bate, P.J., Thuy, M.N.T., Bernhardt, J., 2018. Very early versus delayed mobilisation after stroke. Cochrane Database of Systematic Reviews (10), CD006187. https://doi.org/10.1002/14651858.CD006187.pub3. Law, L.L., Barnett, F., Yau, M.K., et al., 2014. Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review. Ageing Research Reviews 15, 61–75. Lee, I., Park, S., 2013. Balance improvement by strength training for the elderly. Journal of Physical Therapy Science 25, 1591–1593. Lesinski, M., Hortobágyi, T., Muehlbauer, T., et al., 2015. Effects of balance training on balance performance in healthy older adults: A systematic review and meta-analysis. Sports Medicine 45, 1721–1738. Martindale, R.G., McClave, S.A., Taylor, B., Lawson, C.M., 2013. Perioperative nutrition: What is the current landscape? JPEN Journal of Parenteral and Enteral Nutrition 37 (5 Suppl), 5S–20S. Melvin, J.L., 1988. Rehabilitation in the year 2000. American Journal of Physical Medicine & Rehabilitation 67, 197–201. Molton, I.R., Jensen, M.P., 2010. Ageing and disability: Bio psychosocial perspectives. In: Jensen, M.P., Molton, I.R. (Eds.), Ageing with a physical disability: Physical medicine and rehabilitation clinics of North America. Saunders, Pennsylvania, pp. 253–265. Morley, J.E., Vellas, B., Abellan van Kan, G., et al., 2013. Frailty consensus: A call to action. Journal of the American Medical Directors Association 14, 392–397. Morton, N.A., Keating, J.L., Jeffs, K., 2007. Exercise for acutely hospitalised older medical patients. Cochrane Database of Systematic Reviews (1), CD005955. Ramstrand, N., Ramstrand, S., 2010. AAOP state of the science evidence report: The effect of ankle-foot othosis on balanceda systematic review. American Academy of Orthotists and Prosthetists 10, 4–23. Rauch, A., Cieza, A., Stucki, G., 2008. How to apply the International Classification of Functioning Disability and Health (ICF) for rehabilitation management in clinical practise. European Journal of Physical and Rehabilitation Medicine 44, 329–342. Rockwood, K., 1994. Setting goals in geriatric rehabilitation and measuring their attainment. Reviews in Clinical Gerontology 4, 141–149. Rothberg, J.S., 1981. The rehabilitation team: Future direction. Archives of Physical Medicine and Rehabilitation 62, 407–410. Santa Mina, D., Clarke, H., Ritvo, P., Leung, Y.W., Matthew, A.G., Katz, J., et al., 2014. Effect of total-body prehabilitation on postoperative outcomes: A systematic review and meta-analysis. Physiotherapy 100 (3), 196–207. Sherrington, C., Tiedemann, A., Fairhall, N., et al., 2011. Exercise to prevent falls in older adults: An updated meta-analysis and best practice recommendations. New South Wales Public Health Bulletin 22, 78–83. Stroke Unit Trialists’ Collaboration, 2007. Organised inpatient (stroke unit) care for stroke. Cochrane Database of Systematic Reviews 4, CD000197. R. Teasell, N. Foley, N. Hussein, A. Cotoi, The efficacy of stroke rehabilitation, www.ebrsr.com 2018 (accessed on 22.10.2018). Tyson, S.F., Kent, R.M., 2013. Effects of an ankle-foot orthosis on balance and walking after stroke: A systematic review and pooled meta-analysis. Archives of Physical Medicine and Rehabilitation 94, 1377–1385. Wick, E.C., Grant, M.C., Wu, C.L., 2017. Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques: A review. JAMA Surgery 152 (7), 691–697. Winter, J., Hunter, S., Sim, J., Crome, P., 2011. Hands-on therapy interventions for upper limb motor dysfunction following stroke. Cochrane Database of Systematic Reviews (6), CD006609. https://doi.org/10.1002/14651858.CD006609.pub2.

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World Health Organization. International Classification of Impairments, Disabilities. and Handicaps. http://www.who.int/classifications/icf/en/, 1980 (accessed on 06.10.18). World Health Organization 2002 The World Health Report 2002dReducing Risks Promoting Healthy Life. http://www.who.int/whr/2002 (accessed on 22.10.2018). World health organization, World report on health and ageing. http://www.who.int/ageing/publications/world-report-2015/en, 2015 (accessed on 6.10.18).

Further Reading Cadore, E.L., Pinto, R.S., Bottaro, M., Izquierdo, M., 2014. Strength and endurance training prescription in healthy and frail elderly. Aging and Disease 5, 183–195. Cruz-Jentoft, A.J., Baeyens, J.P., Bauer, J.M., et al., European Working Group on Sarcopenia in Older People, 2010. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age and Ageing 39, 412–423. Etzioni, D.A., Liu, J.H., Maggard, M.A., Ko, C.Y., 2003. The aging population and its impact on the surgery workforce. Annals of Surgery 238 (2), 170–177. Fiatarone, M.A., Marks, E., Meredith, C.N., Lipsitz, L.A., Evans, W.J., 1990. High intensity strength training in nonagenarians: Effects on skeletal muscle. Journal of the American Medical Association 263, 3029–3034. Fried, L.P., Tangen, C.M., Walston, J., et al., 2001. And cardiovascular health study collaborative research group, frailty in older adults: Evidence for a phenotype. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56, M146–M156. Guralnik, J.M., Ferrucci, L., Balfour, J.L., Volpato, S., Di Iorio, A., 2011. Progressive versus catastrophic loss of the ability to walk: Implications for the prevention of mobility loss. Journal of the American Geriatrics Society 49, 1463–1470. https://www.movementdisorders.org/MDS-Files1/PDFs/Rating-Scales/MDS-UPDRS_English_FINAL.pdf. https://www.parkinsons.org.uk/professionals/resources/unified-parkinsons-disease-rating-scale-updrs. Kus, S., Müller, M., Strobl, R., et al., 2011. Patient goals in post-acute geriatric rehabilitation: Goal attainment is an indicator for improved functioning. Journal of Rehabilitation Medicine 43, 156–161. Papathansiou, J., 2018. Postoperative rehabilitation of elderly patients. In: Masiero, S.C.U. (Ed.), Rehabilitation medicine for elderly patients practical issues in geriatrics. Springer, Cham, pp. 469–475. PD Non Motor Symptoms Questionnaire, https://www.movementdisorders.org/MDS-Files1/PDFs/MDS-UPDRS-Rating-Scales/NMSQ.pdf. Phu, S., Boersma, D., Duque, G., 2015. Exercise and sarcopenia. Journal of Clinical Densitometry 18, 488–492. Rockwood, K., 1994. Setting goals in geriatric rehabilitation and measuring their attainment. Reviews in Clinical Gerontology 4, 141–149. Silver, J.K., Baima, J., Mayer, R.S., 2013. Impairment-driven cancer rehabilitation: An essential component of quality care and survivorship. CA: A Cancer Journal for Clinicians 63, 295–317. Taaffe, D.R., 2006. Sarcopenia: Exercise as a treatment strategy. Australian Family Physician 35, 130–134. Topp, R., Ditmyer, M., King, K., Doherty, K., Hornyak 3rd, J., 2002. The effect of bed rest and potential of prehabilitation on patients in the intensive care unit. AACN Clinical Issues 13 (2), 263–276. Valkenet, K., van de Port, I.G., Dronkers, J.J., et al., 2011. The effects of preoperative exercise therapy on postoperative outcome: A systematic review. Clinical Rehabilitation 25, 99–111.

Renal Cystic Disease in the Elderly Mo´nica Furlano and Roser Torra Balcells, Universitat Autónoma de Barcelona, Barcelona, Spain; and Nephrology department, Fundació Puigvert, Barcelona, Spain © 2020 Elsevier Inc. All rights reserved.

Introduction Diagnostic Tools Genetic Testing Radiologic Imaging Ultrasound Computed tomography Magnetic resonance imaging Angiography Nuclear medicine techniques Percutaneous aspiration or biopsy Cystic Kidney Disorders Simple Cysts Pathology Pathogenesis Clinical manifestations Imaging Treatment Medullary Sponge Kidney Pathology Pathogenesis Clinical manifestations Imaging Treatment Acquired Cystic Disease of the Kidneys in Chronic Kidney Disease Pathology Pathogenesis Clinical manifestations Imaging Treatment Autosomal Dominant Polycystic Kidney Disease Pathology Pathogenesis Clinical manifestations Hypertension and left ventricular hypertrophy Nephrolithiasis and obstruction Laboratory findings Diagnosis Hepatic cysts Intracranial aneurysms Other associated clinical manifestations Carcinoma in polycystic kidneys Clinical course Treatment Autosomal Dominant Tubulointerstitial Kidney Disease Pathology Pathogenesis Clinical manifestations Imaging Treatment Solitary Multilocular Renal Cysts Cystic Disease of the Renal Sinus Pelvicalyceal Diverticula

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Renal Cystic Disease in the Elderly Renal Cysts Associated With Drug Treatments Neoplastic Renal Cysts References Further Reading Relevant Websites

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Introduction Renal cysts result from different processes in a very heterogeneous group of diseases, with involvement of both genetic and nongenetic factors. They are categorized as simple or complex, unilateral or bilateral, and benign or malignant, and their prevalence increases with age. The introduction of next-generation sequencing techniques has revolutionized genetic analysis in recent decades and enabled the analysis of potential disease-causing mutations in patients with atypical cystic kidney disease (Hildebrandt et al., 2011). Different classifications have been proposed to organize the knowledge of renal cystic disease, taking into account genetic tests, radiologic tools, pathologic findings, and clinical presentation. A classification of the most prevalent renal cystic diseases in the elderly is shown in Table 1. Some renal cystic diseases are excluded from this classification because they are seen most frequently in individuals younger than 65 years (e.g., nephronophthisis, Joubert syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome, Alström syndrome, etc.).

Diagnostic Tools Genetic Testing The genetic analysis includes Sanger-based single-gene analysis, kidney panel genes, whole-exome sequencing, and whole-genome sequencing. The most useful genetic test in specialized centers is kidney panels, including hundreds of genes involved in kidney diseases (Bullich et al., 2018). Identification of the causative variant can be helpful for testing at-risk relatives, especially those with mild or doubtful clinical features. Nowadays, it is important to take into account modifier genes, the presence of mosaicism, and epigenetic and environmental factors which may explain some atypical phenotypes and may also be significant in the transplant setting (Ars and Torra, 2017).

Radiologic Imaging Ultrasound Ultrasound provides a rapid way to assess renal location and size without radiation exposure. It is the recommended follow-up examination for renal cystic disease. Simple cysts can be identified as anechoic lesions, with a simple thin wall without septations. Ultrasound usually identifies renal masses as cystic or solid, but sometimes hemorrhagic cysts may have increased echogenicity and could be defined as solid, generating doubts regarding the diagnosis that may require further evaluation using a contrast-enhanced imaging tool. The Bosniak classification of cystic renal masses is widely used for ultrasound or computed tomography (CT) scanning (Table 2) (Israel and Bosniak, 2005).

Table 1

Classification of cystic kidney disorders in the elderly

Simple cysts Medullary sponge kidney Acquired cystic kidney disease in chronic kidney disease Familial cystic disease Autosomal dominant polycystic kidney disease (ADPKD) Autosomal dominant tubulointerstitial kidney disease (previously known as medullary cystic kidney disease) Solitary multilocular renal cyst Cystic disease of the renal sinus Pelvicalyceal diverticula Renal cysts associated with drug treatments Neoplastic cysts

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Bosniak classification of cystic renal masses by ultrasound or CT scanning

Bosniak

Class

Features on imaging

Comment

Class I

Simple benign cyst

Majority of asymptomatic cystic lesions

Class II

Benign cyst

Class IIF

Probable benign cyst

Class III

Indeterminate cystic lesions

Class IV

Presumed malignant cystic masses

Round or oval Uniform density < 20 HU Unilocular No perceptible wall No contrast enhancement One or two nonenhancing septa Calcifications in the wall or septum Hyperdense lesions 3 cm One or more of the following: - Thick, irregular borders - Irregular calcifications - Thickened or enhancing septa - Multilocular form - Uniform wall thickening - Small nonenhancing nodules Appear malignant Heterogeneous cysts Shaggy, thickened walls or enhancing nodules

“Perceived” enhancement resulting from contrast within capillaries of septa About 40% are neoplastic MRI may improve characterization

Appearances result from necrosis and liquefaction of a solid tumor or a tumor growing in the wall

Adapted from Israel, G. M. and Bosniak, M. A. (2005). An update of the Bosniak renal cyst classification system. Urology 66(3), 484–488.

Computed tomography CT is the gold standard for the evaluation of renal masses. CT has the advantages that contrast can be used to evaluate masses and complex renal cysts and that images can be reconstructed retrospectively at any level. Non-contrast imaging allows the evaluation of calcium deposition and hemorrhage, which cannot be assessed after the administration of intravenous contrast material. However, the fact that CT imaging entails a significant radiation exposure to the patient must be taken into account when CT is requested. Limitations of CT include the effects of metal artifacts and allergy to intravenous contrast, and CT is also of limited value in patients with impaired renal function. If contrast administration is mandatory in patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, intravenous saline and/or bicarbonate solution should be administered to reduce the risk of contrast-induced nephropathy (Baldari et al., 2015).

Magnetic resonance imaging Magnetic resonance imaging (MRI) is rarely the first examination requested for routine evaluation of renal cysts. In certain situations, however, such as a patient with intravenous contrast allergy, reduced renal function, or a hyperdense renal cyst with suspicion of malignancy, MRI may be safer or more accurate than CT. Additionally, MRI can assess extension into perirenal tissues and organs and venous and collecting system involvement by renal cell carcinoma (RCC). High-field MRI is, therefore, a valid alternative to CT in the evaluation of renal masses, avoiding exposure to ionizing radiation (Baldari et al., 2015). However, the administration of gadolinium during MRI has been strongly linked to nephrogenic systemic fibrosis, a fibrosing disorder of the skin that develops in patients with reduced eGFR, particularly those receiving dialysis. As a result, gadolinium-based imaging must be avoided in patients with an eGFR < 30 mL/min/1.73 m2.

Angiography Following the development of the high-resolution and scanning techniques, CT and MRI have replaced conventional angiography for the analysis of renal vascularization in patients with renal incidental findings suggestive of RCC and simple or complex renal cysts. However, angiography is still the gold standard test for the diagnosis of renal artery stenosis, fibromuscular dysplasia, large-vessel vasculitis, and renal infarction in elderly patients with a secondary renal pathology in addition to renal cystic disease.

Nuclear medicine techniques Nuclear scintigraphy evaluates kidney function as well as kidney anatomy, providing an accurate assessment of reduction in renal function in chronic kidney diseases, including renal cystic lesions. Dimercaptosuccinic acid scintigraphy was formerly used for the study of renal pseudotumors but has largely been replaced by CT. Positron emission tomography (PET) scanning uses

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radiopharmaceuticals labeled with radioactive positron emitters, most often 18F-labeled fluorodeoxyglucose (18F-FDG), with a uniform distribution according to metabolic activity. 18F-FDG PET/CT is a safe diagnostic tool in combination with clinical and biochemical parameters for identification of kidney cyst infection in patients with autosomal dominant polycystic kidney disease (ADPKD).

Percutaneous aspiration or biopsy Renal biopsy is not recommended for healthy patients with a simple renal cyst. The number of situations in which needle biopsy is used to evaluate an indeterminate renal mass or renal cyst is likely to grow since such findings are increasingly being identified on CT and MRI.

Cystic Kidney Disorders Simple Cysts Simple renal cysts are commonly observed in normal kidneys; they are especially frequent in patients > 65 years old and their incidence increases with age. Not only are more renal parenchyma cysts encountered with aging, but it also needs to be borne in mind that the size of the cysts increases with age (Eknoyan, 2009). Most simple renal cysts are detected incidentally. They are benign lesions, can be single or multiple and rarely present complications or require treatment. Their prevalence varies widely according to the population studied and whether high-resolution imaging modalities are used. Renal cyst formation was twice as likely in men as in women. The prevalence of cortical or medullary cysts was higher among kidney donors aged 50–75 years than in those aged 18–49 years (Rule et al., 2012). The principal clinical issue is to distinguish simple or multiple cysts from renal cysts associated with ADPKD, hypernephroma, or malignant renal cysts.

Pathology A single epithelial cell layer, filled with a serous fluid that is essentially an ultrafiltrate of plasma, usually lines simple renal cysts. The size of renal cysts is variable and simple cysts do not communicate with the renal pelvis. They can protrude into the renal cortex or be located in the corticomedullary junction or the renal medulla.

Pathogenesis The simple renal cysts likely originate from distal convoluted tubules or collecting ducts, but the pathogenic mechanisms remain unknown. In recent studies, age, smoking, atherosclerotic vascular disease, renal dysfunction, and hypertension have been associated with the development of renal cysts. The composition of simple renal cyst fluid resembles an ultrafiltrate of plasma, as proven by the intravenous infusion of small molecular tracers; the fluid composition differs from that of ADPKD cysts, which is enriched with specific proteins involved in their development (Lai et al., 2008).

Clinical manifestations Simple renal cysts are typically asymptomatic. Very infrequently, patients present with abdominal or flank pain and fever with evidence of cyst infection. Although simple renal cysts do not communicate with the renal pelvis, microhematuria is observed in some patients. When simple cysts are located near the hilus, it is likely that a calyceal or renal pelvis obstruction or hydronephrosis will be observed. Unless obstruction is present, simple renal cysts do not cause a reduction in renal function. Certain studies have reported an association between renal cysts and hypertension, red blood cell abnormalities, higher albumin excretion, and hyperfiltration. Hypertension in elderly patients with simple renal cysts is most commonly due to essential hypertension. Infection of a simple renal cyst is a rare cause of renal abscess, but the clinical presentation is characterized by high fever, flank pain, faintness, dizziness, and sometimes septicemia. The pathogens that have been reported in simple renal cyst infections are Escherichia coli, Staphylococcus, and Proteus. Urine cultures are frequently negative. Infected cysts have irregular borders with internal echoes on ultrasound. If the ultrasound pattern is indeterminate, CT should be performed to achieve a better understanding of the nature of the cyst.

Imaging Ultrasound is the recommended imaging tool for the identification and follow-up of simple cystic lesions. Further evaluation is not necessary if all of these criteria are satisfied, since the likelihood of malignancy is very low. The CT diagnostic criteria for benign simple cysts consist in a similar density to water, a thin or imperceptible wall, a sharp interface with renal parenchyma, and no significant increase in density after intravenous contrast injection. CT findings suggestive of renal cyst malignancy include thickened or irregular walls, presence of septa, and enhancement after contrast injection. Based on imaging tools (ultrasound and CT), renal cysts have been classified into four widely used categories by Bosniak (Table 2). Benign simple renal cysts, classified as Bosniak class I, have no contrast enhancement and present thin smooth walls without calcifications. Simple renal cysts may be numerous within one or both kidneys. When both kidneys are large and diffusely involved, the critical clinical issue is to distinguish multiple simple cysts from ADPKD. This distinction is usually made on the basis of family history, presence of end-stage renal disease (ESRD), and renal imaging patterns. In the presence of chronic kidney

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Management of renal cysts according to the Bosniak classification

Bosniak class

Management

Class I and II

No further intervention required. If class II is not easily distinguishable from class IIF, follow-up imaging should be performed. In addition to ultrasound, another study may be required for further characterization, such as contrast-enhanced CT or MRI. Surveillance with CT every 6–12 months. Performance of another contrast-enhanced study for further characterization of the cyst. Treatment options include surveillance, fine-needle biopsy, or surgery with partial nephrectomy. Most category III lesions are either removed or closely followed up. Lesions require surgery, with 85%–100% being malignant.

Class IIF Class III

Class IV

Adapted from Israel, G. M. and Bosniak, M. A. (2005). An update of the Bosniak renal cyst classification system. Urology 66(3), 484–488 and Israel, G. M. and Silverman, S. G. (2011). The incidental renal mass. Radiologic Clinics of North America 49 (2), 369–383.

disease (CKD), ADPKD always shows enlargement of bilateral total kidney volume (TKV) whereas kidneys with CKD and simple cysts are usually normal or small in size.

Treatment The majority of simple renal cysts require no treatment, but it is important to bear in mind the implications of the Bosniak classification when deciding upon cyst management (Table 3). A painful simple cyst is treated with painkillers or, if the renal function is normal, a nonsteroidal antiinflammatory drug for 3–5 days may be useful. When the pain is persistent, percutaneous aspiration with ultrasound guidance, often with instillation of a sclerosing agent into the cyst, will improve the symptoms. On the other hand, in large cysts sized from 5 to 20 cm, laparoscopic or retroperitoneoscopic cyst unroofing is more efficient and offers better results than percutaneous aspiration/sclerotherapy (Bas et al., 2015).

Medullary Sponge Kidney Medullary sponge kidney (MSK), or precalyceal canalicular ectasia, is a benign congenital abnormality. It is characterized by tubular dilatation of the collecting ducts and cyst formation strictly confined to the medullary pyramids, especially to their inner, papillary portions. The numerous small cysts range in diameter from 1 to 8 mm and if the kidney is cut, it presents a spongy appearance. MSK is one of several common causes of medullary nephrocalcinosis, which is defined as the deposition of calcium salts in the medulla of the kidney. The prevalence of MSK is one out of every 5000 individuals, but among patients with calcified renal stones it increases to 12%– 20%. The mean age at diagnosis is 27 years but the clinical features may appear for the first time in elderly patients (Gambaro et al., 2013).

Pathology MSK may involve one or more renal papillae in one or both kidneys. These dilated tubules may be surrounded by a normalappearing medullary interstitium or, in cases of more prominent cystic disease, inflammatory cell filtration and interstitial fibrosis. The renal size is usually normal or slightly enlarged. The cortex of the kidney is normal and unaffected.

Pathogenesis MSK is considered to be an acquired sporadic disorder. In rare cases, strong evidence has been provided for familial clustering of MSK with an autosomal dominant pattern of inheritance (Fabris et al., 2013). Progression of tubular ectasia and development of new tubular dilatation and medullary cysts have been documented in some patients.

Clinical manifestations MSK is an asymptomatic disease unless complications such as nephrolithiasis, hematuria, renal failure, or infection arise. Most patients are diagnosed in their fourth or fifth decade, but infrequently the diagnosis is not made until the sixth or eighth decade of life. The association with renal hypercalciuria, distal tubular acidosis, and hypocitraturia triggers the formation of calcium phosphate and/or calcium oxalate stones.

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In addition to the morphologic abnormalities of the precalyceal ducts, MSK is associated with other abnormalities of the lower tubule, such as a decrease in renal concentrating ability, distal renal tubular acidosis, and hypocitraturia. In most such cases, the acidification defect is not associated with overt systemic acidosis but the risk of mineral bone defects is well documented. Renal failure seems to be related to renal infections and the formation of renal stones. Other causes of medullary nephrocalcinosis include hyperparathyroidism, hypervitaminosis D, milk-alkali syndrome, and other hypercalcemic or hypercalciuric states (Gambaro et al., 2013).

Imaging Abdominal plain radiography reveals radiopaque concretions in the medulla suggestive of the diagnosis of MSK. Renal ultrasound shows characteristic echogenic medullary pyramids, but the diagnosis is easily missed by an inexperienced operator. In the past, intravenous urography was the principal test for study of the dilated medullary collecting ducts. Nowadays, however, contrastenhanced CT scan shows the distinctive papillary blush and allows the detection of related complications such as hydronephrosis, renal stones, and pyelonephritis (Koraishy et al., 2014).

Treatment There is no specific treatment for this entity. The treatment of complications such as nephrolithiasis and urinary tract infection is the same as it would be in the general population. In the case of calcium stones, the initial recommendations include high fluid intake, low sodium intake diet, and normal calcium diet. Thiazides and inorganic phosphates are an effective treatment in preventing lithiasis (Fabris et al., 2010)

Acquired Cystic Disease of the Kidneys in Chronic Kidney Disease The acquired cystic disease of the kidneys is a term used to describe the renal cystic degeneration in patients with prolonged ESRD, associated with multiple and bilateral renal cysts that are usually < 0.5 cm in diameter but can be as large as 2–3 cm. This phenomenon is likely to be related to the uremic state rather than to be a consequence of dialysis procedures. The role of uremia is also supported by the fact that regression of these cystic changes can occur after successful renal transplantation. Renal cysts increase progressively throughout the duration of dialysis. After  10 years on dialysis, around 50%–80% of patients are affected, suggesting that the duration of CKD is a major risk factor for renal cyst development.

Pathology The cysts, which are usually smaller than in ADPKD, tend to occur in the renal cortex, but the renal medulla may also be involved. They may be lined by a simple cuboidal epithelium or by a hyperplastic multilayered epithelium with papillary projections. Deposition of oxalate crystals is frequently observed in the renal interstitium, in the walls of the cysts, and in the lumen.

Pathogenesis The cysts are limited to the kidney (unlike in ADPKD), suggesting that local, intrarenal events are of primary importance. The cyst fluid is an ultrafiltrate of the plasma secreted into the cyst. Compensatory renal hypertrophy is driven by activation of protooncogenes and release of growth factors, which, over a prolonged period of time, can lead to tubular hyperplasia and cyst formation. In addition, one of these proto-oncogenes has been implicated in the pathogenesis of RCC in acquired cystic disease (Oya et al., 2005). Tubular obstruction by deposition of oxalate, ischemia, fibrosis and toxic metabolites have all been proposed to play a role in the pathogenesis. Nephron loss of any cause leads to compensatory hypertrophy in the remaining normal nephrons. The cysts may stabilize or regress after renal transplantation, a setting in which the level of growth factors is reduced due to the restoration of normal renal function.

Clinical manifestations Most patients with acquired cystic disease of the kidneys are asymptomatic, but some develop symptoms, with hematuria, lumbar pain, and urinary tract infection. The number of patients with cysts, as well as the number and size of the cysts and the kidney volume, increases with the duration of dialysis. Complications of acquired cystic disease of the kidneys include intracystic bleeding, gross hematuria, retroperitoneal hemorrhage, and malignant transformation. Rupture of a cystic blood vessel occurs in up to 50% of cases at some time and can be the cause of unexplained flank or back pain in hemodialysis patients. Although most episodes are asymptomatic, local pain and gross hematuria may occur. Less often, in patients with very large cysts, the hemorrhage may extend into the perirenal area and be sufficiently severe to induce hypotension or death. Heparinization during hemodialysis and the use of anticoagulants to prevent the clotting of arteriovenous fistulas may play a contributory role. In some cases, fever, femoral nerve compression, and obstructive jaundice have been observed. The reported incidence of RCC as a complication of acquired cystic disease varies. Malignancy generally develops after at least 8– 10 years of dialysis, although it can occur after a shorter interval. Screening for acquired cystic disease and RCC in patients in dialysis is controversial. However, screening is recommended in patients who have been on dialysis for 3 or more years and do not have a shortened life expectancy (Sarasin et al., 1995).

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Imaging Ultrasound, CT scan, and MRI are useful imaging techniques for the initial diagnosis of acquired cystic disease. It seems reasonable to follow small renal masses (< 3 cm) by serial ultrasound, CT or MRI examinations aimed at the early diagnosis of malignancies.

Treatment Only the complications may require treatment. Surgical intervention is indicated for large solid tumors with invasive features or when there is evidence of progressive tumor enlargement. Retroperitoneal bleeding may require therapeutic embolization or nephrectomy in some cases, but usually conservative treatment will control this complication.

Autosomal Dominant Polycystic Kidney Disease ADPKD is the most important inherited kidney disease and is a major burden on public health. ADPKD is characterized by renal cyst development and progressive loss of renal function. In recent decades, great advances have been achieved in the study of developmental renal cysts and the clinical features of ADPKD, increasing dramatically our understanding of the disease. The life expectancy of patients with ADPKD has been prolonged by advances in preventive health decisions, dialysis techniques, and kidney transplantation. ADPKD is a systemic disease that affects 1 in 2000 individuals worldwide. Patients with ADPKD account for nearly 10% of European patients on dialysis or living with a renal transplant. In the Unites Staes, Australia, and New Zealand, 1 in 20 patients with ESRD has ADPKD and approximately 70% of patients with ADPKD progress to ESRD at a median age of 58 years (Spithoven et al., 2014; Reule et al., 2014).

Pathology The kidney involvement is diffuse, symmetric and bilateral, with progressive enlargement of innumerable fluid-filled cysts of the renal cortex and medulla, but numerous cases with asymmetric renal involvement have been described. Lai et al. (2008) identified a large number of distinct proteins in the ADPKD cystic fluid, with hundreds of protein precursors. The main proteins present include vitronectin, clusterin, SERPIN family proteins, hemopexin, fetuin-A, and complement components. These proteins may offer mechanistic explanations for cyst development or serve as diagnostic markers or as potential targets for future ADPKD therapies (Lai et al., 2008). Unlike in idiopathic conditions, in ADPKD the interplay among the new cellular components of cyst fluid in association with tubule basement membrane thickening and interstitial inflammation causes the renal architecture to deform very slowly over time. In late stages of the disease, the enlargement of the kidneys is massive, with thick bands of fibrotic tissue sequestering the remaining functional renal parenchyma.

Pathogenesis ADPKD is a genetically heterogeneous disease caused by functional deficiency in polycystin 1 (PC1; encoded by PKD1) or polycystin 2 (PC2; encoded by PKD2). PC1 is involved in cell cycle regulation and intracellular calcium transport and localizes in the primary cilia of renal epithelial cells. PC2 is a member of the family of voltage-activated calcium channels and colocalizes to the primary cilia of renal epithelial cells. Intracellular calcium is low in the ADPKD cells and this may cause a proliferative response and play a significant role in fluid secretion. Additionally, cyst formation itself is accompanied by inflammation, ischemia, cytokine production, macrophage activation, and renal tubular obstruction, which promote further cyst formation. Recently, new genes have been reported to be involved in ADPKD, such as GANAB and DNAJB11. Mutations in GANAB cause a mild phenotype, with a few large cysts in the kidneys and polycystic liver disease (PLD) but without progression to ESRD (Porath et al., 2016). Mutations in DNAJB11 have been described in patients, with a mild phenotype with an overlap between the clinical features of ADPKD and those of autosomal dominant tubulointerstitial kidney disease (ADTKD) (Cornec-Le Gall et al., 2018).

Clinical manifestations The clinical diagnosis of ADPKD may be made at any time in life, but it is more frequently made during family screening or as an incidental finding on imaging studies. The most frequent symptom is abdominal, flank, or back pain, which is present in the majority of ADPKD patients. The pain can be caused by various situations such as cyst bleeding or gross hematuria, perinephric hematoma, acute urinary tract infection (pyelonephritis, infected cysts, perinephric abscess), or renal stones. ADPKD patients on dialysis present an increase in episodes of diverticulitis that may simulate the abdominal pain caused by renal cyst infection.

Hypertension and left ventricular hypertrophy Arterial hypertension is one of the most common early manifestations of ADPKD and is highly prevalent in these patients compared with those who have other renal diseases. Ambulatory blood pressure monitoring may help in the early diagnosis of hypertension, because early onset of hypertension may lead to earlier onset of ESRD. Activation of the renin–angiotensin–aldosterone system (RAAS) seems to play a major role in the pathogenesis of hypertension in ADPKD patients, as indicated by the fact that use of angiotensin-converting enzyme (ACE) inhibitors ameliorates the target organ damage such as left ventricular hypertrophy (Perrone et al., 2011). The HALT clinical trial contributed in establishing a target blood pressure in ADPKD patients. In general, the recommended target is < 140/90 mmHg with an ambulatory target of around 130–135/80–85 mmHg. However, in young patients (< 50 years) with normal renal function, the HALT A study demonstrated that a very strict target blood pressure of around 95–

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110/60–75 mmHg delivered benefits in terms of end organ damage as compared with a standard control of < 130/80 mmHg (Schrier et al., 2014a; Torres et al., 2014). Changes in lifestyle, weight loss, regular exercise, cessation of smoking and limiting salt intake may help to avoid the development of hypertension. Since the RAAS activation is the main cause of hypertension in ADPKD, ACE inhibitors or the angiotensin II receptor antagonists (ARBs) must be the first-line treatment. Calcium channel blockers (because they reduce the intracellular calcium concentration) and diuretics (because they may activate the RAAS) should be reserved for cases of resistant hypertension and for those patients with CKD and hydrosaline overload; thus beta-blockers are likely to be the second-line treatment (Ars et al., 2014; Chapman et al., 2015).

Nephrolithiasis and obstruction The prevalence of nephrolithiasis is approximately twice as high in ADPKD patients as in the general population. Uric acid stones are more frequent than calcium oxalate or calcium phosphate stones. Metabolic abnormalities predisposing to stone formation and the increased incidence of stones are influenced by the distorted renal anatomy, urinary stasis, reduced urinary pH, decreased ammonium excretion, and low urinary citrate concentration (Torres et al., 2007). CT scanning is the best imaging tool for identification of small or radiolucent kidney stones and for differentiation of stones from tumors, clot, or renal calcification. Potassium citrate is the treatment of choice for urinary stones. Extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy can be used in most ADPKD patients without increased complications compared with the same procedures in the general population. Flexible ureterorenoscopy with laser fragmentation has also been used safely and effectively, with less risk of an effect on renal function (Mufti and Nalagatla, 2010).

Laboratory findings The presence of albuminuria or proteinuria in ADPKD patients is an important biomarker of CKD progression and a prognostic indicator for increase in renal volume. Hyperuricemia have been associated with earlier onset of hypertension, enlargement of the TKV, and increased risk of ESRD. A variety of urinary and serum predictors not currently used in routine clinical practice are associated with renal and cardiovascular disease progression in ADPKD, examples including MCP-1, NGAL, IL-8, kidney injury molecule-1, heart-type fatty-acid binding protein, vascular endothelial growth factor, and angiopoietin 1 (Schrier et al., 2014b). It is remarkable that in ADPKD patients the capacity to dilute the urine is normal, whereas the capacity to concentrate the urine is diminished. On the other hand, patients are not able to acidify the urine and have a reduced capacity for ammonium formation, but this defect may also be present in other patients with advanced CKD.

Diagnosis Imaging tools Ultrasound is used as a screening test in presymptomatic patients (Fig. 1). The modified Ravine criteria have been established to improve diagnosis by ultrasound in ADPKD patients according to patient age and the number of renal cysts (Table 4) (Pei et al., 2009). When a normal or indeterminate kidney image is observed on ultrasound, MRI or contrast-enhanced CT should be performed to provide a better diagnosis (Fig. 2). In recent years, the Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease investigators has demonstrated a clear relationship between decline in renal function and TKV. A helpful classification has been

Fig. 1

Polycystic kidney by ultrasound.

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Modified Ravine ultrasound criteria

Age

Criteria

15–39 40–59 60

3 cysts, unilateral or bilateral 2 cysts in each kidney 4 cysts in each kidney

Adapted from Pei, Y., Obaji, J., Dupuis, A., Paterson, A. D., Magistroni, R., Dicks, E., et al. (2009). Unified criteria for ultrasonographic diagnosis of ADPKD. Journal of the American Society of Nephrology 20(1), 205–212.

proposed for typical radiologic ADPKD cases according to age, eGFR, and height-adjusted TKV (Irazabal et al., 2015). It has been observed that TKV is an important prognostic biomarker for prediction of decline in renal function and can help to assess rapid disease progression and therefore to guide choice of treatment. Genetic testing Nowadays, kidney panels for genetic diagnosis include PKD1, PKD2, GANAB, and DNAJB11 genes, which is very helpful not only for the diagnosis of ADPKD but also for the differential diagnosis from other less frequent cystic diseases and atypical ADPKD cases (Bullich et al., 2018). In patients aged > 65 years, the main indication for genetic testing is to establish diagnosis in doubtful cases. High phenotypic variability has been observed in ADPKD patients and is attributed to the presence of allelic heterogeneity as well as gene-modifier effects. It is important to take into account the fact that 75% of the PKD1 gene is reiterated on the same chromosome with a high degree of homology (pseudogenes), which complicates the analysis; for this reason it is important to refer genetic testing to laboratories with the appropriate expertise. Study of a large cohort of ADPKD patients has shown that the type of PKD1 mutation correlates strongly with renal survival: the median age of ESRD was 55 years for carriers of truncating pathogenic variants and 67 years for carriers of nontruncating variants (Cornec-Le Gall et al., 2013). It is important to consider that genetic testing has been proposed as a predictive tool in ADPKD patients, through implementation of the PRO-PKD score to identify patients with rapid disease progression (Ars et al., 2014; Cornec-Le Gall et al., 2016).

Hepatic cysts PLD is the most common association with ADPKD, occurring in > 80% of cases. Recently numerous genes have been described in PLD. PLD in ADPKD is defined by the presence of at least 20 simple cysts in the liver (Lantinga et al., 2013). It has been observed that women develop more cysts and at an earlier age than men, and this situation is worsened by the use of estrogen drugs or in the postmenopausal period. The majority of the affected patients are asymptomatic, but nearly 20% have been reported to have hepatomegaly, liver cyst ruptures, hemorrhages, or infections. Hepatic insufficiency is rare, but it has been reported as a complication of long-standing polycystic involvement of the liver and may require liver transplantation.

Fig. 2

Polycystic kidney disease by magnetic resonance.

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Liver cyst infections manifest with localized pain, fever, elevated sedimentation rate, and leukocytosis, suggesting inflammation. It should be taken into account that increases in gamma-glutamyltransferase, aspartate aminotransferase, alkaline phosphatase, and CA 19.9 may occur during an infection episode, but that the diagnosis of cyst infection cannot be ruled out if these liver tests are normal (Lantinga et al., 2015). The recommended tool for diagnosis of liver cyst infection is CT or MRI. When signs of infection persist after 3–5 days on antibiotics, 18F-FDG PET should be performed in order to locate the infected cyst. A prolonged course of antibiotics, combined with percutaneous cyst drainage when necessary, provides the best treatment for infected liver cysts. However, recurrence of liver cyst infection is frequent. Somatostatin analogs, such as octreotide and lanreotide, have been shown to be able to reduce or stabilize the liver volume in severe cases of PLD over a period of 1–2 years but mTOR inhibitors do not demonstrate efficacy in PLD (Hogan et al., 2012; Neijenhuis et al., 2015). The ADPKD guidelines recommend avoidance of estrogens as well as avoidance of drugs that stimulate cAMP accumulation (e.g., caffeine). Partial hepatectomy to reduce liver volume is indicated only when the patient is highly symptomatic and should be performed by a surgeon with expertise in PLD owing to the high morbidity of these surgical procedures (Ars et al., 2014; Chapman et al., 2015).

Intracranial aneurysms The association of intracranial aneurysms (ICAs) and ADPKD occurs in about 9%–12% of patients with ADPKD compared with 2%–3% in the general population. The risk of rupture correlates with the location and size of the aneurysm, a family history of ICA, hypertension, cocaine abuse, estrogen therapies, and anticoagulant treatments. MRI angiography without contrast is the recommended imaging tool for diagnosis of ICAs. Regular screening is not indicated for all ADPKD patients without a family history of ICAs because many ICAs have a low risk of rupture and require no treatment based on the fact that the risk of the therapy exceeds the risk of rupture. If MRA is not feasible, CT angiography is an alternative imaging tool. Unruptured ICAs < 7 mm should be managed in collaboration with neurosurgery experts and re-evaluated every 6–24 months. Prophylactic repair of unruptured ICAs is recommended if there is a bleeding risk. All symptomatic ICAs require surgical clipping of the neck of the aneurysm (Ars et al., 2014; Chapman et al., 2015).

Other associated clinical manifestations Cyst formation has been described in other organs: seminal vesicle, pancreas, arachnoid membrane and spinal meningeal. The majority of cysts in other organs are asymptomatic and do not justify routine screening (Chapman et al., 2015; Torra et al., 2008).

Carcinoma in polycystic kidneys The incidence of RCC in ADPKD patients is not increased as compared with patients with other kidney diseases, although in some studies investigation of removed ADPKD kidneys revealed a 5%–8% incidence of RCC (Jilg et al., 2013). If a solid mass is observed on routine ultrasound with speckled calcifications, a CT scan or contrast-enhanced MRI should be performed. In ADPKD patients aged > 50 years with gross hematuria lasting longer than 1 week, imaging should be performed to screen for kidney cancer (Ars et al., 2014; Chapman et al., 2015).

Clinical course ADPKD patients have a prolonged period of stable renal function followed by a slow decline in renal function according to the increase in the TKV. PKD2 patients have a better outcome than PKD1 patients. The recent approval of tolvaptan for treatment in ADPKD patients will probably ameliorate the decline in renal function and result in better outcomes in the near future.

Treatment Until recently no therapy was available for ADPKD patients. As already mentioned, tolvaptan has recently been approved for use in ADPKD patients with evidence of rapid disease progression, which is not usually observed in elderly patients. Tolvaptan is a selective vasopressin V2 receptor antagonist that decreases the intracellular cAMP in the kidney cyst cell proliferation and reduces the total kidney enlargement. Although tolvaptan is not considered as an initial treatment in ADPKD patients aged > 65 years, its development is an important achievement that will change the history of the disease, increasing renal life expectancy and improving quality of life (Torres et al., 2012, 2017). When ADPKD patients reach ESRD, renal replacement therapy, including dialysis and renal transplantation, are the treatment options. Peritoneal dialysis is a good choice, but it is important to take into account the presence of abdominal wall hernias, reduced intra-abdominal space, or colonic diverticula. Bleeding of the urinary tract secondary to heparinization during dialysis may occur but it can be managed by means of low or regional heparinization. However, removal of the kidneys prior to transplantation may be appropriate in special circumstances, including space restrictions, recurrent cyst infection, symptomatic nephrolithiasis, severe bleeding, intractable pain, and suspicion of malignant renal cysts (Chapman et al., 2015). Finally, when ADPKD is diagnosed in an elderly patient, relatives at risk with childbearing potential should receive genetic counseling.

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Autosomal Dominant Tubulointerstitial Kidney Disease ADTKD is the new name for a rare cause of ESRD, previously known as adult medullary cystic disease. In 2014, KDIGO (Kidney Disease: Improving Global Outcomes) proposed this new terminology for a group of families with ESRD and an autosomal dominant pattern of inheritance, unspecific symptoms, and wide variability in the age of onset of ESRD. These diseases are clinically similar but are caused by mutations in at least five different genes: MUC1, UMOD, HNF1B, REN, and SEC61A1. There is no evidence to establish the prevalence of the different types of ADTKD, but ADTKD-UMOD and ADTKD-MUC1 are the most frequent forms, as reported in a large cohort (Ayasreh et al., 2018; Eckardt et al., 2015).

Pathology The kidneys are small with multiple cysts in the corticomedullary junction and along the medullary collecting ducts. The usual findings on renal histology in patients with ADTKD consist in: interstitial fibrosis, tubular atrophy, thickening and lamellation of tubular basement membranes, possibly tubular dilatation (microcysts), and negative immunofluorescence for complement and immunoglobulins.

Pathogenesis The locus of MCKD (medullary cystic kidney disease) 1 was first identified on chromosome 1q21. Although the locus of the gene involved in MCKD1 was subsequently refined, it remained unknown for a long time, until mutation in MUC1 was demonstrated to be responsible for the disease in 2013 (Kirby et al., 2013). On the other hand, mutations in the gene UMOD have been identified in so-called MCKD2 patients. ADTKD-UMOD is caused by pathogenic variants in the UMOD gene, which encodes uromodulin, the most abundant protein in human urine. Clarification of the role that uromodulin plays in renal physiology remains a challenge; some known functions are protection against urinary tract infections, prevention of renal stones, ensuring water impermeability, and creating the countercurrent gradient. The resulting defect in urinary concentration and consequent mild volume depletion can secondarily increase proximal reabsorption of uric acid as a possible cause of hyperuricemia. ADTKD-MUC1 is caused by a mutation in the MUC1 gene. Recently, Ayasreh et al. (2018) reported that MUC1 mutations are the main cause of ADTKD and that affected patients present worse renal survival than patients with UMOD variants. ADTKD-HNF1B encodes hepatocyte nuclear factor 1b, a transcription factor that regulates multiple genes expressed in the kidney, liver, and pancreas, but the mechanism of tubulointerstitial fibrosis remains unknown (Faguer et al., 2011). ADTKD-REN encodes preprorenin, which is subsequently proteolytically processed to prorenin and renin. Prorenin modulates various signaling pathways in the kidney through its interaction with the prorenin receptor. However, the mechanisms by which REN mutations produce tubulointerstitial fibrosis remain unclear (Eckardt et al., 2015).

Clinical manifestations ADTKD is characterized by progressive loss of kidney function, bland urinary sediment, absent-to-mild albuminuria/proteinuria, severe hypertension during the early stages, normal or small-sized kidneys on ultrasound, and nocturia (owing to loss of renal concentration ability). The median age at diagnosis was 32 and 40 years for ADTKD-UMOD and ADTKD-MUC1 families, respectively. The prevalence of hyperuricemia has been reported to be significantly higher in ADTKD-UMOD individuals than in those with ADTKD-MUC1, at 87% and 54% respectively (Ayasreh et al., 2018). Late onset of the disease, during the seventh and eighth decades of life, has been observed in some families, and ADTKD should therefore be considered in the differential diagnosis of CKD even in the elderly. In some elderly patients, the clinical course has been unusually prolonged. Certain diagnostic criteria have been established for ADTKD: (a) Criteria for suspecting a diagnosis of ADTKD: - Family history compatible with autosomal dominant inheritance of CKD fulfilling the clinical characteristics. - In the absence of a positive family history of CKD fulfilling the clinical characteristics, demonstration of compatible histology on kidney biopsy or extrarenal manifestations compatible with HNF1B mutations or history of early-onset hyperuricemia and/or gout. (b) Criteria for establishing the diagnosis of ADTKD: - Family history compatible with autosomal dominant inheritance of CKD fulfilling the clinical characteristics and compatible histology in at least one affected family member. - Demonstration of a mutation in one of the five genes in an affected individual or at least one family member.

Imaging Ultrasound may reveal a normal kidney size with or without cysts, small hyperechogenic kidneys, or hyperechogenic kidneys with cortical cysts. The increased echogenicity of kidneys may be comparable with the liver density.

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Treatment The treatment of medullary cystic disease is merely supportive, with good control of renal risk factors, e.g., arterial hypertension, hyperuricemia, diabetes, obesity, and smoking. Diuretics should be avoided in ADTKD patients as they may aggravate hyperuricemia and volume depletion. Liberal water intake is recommended to compensate for possible urinary concentration defects. Unnecessary low-salt diet restriction is not recommended for ADTKD-UMOD and ADTKD-REN patients as it may aggravate hyperuricemia in the former and volume depletion in the latter. Fludrocortisone should not be used in those patients with declining kidney function, hypertension, hyperkalemia, or edema against the possible risk of aggravating interstitial fibrosis (Eckardt et al., 2015; Bockenhauer and Jaureguiberry, 2016).

Solitary Multilocular Renal Cysts Solitary multilocular renal cysts constitute an encapsulated renal mass composed of multiple cysts of varying size that do not communicate with the renal pelvis. A bimodal distribution has been observed, with half of the cases occurring in children under 4 years and half in adults (Freire and Remer, 2009). The pathogenesis of multilocular cysts is unknown but they are considered benign neoplasms that arise from the metanephric blastema. Multilocular cysts are typically solitary and unilateral. The clinical features are usually an abdominal mass, flank pain, or hematuria. Multilocular cysts may replace an entire pole and enlarge the kidney. Rarely they produce urinary tract infection or kidney stones. Multilocular cysts are usually detected on ultrasound as complex masses with well-defined cysts mixed with highly echogenic stroma. CT scan permits visualization of this type of cyst and renal malignancy must be excluded (Israel and Bosniak, 2005). Typically, the prognosis of solitary multilocular cysts is excellent. In some cases, where malignancy cannot be ruled out, partial nephrectomy is required.

Cystic Disease of the Renal Sinus Renal sinus cysts are benign and usually asymptomatic. Cysts involving the renal pelvis are classified as parapelvic or peripelvic according to their site of origin. Parapelvic cysts originate in the renal parenchyma and extend into, and primarily expand within, the renal sinus. Peripelvic cysts originate in sinus structures which presumably represent mostly lymphatic collections (Krishna et al., 2018). They are usually discovered during the course of evaluations for conditions such as urinary tract infections, nephrolithiasis, hypertension, and prostatism. Occasionally, parapelvic cysts are the only finding during the course of evaluations for otherwise unexplained lumbar or flank pain. Of note, parapelvic cysts are a common finding in adult males with classical Fabry disease. The therapeutic approach should be conservative, since this is a benign entity.

Pelvicalyceal Diverticula Pelvicalyceal diverticula are cystic cavities that contain urine and are lined by transitional epithelium. There is no consensus regarding the cause of pelvicalyceal diverticula, although most investigators have favored a congenital over an acquired origin. They are usually asymptomatic, but some patients may present flank pain, hematuria, nephrolithiasis, or infection. Differential diagnoses that must be distinguished from pelvicalyceal diverticula on imaging include hydrocalyx, simple cyst, parapelvic cyst, tubercular cavity, papillary necrosis, and renal tumor. Surgical intervention is indicated rarely, when conservative management of the complications fails (Waingankar et al., 2014).

Renal Cysts Associated With Drug Treatments Novel therapeutic agents recently introduced for the treatment of cancer have several unusual side effects. Recently, an apparent causal association between crizotinib treatment and renal cyst development emerged during clinical trials in anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC). While close monitoring is recommended, dosing modification is not generally necessary, allowing continuation of the treatment (Schnell et al., 2015). Other drugs, such as lithium, may induce renal disease with microcysts in the renal medulla and cortex, although the most important manifestation is direct injury to the renal tubules due to lithium salt. This unusual manifestation of chemotherapy and other drugs should be recognized, particularly by radiologists, to avoid inappropriate treatment decisions.

Neoplastic Renal Cysts Malignant transformation is the most feared complication of acquired cystic kidney disease, especially in uremic patients. Compared with sporadic RCC, acquired cystic kidney disease associated with RCC is characterized by a younger age of onset, male predominance, more frequent multicentric and bilateral manifestations, and a lower frequency of metastases. CT scan or MRI with contrast is the best imaging tool to characterize the suspected malignant lesions, with use of the Bosniak classification for differential diagnosis. Recent studies suggest a role for 18F-FDG PET/CT as an “imaging biomarker” in monitoring response to molecular targeting therapy in patients with metastatic renal cancer (Jouret et al., 2011). It is important to take into account other

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renal masses such as angiomyolipomas, oncocytomas, metastatic disease, renal abscess, adenomas, and RCC. Acquired cystic disease associated with RCC was incorporated into the 2016 WHO Classification of Tumors of the Urinary System and Male Genital Tract as a distinct entity and is reportedly the most common RCC arising in ESRD. Usually, when Bosniak class III and IV appear to be diagnostic, interventional therapeutic options may be required according to the decisions of the multidisciplinary medical team (Gallardo et al., 2018).

References Ars, E., Torra, R., 2017. Rare diseases, rare presentations: Recognizing atypical inherited kidney disease phenotypes in the age of genomics. Clinical Kidney Journal 10 (5), 586–593. Ars, E., Bernis, C., Fraga, G., Martínez, V., Martins, J., Ortiz, A., et al., 2014. Spanish guidelines for the management of autosomal dominant polycystic kidney disease. Nephrology, Dialysis, Transplantation 29. Ayasreh, N., Bullich, G., Miquel, R., Furlano, M., Ruiz, P., Lorente, L., et al., 2018. Autosomal dominant Tubulointerstitial kidney disease: Clinical presentation of patients with ADTKD-UMOD and ADTKD-MUC1. American Journal of Kidney Diseases 72 (3), 411–418. Baldari, D., Capece, S., Mainenti, P.P., Tucci, A.G., Klain, M., Cozzolino, I., et al., 2015. Comparison between computed tomography multislice and high-field magnetic resonance in the diagnostic evaluation of patients with renal masses. Quantitative Imaging in Medicine and Surgery 5 (5), 691–699. Bas, O., Nalbant, I., Can Sener, N., Firat, H., Yesil, S., Zengin, K., et al., 2015. Management of renal cysts. Journal of the Society of Laparoendoscopic Surgeons 19 (1) e2014.00097. Bockenhauer, D., Jaureguiberry, G., 2016. HNF1B-associated clinical phenotypes: The kidney and beyond. Pediatric Nephrology 31 (5), 707–714. Bullich, G., Domingo-Gallego, A., Vargas, I., Ruiz, P., Lorente-Grandoso, L., Furlano, M., et al., 2018. A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases. Kidney International 94 (2), 363–371. Chapman, A.B., Devuyst, O., Eckardt, K.-U., Gansevoort, R.T., Harris, T., Horie, S., et al., 2015. Autosomal-dominant polycystic kidney disease (ADPKD): Executive summary from a kidney disease: Improving global outcomes (KDIGO) controversies conference. Kidney International 88, 17–27. Cornec-Le Gall, E., Audrezet, M.-P., Chen, J.-M., Hourmant, M., Morin, M.-P., Perrichot, R., et al., 2013. Type of PKD1 mutation influences renal outcome in ADPKD. Journal of the American Society of Nephrology 24 (6), 1006–1013. Cornec-Le Gall, E., Audrezet, M.-P., Rousseau, A., Hourmant, M., Renaudineau, E., Charasse, C., et al., 2016. The PROPKD score: A new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology 27 (3), 942–951. Cornec-Le Gall, E., Olson, R.J., Besse, W., Heyer, C.M., Gainullin, V.G., Smith, J.M., et al., 2018. Monoallelic mutations to DNAJB11 cause atypical autosomal-dominant polycystic kidney disease. American Journal of Human Genetics 102 (5), 832–844. Eckardt, K.-U., Alper, S.L., Antignac, C., Bleyer, A.J., Chauveau, D., Dahan, K., et al., 2015. Autosomal dominant tubulointerstitial kidney disease: Diagnosis, classification, and managementda KDIGO consensus report. Kidney International 88 (4), 676–683. Eknoyan, G., 2009. A clinical view of simple and complex renal cysts. Journal of the American Society of Nephrology 20 (9), 1874–1876. Fabris, A., Lupo, A., Bernich, P., Abaterusso, C., Marchionna, N., Nouvenne, A., et al., 2010. Long-term treatment with potassium citrate and renal stones in medullary sponge kidney. Clinical Journal of the American Society of Nephrology 5 (9), 1663–1668. Fabris, A., Lupo, A., Ferraro, P.M., Anglani, F., Pei, Y., Danza, F.M., et al., 2013. Familial clustering of medullary sponge kidney is autosomal dominant with reduced penetrance and variable expressivity. Kidney International 83 (2), 272–277. Faguer, S., Decramer, S., Chassaing, N., Bellanne-Chantelot, C., Calvas, P., Beaufils, S., et al., 2011. Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood. Kidney International 80 (7), 768–776. Freire, M., Remer, E.M., 2009. Clinical and radiologic features of cystic renal masses. American Journal of Roentgenology 192 (5), 1367–1372. Gallardo, E., Mendez-Vidal, M.J., Perez-Gracia, J.L., Sepulveda-Sanchez, J.M., Campayo, M., Chirivella-Gonzalez, I., et al., 2018. SEOM clinical guideline for treatment of kidney cancer (2017). Clinical & Translational Oncology 20 (1), 47–56. Gambaro, G., Danza, F.M., Fabris, A., 2013. Medullary sponge kidney. Current Opinion in Nephrology and Hypertension 22 (4), 421–426. Hildebrandt, F., Benzing, T., Katsanis, N., 2011. Ciliopathies. The New England Journal of Medicine 364 (16), 1533–1543. Hogan, M.C., Masyuk, T.V., Page, L., Holmes 3rd, D.R., Li, X., Bergstralh, E.J., et al., 2012. Somatostatin analog therapy for severe polycystic liver disease: Results after 2 years. Nephrology, Dialysis, Transplantation 27 (9), 3532–3539. Irazabal, M.V., Rangel, L.J., Bergstralh, E.J., Osborn, S.L., Harmon, A.J., Sundsbak, J.L., et al., 2015. Imaging classification of autosomal dominant polycystic kidney disease: A simple model for selecting patients for clinical trials. Journal of the American Society of Nephrology 26 (1), 160–172. Israel, G.M., Bosniak, M.A., 2005. An update of the Bosniak renal cyst classification system. Urology 66 (3), 484–488. Jilg, C.A., Drendel, V., Bacher, J., Pisarski, P., Neeff, H., Drognitz, O., et al., 2013. Autosomal dominant polycystic kidney disease: Prevalence of renal neoplasias in surgical kidney specimens. Nephron. Clinical Practice 123 (1–2), 13–21. Jouret, F., Lhommel, R., Beguin, C., Devuyst, O., Pirson, Y., Hassoun, Z., et al., 2011. Positron-emission computed tomography in cyst infection diagnosis in patients with autosomal dominant polycystic kidney disease. Clinical Journal of the American Society of Nephrology 6 (7), 1644–1650. Kirby, A., Gnirke, A., Jaffe, D.B., Baresova, V., Pochet, N., Blumenstiel, B., et al., 2013. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nature Genetics 45 (3), 299–303. Koraishy, F.M., Ngo, T.-T.T., Israel, G.M., Dahl, N.K., 2014. CT urography for the diagnosis of medullary sponge kidney. American Journal of Nephrology 39 (2), 165–170. Krishna, S., Schieda, N., Flood, T.A., Shanbhogue, A.K., Ramanathan, S., Siegelman, E., 2018. Magnetic resonance imaging (MRI) of the renal sinus. Abdominal Radiology (New York) 43 (11), 3082–3100. Lai, X., Bacallao, R.L., Blazer-Yost, B.L., Hong, D., Mason, S.B., Witzmann, F.A., 2008. Characterization of the renal cyst fluid proteome in autosomal dominant polycystic kidney disease (ADPKD) patients. Proteomics. Clinical Applications 2 (7–8), 1140–1152. Lantinga, M.A., Gevers, T.J.G., Drenth, J.P.H., 2013. Evaluation of hepatic cystic lesions. World Journal of Gastroenterology 19 (23), 3543–3554. Lantinga, M.A., Drenth, J.P.H., Gevers, T.J.G., 2015. Diagnostic criteria in renal and hepatic cyst infection. Nephrology, Dialysis, Transplantation 30 (5), 744–751. Mufti, U.B., Nalagatla, S.K., 2010. Nephrolithiasis in autosomal dominant polycystic kidney disease. Journal of Endourology 24 (10), 1557–1561. Neijenhuis, M.K., Gevers, T.J.G., Nevens, F., Hogan, M.C., Torres, V.E., Kievit, W., et al., 2015. Somatostatin analogues improve health-related quality of life in polycystic liver disease: A pooled analysis of two randomised, placebo-controlled trials. Alimentary Pharmacology & Therapeutics 42 (5), 591–598. Oya, M., Mikami, S., Mizuno, R., Marumo, K., Mukai, M., Murai, M., 2005. C-jun activation in acquired cystic kidney disease and renal cell carcinoma. The Journal of Urology 174 (2), 726. Pei, Y., Obaji, J., Dupuis, A., Paterson, A.D., Magistroni, R., Dicks, E., et al., 2009. Unified criteria for ultrasonographic diagnosis of ADPKD. Journal of the American Society of Nephrology 20 (1), 205–212. Perrone, R.D., Abebe, K.Z., Schrier, R.W., Chapman, A.B., Torres, V.E., Bost, J., et al., 2011. Cardiac magnetic resonance assessment of left ventricular mass in autosomal dominant polycystic kidney disease. Clinical Journal of the American Society of Nephrology 6 (10), 2508–2515.

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Porath, B., Gainullin, V.G., Cornec-Le Gall, E., Dillinger, E.K., Heyer, C.M., Hopp, K., et al., 2016. Mutations in GANAB, encoding the glucosidase IIa subunit, cause autosomaldominant polycystic kidney and liver disease. American Journal of Human Genetics 98 (6), 1193–1207. Reule, S., Sexton, D.J., Solid, C.A., Chen, S.-C., Collins, A.J., Foley, R.N., 2014. ESRD from autosomal dominant polycystic kidney disease in the United States, 2001–2010. American Journal of Kidney Diseases 64 (4), 592–599. Rule, A.D., Sasiwimonphan, K., Lieske, J.C., Keddis, M.T., Torres, V.E., Vrtiska, T.J., 2012. Characteristics of renal cystic and solid lesions based on contrast-enhanced computed tomography of potential kidney donors. American Journal of Kidney Diseases 59 (5), 611–618. Sarasin, F.P., Wong, J.B., Levey, A.S., Meyer, K.B., 1995. Screening for acquired cystic kidney disease: A decision analytic perspective. Kidney International 48 (1), 207–219. Schnell, P., Bartlett, C.H., Solomon, B.J., Tassell, V., Shaw, A.T., de Pas, T., et al., 2015. Complex renal cysts associated with crizotinib treatment. Cancer Medicine 4 (6), 887–896. Schrier, R.W., Abebe, K.Z., Perrone, R.D., Torres, V.E., Braun, W.E., Steinman, T.I., et al., 2014a. Blood pressure in early autosomal dominant polycystic kidney disease. The New England Journal of Medicine 371 (24), 2255–2266. Schrier, R.W., Brosnahan, G., Cadnapaphornchai, M.A., Chonchol, M., Friend, K., Gitomer, B., et al., 2014b. Predictors of autosomal dominant polycystic kidney disease progression. Journal of the American Society of Nephrology 25 (11), 2399–2418. Spithoven, E.M., Kramer, A., Meijer, E., Orskov, B., Wanner, C., Caskey, F., et al., 2014. Analysis of data from the ERA-EDTA registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease. Kidney International 86 (6), 1244–1252. Torra, R., Sarquella, J., Calabia, J., Martí, J., Ars, E., Fernández-Llama, P., et al., 2008. Prevalence of cysts in seminal tract and abnormal semen parameters in patients with autosomal dominant polycystic kidney disease. Clinical Journal of the American Society of Nephrology 3 (3), 790–793. Torres, V.E., Harris, P.C., Pirson, Y., 2007. Autosomal dominant polycystic kidney disease. Lancet (London, England) 369 (9569), 1287–1301. Torres, V.E., Chapman, A.B., Devuyst, O., Gansevoort, R.T., Grantham, J.J., Higashihara, E., et al., 2012. Tolvaptan in patients with autosomal dominant polycystic kidney disease. The New England Journal of Medicine 367 (25), 2407–2418. Torres, V.E., Abebe, K.Z., Chapman, A.B., Schrier, R.W., Braun, W.E., Steinman, T.I., et al., 2014. Angiotensin blockade in late autosomal dominant polycystic kidney disease. The New England Journal of Medicine 371 (24), 2267–2276. Torres, V.E., Chapman, A.B., Devuyst, O., Gansevoort, R.T., Perrone, R.D., Koch, G., et al., 2017. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. The New England Journal of Medicine 377 (20), 1930–1942. Waingankar, N., Hayek, S., Smith, A.D., Okeke, Z., 2014. Calyceal diverticula: A comprehensive review. Revista de Urología 16 (1), 29–43.

Further Reading Johnson, R., Feehally, F., Floege, J., Tonelli, M., 2015. Comprehensive clinical nephrology, 5th edn. Elsevier Saunders. Lanktree, M., Chapman, A., 2017. New treatment paradigms for ADPKD: Moving towards precision medicine. Nature Reviews. Nephrology 13 (12), 750–768. Moch, H., Cubilla, A.L., Humphrey, P.A., Reuter, V.E., Ulbright, T.M., 2016. The 2016 WHO classification of tumors of the urinary system and male genital organs-part a: Renal, penile, and testicular tumors. European Urology 70 (1), 93–105. Schrier, R.W., 2015. Manual of nephrology, 8th edn. Wolters Kluwer. Skorecki, K., Chertow, G., Marsden, P., Taal, M., Yu, A., 2015. Brenner & Rector’s the kidney, 10th edn. 2 vols. Elsevier.

Relevant Websites https://kdigo.org/guidelines/ckd-evaluation-and-management/dKidney Disease: Improving Global Outcomes. http://www.pkdb.mayo.edu/dAutosomal Dominant Polycystic Kidney Disease Mutation Database: PKDB. PKD Foundation. https://kdigo.org/wp-content/uploads/2017/02/KDIGO-ADPKD-Supplemental-Full-Report-FINAL.pdfdKidney Disease: Improving Global Outcomes. http://www.senefro.org/contents/webstructure/Grupos%20de%20Trabajo/Guia_PQRAD.pdfdSpanish Society of Nephrology. https://www.uptodate.com/contents/simple-and-complex-renal-cysts-in-adultsdWolters Kluwer. http://uroweb.org/individual-guidelines/oncology-guidelines/dEuropean Association of Nephrology. https://ghr.nlm.nih.gov/dGenetics Home Reference. https://www.omim.org/dOnline Mendelian Inheritance in Man, Johns Hopkins University. http://www.orpha.net/dWebsite of information on rare diseases and orphan drugs.

Rheumatoid Arthritis Keith Lim, Matthew Jiang, and Thilinie De Silva, Department of Rheumatology, Western Health, Melbourne University Department of Medicine and Australian Institute of Musculoskeletal Science, Footscray, VIC, Australia © 2020 Elsevier Inc. All rights reserved.

Introduction Epidemiology Risk Factors Genetic Susceptibility Smoking Infections Occupational Exposures Pathophysiology Clinical Features Articular Manifestations Extra-Articular Manifestations Cutaneous Ocular Pulmonary Neurological Hematological Elderly Onset RA Differential Diagnoses Osteoarthritis Crystal Arthritis Polymyalgia Rheumatica (PMR) Remitting Seronegative Symmetrical Synovitis With Pitting Edema (RS3PE) Psoriatic Arthritis (PsA) Reactive Arthritis/Viral Arthritis Other Systemic Autoimmune Diseases Diagnosis Investigations Serological Markers Rheumatoid factor (RF) Anti-citrullinated protein antibody (ACPA) Inflammatory Markers Imaging X-ray Ultrasound MRI Management Pre-Treatment Evaluation Pharmacological Treatment csDMARDs Methotrexate Leflunomide Sulfasalazine Hydroxychloroquine Other csDMARDs Monitoring for csDMARDs Anti-Inflammatory Medications Nonsteroidal anti-inflammatories (NSAIDs) Glucocorticoids bDMARDs Pretreatment evaluation TNF inhibition Co-stimulation inhibition B-cell inhibition IL-6 inhibition

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Rheumatoid Arthritis Targeted Synthetic DMARDs (tsDMARDs) Vaccinations in Patients on bDMARDs/tsDMARDs Non Pharmacological Treatment Role of Surgery Geriatric Syndromes in RA Other Clinical Issues Associated With RA in Elderly Patients Cardiovascular Disease (CVD) Infection Osteoporosis Patient Perspective on Disease Conclusion References Further Reading

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Introduction Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder characterized by inflammation of synovial joints, autoantibody production and other systemic manifestations. This article will cover a review of the topic including the pathophysiology, clinical features, diagnosis and management of RA, and will discuss some of the issues related to RA in elderly patients.

Epidemiology The worldwide prevalence of RA varies by country and ethnicity but is estimated to be around 1% (Spector, 1990). The prevalence is about three times higher in women (Srikanth et al., 2005). The incidence of RA peaks between the ages of 50–75, but can occur at any age. With an aging population worldwide, there is an increasing number of elderly patients living with RA.

Risk Factors Genetic Susceptibility Genetic factors are thought to have an important role in the development of RA. Concordance rates between monozygotic twins have been shown to be between 12% and 15% (Aho et al., 1986; Silman et al., 1993). An increased risk has also been demonstrated in family members of those with RA, with offspring of parents with RA having a relative risk of 3.02 for developing RA, and 4.64 for siblings (Hemminki et al., 2009). The overall contribution of genetic factors to the pathogenesis of RA is estimated to be up to 60%. The apparent partial role of genetics in the development of RA supports the theory that environmental and/or epigenetic factors are also involved in the pathogenesis. A number of genetic factors have been identified that may be implicated in the pathogenesis of RA. The most important of these appears to be a set of human leucocyte antigen (HLA) alleles (HLA DRB1*01 and HLA DRB1*04), which code for major histocompatibility complex (MHC) molecules, which present antigens to immune cells. These alleles are known as the “shared epitope” and confer the highest susceptibility for developing RA (Karami et al., 2019). The shared epitope refers specifically to a sequence of five amino acids in residues 70–74 of the HLA-DRb chain. The exact pathogenic mechanism is unclear, however most hypotheses relate to the increased presentation of arthritogenic antigens, such as citrullinated proteins. Presence of the shared epitope has also been shown to be associated with increased disease severity (Van Zeben et al., 1991).

Smoking Smoking is the most important environmental risk factor for developing RA. The risk is roughly doubled in men and 1.4 times in women (Chang et al., 2014). The conferred risk is even higher in those with the shared epitope. It is thought that the combination of these two risk factors may contribute to the development of anti-citrullinated protein antibodies (ACPA). There are several other hypotheses regarding the role of smoking in RA development, such as an increased numbers of inflammatory cells and cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) (Arnson et al., 2010).

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Infections The role of infections in RA pathogenesis remains unclear. There have been proposed associations with various viral and bacterial infections. The most commonly implicated bacterial pathogen is Porphyromonas gingivalis, which is a major causative factor in periodontitis, with the association between periodontal disease and RA being widely reported (Bartold et al., 2005). It possesses the enzyme, peptidylarginine deaminase (PADI), which has the ability to citrullinate proteins, potentially leading to formation of ACPAs (Rosenstein et al., 2004). Potential associations with other viruses including Epstein-Barr virus (EBV) (Ferrell et al., 1981) and human T-lymphotrophic virus 1 (HTLV-1) (Sato et al., 1991) have also been investigated, however no convincing causative link has been identified.

Occupational Exposures Certain occupational exposures may increase the risk of developing RA with the strongest association being for silica exposure (Khuder et al., 2002).

Pathophysiology The pathogenesis of RA is still incompletely understood, however there have been significant advances in our understanding of the underlying molecular mechanisms which have led to more targeted therapies for RA. As discussed earlier, the role of genetic factors such as the shared epitope are thought to be an important primary factor. The lungs are also a central focus in our current understanding of RA pathogenesis, as smoking and other pulmonary stressors have been shown to increase the production of citrullinated proteins. The interaction of environmental factors in those who are genetically susceptible is thought to lead to a loss of tolerance to certain self-antigens (such as citrullinated proteins), which then transitions towards development of inflammatory arthritis and other inflammatory manifestations. However, it is still not clear why the systemic loss of tolerance leads predominantly to synovial inflammation. The adaptive immune response is thought to be central in the pathogenesis of RA, particularly given the recognition of antigen presentation and antibody formation as important factors (Fig. 1). At a cellular level, T cells (particularly type 1T-helper cells) are known to have a central role and are present in the inflamed synovium of individuals with RA. Blockade of T-cell co-stimulation via cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with abatacept has been shown to be an effective treatment for RA. Humoral immunity through B-cells also appears has an important role, particularly in relation to the formation of autoantibodies. This is supported by the efficacy of rituximab in treating RA, which blocks CD-20 which is a surface marker present on B-cells, leading to reduction in circulating B-cells (McInnes, 2011). The cells of the innate immune system, chiefly macrophages (as well as neutrophils and mast cells) are also important mediators of inflammation and synovitis in RA. The interaction between immune cells involves a complex interplay of various receptors and cytokines (McInnes, 2011). Several extracellular cytokines and intracellular signaling pathways have been identified to be fundamental in the pathogenesis of RA. Identification of these pathways has subsequently led to the development of targeted treatments. Some of the more important cytokines are tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and the intracellular signaling pathway involving Janus kinase (JAK) (McInnes, 2011; Guo et al., 2018). On a structural level, synovial proliferation is one the principal changes, which is mediated by various cells, with synovial-type fibroblasts being the most important. These cells also contribute to cartilage damage through various factors such as metalloproteinases that degrade the collagen structure of cartilage. Articular cartilage has a limited ability to repair itself, and this is further impaired by the effect of cytokines on chrondocytes leading to apoptopsis. Eventually, bone erosions occur in the setting of prolonged inflammation, and this process is driven primarily by osteoclasts. Osteoclast differentiation is stimulated by various proinflammatory cytokines such as TNF-alpha and receptor activator of NF-kB ligand (RANKL).

Clinical Features Articular Manifestations The classic presentation of rheumatoid arthritis is joint pain and swelling, typically in a symmetrical distribution involving the small joints of the hands and feet. The most commonly affected joints are the wrists, metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the hands, and the metatarsophalangeal (MTP) joints of the feet. Characteristic deformities can develop over time, including ulnar deviation and/or palmar subluxation of the MCP joints, swan neck and Boutonniere deformities of the fingers and squaring of the thumb. The larger joints such as the elbow, shoulders and knees can also be affected. In the axial skeleton, cervical spine involvement, particularly at the atlanto-axial joint is common, however involvement of the thoracolumbar spine is rare. Inflammation of tendons, or tenosynovitis can also occur. Morning stiffness is a common feature and prolonged

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Lymph node

B cell Th0

Th17

Th1 Rheumatoid factor autoantibodies

Plasma cell

Th17

Plasma cell

Inflammation

Th17 Macrophage

Neutrophil TNF-α, Interleukins, VEGF, Chemokines Synovium

Fibroblast-like synoviocyte

MMPs, Chemokines, Prostaglandins, Nitric oxide

Fig. 1 The adaptive immune pathway plays an important role in the pathway to RA, with interactions between dendritic cells, T cells, and B cells, which occur in the lymph nodes. This leads to production of autoantibodies against citrullinated peptides. Within the synovium and adjacent bone, the innate and adaptive immune pathways combine, resulting in inflammation and tissue damage. Th0 type 0 helper T cell, Th1 type 1 helper T cell, Th17 type 17 helper T cell, TNF-a tumour necrosis factor a, MMP matrix metalloproteinase, VEGF vascular endothelial growth factor.

morning stiffness can be an useful indicator of inflammatory joint disease in contrast to degenerative joint symptoms which are usually worse with activity and towards the end of the day. Uncontrolled joint inflammation eventually leads to erosions and joint damage, with subsequent joint deformity, pain and loss of function (Fig. 2). Another important clinical phenotype is that of palindromic rheumatism, which is characterized by episodes of inflammatory mono- or oligoarthritis, with intervening asymptomatic periods. A proportion of these patients may progress to develop RA, however it can also be a precursor for other inflammatory diseases such as systemic lupus erythematosus (SLE). Presence of ACPAs may be useful for predicting which patients with palindromic rheumatism will progress to RA (Katz and Russell, 2012).

Extra-Articular Manifestations Extra-articular manifestations in RA are reported to occur in up to 40% of patients (Cimmino et al., 2000). They are more common in individuals who are positive for rheumatoid factor (RF) or have the shared epitope.

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Typical hand deformities in rheumatoid arthritis.

Cutaneous The most common extra-articular feature is the development of rheumatoid nodules (present in about 30%), which histologically are characterized by central fibrinoid necrosis surrounded by fibroblasts. Nodules occur predominantly in those who are RF positive and are commonly located on pressure areas such as the elbows. It is thought be related to small vessel vasculitis. The other clinical sequelae of small vessel vasculitis in RA is cutaneous ulceration which typically occurs in the lower limbs.

Ocular Sicca symptoms occur in about 10% of individuals, representing a form of secondary Sjogren’s syndrome. Other ocular manifestations include scleritis, episcleritis, and ulcerative keratitis.

Pulmonary As discussed previously, the lungs are thought to be a major contributor to the pathogenesis of RA. There are several pulmonary manifestations of RA, of which interstitial lung disease (ILD) is the most common. ILD causes clinically relevant disease in about 5% of patients (Kim et al., 2009) but subclinical disease is thought to be more common (in up to 35%). Histologically, a usual interstitial pneumonia (UIP) pattern is the most common form. The presence of ILD, particularly the UIP pattern, carries a poorer prognosis with an increased risk of disease progression. Risk factors for developing RA-ILD include smoking, RF/ACPA positivity and male gender. More recently, a mutation in the MU5B promotor gene, which is associated with the development of idiopathic pulmonary fibrosis (IPF) has been found to increase the risk of developing RA-ILD (odds ratio of 3.1) (Juge et al., 2018). The risk associated with medications such as methotrexate is still unclear. Pulmonary rheumatoid nodules are quite specific for RA and histologically have similar features to subcutaneous nodules. Pleural involvement can also occur, with manifestations including pleural effusions and pneumothorax.

Neurological Neurological manifestations such as peripheral neuropathy are uncommon, and can present as a sensorimotor neuropathy or mononeuritis multiplex, with carpal tunnel syndrome being the most common manifestations.

Hematological Hematological manifestations are typically cytopenias. Anemia is the most common and is generally multifactorial in nature, with anemia of chronic disease often occurring secondary to active inflammation, as well as bone marrow suppression which can be related to medications such as methotrexate. Neutropenia can occur in isolation, but also as part of Felty’s syndrome, which is characterized by seropositive disease, neutropenia and splenomegaly. Lymphadenopathy can also occur, typically in the form of benign hyperplasia in active RA. Individuals with RA have roughly double the risk of developing lymphoma (additional increased risk in those with severe disease), with the most common type being large B-cell lymphoma (Franklin et al., 2006).

Elderly Onset RA Elderly onset rheumatoid arthritis (EORA), also known as late-onset RA is generally defined as the onset of disease above the age of 60–65 years (Sugihara and Harigai, 2016; Tan et al., 2017). This is in comparison to younger-onset RA (YORA) which generally presents in the 30–55 year old age group.

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It has been recognized that EORA is more likely to present with atypical features such as a polymyalgia rheumatica (PMR) type syndrome, lymphadenopathy and neuropathy. In contrast to YORA, there are a higher proportion of males with EORA and as expected there are a higher number of comorbidities at presentation. They are less likely to be RF positive, however the disease severity and progression has been shown to be similar in some cohorts (Tan et al., 2017; Mueller et al., 2013). It has also been shown that patients with EORA receive less intensive treatment despite similar disease activity (Radovits et al., 2009).

Differential Diagnoses In the evaluation of patients with joint symptoms who are suspected of having RA, other differential diagnoses should be considered.

Osteoarthritis Osteoarthritis (OA) is a predominantly degenerative form of arthritis which has an increased prevalence with age. It can also present as a symmetrical polyarthritis, but typically has less inflammatory features such as morning stiffness and joint swelling. Joint effusions can still occur, particularly in knee OA. Involvement of the distal interphalangeal (DIP) joints with Heberden’s nodes is more typical in OA, however secondary OA in patients with RA is common. Radiographically, erosions are uncommon in OA.

Crystal Arthritis Gout and pseudogout (also known as calcium pyrophosphate deposition disease [CPPD]) typically present as an acute mono- or oligoarthritis of large joints. The 1st MTP joint and the knee being the most common joints involved in gout. In CPPD, the knee and wrist are the most common joints affected. Both conditions can develop into a more chronic form with polyarthritis that may resemble RA. The prevalence of CPPD increases with age and is associated with the presence of osteoarthritis. An important diagnostic feature is the presence of crystals (urate or calcium pyrophosphate) on synovial fluid analysis.

Polymyalgia Rheumatica (PMR) PMR typically presents with pain and stiffness involving the hip and shoulder girdle. The periarticular structures (tendons, bursa) have been shown to involved, rather than the musculature. It is almost exclusively a disease of the elderly (over the age of 50) and is associated with giant cell arteritis (GCA). Some individuals with RA can present with a polymyalgic onset of symptoms, that later manifests in peripheral joint symptoms, and there is significant clinical overlap between the two diagnoses.

Remitting Seronegative Symmetrical Synovitis With Pitting Edema (RS3PE) RS3PE is a syndrome characterized by bilateral symmetrical synovitis and tenosynovitis of the hands associated with marked pitting edema, that is typically seronegative in nature. It is generally very steroid responsive with sustained remission in most patients after steroid withdrawal. In contrast to RA, it is not associated with erosive disease, and is thought to be on a clinical spectrum with PMR.

Psoriatic Arthritis (PsA) PsA is generally associated with the presence of cutaneous psoriasis, however the joint symptoms can precede the onset of skin manifestations in about 15% of patients. A symmetrical polyarthritis resembling RA is one of the disease phenotypes of PsA, however other features include nail dystrophy, dactylitis, enthesitis and axial spine involvement, which can help differentiate it from RA. Patients with PsA are typically negative for RF and ACPA.

Reactive Arthritis/Viral Arthritis Reactive arthritis is generally defined as arthritis associated with bacterial pathogens, typically urogenital or gastrointestinal infections with symptoms developing between 1 and 6 weeks after infection. It is classified as a type of spondyloarthropathy and typically presents with asymmetrical oligoarthritis or axial spine involvement. Individuals who are positive for HLA-B27 have a higher risk of developing reactive arthritis. Acute polyarthritis can also occur following viral infections, such as Hepatitis B and C, rubella, parvovirus and alphaviruses, however these are usually self-limiting.

168

Rheumatoid Arthritis Table 1

2010 ACR/EULAR classification criteria for rheumatoid arthritis.

Joint involvement

Score

1 large joint 2–10 large joints 1–3 small joints 4–10 small joints >10 small joints Serology Negative RF AND negative ACPA Low positive RF OR low positive ACPA High positive RF OR high positive ACPA Symptom duration 75 µV

Stage R

Low-amplitude, mixed-frequency EEG activity without K complexes or sleep spindles

EEG characteristics in wakefulness and sleep stages.

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Sleep Disorders

Lack of proper fulfillment of the sleep need may result in numerous negative health consequences including increase of the risk of cardiovascular disease, obesity, diabetes and other metabolic disorders as well as mental disorders. Inadequate sleep also impairs cognitive functions and emotion processing. Those who do not get enough sleep may show emotional lability, irritability, proneness to hazardous and risky behaviors, are also at increased the risk of accidents and falls.

Sleep Regulation Sleep is regulated by many complementary and partially substituting centers in the brain. Even a brain which underwent a heavy organic damage does not lose the ability to sleep. The only exception is a fatal insomnia. It is a rare disorder of prion etiology with a prevalence of not more than 1–1.5 per million, which constitutes about 10% of all cases of prion disorders, and results in death within a few months (Khan and Bollu, 2018). The key brain structure involved in sleep regulation is the hypothalamus (Fig. 2). Its frontal part, the preoptic area promotes sleep through mechanisms dependent on gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter of the brain. The posterior part of the hypothalamus contains histaminergic neurons in tuberomammillary nucleus that promote wakefulness by influence on the histamine receptors. The lateral part of the hypothalamus plays a key role in stabilizing the states of sleep and wakefulness through the activity of neurons containing hypocretins (orexins). Succession of NREM and REM sleep within sleep cycles is regulated in the brainstem by reciprocal interactions between monoaminergic neurons, that is, serotonin-containing neurons of the dorsal raphe nucleus, norepinephrine-containing neurons of locus coeruleus, which inhibit REM sleep and cholinergic structuresdpedunculopontine tegmentum and laterodorsal tegmentum, which promote REM sleep. Another important neurotransmitter that regulates sleep is adenosine. Its level increases with the length of the waking period, causing drowsiness and making it easier to fall asleep. This effect is partially reversible by the adenosine antagonistdcaffeine. During sleep, the level of adenosine gradually decreases. A very practical model explaining the sleep regulation is the two-factor model (Borbély et al., 2016). Its understanding is necessary to grasp the rules of behavioral interventions used in the treatment of sleep disorders. This model indicates that sleep is regulated by two basic sleep mechanismsdhomeostatic sleep need (process S) and circadian sleep rhythm (process C). The homeostatic sleep need is the stronger the shorter was the sleep during previous nights and the longer was the wakefulness period since last sleep episode. What is more is that physical activity during daytime increases the need for sleep. The first role of homeostatic sleep need is to regulate amount of deep sleep, but it also increases the sleep duration. Many older people have sedentary life style and spend too much time in bed therefore their homeostatic sleep need is low, the amount of deep sleep is reduced and total sleep time is shortened. Circadian rhythm is a basic physiological process that regulates, among others, the sleep rhythm. It indicates the time of the day, which is the most beneficial for sleep. Sleep quality is best when it is colder, quiet and dark and when it occurs at a usual, regular time following an active day. Sleep in the first half of the night, especially when it comes to its depth, is mostly regulated by homeostatic processes. In the second half of the night, when the need for sleep is already partially fulfilled, sleep quality depends primarily on strong and healthy circadian rhythm. The circadian rhythm is shaped by proper light exposition,

AWAKE / SLEEP

LC TMN Raphe on

VLPO eVLPO

ORX

LC TMN Raphe

VLPO eVLPO

ORX

off

Fig. 2 Sleep regulationda reciprocal interactions between sleep and wake promoting structures. LC, locus coeruleus; TMN, tuberomammillary nuclei; Raphe, dorsal raphe nuclei; VLPO, ventrolateral preoptic nucleus; eVLPO, extended ventrolateral preoptic nucleus; ORX, hypocretines/orexins. During wakefulness the activating nuclei (noradrenergic LC, histaminergic TMN, serotonergic Raphe) inhibit the sleep-promoting, gamma -aminobutyric acid (GABA)-containing neurons in the VLPO. Additionally, the orexinergic neurons reinforce the monoaminergic tone. During prolonged wakefulness the level of adenosine increases in space between neurons of the basal forebrain (BF), and inhibits its cholinergic activity. This activates VLPO neurons that inhibit the wakefulness promoting nuclei, thereby relieving their own inhibition. This also prevents the monoaminergic activation by orexinergic neurons that might interrupt sleep.

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which regulates activity of suprachiasmatic nuclei in the anterior hypothalamus and the secretion of melatonin from the pineal gland. In addition to the rhythm of exposure to light during day and night, the circadian rhythm is influenced and reinforced by regular daily activitiesdthe rhythm of meals through regulation of activity of dorsomedial hypothalamic nuclei, physical and social activitiesdwith the second’s impact being processed through intergeniculate leaflet of the thalamus. Many patients in the old age lose their regular daily structure after retirement which weakens their circadian sleep-wake rhythm. Moreover, the nocturnal secretion of melatonin is very low after the age of 55 years, what additionally makes them susceptible to sleep rhythm disorders.

Methods of Sleep Assessment The most accurate method of sleep assessment is polysomnography. The scoring of sleep stages based on polysomnography enables the calculation of numerous parameters that allow the assessment of the length, continuity and quality of sleep (Shrivastava et al., 2014) (Table 2). Polysomnography is the main sleep assessment method in research studies. In sleep medicine the most common indications for polysomnography is the diagnostics of sleep related breathing disorders and central hypersomnias. In diagnostic assessment of other sleep disorders, the ability to measure sleep over longer time periods than 1–2 nights is often more important than the high accuracy of polysomnography (Table 3). PSG is a costly medical procedure and requires a trained person to supervise sleep recording during the night. Actigraphy is an objective method of evaluating rhythm, length and efficiency of sleep. It is performed using a small watch-sized, wrist-worn device, which is put on a person’s nondominant wrist for 7–14 days. Longer period of assessment is possibledeven for a few months. Apart from sleep evaluation, actigraphy enables measuring physical activity during the day, which is too low among most citizens of developed countries. Technical solutions available give a possibility to complement the standard actigraphy with the measurement of additional parameters, such as light intensity, body surface temperature, ECG or EEG from one or two derivations. In everyday clinical practice the most widely used methods of sleep assessment are sleep diaries, sleep logs and clinical scales. In the recommended standard form of a sleep diary patients record the time they went to bed, turned the light off, woke up and got up

Table 2

Sleep parameters based on scoring of sleep stages in polysomnography that are used to describe sleep pattern.

Sleep parameter

Definition

Sleep latency (SL)

The length of time it takes from start of the recording (“lights out”) to the onset of sleep. Normal values are typically below 30 min in young and below 45 min in older patients. Sleep latency is frequently expressed as a latency to persistent sleep (LPS), which means latency to the first 10 min long period of uninterrupted sleep. LPS is related to subjective feeling of time needed to fall asleep, especially for older persons. The number of minutes from the onset of sleep to the onset of the first REM sleep period. Reduced valuesdtypically below 65 min in young and 50 min in older patients, are a biomarker of depression. The amount of actual sleep time in a sleep episode. This is equal to time in bed minus time awake or sum of duration of all sleep stages (N1 þ N2 þ N3 þ R). In insomnia research values below 6.5 h are considered as shortened sleep time, although in older people 6 h may be more appropriate (these values are not applicable to short sleepers). The ratio of total sleep time to time in bed (TST/TIB  100%). The percentage of time spent asleep during the recording period. Normal values are typically above 90% in young and above 85% in older patients. The total time scored as awake occurring after sleep onset. Typically WASO should not exceed 30 min. Total duration in minutes and as percentage relative to total sleep time or time in bed of sleep stages Wake, N1, N2, N3 and R. Stage N1 normally represents 4%–5%, stage N2 45%–55%, stage N3 5%–20%, stage REM 20%–25%, Wake 5%–10% of time in bed.

REM latency (RL) Total sleep time (TST)

Sleep efficiency (SE) Wake after sleep onset (WASO) Total and relative amounts of stages Wake, N1, N2, N3 and REM

Table 3

Methods for assessment of sleep.

Single night assessment Long time assessment (at least 7–14 days recommended)

Objective assessment

Subjective assessment

• •

• • •

Polysomnography Actigraphy

Clinical scales Clinical scales Sleep diaries and logs

224

Sleep Disorders Table 4 1. 2. 3. 4. 5. 6. 7. 8.

Standard questions recommended for a sleep diary.

What time did you get into bed? What time did you try to go to sleep? How long did it take for you to fall asleep? How many times did you wake up, not counting your final awakening? In total, how long did these awakenings last? What time was your final awakening? What time did you get out of bed for the day? How would you rate the quality of your sleep?

in the morning. Sleep diary assesses a subjective sleep latency, total sleep time, number and length of awakenings at night as well as sleep quality and feeling of being well-rested in the morning (Table 4). Examples of clinical scales most often used in diagnosing sleep disorders are included in Table 5. In diagnostics of excessive sleepiness there are two objective methods that are based on the technique used in polysomnography. The Multiple Sleep Latency Test (MSLT) measures how long it takes for a person to fall asleep based on four to five 20–35 min rest periods in a lying position, which are scheduled every 2 h during the day. The Maintenance of Wakefulness Test (MWT) measures the ability to stay awake during four 40-min periods of rest in a comfortable sitting position, which are scheduled like in the MSTLdevery 2 h during the day. In addition, there are also many psychomotor tests that are used in assessing excessive daytime sleepiness. Two most popular are Psychomotor Vigilance Task and Mackworth Clock Test.

The Impact of Aging on Sleep The physiological changes in sleep associated with age include: increase of sleep latency, shortening of total sleep time (Fig. 3), reduction of sleep efficiency, increase in the amount of light sleep at the expense of deep sleep, increase in the number and duration of awakenings during sleep. Moreover, aging results in changes of sleep rhythm, and causes the advance of sleep phase, that is, the shift of sleep period to earlier hours. After the age of 60 years it becomes typical of people to go to bed early and wake up early in the morning. Physiological changes of sleep associated with aging may lead to complaints of elderly people about difficulties initiating sleep, too short sleep duration, shallow and easily interrupted sleep, reduced restorative sleep and waking up too early. Additionally the age related physiological worsening of sleep quality may be further aggravated through many factors present in older age. Nocturia is a common problem among older people, but it frequently does not get enough recognition. It is the need to get up at night to urinate. Nocturia is problematic not only due to the need to go to the toilet, but most of all because of the long-lasting feeling of urgency to urinate. It worsens sleep quality, causes awakenings at night and dilemma, whether to stay in bed or get up to urinate. Furthermore, a lot of elderly people report severe difficulties in falling asleep again after coming back to bed at night. The necessity to get up to go to the toilet at least once during the night is reported by over 70% of people over 70 years of age (Fine et al., 2017). It is an important issue when it comes to treatment of insomnia with sleep promoting drugs, especially with potent hypnotics. Their usage combined with the need to get up at night is associated with a high risk of a falls, femoral neck and other fractures as well as further serious complications connected with them, including increased mortality. Mental disorders and medical diseases, which negatively impact sleep quality are a common occurrence among older people. The most common when it comes to mental health disorders are depression, organic and dementia syndromes, and disturbances of consciousness in the form of evening and nocturnal agitation called sundowning syndrome. The impact of these disorders on sleep will be described in detail in the section of this article devoted to mental health disorders. Most common somatic disorders which negatively influence sleep among older people will also be focused on separately. It is important due to the occurrence of at least two somatic disorders among close to 70% of people over the age of 65. The quality of sleep of older people is also significantly influenced by psychological factors, such as the frequent experience of bereavement, feelings of loneliness and lowered economic status. Taking all these aspects into account is necessary to accurately diagnose and treat sleep disorders among older adults. The diagnostic assessment scheme should therefore include all of the following six elements: 1. 2. 3. 4. 5. 6.

Physiological sleep changes associated with ages. Mental health. Somatic diseases. Use of drugs and psychoactive substances. Environmental, behavioral and psychological factors. Primary sleep disorders.

Sleep Disorders Table 5

225

Examples of clinical rating scales used in sleep medicine.

Indication

Scale

Description

Insomnia

Insomnia Severity Index (ISI)

7-item self-report designed as a brief screening tool for insomnia. The items are added up to get the total score. 0–7 ¼ no clinically significant insomnia, 8–14 ¼ subthreshold insomnia, 15–21 ¼ clinical insomnia (moderate severity), 22–28 ¼ clinical insomnia (severe). 8-item self-assessment scale designed for quantifying sleep difficulty based on the ICD-10 criteria. The items are added up to get the total score. A total score of 6 or higher suggests a diagnosis of insomnia. 30 or 16-item self-report measure designed to evaluate a subset of sleep related cognitions that play an important role in perpetuating insomnia. 9-item self-report instrument to measure the likelihood that an individual will get sleep disturbances following various stressful events. The items are added up to get the total score. Cutoff value >16 identifies at-risk individuals for acute and chronic insomnia due to increased stress reactivity. 8-items self-administered questionnaire to screen for obstructive sleep apnea, evaluates 8 risk factors: snoring, tiredness, observed apnea, high blood pressure, high BMI, high age, neck circumference, gender. Yes to 0–2 questions means low risk, Yes to 3–4 questionsdmoderate risk, Yes to 5–8 questions high risk for sleep apnea. 10-items self-administered questionnaire developed to identify subjects with obstructive sleep apnea in primary care settings. Questions are evaluated in three categories. High-risk subjects for OSA are indicated as scoring in at least two out of three categories. 4-item test is to assess the risk of sleep apnea based on body height and weight, age and neck circumference. A score over 8 points suggests a risk for sleep apnea. 8-items self-administered questionnaire developed to assesses patient’s likelihood of falling asleep in typical everyday situations. The items are added up to get the total score. 0–10 means normal, 11–15 excessive, 16–24 severe excessive daytime sleepiness. 5-items questionnaire validated as a tool for screening for narcolepsy with cataplexy in patients with excessive daytime sleepiness. Each answer is weighted by a positive or negative factor to calculate the total score. SNS score of 2–4 times per week. Strengthening sleep rhythm 5) Your lifestyle should be regular and you should get up at the same time every morning Getting up at the same time every morning, combined with an active beginning of the daydwashing up, eating breakfast, going outside in the sunlight or turning bright lights inside, beginning of mental or physical work, synchronizes sleep and wake rhythms. It results in sleepiness and the need to go to sleep appearing 17 h after getting up in the morning. Staying in bed longer on days off-work may lead to sleep rhythm shifting to later hours. Then falling asleep before midnight may become impossible. 6) Avoid bright or blue light in the evening and during the night Bright light and every light source with a lot of blue color, even as weak as screen of smartphone or tablet, influences biological clock. It can extend the time needed to fall asleep and increase the risk of awakenings at night. People with sleep disorders should not watch TV or use electronics at night. Exposure to light at night intensifies sleep problems. Reduction of mental tension 7) Do not try to fall asleep if you cannot sleep, go to sleep and stay in bed only if you feel comfortable and sleepy Sleep cannot be controlled consciously. The more you try to fall asleep, the greater the risk that you will not. 8) Leave bed if you cannot fall asleep The longer you lay in bed and wait for sleep to come, the more frustrating it becomes. The bed stops to be a nice place that allows relaxation. Lying in it without sleep increases feelings of tension and triggers physiological reactions, which prevent from falling asleep. If you cannot fall asleep you should leave bed and come back to it after 15–20 min, when the tension disappears. 9) Remove clock from sight in the bedroom Counting how much time are left until it’s time to get up in the morning causes psychological tension. If you absolutely have to check the time it’s better to do it outside of the bedroom. 10) Keep sleep diary Sleep is a biological rhythm, which should be evaluated in longer periods of time. Sleep diaries enable just that. It is also useful for a physician in order to adjust the method of treatment of sleep disorders. Sleep diary should be filled in the morning, according to one’s subjective assessment. The physician does not expect perfect accuracy. A watch should not be used at night.

cartilage and bone tissue, which prevents their collapse. However, the patency of the lower part of the upper respiratory tract depends only on the stabilizing muscles tension of the throat, soft palate and tongue. When the negative pressure in the airways during inspiration exceeds stabilizing muscle tone, respiratory tract narrows or closes completely. The resulting apnea episodes cause frequent arousals and awakenings, leading to disturbed sleep and daytime sleepiness. As the severity of the disease increases oxygen desaturations occur. These are associated with excessive changes of cardiac rhythm and increase of arterial blood pressure. In this mechanism sleep apnea poses a significant health risk. Untreated severe sleep apnea increases the risk of severe cardiovascular events including heart attack and stroke. It also aggravates the metabolic disorders including diabetes (Fig. 6). Sleep apnea also has a negative effects on mental health. It is associated with an increased risk of mental disorders, especially depression, but also dementia in the longer perspective. Current data support the role of OSA not only in the pathogenesis of vascular dementia, but also in primary neurodegenerative dementias including Alzheimer’s disease (Gosselin et al., 2018). The incidence of sleep apnea in the general population is high. Mild forms of OSA, defined as those in which the apnea-hypopnea index (AHI)dthe number of respiratory events per hour of sleep, is higher than 5 and lower than 15, may occur in up to 20% of women

230

Sleep Disorders

Fig. 5

Methods for treatment of insomnia.

Fig. 6

Somatic consequences of untreated sleep apnea.

and 40% of men. Moderate severity of OSA, defined as AHI > 15/h and lower than 30/h is present in 6%–17% of people in the general population (Senaratna et al., 2017). Among older adults the risk of OSA is 2–4 times higher than in young adults (Lee et al., 2014). OSA may occur even in over 1/3 of older people (Young et al., 2002). This is an important information, because the use of hypnotics and sedative drugs is relatively contraindicated in patients with OSA. So such treatment should be avoided

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in people at high risk for OSA. The most important factor increasing the risk of OSA is obesity. It may be, however, both a cause and consequence of sleep apnea. Other risk factors include male gender, older age (although the most severe forms of apnea tend to occur in younger age groups) and increased neck circumference (collar circumference  43 cm in men and  41 cm in women), hypothyroidism, acromegaly, alcohol consumption and smoking. Risk factors of OSA are assessed with sleep apnea screening questionnaires, for example, STOP-BANG, NoSAS, Berlin questionnaire (Table 5). There is no effective pharmacological treatment of OSA. The main form of treatment consists of changing the modifiable OSA risk factors, that is, obesity, or avoiding sleeping on the back. Treatment may also include laryngological surgical procedures to eliminate nasal obstruction, for example, septoplasty (straightening of the deviated nasal septum) or turbinate reduction, tonsillectomy (this procedure is mainly used among children). Other surgical procedures include: uvulopalatopharyngoplasty (UPPP), radiofrequency volumetric tissue reduction (RFVTR), genioglossus advancement, hyoid suspension, maxillomandibular osteotomy (MMO) and advancement (MMA). However, if the nose patency is undisturbed the main form of therapy is the use of a medical therapeutic device called CPAP, as it maintains continuous positive airway pressure during sleep. In mild forms of OSA and in obstructive snoring it is also possible to use oral appliances that repose the lower jaw and tongue. Further treatment method is the hypoglossal nerve stimulation. Central breathing disturbances during sleep (central sleep apnea) are much less frequent than OSA and are not caused by airway obstruction. They are a result of a disturbances in central respiratory control mechanisms. The main form of their treatment is the therapy of underlying conditions, such as heart failure or stroke. Symptomatic treatment is possible with the use of bilevel positive airway pressure (BiPAP) or adaptive servo-ventilation (ASV) devices. Further, currently being developed method of treatment of central sleep apnea is stimulation of diaphragmatic nerves.

Central Disorders of Hypersomnolence Excessive daytime sleepiness in elderly people is most often associated with medical, neurological and mental diseases or side effects of medication. Although the lifestyle-related sleep deprivation is a much smaller problem in this age group than in young people, in differential diagnostics of hypersomnias it is also necessary to verify the time and regularity of patient’s sleep. It can be performed with help of a sleep log. The prevalence of narcolepsy, the most common disorder of central hypersomnias, is < 0.5& (i.e. < 1: 2000 people in the general population). Although during late adulthood the first occurrence of narcolepsy is raredits usual age at onset falls during second or third life decade, it is worthy to know the main facts about this disease. Narcolepsy is a chronic hypersomnia associated with damage of neurons located in the lateral hypothalamus containing hypocretins (orexins). The main symptoms of narcolepsy include excessive daytime sleepiness, sleep attacks, hypnagogic hallucinations and sleep paralysis. The hallmark symptom of narcolepsy is cataplexy defined as a sudden loss of muscle tone associated with emotions. The correct diagnosis of the narcolepsy is important due to a large negative impact of the disorder on the quality of life and the functioning of patients. Importantly, an effective treatment can substantially improve it. The standard of care in narcolepsy are behavioral interventions: regular and sufficiently long night sleep, and naps planned every 3–4 h during the day. As pharmacological treatment of excessive sleepiness stimulants like armodafinil and modafinil are most often used, followed by methylphenidate, less frequently amphetamine derivatives and selegiline. In severe forms of the disease with a large number of cataplexies, sodium oxybate allows to treat the full spectrum of disease symptoms. In the treatment of cataplexy antidepressants are also useddmostly from the group of selective serotonin reuptake inhibitors (SSRI), for example, sertraline, paroxetine, fluoxetine, serotonin and noradrenaline reuptake inhibitors (SNRI), for example, venlafaxine or duloxetine, and a tricyclic antidepressant clomipramine. A significant improvement in the field of narcolepsy treatment was provided by pitolisant, a recently introduced drug specifically targeting the histamine H3receptors.

Circadian Rhythm Sleep-Wake Disorders Circadian Rhythm Sleep-Wake Disorders (CRSWD) are characterized by a chronic or recurrent pattern of the sleep-wake rhythm disruptions, symptoms of insomnia, excessive sleepiness, or both, and clinically significant distress or impairment in mental, physical, social, occupational, educational, or other important areas of functioning. The reason for disruption of sleep-wake rhythm may be intrinsic (endogenous) or extrinsic (exogenous). In intrinsic CRSWD the disorder is caused by an alteration of genetically regulated endogenous circadian timing system or a misalignment between the endogenous circadian rhythm and the sleep-wake schedule desired or required by an individual. It results in complains about insomnia symptoms occurring during the preferred sleep times or the excessive sleepiness when the patients want to stay awake. Among the intrinsic CRSWD there are four disorders: advanced sleepdwake phase disorder (ASWPD), delayed sleepdwake phase disorder (DSWPD), non-24-h sleep-wake rhythm disorder (N24SWRD), and irregular sleepdwake rhythm disorder (ISWRD). The extrinsic disorders include shift work disorder (SWD) and jet lag disorder (time zone change disorder). The guidelines for their diagnosis and treatment are extensively described elsewhere (Auger et al., 2015; Wichniak et al., 2017a,b). Here, we will focus on two CRSWD most typical in late adulthood: the advanced and irregular sleepdwake rhythm disorder (ASWPD and IRSWD). ASWPD is characterized by an advance (too early timing) of the major sleep episode in relation to the desired or required sleep time and wake up time. The duration of the disorder has to be at least 3 months in order for it to be diagnosed. Too early timing of sleep phase results in complaints of the elderly people about difficulties staying awake until the desired time of going to bed and

232

Sleep Disorders Table 8

Behavioral instructions for patients with advanced sleep wake phase disorder (ASWPD).

People with a morning chronotype wanting to shift their sleep rhythm for later hours should follow these rules: • in the morning avoid exposure to sunlight and staying in brightly lit rooms. • cover windows tightly for the night so that the morning light does not wake you up • wear sunglasses in the morning • use electrical light and stay in brightly lit rooms in the evening • social and mental activities should be shifted from the morning hours to the afternoon and evening hours • in the evening it is worth planning meetings with family, friends or arranging for phone calls. • exercise physically in the evening.

inabilities to remain asleep until the desired time of awakening. However, the physician is rarely spontaneously informed that the bedtimes are very early. Most often the patients reports that short sleep time is the issue. In such cases the disorder is frequently misdiagnosed as insomnia with sleep maintenance difficulties and treated with sleep promoting drugs. It partially alleviates the symptoms, but cannot normalize the advanced circadian sleep rhythm. Therefore it is necessary to evaluate not only the sleep quality, but also the usual bedtimes of the elderly patients. The assessment of sleep rhythm is usually performed with sleep logs, and in some specialized sleep centers additionally with actigraphy. Typically in ASWPD there is an evidence in sleep logs and actigraphy that patients’ sleep quality and duration are improved with early bedtimes and getup-times consistent with advanced timing of sleep rhythm. The irregular sleepdwake rhythm disorder (IRSWD) is characterized by a pattern of irregular sleep and wake episodes throughout the 24-h period, which results in symptoms of insomnia during the scheduled sleep period (usually at night), excessive sleepiness (napping) during the day, or both. In order to diagnose IRSWD the duration of symptoms have to be at least 3 months. Among the elderly patients the IRSWD mostly occurs due to a brain dysfunction caused by other disorders severely affecting brain tissue, for example, neurodegenerative disorders. Sleep logs done by a patient with IRSWD or patient’s caregiver show no major sleep period and multiple, irregular sleep episodes (at least three) during a 24-h period. Chronotherapy is the treatment of choice for CRSWD, which involves melatonin application, light therapy, and behavioral interventions. While melatonin and its receptor agonists play an important role in the treatment of majority of CRSWD: delayed sleepwake phase disorder, non-24-h sleep-wake rhythm disorder and irregular sleep-wake rhythm disorder in children/adolescents with neurodevelopmental disorders and autism spectrum disorders, it is less efficacious in ASWPD and IRSWD in elderly patients with dementia (Auger et al., 2015; Wichniak et al., 2017a,b). In this group of patients the best treatment results can be obtained with a good structure of daytime activity and proper exposure to light during daytime and avoidance of light at night. Patients with ASWPD disorders should stay active as long as possible in the evening. If possible they should be involved in social activities with their families and friends in the evening. Examples of behavioral interventions for patients with ASWPD are shown in Table 8. Patients with IRSWD should have a well-structured daily schedule. The emphasis has to be put on stable rhythm of meals, social and physical activity. Among them, just as among patients with ASWDP, efforts have to be made to ensure an adequate amount of light during the day, in the second group of patients especially in the evening. However, the exposure to light should be avoided at night. This is crucial in patients with ASWPD who frequently switch on TV after early morning awaking, which results in further advancement of their sleep phase. Additional improvement can be achieved with bright light therapy, which is usually delivered to patients with ASWPD for 2 weeks in lower intensity (2500 lx) for 2 h in the evening and in patients with IRSWD with higher intensity (5000–10,000 lx) in the morning. Last but not least it should not the forgotten that physical activity, especially when it is preformed outside in the sunlight, has a strong synchronizing effect on sleep rhythm.

Parasomnias Parasomnias is a group of many heterogeneous disorders characterized by undesirable physical events or experiences that occur during entry into sleep, within sleep, or during arousal from sleep (Table 9). While many parasomnias, for example, NREM sleep related confusional arousals, sleepwalking and sleep terrors are related to young age, REM sleep behavior disorder (RBD) is typically associated with older age. RBD is characterized by repeated episodes of sleep-related vocalization and/or complex motor behaviors which may be forms of dream-enactment behavior. The disorder was scientifically described for the first time in 1986 (Schenck et al., 1986), however the historical descriptions of RBD go back to as early as year 1605 and can be found in Don Quijote de la Mancha by Miguel de Cervantes (Iranzo et al., 2004). RBD gained larger attention after it had been documented to be associated with neurodegeneration in synucleinopathies. This sleep disorder is present in as many as 80%–95% of patients with multisystem atrophy, about 50%–80% of patients with Lewy Body Dementia and about 30%–50% patients with Parkinson’s disease. However, the most important finding was that RBD may precede other symptoms of neurodegenerative disorders and the time from the first occurrence of RBD to its conversion to neurodegenerative disease may be as long as over 10 years. So RBD can be considered as a biomarker of neurodegeneration, present in 0.4%–0.5% of the general and between 2% and 6% of the elderly population (Howell and Schenck, 2015). In this regard it is important to differentiate between idiopathic RBD related to synucleinopathies and secondary cases related to other

Sleep Disorders Table 9

233

Sleep disorders form the diagnostic group of parasomnias classified in the International Classification of Sleep Disorders (ICSD-3).

NREM-sleep related parasomnias Disorders of Arousal (From NREM Sleep) - Confusional arousals - Sleepwalking - Sleep terrors Sleep related eating disorder REM-sleep related parasomnias REM sleep behavior disorder Recurrent isolated sleep paralysis Nightmare disorder Other parasomnias Exploding head syndrome Sleep related hallucinations Sleep enuresis Parasomnia due to a medical disorder Parasomnia due to a medication or substance Parasomnia, unspecified

factors. RBD can be caused by severe sleep apnea disrupting REM sleep, disturbances of muscle atonia in REM sleep caused by pharmacological treatment, especially antidepressant drugs, brain tumor of cerebellopontine angle or vascular or inflammatory pontine lesions. RBD also frequently occurs in patients with narcolepsy. RBD is predominantly present among males with male/female ratio being as high as up to 9:1. Treatment of RBD includes behavioral interventions to ensure safety of a patient and their bed partner. Patients are asked to remove all items that could be hit, cached or thrown while they sleep and dream from the surrounding of their beds. Bed should ideally be without headboard and rails that could cause harm when hit with arms or legs in the sleep. Violent leg movements are typical for RBD. When there is a risk of falling from bed, which makes the use of rails necessary, a use of a very low bed or sleeping mattress lying directly on the floor should be considered instead. It is also recommended to protect patients with soft materials on the floor in case of a fall. As motor disturbances in RBD are dangerous not only for a patient, but also for their bed partner, they should be advised to sleep in separate beds until symptoms are under control. The pharmacological treatment of RBD can be safe but not very effective (melatonin in a dose 2–15 mg) or effective but related to many side effects (clonazepam in a dose 0.5–2 mg). Clonazepam increases risk of falls, may cause excessive sedation during the day and worsens cognitive functions. In case of Parkinson’s syndrome symptoms being present dopamine receptors agonists (e.g. ropinirole, pramipexole) can be considered. Treatment with clonazepam should be offered in the lowest effective dose only in severe case. Most of the time it is necessary only among patients with vocalization during REM sleep. The vocalizations may sometimes be so loud, aggressive and vulgar that they wake up family members, sometime even neighbors, and are very embarrassing for the patients. Before administering clonazepam to patients, sleep apnea should be always excluded.

Sleep Related Movement Disorders Sleep related movement disorders is a group of disorders characterized by occurrence of usually simple stereotyped movements that occur during sleep disturbing sleep maintenance or its onset (Table 10). A distinct sleep related movement disorder is the restless legs syndrome. It is characterized by stereotyped periodic leg movements during sleep in about 90% of patients, but first of all by sensory symptomsdthe urge to move one’s legs and uncomfortable and unpleasant sensations in them which delays sleep onset. As RLS is a frequent sleep disorder with a prevalence of up to 15% in the elderly population (Ohayon et al., 2012), it is necessary to screen each elderly patient for RLS. Otherwise the disorder may be falsely classified as sleep onset insomnia. The screening for RLS is very simple and can be done with one single question “When you try to relax in the evening or sleep at night, do you ever have unpleasant, restless feelings in your legs that can be relieved by walking or movement?.” It allows to identify patients with RLS with high sensitivity and specificity (Ferri et al., 2007). The clinical usefulness of this simple screening question is related to symptoms that are very typical for RLS and are included in its diagnostic criteria: 1) beginning or worsening of the symptoms during periods of rest or inactivity, 2) noticeable improvement or resolution of the symptoms by movement, 3) presence of the symptoms predominantly or exclusively in the evening and at night. After identifying the symptoms and diagnosing RLS, it is necessary to look for possible underlying disorders. While idiopathic RLS, also called WillisEkbom disease, begins usually in the second decade of life, slowly progresses and leads to first consultation with a physician after the age of 50 years, nearly 50% of all RLS cases are caused by other factors and some of them can be very easily treated. The most frequent cause of secondary RLS is iron deficiency, that may be hidden and is only revealed with assessment of serum ferritin levels.

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Sleep disorders form the diagnostic group of sleep related movement disorders classified in the International Classification of Sleep Disorders (ICSD-3).

Restless legs syndrome Periodic limb movement disorder Sleep related leg cramps Sleep related bruxism Sleep related rhythmic movement disorder Benign sleep myoclonus of infancy Propriospinal myoclonus at sleep onset Sleep related movement disorder due to a medical disorder Sleep related movement disorder due to a medication or substance Sleep related movement disorder, unspecified

Iron supplementation should be recommended in case of RLS symptoms in patients with serum ferritin level below 75 ng/mL. Other possible causes of secondary RLS are: neuropathy, for example, diabetic neuropathy, kidney failure and side effects of pharmacotherapy, for example, of antipsychotic drugs. In mild RLS cases treatment may include only behavioral interventions such as avoidance of caffeine and nicotine, especially in the evening, increase of physical activity, for example, routine evening walking, sleep hygiene, physical exercises and interventions like stretching, massages, warm and cold showers or legs wraps before bedtime. However in moderate and severe cases related to disturbed sleep, pharmacological treatment is usually necessary. Current guidelines recommend a use of two classes of drugs: the dopaminergic agents and alpha-2-delta ligands (Garcia-Borreguero et al., 2012) (Table 11). The dopaminergic drugs were for years the mainstay of RLS pharmacological treatment. However, after their use had been connected to RLS augmentation their use as a first line treatment, especially of levodopa, declined (Garcia-Borreguero et al., 2016). Augmentation of RLS is defined as worsening of RLS symptoms that occurs usually several years after starting of a dopaminergic medication (for levodopa this time period may be much shorter, even as short as several months). It usually includes: 1) the earlier onset of symptoms in the evening and shortened therapeutic effect of medication, 2) increased in the overall severity of symptoms and the presence of symptoms also during the day, 3) progress of symptoms to other body parts, firstly to all upper

Table 11

Recommended pharmacological treatment for restless legs syndrome (RLS).

Drug name

Time to maximum plasma Half-life time concentration (Tmax) [hours] (t1/2) [hours]

Recommended dose Clinical remarks

Pramipexole

1–3

8

0.088–0.7

Ropinirole

2.6

6

0.5–4

Rotigotine

Transdermal system, 1–2 days of continuous release 1 2–3

5–7

1–3 mg/24 h

1.5 1.5

125–375

Gabapentin 2–3 Gabapentin enacarbil 5–7

5–7 5–6

Pregabalin

6.3

300–2400 mg 600 mg once daily taken at about 5 pm 300 mg

Levodopa Levodopa extended release

1–2.5

Main drug for the treatment of RLS, treatment starts with lowest dose of 0.088 mg/day that is increased every 4–6 days till satisfactory clinical effect. Main drug for the treatment of RLS, treatment starts with lowest dose of 0.25 mg/day that is increased every 4–6 days till satisfactory clinical effect. 2, 4, 6 and 8 mg patches are available, the lowest risk of augmentation among dopaminergic drugs, less frequent used in many countries due to higher cost of treatment. Due to the risk of augmentation recommended only for the treatment of sporadic RLS, it is not recommended to exceed the dose of 200 mg/day. Treatment usually combines the immediate release form taken 1 h before sleep that has quick onset of action and allows to fall asleep, and the extended release form taken just before sleep and effective in the second half night. The alfa-2-delta ligands do not cause augmentation, do not intensify impulsive behaviors, are more effective in RLS forms coexisting with pain and overlapping with polyneuropathy, are also recommended with coexisting insomnia and anxiety disorders. They can, however, cause weight gain, balance disturbances and falls, excessive sleepiness and worsening of mood. In such patients, the use of dopaminergic drugs is more beneficial.

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limbs (García-Borreguero et al., 2007). The highest risk for RLS symptom worsening is connected to treatment with levodopa. In case of this drug RLS augmentation may occur even in 80% of treated patients. Therefore levodopa is currently recommended only for intermittent treatment of sporadic RLS symptoms. Among dopamine receptor agonists the lowest risk of RLS augmentation is posed by rotigotine patches, moderate by ropinirole and pramipexole. To reduce such complication of treatment it is recommended to use the lowest possible dose of dopamine agonists, avoid high doses through combining pharmacotherapy with behavioral interventions and supplement iron in every patient with ferritin level below 75 ng/mL. The alfa-2-delta ligands that include gabapentin, gabapentin enacarbil, and pregabalin have little risk of RLS augmentation. Therefore these are more and more frequently considered as first line RLS pharmacological treatment (Garcia-Borreguero et al., 2016). However many elderly patients react with excessive sedation and dizziness to treatment with these drugs. Therapy should always start with the lowest possible dose slowly increased to achieve the effective dose. Third line of treatment to refractory RLS cases are opioids. Clonazepam which was previously frequently used in the treatment of RLS, is currently not recommended due to other agents having more favorable drug safety profiles. Periodic leg movements in sleep (PLMS) include repetitive cramping or jerking movement of the legs during sleep. They typically occur every 20–40 s, but may be as frequent as every 5–10 s or rare occurring every 60–90 s. As a motor symptom, they are present in majority of patients with RLS, but may be also a distinct disorder without presence of sensory RLS symptoms. To diagnose PLMS as a periodic leg movement disorder (PLMD) it is necessary not only to document PLMS with PSG with a frequency of > 15/h (not a rare finding in the elderly), but also to find presence of clinical symptoms such as significant sleep disturbances or impairment of daytime functioning. PLMS should also have a clear sleep disturbing effects in PSG. It means they should be connected to numerous arousals in sleep EEG (Iranzo, 2018).

Sleep in Mental Disorders Mental disorders strongly influence sleep architecture (Baglioni et al., 2016). When considering mental disorders related to sleep problems in the elderly, there is always a need to screen for depression. Disturbed sleep is a core symptom of depression. Chronic insomnia frequently precedes the onset of depression for years. During a depressive episode 60%–90% of patients (depending on the episode’s severity) complain of disturbed sleep, mostly insomnia, however, the occurrence of prolonged sleep and excessive daytime sleepiness in depression is also possible (Wichniak et al., 2013). The impairment of sleep pattern in depression include disturbances of sleep continuity (prolonged sleep latency, decreased total sleep time, increased number and duration of awakenings from sleep and reduced sleep efficiency) and reduction of deep sleep. Disruptions of REM sleepdshortened REM sleep latency, increased total REM sleep time and increased REM density (number of rapid eye movements per minute of REM sleep) are most common in depression (Baglioni et al., 2016; Wichniak et al., 2013). The sleep disturbances in depression can persist into the remission phase and are the most frequent residual symptom of depression. It should be noted that although effective pharmacological treatment of depression improves sleep quality, some antidepressant may promote and improve sleep, while other may negatively impact sleep continuity especially in the first week of treatment (Wichniak et al., 2017c) (Table 12). Moreover, the sleep disrupting effect of these activating antidepressant may persist and up to one third of patients treated with such antidepressant may report sleep problems even in the maintenance phase of treatment (Iovieno et al., 2011). It is important to consider these differences in effects of antidepressant drugs on sleep when planning treatment. Early relief from sleep disturbance improves patient’s adherence to treatment, improves quality of life and most importantly reduces the risk of suicidal attempts. Another mental disorder associated with disturbances of sleep in elderly patients is dementia. While depression decreases the amount of sleep, dementia primarily affects sleep rhythm. Circadian dysfunction is a common symptom of dementia. In most severe cases it manifest as a so called “sundowning syndrome” characterized by an emergence of agitation, confusion, anxiety, and aggressiveness late in the evening or at night (Canevelli et al., 2016). Sleep disturbances and nocturnal periods of agitation, although frequently not recognized as a major symptom of dementia, are one of the symptoms most profoundly affecting the quality of life of a patient’s caregiver. Their presence requires the caregiver to provide a 24-h care to the patient. For these reasons sleep problems in patients with dementia are connected to frequent placing of them in centers for long term care (Ye and Richards, 2018). It is also related to increased use of sedative drugs, also sedative antipsychotics, that may be associated with increased mortality of these patients (Ralph and Espinet, 2018). Therefore as far as it is possible non-pharmacological interventions strengthening the homeostatic sleep need and circadian rhythm should be preferred and pharmacological treatment should be administered in the lowest dose possible.

Sleep in Somatic Disorders Sleep disorders, especially insomnia, are associated with many comorbidities. The most frequent medical comorbidities found in elderly patients with insomnia include cardiovascular disorders, chronic obstructive pulmonary disease, diabetes mellitus, chronic kidney disease, malignancy, osteoarthritis and rheumatoid disorders, gastrointestinal diseases and chronic pain

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Table 12

Acute effects of antidepressant on sleepa.

Drug name TCA Amitriptyline, doxepin, nortriptyline Desipramine, imipramine Trimipramine MAOI Phenelzine, tranylcypromine, moclobemide SSRI Citalopram Escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline SNRI and NRI Duloxetine, reboxetine, venlafaxine Other Agomelatine Bupropion Mirtazapine Mianserin Nefazodone Trazodone

Sleep continuity

SWS

REM latency

REM sleep

[ Y [

[ Y [

[ [ 0

Y Y 0/[

Y/0

N

[

Y

Y/0 Y/0

0/[ 0/Y

[ [

Y Y

Y/[

0

[

Y

[ 0/[ [ [ [ [

[ Y [ [ [ [

0 Y 0 0/[ 0 0

0 [ 0 0 [ 0

TCA, tricyclic antidepressants; MAOI, monoamine oxidase inhibitors; SSRI, selective serotonin reuptake inhibitors; SNRI, serotonin and norepinephrine reuptake inhibitors; NRI, norepinephrine reuptake inhibitors. Increase of sleep continuity includes: shortening of sleep latency, increase of sleep efficiency, decrease of wake after sleep onset, increase of total sleep time; [, increase; Y, decrease; 0, no change; N, no data found. a Chronic effects of antidepressants on sleep (>14 days of treatment) are generally less pronounced and are dependent on the improvement of the symptoms of depression. Based on review from A. Wichniak, A. Wierzbicka, and W. Jernajczyk. (2012). Sleep and antidepressant treatment. Current Pharmaceutical Design 18, 5802–5817.

(Riemann et al., 2017). More than two thirds of elderly patients have multiple medical comorbidities and more than one third of them take at least five medications (Li et al., 2018). Diagnosing and treating an underlying cause of the sleep disturbances is critical for their effective management. It should be remembered that medical disorders contribute to insomnia not only as a consequence of disease-specific pathomechanisms or pain, but also by generally influencing the lifestyle of elderly people. Many patients with medical comorbidities reduce their physical activity, increase time in bed and introduce a more sedentary life style. It may sometimes be recommended in the treatment of medical disorders, however not as frequent and in such excess as many patients do it. In order to treat such patients it is crucial to find a good balance between their need to rest and a need to move, for example, in form of medical rehabilitation and patient education on recommended physical activity. Insomnia and chronic pain have a unique strong relationship. Fifty percent to 70% of patients with pain syndromes report symptoms of insomnia. Criteria for insomnia are met by about 40% of patients with fibromyalgia, 27% with osteoarthritis, 18% with tension headaches and 17% with migraine. Short sleep time or poor sleep quality significantly increases the sensitivity to pain (reduces pain threshold), because sensation of pain and regulation of sleep involve partially overlapping brain structures, for example, periaqueductal gray (PAG) in the midbrain and nucleus reticular in the thalamus (Smith and Haythornthwaite, 2004). Moreover both insomnia and pain are frequently comorbid with depression which further deteriorates sleep quality (Finan and Smith, 2013). All of these factors should be addressed in treatment of such patients. Treatment of medical disorders improves sleep and treatment of sleep disorders improves results of treatment of medical disorderdincluding reduction of pain which has been documented for both pharmacotherapy (Dimsdale et al., 2011) and cognitive-behavioral therapy (Edinger et al., 2013).

Conclusions Sleep disturbances are a frequent health problem in elderly patients. They are related to excessive and chronic use of hypnotics in this population, although there is not enough data to support the efficacy and safety of such treatment. Therefore it is highly recommended to pay more attention to effectively treat sleep problems of the elderly. Patients should be informed about the physiological changes of sleep architecture with age and how they can preserve good sleep quality, for example, with good sleep habits and physical activity. Each patients should be carefully interviewed for presence of mental, medical and neurological disorders which negatively influence sleep. It is recommended to screen each patient for sleep apnea, restless legs syndrome and circadian rhythm sleep wake disorders. The effective treatment of sleep disturbances improves not only sleep and quality of life, but also results of treatment of other medical and mental disorders. Good sleep is a necessary condition for successful aging and reduces the risk of cognitive decline and dementia.

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237

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Further Reading Abad, V.C., Guilleminault, C., 2018. Insomnia in elderly patients: Recommendations for pharmacological management. Drugs & Aging 35, 791–817. Alessi, C., Vitiello, M.V., 2015. Insomnia (primary) in older people: Non-drug treatments. BMJ Clinical Evidence 2015 pii: 2302. Brewster, G.S., Riegel, B., Gehrman, P.R., 2018. Insomnia in the older adult. Sleep Medicine Clinics 13, 13–19. Chowdhuri, S., Patel, P., Badr, M.S., 2018. Apnea in older adults. Sleep Medicine Clinics 13, 21–37. Gulia, K.K., Kumar, V.M., 2018. Sleep disorders in the elderly: A growing challenge. Psychogeriatrics 18, 155–165. Kim, J.H., Duffy, J.F., 2018. Circadian rhythm sleep-wake disorders in older adults. Sleep Medicine Clinics 13, 39–50. Nadorff, M.R., Drapeau, C.W., Pigeon, W.R., 2018. Psychiatric illness and sleep in older adults. Sleep Medicine Clinics 13, 81–91. Netzer, N.C., Ancoli-Israel, S., Bliwise, D.L., et al., 2016. Principles of practice parameters for the treatment of sleep disordered breathing in the elderly and frail elderly: The consensus of the International Geriatric Sleep Medicine Task Force. The European Respiratory Journal 48, 992–1018. Onen, S.-H., Onen, F., 2018. Chronic medical conditions and sleep in the older adult. Sleep Medicine Clinics 13, 71–79. Pandi-Perumal, S.R., Monti, J.M., Monjan, A.A. (Eds.), 2009. Principles and practice of geriatric sleep medicine. Cambridge University Press, Cambridge. Patel, D., Steinberg, J., Patel, P., 2018. Insomnia in the elderly: A review. Journal of Clinical Sleep Medicine 14, 1017–1024. Schroeck, J.L., Ford, J., Conway, E.L., et al., 2016. Review of safety and efficacy of sleep medicines in older adults. Clinical Therapeutics 38, 2340–2372. Suzuki, K., Miyamoto, M., Hirata, K., 2017. Sleep disorders in the elderly: Diagnosis and management. Journal of General and Family Medicine 18, 61–71. Vaughan, C.P., Bliwise, D.L., 2018. Sleep and nocturia in older adults. Sleep Medicine Clinics 13, 107–116. Yaremchuk, K., 2018. Sleep disorders in the elderly. Clinics in Geriatric Medicine 34, 205–216.

Social Determinants of Life Expectancy and Inequality in Lifespan Alyson A van Raalte and Rosie Seaman, Max Planck Institute for Demographic Research, Rostock, Germany © 2020 Elsevier Inc. All rights reserved.

Introduction Social Determinants of Mortality Theoretical Explanations Artefact Health Selection Cultural and Behavioral Explanations Materialist or Structural Explanations Fundamental Causes Social Participation Psychosocial The Spirit Level Neo-Materialist Welfare Regimes and Social Protection How Social Determinants Differ Over the Life Course Age Patterns of Mortality and Summary Measures of Population Health Conclusion References Further Reading Relevant Website

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Glossary Absolute inequality Differences in rates or life expectancies between populations, typically measured in years Life expectancy The average age at death if death rates remain fixed throughout the life course to the levels observed in the period (period life expectancy) Lifespan inequality The variation in ages at death obtained from the life table. This can be measured with statistical indices of variability (standard deviation, variance, interquartile range, etc.), with indices of inequality (i.e. Gini coefficient), with entropy measures (i.e. Theil index), or life table-based measures of dispersion (life disparity) Relative inequality Proportional differences in rates or life expectancies between populations

Introduction It has long been known that wider social forces influence the health and mortality of individuals. The Commission on Social Determinants of Health at the World Health Organization defines social determinants as the conditions in which people are born, grow, live, work and age. At its core is the recognition that these conditions are shaped by the distribution of power, money and resources (Marmot et al., 2008). A social gradient to mortality is repeatedly found according to the distribution of income, educational level, occupational class, and wealth (Elo, 2009). Individuals living in more deprived neighborhoods experience higher mortality than those from better neighborhoods (Seaman et al., 2015). In the vast majority of studies, a monotonic gradient is found running from the lowest mortality among the most privileged groups to the highest mortality among the least privileged groups. Social gradients in mortality are generally monitored by differences in an average outcome variable, such as life expectancy or age-standardized death rates, between predefined social groups. To date, far less attention has been paid to differences in the variation in age at death, what is also known as lifespan inequality (Wilmoth and Horiuchi, 1999). These differences should not be overlooked, because lower socioeconomic groups not only have shorter average lifespans, but tend to die over a more dispersed age range (van Raalte et al., 2011, 2014; Sasson, 2016). We begin this article with an overview of the theories underlying the social determinants of health and mortality. We follow this with a discussion about the importance of disaggregating the analysis of social differentials in mortality by age, and end by stressing the case to monitor lifespan inequality as an additional summary measure of longevity.

Encyclopedia of Biomedical Gerontology, Volume 3

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Social Determinants of Mortality Theoretical Explanations The existence of a mortality gradient in the United Kingdom came somewhat as a surprise when the Black report was first published in 1980 (Whitehead et al., 1992) for at least two reasons. Firstly, the UK population had access to free healthcare funded entirely by general taxation for over 30 years. Secondly, improvements in income were perceived to have been large enough so that poverty no longer directly impacted poor health and mortality (Bartley, 2004). This prompted some to comment that a welfare state founded on progressive taxation and public service investments may be ineffective for reducing social inequalities in mortality. Others used the existence, and persistence, of mortality inequalities in all societies as a reason to undermine the value of social determinants research and its applications (Marmot and Wilkinson, 2005). The Black report did not. Instead it proposed four explanations for the existence of health inequalities, which transcended national explanations: the artefact explanation, health selection, cultural and behavioral, and material(ist) and structural. In the years since the Black report this fourfold classification has been debated, a number of modifications presented, and several alternatives proposed (Mackenbach, 2012; Macintyre, 1997; Bambra, 2011). For example Macintyre (1997) set out to distinguish between hard and soft interpretations of each theory. Mackenbach (2012) grouped a number of theoretical developments in terms of whether they focused on: (1) social mobility and the composition of socioeconomic groups over time, (2) the distribution of resources (material and psychosocial), or (3) the ability for resources to enable health improvement. Further critical reflections have focused on the ability of each theory to explain the persistence of health inequalities over time, against its ability to explain the widening of health inequalities over time (Mackenbach, 2012; Bambra, 2011). All of this research reflects the recognition that health and mortality inequalities are influenced by nonmedical factors (social determinants). The phrase social determinants has been used to refer to a myriad of individual level characteristics and behaviours, physical and social environments, and institutional or organisational processes. The following section summarises the development of different theoretical explanations for the mortality gradient in order to demonstrate the complex interplay between social determinants from the individual level to the societal level as depicted by Dahlgren and Whitehead (Dahlgren and Whitehead, 1991).

Artefact The artefact explanation suggested that the measures used to capture social deprivation or social status may have no empirical significance. It was argued that empirical measures failed to reflect the decreasing proportion of the population in the lowest social class category. Therefore, the mortality gap could be interpreted as an inevitable consequence of social mobility within the UK if upward mobility improved the health of the majority relative to those left behind. Whitehead et al. (1992) were quick to discredit this perspective. It was reported that the reduction in the size of the lowest social class was relatively small. In addition, this did not account for why the mortality of those near the top of the hierarchy was worse than those at the very top (Marmot, 2001).

Health Selection A health selection explanation proposed that the social structure of society reflected the health structure: healthy individuals experience upward social mobility and sick individuals find themselves in the most disadvantaged groups (Bartley, 2004). This flips the causal relationship: social position is dependent upon health rather than social position having implications for health (Whitehead et al., 1992; Boyle et al., 2009). The lowest infant mortality rate experienced by the highest social class was used as supporting evidence for this hypothesis: it was perceived to be a reflection of the fact that this sub-group of the population was comprised of the fittest and healthiest men and women (Fox et al., 1985). As a result it is hypothesized that mortality inequalities between socioeconomic groups, could have widened as a consequence of healthy individuals experiencing upward social mobility and unhealthy individuals experiencing downward social mobility (Boyle et al., 2009). Earlier interpretations of selection effects saw health as a direct explanation for socioeconomic position (e.g. reverse causality). It was strongly linked to Darwin’s notion of natural selection, with Macintyre (1997) highlighting that ‘natural’ has both biological and moral connotations when referring to health inequalities. Later approaches saw selection effects as reflecting the relationship between health and socioeconomic position, which is confounded by many other factors (Mackenbach, 2012). For example the argument that psycho-social and behavioral changes associated with downward selection are detrimental to health rather than health being the underlying process causing downward selection (Fox et al., 1985).

Cultural and Behavioral Explanations The third Black report explanation suggested that health inequalities persisted because of different shared cultural practices that impacted health behaviors. There is large body of research findings documenting systematic differences in health behaviors across the social hierarchy: from the consumption of fats, sugars, and salt to exercise, smoking, and drinking (Lahelma et al., 2010; Laaksonen et al., 2008). Furthermore these behaviors can be clearly identified along the causal pathways in the onset of disease and death. However Whitehead et al. (1992) point out at least four reasons why health behaviors, by themselves, were an inadequate explanation: (I) health behaviors captured in empirical research are only indicators of health which have limited interpretation out of context; (II) a logical economic explanation for the social patterning of negative health behaviors is often missing when

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emphasizing individuals as independent and autonomous decision-makers in relation to their health (Bartley, 2004); (III) the prominent finding from the Whitehall study was that health behaviors were unable to fully account for the mortality gap between social groups. Only 25% of the risk of death between occupation grades was due to the observed health behavior patterns (Marmot et al., 1991); (IV) types of health behaviors have changed over time, becoming more or less predominant, but the mortality gradient has remained (Link and Phelan, 1995). Despite these weaknesses, commentators point towards the tendency for Government initiatives to rest upon the assumption that individuals act autonomously in relation to their health (McCartney et al., 2013). Studies applying a cultural and behavioral framework tended to overly focus on behavior as the cause, arguing that behaviors are the responsibility of the individual, and that behaviors are ‘freely taken’ by individuals (Bartley, 2004). Although a health behaviors perspective contributes to our understanding of the socioeconomic gradient it does not fully explain its persistence or its steepening over time. Instead questioning the social patterning of health behaviors should be a catalyst to push back the explanatory framework and question why differences in health behaviors exist in the social contexts which they exist in. This task is addressed within a materialist/structural hypothesis.

Materialist or Structural Explanations A materialist/structural explanation seeks to understand the impact economic and social resources have in explaining the distribution of resources that determine health and mortality (Mackenbach, 2012; Macintyre, 1997). It states that health inequalities result from the unequal accumulation of exposures and experiences that stem from the material inequalities (Lynch et al., 2001). It is not difficult to decipher why material poverty would have previously explained the burden of mortality on the lowest socioeconomic groups: historically overcrowded and poorly sanitized living conditions experienced by these groups fuelled the spread of infectious disease (Link and Phelan, 1995). It is more challenging to understand why this burden has persisted in capitalist economies that have driven economic growth, reduced over-crowding, improved sanitation, enabled material gains in wealth, and lowered absolute mortality rates (Whitehead et al., 1992; Bartley, 2004). Although the Black report introduced this hypothesis by discussing exploitation, poverty and disease as causes of health inequality, Macintyre (1997) highlights that greater emphasis within the report was placed on clarifying material versus materialist interpretations. A material interpretation assumes that material resources only impact health if access to resources falls below optimal condition. Therefore a strict material perspective fails to see poverty in relation to the current level of economic prosperity or the prevailing social norms of society. Materialist interpretations of poverty recognize that poverty is not a static entity but a relative concept that changes within different contexts (Townsend, 1987). Inequalities in access to material resources have remained a universal problem throughout history (Mackenbach, 2012) and, as societies have developed, new opportunities for inequalities have emerged. This is somewhat supported by the fact that health inequalities have remained despite radical changes in the diseases and risk factors assumed to explain them (Link and Phelan, 1995).

Fundamental Causes The evolving nature of new opportunities for inequality was summarized by Link and Phelan (1995) in their ‘Fundamental causes’ theory. They proposed that the persisting socioeconomic gradient for health, and ultimately death, were the consequence of the resources embodied within socioeconomic groups: money, knowledge, power, and social capital. These resources were beneficial for health against any prevailing disease profile in society and helped to negotiate all types of mechanisms. In addition, mortality remained strongly patterned by material resources because the types of resources that drove health improvements or enabled individuals to negate risks were not finite: for example there was no absolute level of wealth, knowledge or education that could be achieved. The gradient in material welfare and health was therefore a consequence of the most advantaged social groups disproportionately gaining more resources that enabled them to improve health and experience the greatest fall in deaths. Subsequently, the position of the most disadvantaged has become relatively worse off over time, but within the context of absolute improvements, meaning it may actually be harder to partake in the socially accepted functions of a richer society (Bartley, 2004; Townsend, 1987; Sen, 1992).

Social Participation In this context Sen (1992) argued that relative material deprivation can lead to absolute deprivation in terms of capabilities: the ability to transform material resources into valuable activities via real freedom and equal access to opportunity. Bartley (2004) reiterated that a materialist approach did not see the absence of enough material wealth as impacting health but that balancing psychosocial and biological needs was now dependent upon material wealth. Therefore the distinction between a material and materialist hypothesis tends to be that money itself was not the causal factor impacting health. Instead it was the level of relative resources and the ability those resources provide to mitigate risks that was important (Bartley, 2004). The difference, according to Marmot and Wilkinson (2001), was between the damage done by absolute poverty versus the health implications of relative inequality. This theoretical framework clearly conveys the notion that poverty in modern societies is more related to social participation than bare minimum survival (Dowler and Spencer, 2007). The materialist framework for understanding health inequalities has also

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evolved to encompass different mechanisms, in particular psychosocial resources and social protection policies under a neomaterialist perspective.

Psychosocial Psychosocial mechanisms may provide a biologically plausible account for why health is socially patterned: which in turn leads to the mortality gradient (Dowler and Spencer, 2007). Within this theoretical framework psychological conditions, which are seen as a direct consequence of social inequality, have a direct impact on the body’s biological processes. Research evaluating the possible psychosocial mechanisms was initially motivated by the so called ‘fight or flight’ changes that happen in response to external stimuli that are perceived to be dangerous. Psychological mechanisms which link social exposure and physiological response may be worry, stress, anxiety, insecurity, depression and vulnerability (Marmot and Wilkinson, 2001). Studies have demonstrated that perceived levels of stress or acute mental stress (psychosocial mechanisms) are associated with heightened cardiovascular responses and increases in blood pressure (biomedical responses) (Carroll et al., 2011). Allostatic load, a cumulative measure of biological dysregulation associated with higher mortality risk, is higher in individuals from lower socioeconomic groups, which is thought to be related to differential accumulation of chronic and acute stressors (Seeman et al., 2004). Psychological conditions, triggered by the social environment, might interact with the biological processes which facilitate the adoption of negative health behaviours. One example that links to health behaviours is that biological response to addictive substances may be altered under different psychological conditions (Bartley, 2004). This example takes account of the distribution of adverse social experiences, the distribution of health behaviours, and subsequent distribution of health outcomes because social exposures are seen to be embodied in our psychology and biology.

The Spirit Level Wilkinson and Pickett (2010) argue in favour of psychosocial mechanism by stating that health is not only damaged by material conditions but by our responses to our social circumstance. Their understanding of social circumstance was explicitly referring to the level of social stratification and the hierarchical structure of society at a macro level (Wilkinson and Pickett, 2010). They suggested that the distribution of wealth within a country may be more important for health than the absolute level of wealth and that this acts through psychosocial mechanisms (Wilkinson and Pickett, 2006, 2010). However it is still a theory that has been the subject of critical evaluation. In a similar vein to critiques of health behaviour theories, Lynch et al. (2000) argue that psychosocial theories can be unintentionally decontextualized if they focus on individual level perceptions of inequality. This may distract attention away from structural causes and reinforce low expectations for structural change. Marmot and Wilkinson (2001) dispute this interpretation. In their view social structure and relative deprivation have profound psychosocial impacts; to deny this burdens the responsibility for depression, anxiety and insecurity on individuals. They further emphasize that psychosocial mechanisms are important for clarifying a materialist perspective from a neo-materialist perspective.

Neo-Materialist A neo-materialist theory sees inequalities in material wealth as reflective of the negative exposures and lack of resources held by individuals due to inadequacies in the social infrastructure (Lynch et al., 2000). The relationship between lower social inequality and better population health may be explained by the psychosocial benefits provided by an egalitarian welfare system that ensures higher levels of social protection for all of its citizens even in the context of high income inequality (Bambra, 2011, 2013). Social protection policies are a means of redistributing wealth. They generally aim to protect the most vulnerable members of society from the effects of social and economic risks. This approach suggests that high income inequality in itself is not problematic. Rather a country could demonstrate high income inequality without there being implications for health if other aspects of the social infrastructure improved the psychosocial responses. This is somewhat of a contrast to a strictly materialist explanation for health inequalities where income inequality is always problematic because perceptions of relativity will always exist (Lynch et al., 2000). A neo-materialist view still recognises the importance of relative deprivation but sees redistribution as the solution for eradicating mortality inequalities: the redistribution of income and resources through tax, cash and non-cash benefits (Mackenbach, 2012).

Welfare Regimes and Social Protection There is a growing body of research which supports a neo-materialist hypothesis by demonstrating the links between welfare redistribution, social protection policies and lower mortality (Marmot et al., 2008). Perhaps the most widely cited examples are Scandinavian countries which tend to afford high levels of social protection to the unemployed and retired members of society but also ensure that publicly provided health care and education are of a high standard for all (Bambra, 2011; Popham et al., 2013). Access to these resources in these societies is independent of individual socioeconomic position explaining why there might be lower levels of health inequality (Marmot et al., 2008). This is often contrasted to the social structure in the USA where access to the resources which are required for social participation is more dependent upon individual socioeconomic position.

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However empirical evidence from Mackenbach et al. (2008) did not entirely agree with this theoretical approach. They find that the magnitude of health inequalities, when measured across socioeconomic groups, was not systematically lower in countries which have a history of egalitarian welfare policies. From this finding they concluded that a certain level of social protection may mitigate health inequalities but may not provide a universal explanation for their reduction across different countries. Somewhat in contrast to this study Popham et al. (2013) demonstrated that inequalities in countries with egalitarian welfare systems could be interpreted as the smallest when measured using lifespan variation. This is considered a measure of total inequality as it reflects the distribution of health across all individuals rather than the difference in average health between socioeconomic groups. The seemingly contradictory conclusions drawn from these two studies reflect the fact that different approaches for measuring inequalities in mortality were taken.

How Social Determinants Differ Over the Life Course Many of the aforementioned theories could be criticized for failing to account for how social structures differently impact an individual’s risk of mortality over the life course. Fig. 1 depicts relative differences in mortality between the most disadvantaged and most advantaged socioeconomic group in Finland, a country with an exceptionally long and good quality time series of registry data, by three markers of social position: education, (less than 10 years of education compared to some tertiary education); income (bottom quintile of household disposable income per consumption unit, based on the OECD equivalence scale); and occupational class (manual workers compared to upper non-manual workers). A mortality rate ratio of five would mean that death rates were five times larger in the disadvantaged socioeconomic group compared to the privileged group. To put a five-fold difference in mortality into perspective, mortality at age 90 was roughly five times higher than mortality at age 80 in Finland in 2015 (HMD, 2018). Two important points are worth noting from this figure: (I) in all cases relative differences in death rates were many times larger over working ages, and converged to similar levels at older ages (a rate ratio of one, depicted by the black horizontal line, implies no socioeconomic differences in mortality); (II) the age profile of relative risks differs by socioeconomic indicator. To date, some scholars have tried to explain the existence of point number one, but there is surprisingly little research into point number two. This is likely because most research comparing mortality differentials across different socioeconomic indicators have used agestandardized death rates as the outcome variable (Davey Smith et al., 1998). An exception is a study by Martikainen et al. (2007), which compared education and occupational class mortality risks over the life course, with similar data to that presented here. Inequalities in mortality are repeatedly found to be highest over early adulthood (Huisman et al., 2004), where the confluence of health-adverse behavior and negative contextual influences appear to be at their highest (Montez et al., 2011). However, it is still to some extent surprising that complete or near-complete convergence in mortality risk is observed between socioeconomic groups at older ages. The most likely explanations are owing to a combination of selection effects (i.e. the most vulnerable individuals in the lower socioeconomic classes die out first, leaving a particularly robust group of survivors), social transfers playing a greater role in

Figure 1 Mortality rate ratios between (Panel 1) low and high educated (less than 10 years of education compared to at least some tertiary education); (Panel 2) lowest and highest income (quintile of household disposable income per consumption unit, based on the OECD equivalence scale); and (Panel 3) manual workers versus upper non-manual workers (based on most recent occupation or occupation of household head). Death rates are courtesy of Pekka Martikainen based on aggregate data from Statistics Finland. More details on the underlying data can be found in the following publications (van Raalte et al., 2014, 2018; Martikainen et al., 2007; Tarkiainen et al., 2012).

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reducing socioeconomic difference at older ages, the gradual weakening of hazards related to past working conditions, and a changing cause of death structure toward mortality that is less related to life course behaviors (Hoffmann, 2008; Mirowsky and Ross, 2005). The relative importance of each of these factors remains an open question. Finally it should be noted that these age patterns in relative risks pertain to mortality, not morbidity. Socioeconomic differences in chronic health conditions or disability tend to peak at later ages than mortality, because risk factors for disabling conditions are more closely related to cumulative disadvantage in life course stressors and behaviors (House et al., 1990). Meanwhile mortality rate differences (as opposed to ratios) between socioeconomic groups continue to increase up to older ages, in line with overall increases in mortality rates (Huisman et al., 2004).

Age Patterns of Mortality and Summary Measures of Population Health As the previous section made clear, mortality inequalities vary strongly over the life course, and differ depending on the indicator of socioeconomic position. Typically, studies of socioeconomic inequalities in mortality use either age-standardized death rates or life expectancy as outcome variables to monitor these inequalities, obscuring these age variations. One way to shine light on different age patterns of mortality is to use life table decomposition techniques. For instance, a life expectancy difference between two populations can be decomposed into the contribution of each age group, or even each age and cause of death (van Raalte et al., 2011). However, life expectancy is most sensitive to changes in mortality at ages where there are both many remaining life years for individuals who are saved, and where there is an overall high level of mortality. In low mortality populations, the peak age where a one percent reduction in mortality would cause the largest increase in life expectancy is found around the life expectancy at birth (Vaupel, 1986). As a result of this age sensitivity, in a European-wide comparison over the 1990s, life expectancy differentials between educational groups were dominated by differences in chronic disease mortality (van Raalte et al., 2011). There is increasing awareness that summarizing mortality exclusively by mean outcomes overlooks important differences in the distribution of ages at death. The left panel of Fig. 2 depicts the period life table age-at-death distributions for male manual and upper non-manual workers above age 30 in Finland, over the 2011–14 period. Age 30 was used as a starting age, because assigning an occupational status below age 30 is complicated by individuals still in education. These are left-skewed distributions with means denoted by the dashed vertical lines (i.e. life expectancies conditional upon survival to age 30 was 76.7 years for manual and 82.6 years for upper-non manual workers). The interquartile range in age at death, a measure of lifespan inequality or age-at-death variation, is the shaded region under the curve. This represents the age range over which the middle half of all individuals die, when lined up from shortest to longest living. From this figure we can conclude that manual workers have both lower life expectancy and higher lifespan inequality. Lifespan inequality can be measured by any number of indices of variation, for instance the interquartile range, the standard deviation, the Gini coefficient, and the life disparitydall of which are highly correlated (Wilmoth and Horiuchi, 1999; Vaupel et al., 2011).

Figure 2 Left panel-A comparison of period life table male age-at-death distributions for manual workers and upper non-manual workers, Finland 2011–14. Right panels-Trends in life expectancy (top panel) and lifespan inequality measured by the interquartile range (bottom panel), Finland males. Data are from Statistics Finland. More details on the data and methods can be found in the following publications (van Raalte et al., 2014, 2018). Figure adapted from van Raalte et al. (2014) with permission.

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Meanwhile, the right panels of Fig. 2 depict trends in these two metrics. Although life expectancy differences have widened, all groups have experienced increases. Trends in lifespan inequality, here again measured by the IQR, were stagnant for manual workers and showed a decreasing trend for upper non-manual workers. A more detailed study of these trends can be found in van Raalte et al. (2014). Over most of the past 150 years, life expectancy and lifespan inequality have been negatively correlated, because progress at averting mortality over younger ages, which compresses the age at death distribution, has outpaced progress at averting mortality over older ages (Wilmoth and Horiuchi, 1999; Vaupel et al., 2011). However, as Fig. 2 depicted, this does not need to be the case. Differences in life expectancy and lifespan inequality arise from different causes of death (Seligman et al., 2016). Increases in lifespan inequality often coincide with rising or stagnant early adult mortality, to which it is highly sensitive (Sasson, 2016; Aburto and van Raalte, 2018). Higher lifespan inequality signals both higher within-group heterogeneity at the population level, and higher uncertainty in the timing of death at the individual level (Sasson, 2016; van Raalte et al., 2014). That less advantaged groups are dying both at younger ages, and facing higher and increasing uncertainty about the eventual timing of death compared to more advantaged groups is an important neglected concern in population health circles (van Raalte et al., 2011; Sasson, 2016).

Conclusion In this article we reviewed the various perspectives linking the social determinants of health to mortality. These theories are not mutually exclusive, and are likely to differ in intensity depending on the sociopolitical context and time period. Further crossnational and longitudinal studies should be designed to explore these differences. We also stressed the need for future research to explicitly consider the changing socioeconomic mortality gradient over the life course. Theoretical perspectives need to account for how vulnerabilities to social and material deprivation evolve over age, while empirical studies should investigate the stability of these socioeconomic age gradients over time and place, alongside general shifts in the macro-epidemiological environment. Summary measures such as the life expectancy at birth and age-standardized death rates are an important indicator of the evolving population health but they do not tell the whole story. We must also turn our attention away from mean outcomes, to see how the full distribution of mortality is changing for different social groups. A healthy society is not only one where individuals live for a long time on average, but one where longevity is shared in an equitable way across all of society.

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Further Reading Bartley, M., 2004. Health Inequality: An Introduction to Theories, Concepts and Methods. Elo, I.T., 2009. Social class differentials in health and mortality: patterns and explanations in comparative perspective. Annu. Rev. Sociol. 35 (1), 553–572. Huisman, M., Kunst, A.E., Andersen, O., Bopp, M., Borgan, J.K., Borrell, C., et al., 2004. Socioeconomic inequalities in mortality among elderly people in 11 European populations. J. Epidemiol. Commun. Health 58 (6), 468–475. Link, B.G., Phelan, J., 1995. Social conditions as fundamental causes of disease. J. Health Soc. Behav. 80–94. https://doi.org/10.2307/2626958. Macintyre, S., 1997. The Black Report and beyond: what are the issues? Soc. Sci. Med. 44 (6), 723. Mackenbach, J.P., Stirbu, I., Roskam, A.-J.R., Schaap, M.M., Menvielle, G., Leinsalu, M., et al., 2008. Socioeconomic inequalities in health in 22 European countries. N. Engl. J. Med. 358 (23), 2468–2481. Marmot, M.G., Stansfeld, S., Patel, C., North, F., Head, J., White, I., et al., 1991. Health inequalities among British civil servants: the Whitehall II study. Lancet 337 (8754), 1387–1393. Marmot, M., Friel, S., Bell, R., Houweling, T.A.J., Taylor, S., 2008. Closing the gap in a generation: health equity through action on the social determinants of health. Lancet 372 (9650), 1661–1669. Sasson, I., 2016. Trends in life expectancy and lifespan variation by educational attainment: United States, 1990–2010. Demography 53 (2), 269–293. Seligman, B., Greenberg, G., Tuljapurkar, S., 2016. Equity and length of lifespan are not the same. Proc. Natl. Acad. Sci. 113 (30), 8420–8423. Sen, A., 1992. Inequality Reexamined. Clarendon Press. van Raalte, A.A., Kunst, A.E., Deboosere, P., Leinsalu, M., Lundberg, O., Martikainen, P., et al., 2011. More variation in lifespan in lower educated groups: evidence from 10 European countries. Int. J. Epidemiol. 40 (6), 1703–1714. Vaupel, J.W., Zhang, Z., van Raalte, A.A., 2011. Life expectancy and disparity: an international comparison of life table data. BMJ Open 1 (1), 1–6. Whitehead, M., Townsend, P., Davidsen, N., 1992. Inequalities in Health: The Black Report: The Health Divide. Penguin. Wilkinson, R.G., Pickett, K., 2010. The Spirit Level: Why More Equal Societies Almost Always Do Better. Allen Lane.

Relevant Website WHO commission on the social determinants of health: http://www.who.int/social_determinants/en/.

Social Participation in the Second Half of Life Marja Aartsen and Thomas Hansen, Oslo Metropolitan University, Oslo, Norway © 2020 Elsevier Inc. All rights reserved.

Introduction Social Participation and Successful Aging Working Definition of Social Participation Patterns of Social Participation by Country Patterns of Social Participation by Age Gender Differences in Social Participation Socio-Economical Variations in Social Participation Health Benefits of Social Participation Theoretical Perspectives Micro-Level Perspectives Role theory Role accumulation Motivations and the functional approach The socio-emotional selectivity theory A resources perspective Cost-benefit or rational choice perspective Selective optimization with compensation Macro-Level Perspectives on Social Participation Life Course Perspective on Social Participation Concluding Remarks Consequences for Policy and Practice References Further Reading

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Glossary Fourth age The age of frailty, inactivity, dependency, and unproductive aging. Healthy aging The preservation of high cognitive, physical, and mental capacities until advanced ages. Old age dependency ratio Ratio between the number of persons aged 65 and the number of persons aged between 15 and 64. The value is expressed per 100 persons of working age (15–64). Social participation Unpaid activity with other people in the community to achieve common goals or to produce goods (volunteering) or unpaid help provided to others. Social role Social positions (e.g., teacher, mother, customer) and behavior associated with that position. Successful aging Low probability of disease and disease-related disability, high cognitive and physical functioning, and active engagement with life. Third age The age between the completion of the primary family and traditional career responsibilities and old age and frailty.

Introduction The increased longevity of humans has been called a “triumph of science and public policy over many of the causes of premature death which truncated lives in earlier times” (Walker, 2006), but it has also challenged the sustainability of welfare states. Contemporary societies have an increasing proportion of citizens who are in their Third age (Laslett, 1987), the period of life after retirement and caretaking for young children, but before onset of disability. Although attractive at first sight, retirement is also called the “roleless role of old age” (Burgess, 1960), and a period undermining people’s social identity (Rosow, 1973). Hence, social participation can provide older adults with meaningful roles and positions in society and stimulate healthy aging, which are key foci of active aging policies. As will be discussed, social participation varies greatly between individuals, within individuals over time, and across countries. Both individual characteristics, such as life course changes in health, roles, and motivation, and societal structural factors such as economic conditions and prevailing norms and values, provide explanations for inter- and intra-individual variability in social participation. The purpose of this article is to highlight empirical observations about social participation in older age and

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to discuss central sociological and psychological perspectives that shed light on these findings. The article should contribute to integrate knowledge on variations in social participation within and between individuals and societies, and to clarify its consequences for health and well-being.

Social Participation and Successful Aging Social participation, broadly referring to a person’s interaction with people outside the household, is a crucial determinant of healthy aging (see section “Health Benefits of Social Participation”). Not only individuals, but also societies can benefit from older adults’ contributions to society, for example in voluntary work or other forms of prosocial acts which would otherwise need to be provided by the state (Gottlieb and Gillespie, 2008a; Tesch-Roemer, 2012; Fernández-Mayoralas et al., 2015). In addition, maintaining good health into advanced ages reduces health care costs (Kim and Konrath, 2016), which makes social participation a relevant public health issue. Social participation is thus a win-win situation, fostering health benefits for individuals and valuable contributions to society. Not surprisingly therefore, stimulating social participation among older peopledor “active aging”dhas become a key policy aim for many countries in the last decade (Walker and Maltby, 2012). Notable examples are the active aging policies (World Health Organization (WHO), 2002), the designation of 2012 as the European Year of Active Aging, and “a society for all ages” (Eurofound, 2015). Viewing social participation as key to healthy aging is relatively new. Until the end of the previous century, the study of aging was often preoccupied with disability and decline. It was mainly through the work of Rowe and Kahn and the MacArthur Foundation Study of Successful Aging (Rowe and Kahn, 1997, 1998) that studies of human aging integrated the biological and psychological perspective with the sociological perspective. This “new gerontology” emphasized positive outcomes and determinants of “successful aging” (Holstein and Minkler, 2003). However, the term “successful” has not been without critics (Bowling and Dieppe, 2005; Depp and Jeste, 2006). What is a successful aging trajectory for one is not necessarily a successful trajectory for another, and there is therefore a lack of consensus among researchers regarding its constituents (Fagerström and Aartsen, 2013; Kok et al., 2015). Alternative definitions are proposed such as positive aging, productive aging, aging well and precarious aging, but so far successful aging is the most frequently used in gerontological research (Hung et al., 2010; Peel et al., 2004). The aim of the “new gerontology” was in line with earlier ideas by Havighurst, who suggested that the main task of gerontologists is “to provide society and individuals with advice on the making of societal and individual choices.” (Havighurst, 1961). Unraveling predictors and outcomes of social participation in older age is such a task. Although challenging, it is important to understand the nature and correlates of change in social participation over the life course, and how it can affect health and well-being. Before proceeding to theoretical perspectives on social participation, we provide our definition of social participation. While there is consensus that social participation refers to an unpaid interaction with other peoples outside the household, there is no consensus about its more precise nature and scope. Common terms that are interchangeably used with social participation are volunteering, community involvement, social capital, social integration, and social activity. Although highly correlated, these terms may refer to different dimensions of social participation (Levasseur et al., 2010). The lack of consensus is problematic as it can lead to communication difficulties between people discussing and operationalizing the concept. Moreover, it complicates comparability of studies and an integrated understanding of the concept (Levasseur et al., 2004).

Working Definition of Social Participation Levasseur et al. (2010) detected more than 40 different definitions in disciplines that study social participation. Rather than providing one overarching definition of social participation, they propose a hierarchical ordering of social participative activities based on their intensity and goals. They distinguish six levels of involvement. The lowest level is preparation for connecting with others and the highest is the actual interaction with others, such as helping others and doing organized activities with others to reach common goals, such as volunteering. For the purpose of this article, we focus on forms of social participation with the most intense levels of social interaction, as associations with health and well-being should be more apparent for the more intense activities. We do not include helping others or caring for them, sometimes referred to as informal volunteering (Wilson and Musick, 1997), which is often motivated by affection or by demands from people in the social network who need help. Besides, the “informal” and “formal” helping behaviors may have different effects on health, due to their differential connections to neurological substrates (Brown et al., 2012). Due to space limitations, we also exclude activities within the social network such as visiting friends and family members. Although helping others and involvement in the social network are forms of social participation, they open a whole new field of research with different dynamics in the conceptualization of social participation and its health outcomes. We thus define social participation as activities with others in the community with the purpose of achieving common goals or producing goods (volunteering). Crucial features of the definition are that the activities are unpaid and that people must make an effort to engage in interaction with others (Dykstra, 1995).

Patterns of Social Participation by Country Cross-national studies on trends and differences in later-life social participation are still rather sparse, due to lack of comparable data. Some studies present figures on membership in voluntary organizations, others on the frequency of participation, and yet others on the hours contributed to voluntary work. Comparisons are also hampered by inconsistency in conceptualizations and

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operationalizations. Furthermore, the literature is dominated by data from the United States and there is a paucity of studies of poorer, non-Western countries. Nevertheless, the available cross-national studies have produced some valuable insights. First, it is found that social participation in later life is lower in countries with poorer living conditions and welfare supports. For example, European studies show that the rate of seniors (age 60–79) who have done voluntary work at least monthly during the last year ranges from 2% to 3% in southern countries such as Spain and Greece to 20–22% in northern countries such as the Netherlands and the Nordic countries (Erlinghagen and Hank, 2006; Hank and Stuck, 2008; Hansen et al., 2018). For the United States, percentages around 25% are observed for people aged 50 and over (Hendricks and Cutler, 2004; Bureau of Labor Statistics, 2016), and in Canada 36% of older people volunteer (Volunteer Canada, 2013). Little is known about volunteering in the former socialist countries, where formal welfare support structures are largely absent and an increasing number of retirees face severe financial strain (Botev, 2002; Iecovich et al., 2004). Studies further indicate that country differences in social participation rates cannot be (fully) explained by variations in population composition or differences in health status (Erlinghagen and Hank, 2006). This suggests an important moderating role of institutions and cultures on the social participation of older adults.

Patterns of Social Participation by Age How social participation changes with aging cannot be examined on the bases of cross-sectional studies, as lower participation in certain age groups may also reflect cohort effects. We need longitudinal data following the same people into old age to disentangle age from cohort effects, but such examinations are rare. The few available studies observe relative stability in both young-old (Butrica et al., 2009; Hank and Erlinghagen, 2009) and old-old people (Cramm and Nieboer, 2015). According to a German study, social participation in older people remains stable until the age of 80, after which it declines (Bukov et al., 2002a). Although the participation rates may decline with age, older adults’ contribution measured in hours arguably does not. The hours spent on voluntary work are up to twice as high among older volunteers than among their younger counterparts (Gonzales et al., 2015; Morrow-Howell, 2010).

Gender Differences in Social Participation The participation rate of men and women differs, but in most countries not substantially. For the European countries involved in the SHARE study in 2004, the average portion of people involved in voluntary work over the last month prior to the interview was 11% for men and 9% for women. The higher percentage of men was observed in eight of the 10 countries; only in The Netherlands and Switzerland were women more active than men (Erlinghagen and Hank, 2006). Gender differences are negligible in Belgium (Dury et al., 2015), Norway (Hansen et al., 2018), and Australia (Windsor et al., 2008), but in the US women are more involved than are men (Krause and Rainville, 2018). In Canada, gender differences in participation rates are negligible between age 65 to 74 (rates around 40%), but substantial above age 75 (36% for men and 27% for women (Volunteer Canada, 2013). Findings indicate, however, that there are substantial differences in the content of the activities men and women do as volunteers. Women are more likely to be involved in volunteering characterized as more caring, person-to-person tasks, and activities that are churchbased activities or involve fundraising or preparing and serving food, whereas men are more likely to be involved in political or public leadership positions, maintenance work and teaching or coaching (Krause and Rainville, 2018; Jaumot-Pascual et al., 2018; Manning, 2010; Tang, 2006; Rotolo and Wilson, 2007).

Socio-Economical Variations in Social Participation There is a consistent finding that people with higher education and more income do more voluntary work than people with lower education (Bureau of Labor Statistics, 2016; Butrica et al., 2009; Morrow-Howell, 2010; Rotolo and Wilson, 2007; Choi, 2003). It may be that higher educated volunteers have a higher preference for volunteering, it may also be that volunteers with higher education are more often asked for voluntary work because of the capital (knowledge, skills, and status) they bring into the voluntary sector (Morrow-Howell, 2010). It is suggested that older adults from lower socio-economic strata may be more actively involved in informal voluntary work such as helping neighbors, friends and family members (Gottlieb and Gillespie, 2008b). Research on this issue is, however, scarce.

Health Benefits of Social Participation A growing body of empirical evidence shows that social participation is positively associated with health and well-being (Von Bonsdorff and Rantanen, 2011) and a number of pathways from social participation have been suggested. Psychological studies argue that volunteering fosters a greater sense of meaning, autonomy, and competence (Ryff and Singer, 1998; Siegrist et al., 2004), greater self-efficacy and self-esteem, which in turn lower depression and distress and improve health and well-being (for reviews, see Anderson et al., 2014; Proulx et al., 2017). Sociological studies suggest that voluntary work promotes social integration and access to social support (Morrow-Howell et al., 2003a; Wilson, 2000; Moen et al., 1992; Berkman et al., 2000; Pilkington et al., 2012). Finally, social participation may play a useful role in protecting against inactivity and physical decline among older people (Fischer and Schaffer, 1993; Jenkinson et al., 2013). Okun et al. (2013) observed a reduction in the mortality risk by 24% for volunteers compared to non-volunteers which cannot be attributed to age, sex, physical health, socioeconomic status, health behaviors,

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marital status, and emotional health. Luoh and Herzog (2002) found that older adults living in the US who volunteered for at least 100 h per year were significantly less likely to report poor health and limitations in daily living. A longitudinal study by Piliavin and Siegl (2007) also confirmed the benefits of voluntary work for health, in particular when other forms or social integration were limited.

Theoretical Perspectives What can be learned from the empirical literature is that social participation, and volunteering in particular, is the outcome of the dynamic interplay between a wide range of factors, partly depending on the life that people have lived so far, the lives of people to which one are linked, as well as the macro social context. To provide a meaningful understanding of what has been found we proceed with discussing theories that have been central in studies in this field. These theories offer different lenses through which to observe and interpret reality and thus provide different interpretations of the empirical findings. Theories can be divided into micro, macro, and life course perspectives on social participation and its health outcomes in later life. The individual or micro perspective is based on the assumption that to understand variations in social participation and its benefits for health, we have explore the role of individual characteristics and resources, motivations, and experiences. The macro perspective assumes that society’s economic, political, and cultural processes, such as the distribution of social resources and prevailing norms and values about social participation, influence people’s capacities and opportunities to participate in society. The life course perspective suggests that the micro and macro perspectives are actually complementary and mutually dependent. Accordingly, individuals’ current level of social participation can be seen as the outcome of a dynamic interplay between (i) opportunities and decisions in one’s own life, (ii) developments and life events in the lives of people in one’s family or network, and (iii) the larger historical, socioeconomic, and cultural context (Elder, 1998).

Micro-Level Perspectives A classical theory to explain social participation and its emotional consequences is the activity theory (Havighurst, 1961; Cumming and Henry, 1961). This theory assumes that to maximize well-being in later life, individuals should aim to maintain societal roles and activities, and when important roles or activities are lost, for example due to retirement, one should look for alternative forms of participation, such as voluntary work. However, the theory does not pay attention to people that are no longer able to initiate or maintain this level of activity. Since aging is associated with an increasing number of losses (e.g., in health and social connectivity), which eventually tend to outweigh the gains of growing older (Baltes, 1997), it may be functional and adaptive to gradually disengage in later life. This notion is a major tenet of the disengagement theory (Havighurst, 1961). The theory proposes that as people age they reduce social participation and slowly withdraw from society to enhance well-being. At the same time society disconnects from the individual, so that both can prepare for the ultimate end of the individual’s life without disturbing the balance in society. Although activity and disengagement theory are more complex and dynamic than described here, the problem is that they prescribe how people should behave in society to produce well-being, rather than provide an explanation for the underlying mechanisms. Nevertheless, they represent two main standpoints that are still visible in debates and scientific research on the association between social participation and well-being. More recent theories on social participation are less normative, but instead try to understand often observed associations between social participation and the individual’s physical, mental, and social resources on the one hand, and barriers and opportunities for social participation in the society on the other. The theoretical perspectives discussed below focus on social participation, in particular volunteering, and its role in health and well-being.

Role theory Role theory is an often-used explanatory framework for the benefits of volunteering and helping others for health and well-being. Role theory has its origin in the work of the American sociologist Robert Merton (Merton, 1957). Roles refer to the social position people have (e.g., teacher, mother, and customer) and behavior associated with that position. Roles tend to carry certain risks and benefits which may vary by individual characteristics, historical time, and cultural context. Roles can provide connection to other people and access to resources, which in turn may promote feelings of security, status enhancement, and ego gratification. Roles also provide directions for behavior in otherwise uncertain situations (Hogg, 2000), which may serve to reduce stress and improve wellbeing. People often fulfill a set of roles at the same time (e.g., mother, director, and child), and this set may change over the life course (Riley and Riley, 1994; Rotolo, 2000). With aging an increasing imbalance occurs between the number of roles gained and lost (Baltes, 1997). Older people tend to lose more roles than they gain, for example losing roles such as parent, spouse, worker, and active member of society. Volunteering and helping others can act as substitutes for roles lost over the life course, For example, becoming a volunteer after retirement may alleviate any negative consequences associated with losing the worker role, such as a loss of a sense of personal value and identity (Greenfield and Marks, 2004).

Role accumulation The role accumulation theory, originally formulated by Sieber (1974), argues against the view that voluntary work can be stressful when added to an already busy life. Although this may hold in some cases, Sieber argues that the benefits or rewards of maintaining

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multiple roles tend to outweigh the costs of role conflict or overload. Multiple roles creates a greater amount of “by-products” such as access to valuable social and financial resources and thus a greater capacity to compensate for role loss, in addition to broadening the types of engagement that can promote feelings of meaning, status, and achievement. Even in the face of these benefits, volunteering arguably can generate stress and role overload, and there is likely to be an optimal number of roles or overall time-investment to achieve emotional benefits. Below or above this optimum the effects may be reduced, eliminated, or reversed (Windsor et al., 2008).

Motivations and the functional approach The functional approach to volunteering (Clary and Snyder, 1999; Finkelstien, 2009) is based on three propositions: motivations direct individual behavior; the same voluntary behavior can be initiated by different motivations; and voluntary work should satisfy the person’s motivations for doing voluntary work. In other words, the function of volunteering is to satisfy a person’s needs or motivations. Clary and Snyder (Clary and Snyder, 1999) developed the Volunteer Function Inventory (VFI), which distinguishes six different needs or motives for volunteering: (1) contribute to society, (2) improve own skills and knowledge, (3) psychological development, (4) improve opportunities for the labor market, (5) strengthen social relations, and (6) reduce negative feelings such as guilt. Each of these motivations may contribute to generate well-being, as long as there is a match between the motivation and what the activity provides. Hence, forcing people to do “voluntary” work probably does not provide the health and well-being benefits often observed when volunteering is stimulated by one of the abovementioned motives (ibid.). In another paper, six rather similar motivations were distinguished, which the researchers grouped into intrinsic motivations (enjoying doing good, enjoying the type of work, and receiving a “warm glow” from helping others and volunteering), and extrinsic motivations (investment in human capital, investment in social capital, and material and social rewards) (Meier and Stutzer, 2008) Findings suggest that people who put more emphasis on intrinsic goals than on extrinsic goals are more satisfied with life (Meier and Stutzer, 2008).

The socio-emotional selectivity theory Motivations to volunteer may change over the life course, and may for various reasons have stronger implications for health and well-being at higher age. The Socio-emotional Selectivity theory (SST) developed by Carstensen et al. (1999) has been applied to understand how motivations for social participation and benefits for health and well-being may change over the life course. SST is based on the notion that time is fundamental to motivation. As long as the individual’s time horizon is perceived as open ended, knowledge-related goals are prioritized. When time is perceived as limited, emotional goals become more important. Applied to voluntary work, it suggests that older people more often volunteer because of the “warm glow” and the joy of helping others, whereas voluntary work in younger people will be more often motivated by improving skills and acquiring new knowledge. Evidence for the SST is provided in a meta-analysis of 16 studies examining age differences in motivations. It concluded that when age increases, motives to volunteering are less often directed to career and knowledge development, and more often to social connectivity (Okun and Schultz, 2003). Van Willigen (2000) also observed that older people more often do church-based participation and senior center participation than younger volunteers, which may reflect a shift in motivations when people become older. At the same time, older people may also encounter fewer situations in which they feel morally obliged to do voluntary work; younger adults tend to have family responsibilities that requires them to do some voluntary work. Hence, volunteering may become more voluntary with higher age (Van Willigen, 2000).

A resources perspective Wilson and Musick (1997) formulated an integrated theory of volunteer work based on Bourdieu’s conceptualizations of different types of capital (Bourdieu, 1986). They argued that doing voluntary work requires three kinds of capital. Human capital are the individual resources that enable or facilitate voluntary activities, such as education, skills, income, health, time, and social status. Which resource is most appropriate depends on the type of activity. Social capital refers to the social connections people have. Social connections that are particular relevant are those that can provide information about voluntary work or connect people to voluntary organizations. More connections also increase the likelihood of becoming a helper, as it broadens the pool of people that may need help. Finally, cultural capital is the extent to which societal norms and values towards social participation and altruistic behaviors promotes such activity and has been internalized by the individual. This theory provides convincing arguments for the often observed demographic variation in volunteering, but less so for helping others. While more human, social, and cultural capital increases the likelihood of doing organized voluntary work (such as for clubs and associations), it does not explain the informally oriented voluntary work such as helping others, which is primarily determined by gender, education, and health (Wilson and Musick, 1997).

Cost-benefit or rational choice perspective The cost-benefit perspective on volunteering and social participation assumes that people choose to participate as long as the benefits of the activity exceed the costs. If costs increase, for example due to limitations in health or other personal resources, and finally exceed the benefits, people will disengage from social participation. It is argued that the benefits of volunteering are optimal when there is a balance between the costs and benefits of volunteering. Higher costs than benefits may lead to stress and dissatisfaction (Van Willigen, 2000; Morrow-Howell et al., 2003b). This line of reasoning has its origins in rational choice theory (Coleman, 1990). However, people’s rationality have boundaries (Coleman, 1990; Boudon, 1998). Making an optimal choice also requires a complete

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overview of alternatives and their consequences, which is rare. Hence, rational choice theory may be not be valid in all circumstances. Moreover, a too simplistic view on the cost-benefit approach of human behavior may be misleading (Green and Shapiro, 1994).

Selective optimization with compensation One key theory within gerontology is Baltes’ theory on Selective Optimization with Compensation (SOC) (Baltes, 1997; Baltes and Baltes, 1990). This theory contributed to discussions about successful aging, in particular concerning the fourth and final phase of life. In SOC it is argued that in order to manage the accelerated increase in functional limitations and morbidity, people should select only a limited number of activities and try to optimize these such that higher levels of functioning can be attained, to compensate for the losses in other domains of functioning. Applied to voluntary work and helping others, SOC suggests that people may indeed reduce the number of voluntary activities while intensifying the activities that are continued, to compensate for the losses and optimize the selected activities (Gottlieb and Gillespie, 2008b).

Macro-Level Perspectives on Social Participation According to theories on macro-level influences on social participation, patterns of participation vary depending on welfare regime and cultural and institutional frameworks. The structural functionalistic perspective provides some clues for country-differences in social participation. This perspective entails that macro-level factors (e.g., norms and values, economic conditions, and welfare provisions) influence individual behavior and opportunities and motivations for social participation. For example, societies or neighborhoods with a strong cohesion may exert more pressure on individuals to comply with prevailing norms and values. In countries where doing voluntary work is the norm, or highly valued, individuals may thus be more inclined to do voluntary work. In addition, stronger welfare states may prevent or reduce barriers to involvement by providing adequate healthcare and social services, income and housing conditions, public transport, support to family caregivers, and better neighborhoods. Such measures may promote better conditions for social participation especially among elderly with health limitations or low socio-economic resources. Trust may be another macro-level social factor that has particular relevance for voluntary behavior (Tonkiss and Passey, 1999). Trust and social participation reinforce each other; while trust determines or promotes volunteering and other forms of social involvement, such activity in turn fosters trust (Putnam, 2000; Bekkers, 2012). Political upheavals, economic insecurity and greater socio-economic inequalities in certain countries may also erode feelings of trust and social integration, which in turn may increase the risk of excluding people from participating in society (Hansen and Slagsvold, 2016; Rokach et al., 2001). Given the prevalence of these problems among seniors in the Eastern European countries (Hansen and Slagsvold, 2016), one would expect low rates of social participation in this region. Differences in macro social factors may also moderate the health effects of late-life social participation, as discussed by Hansen and colleagues (Hansen et al., 2018). The authors suggest that the degree to which social participation is encouraged, supported, and practiced may matter. For example, in countries where voluntarism is more normative and prevalent, such as the Northern European countries, the activity may be especially rewarding because people may derive satisfaction and self-approval by conforming to social norms. Volunteers in a low-volunteering country may not experience the same social recognition and moral rewards. Furthermore, in low-volunteering countries, those who contribute may not expect their contribution to be reciprocated, which is found to be a condition for positive benefits of volunteering (McMunn et al., 2009). Similarly, in these countries, the fact that few others volunteer may generate feelings of unfairness and resentment among those who are active in this way. These notions aside, arguments can also be made for the benefits being lower in high-volunteering countries and stronger welfare states. In these countries, volunteers may feel less neededdif they do not deliver the services, the state or someone else will (Haski-Leventhal, 2009). Concomitantly, in low-volunteering countries, the few who volunteer may feel more special and receive more favorable social feedback. It may also be that in these countries, perhaps because of missing infrastructure for volunteering, only those who are highly motivated and most likely to benefit from volunteering actually volunteer. Hence, in these countries a strong association between well-being and volunteering might reflect selection into volunteering rather than causal effects. In sum, it is an empirical question whether and how the benefits of volunteering vary across nations and by different macro-level characteristics.

Life Course Perspective on Social Participation To achieve a more complete understanding of how social participation correlates with age, country, and health and well-being, a life course perspective (Elder, 1998) has been adopted by a number of studies (Rowe and Kahn, 1998; Butrica et al., 2009; Bukov et al., 2002b; Li and Ferraro, 2006; Principi et al., 2016). This perspective proposes that an individual’s social participation is shaped by conditions, opportunities, and decisions in earlier life phases, and that social participation and its outcomes vary by historical time and place. According to the theory, participation should vary by institutional aspects of the life course such as norms, values, and policies, and thus show great variation across societies. A key element of the theory is the notion of “linked lives”dthat developments in a person’s life are interconnected with events in other people’s lives. Life course transitions, such as the transition from education to work or from work to retirement or care, may be of particular importance for understanding social participation and its outcomes. In other words, because advantages and disadvantages early in life tend to accumulate over the life course (Dannefer, 2003; Ferraro and Shippee, 2009) and heterogeneity in social participation may intensify in older age. A life course

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perspective often builds on existing knowledge about micro- and macro-level influences on social participation. For example, in a sample of very old Germans, it was observed that current levels of social participation was the result of a cumulative process. People with higher education were more active in social activities and also more active in political activities (Bukov et al., 2002b).

Concluding Remarks This article focused on volunteering as an important aspect of social participation in older age. We provided empirical evidence about the prevalence of social participation in older age, how it varies between people and between countries, and also within a person’s life. We discussed a number of key social and psychological theoretical perspectives on social participation to provide meaningful interpretations of the empirical findings. What appeared is a complicated picture, in which social participation is the resultant of individuals’ decision to participate, stimulated by different motivations or needs that can be fulfilled by the involvement, facilitated by different types of individual resources (education, social connections, financial capital) and modified by the macro-social context. Depending on the perceived benefits and costs of the participation, the changing motivations for social participation, and changes in the different forms of capital, people may decide to change the types and frequency of voluntary activities over the life course or optimize fewer commitments to compensate for losses incurred when they get older. The picture becomes even more complicated when considering that better health and well-being is not only a consequence, but also an antecedent of social participation. In other words, while social participation may influence health and well-being, healthier and happier people are also more likely to select voluntary work (Rowe and Kahn, 1998; Morrow-Howell, 2010; Li and Ferraro, 2006; Principi et al., 2016). The few studies that examined both causation (social participation improves health) and selection (those in better health are more likely to select or be selected for voluntary work) conclude that associations between social participation and health are bidirectional. For example, Thoits and Hewitt (2001) evaluated two waves of the Americans’ Changing Lives study and observed both causation and selection between formal volunteering and various aspect of well-being. Similarly, Li and Ferraro (2006) observed that volunteering lowered depressive symptoms, and people with more depressive symptoms were less likely to do voluntary work. Based on another sample of older Americans, Hao (2008) found that, controlling for selection, people doing formal voluntary work had lower rates of mental health decline, which lends support to the causation hypothesis. Hence, the current state of research is that there is substantial evidence for a positive effect of volunteering on well-being, and that there might be also selection of people with higher socioeconomic resources, health, and well-being into voluntary work.

Consequences for Policy and Practice Given the complexity of influences on social participationdthe nexus between, on the one hand, individual resources, motivation, and competency and, on the other hand, social context and welfare state provisionsddeveloping effective interventions to enhance social participation is not an easy task and probably requires tailored made solutions. Although many governments have adopted active aging policies to combat the consequences of the growing unbalance in the old age dependency ratio they may be emptyhanded when it comes to stimulating older adults to spend their time and energy on social participation to the benefit of local communities and the larger society. Despite the already respectable volume of voluntary work provided by older adults, there is still a large number of older people not involved in voluntary work despite the intention to volunteer (Dury et al., 2015). There seems to be an untapped potential in particular among less educated and socially integrated groups, and people with health problems. Their lower participation may reflect their own lower interest or capability, but could also stem for systemic practices in the recruitment of voluntary organizations. Typically, organizations have not implemented practices to target or to accommodate for marginalized groups. Canada is an interesting exception, as they recently have introduced several initiatives to promote social participation particularly in vulnerable and low-participating groups. Examples are the Personalized citizen assistance for social participation (individual intervention with volunteers), Lifestyle Redesign (a group intervention with occupational therapists), and age-friendly communities (population intervention on policies, services and structures). For aging individuals and societies it is important to promote and facilitate social participation of older adults. For poorer countries in particular, keeping active aging high on the agenda at a time of great economic strain will be no mean feat, but nevertheless important to improve population health and to reduce health inequality. Besides, active and happier people generally are more socially engaged and prosocial in their behavior, which in turn may bolster mental health in their social network and community.

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Further Reading Principi, A., Jensen, P.H., Lamura, G., 2014. Active Aging, Voluntary work by older people in Europe. Policy Press, Bristol UK. Age, U.K., 2011. Older people as volunteers. Evidence review. AgeUK, London. www.ageuk.org.uk. Eurofound, 2011. Volunteering by older people in the EU. Publications office of the European Union, Luxembourg. Gerteis, M., Winston, J., Stanton, F., Moses, S., Grodner Mendoza, T., Roberts, M., 2004. Reinventing aging: Baby boomers and civic engagement. Harvard School of Public Health-MetLife Foundation Initiative on Retirement and Civic Engagement, Cambridge, Mass.

Social Security Systems and Life Expectancy Domantas Jasilionis, Laboratory of Demographic Data, Max Planck Institute for Demographic Research, Rostock, Germany; and Demographic Research Centre, Vytautas Magnus University, Kaunas, Lithuania © 2020 Elsevier Inc. All rights reserved.

Introduction Modern Welfare States and Social Security Systems: Increasing Challenges? Changes in Welfare State and Life Expectancy Complex Pathways Between Welfare State Policies and Individual Health Outcomes Discussion Acknowledgment References

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Introduction Social security or social protection usually refers to a range of state-supported wealth and social transfer programs covering all major social domains such as social insurance and labor market regulations (Eikemo and Bambra, 2008). The instruments of these support programs designed to protect individuals in various life circumstances (often involving partial or full losses of income) include cash benefits and providing social services. An important dimension of social security systems concerns old-age pensions, which are designed to compensate the loss of income due to age. Social security system is often referred as one of the key components of a modern welfare stateda concept widely used to define and classify social regimes in post-war developed capitalist countries (Esping-Andersen, 1990, 1996). This concept is largely based on the state’s role in providing services and social transfers in all key social domains such as education, health, and social protection. In his original classification, Esping-Andersen (1990) distinguishes three main welfare state regimes (conservative, liberal, and social-democratic). This classification relies on three fundamental principles, including (a) decommodification (a degree of ability to pursue acceptable living standards without participating in labor market), (b) social stratification (policies related to social inequalities), and (c) the private-public mix in providing defining the extent of dependence of individual to the state, the family, and the market. In addition, the fourth principle of “defamilisation” was introduced by Esping-Andersen in (1999) to define whether an individual is able to pursue socially acceptable living standards independently from marital status. In order to take into account important specifics of welfare state regimes, three additional types have been defined referring to the Mediterranean countries, some countries of South Asia, and the former communist countries of Central and Eastern Europe (Esping-Andersen, 1999; Ebbinghaus, 2012). Literature highlights new emerging challenges for modern welfare states (Esping-Andersen, 1999). They are related to the consequences of fundamental demographic and economic changes, such as aging and deindustrialization (Beramendi et al., 2015; Huber and Stephens, 2015). The rapidly changing demographic and economic contexts fuel new debates about the validity of standard definitions of the modern welfare state. It has been argued that effective modern social policies must combine and keep an optimal balance between (a) the classical consumption-based policies such as employment protection policies and social transfers and (b) investment-oriented public transfers, including investments in education and science and supporting childbearing and childcare via modernized family policies taking into account the variety of family forms, equitable gender roles, and improved conditions for family-work balance (Ebbinghaus, 2012; Beramendi et al., 2015). Potential impact of social policies and welfare state provisions on variations in population health between and within countries is an important public health research issue because it allows quantifying potentials of policies targeting social determinants of health (Hillier-Brown et al., 2019). It has been suggested that welfare state is a mediator between socio-economic position and individual health (Bambra, 2006; Eikemo et al., 2008). The volume of social transfers and state-supported services (including health) plays an important role for both the magnitude of health inequalities and overall average national health (Eikemo and Bambra, 2008). Therefore, the welfare state regime classification may provide a well-suited conceptual framework to identify the effects of different types of social security systems on population health and mortality. Although it has been widely agreed that countries belonging to social-democratic welfare states (such as Nordic countries) and maintaining strong pro-equitable and universal welfare systems generally show better average health outcomes and lower health inequalities (Eikemo et al., 2008; Navarro et al., 2003, 2006), the evidence confirming such advantage using life expectancy or mortality outcomes is less consistent, especially for the most recent period. International comparisons based on typology of welfare state regimes tend to report the advantage of socialdemocratic countries in infant mortality rates, whereas less systematic relationships was found for life expectancy at birth (Bambra, 2006; Navarro et al., 2006). Therefore, mainly relying on the modernized classification of welfare state regimes by Eikemo and Bambra (2008), this chapter aims to discuss the most recent evidence about potential relationships between four different types of social security systems and the most recent changes in life expectancy in the developed modern welfare states.

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Modern Welfare States and Social Security Systems: Increasing Challenges? Discussions on modern welfare states indicate the importance of the historical context such as the reformism movement of the 19th century or the Great Recession of the 1930s (Esping-Andersen et al., 2002), The emerged three main political ideologies (Socialdemocratic, Liberal, and Conservative-Christian) are still shaping societal structures of modern high income nations as well as define peculiarities of social welfare provision (Esping-Andersen, 1990). For example, the United States and the United Kingdom are characterized by the prevailing ideologies emphasizing individual freedom and market economy, whereas Scandinavian countries refer to the prevailing social-democratic egalitarian values (Esping-Andersen et al., 2002). The third model concerns the conservative social model highlighting the role of employment and family (Esping-Andersen, 1990, 1995). On the basis of the aforementioned three principles (decommodification, social stratification, and the private-public mix), Eikemo and Bambra (2008), define the following three “classical” and three “new” or “modified” types of social welfare states: 1. Liberal/residual welfare state is characterized by high commodification, minimal welfare transfers, and low redistributions of incomes. The social security systems are often market-oriented corporative (also via private welfare schemes) and provide minimal means-tested assistance. These states are characterized by high income inequality. The United Kingdom, United States, Ireland, Canada, and Australia are often assigned to this type of welfare state. The United Kingdom, Australia, and New Zealand are sometimes assigned to the separate type of the Radical or Targeted welfare states with a significant role of various redistributive mechanisms (but still having minimal direct social expenditures and transfers) (Bergqvist et al., 2013). 2. Conservative/corporatist/Bismarckian welfare states refer to the employment- and labor-market related social policies and transfers (strongly depending on prior work experience and salary) and also highlighting the importance of family. Germany, Austria, France, Belgium, Italy, and (to some extent) the Netherlands are typical representatives of this type of welfare state. 3. Social democratic welfare regime states usually refer to the universalism-based approach ensuring equally accessible and adequate social support and income protection to all citizens. In this case, the state ensures high levels of decommodification via strong redistributive policies and pro-equitable social security systems. This type of welfare state has been prevailing in Nordic countries. 4. Southern (European) type of welfare state has been distinguished by identifying quite fragmentary (in terms of coverage and volume of support) system of social welfare and the important role of family or voluntary sectors as social support mechanisms (Ferrera, 1996). 5. Confucian welfare state refers to some countries of South-East Asia, including Japan, South Korea, Taiwan, and Singapore. These welfare states are characterized by high commodification levels, very low state interventions, and a very high role of the family in providing social support in case of emergency (especially in the case of the elderly) (Karim et al., 2010). 6. The formerly communist Eastern European welfare state regime is a recently established regime (in many cases) still undergoing reforms following the turbulent political and socio-economic transition from the state-socialist to the market economy. These countries have largely re-introduced conservative Bismarckian models with some components (or even mixture) of liberal and even universal (inherited from the communist period) principles (Cerami, 2010). The aforementioned welfare state regimes differ substantially not only in terms of decommodification as reflected by the degree of dependence from labor markets, but also in terms of instruments of social protection such as social transfers and welfare services (e.g., health care and education) (Eikemo and Bambra, 2008). Social transfers can be defined as “income maintenance programmes, social security or cash benefits” (Eikemo and Bambra, 2008). Eikemo and Bambra (2008) distinguishes five types of social transfers: (a) contribution-based social insurance; (b) social assistance (often means tested benefits for those not receiving social insurance benefits); (c) categorical benefits for specific groups (e.g., child benefits); (d) occupational benefits such as sickness, disability, and maternity benefits (often managed by employers); (e) fiscal transfers such as tax allowances. There are substantial differences across the welfare state regimes in the extent that these social transfers compensate the absence or losses of wages (e.g. due to disability) (Esping-Andersen, 1990). The welfare state regimes also differ substantially in the amount and mechanisms of compensation with some countries relating the social transfers to prior earnings (Conservative-Bismarckian regime) or providing a minimal flat rate (the Liberal regime). The welfare state regime is a dynamic concept reflecting temporal changes in contents and the importance of social security mechanisms across all welfare state regimes. The classical welfare state capitalism was flourishing during the first two-three postwar decades offering a generous public universalism-based social security and aimed at maintaining full-time employment mainly relying on the male-breadwinner model (Esping-Andersen et al., 2002). The economic crisis of the 1970s affecting many of Western welfare states led to the so called “welfare state retrenchment” (Esping-Andersen, 1999; Eikemo and Bambra, 2008). The “retrenchment” mainly reflects the shrinkage in coverage and amounts of social transfers and privatization and marketization of some welfare services such as health care provision (Eikemo and Bambra, 2008). The shrinkage in the coverage and amount of the support also concerned unemployment benefits, first of all in the Liberal welfare regime countries such as the United Kingdom and the United States (Esping-Andersen, 1999). However, the aforementioned transformations (albeit not at the same scale) took place in all welfare states, including those assigned to the Social democratic welfare regime (Eikemo and Bambra, 2008). The recent decades marking the new economic era of deindustrialization and globalization also poses new challenges to welfare states. In particular, these challenges are related to the transition of economy to high technology-based industries, which may lead to the increasing inequalities between those working in high technology sectors and low-skilled workers (Esping-Andersen et al., 2002). At the same time, the increasing orientation to pro-active labor force policies and market efficiency (also fueled by the

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2008 global financial crisis) pose a threat for the increasing marginalization of some vulnerable groups such as the unemployed (Oesch, 2015). The notable increase in female education and (consequently) employment in the context of post-industrial economy reinforced both the changes in employment structure and decline in male breadwinner industrial model (previously prevailing in the Conservative/Bismarckian welfare states) (Huber and Stephens, 2015; Esping-Andersen, 2010). Huber and Stephens (2015) identified the major modern economic and demographic challenges and striking differences across the welfare states. They suggest that employment and unemployment levels are more important stressors for the welfare states than overall economic growth rates. The social democratic Nordic countries and liberal welfare regime countries showed both the highest employment and the lowest unemployment levels, whereas the worst performance in both indicators was observed in the Southern (Mediterranean) countries (Huber and Stephens, 2015). In most cases, the Conservative-Bismarckian countries fell in between the aforementioned two extremes, mainly due to lower employment indicators of females (Huber and Stephens, 2015). The welfare state regimes also show substantial variation in demographic pressures on social security systems. For example, the countries assigned to the liberal and Eastern European regimes show the lower proportions of the aged population than the social democratic Nordic and conservative-Bismarckian regimes (Huber and Stephens, 2015; Eurostat, 2019). Although the social democratic Nordic model of welfare state is often praised as “internationally unique” due to high decommodification, highly universal income guarantees, and developed social services, it also shows some weaknesses such as high dependency on full employment and economic growth as a precondition of high taxation returns (Esping-Andersen et al., 2002). The fundamental changes in welfare state capitalism during the last decades have also led to the changes in social transfers (Huber and Stephens, 2015). In addition to direct social transfers directed to the immediate compensation of losses of income (“consumption” component), governments also started focussing on the “investment” component directed towards increasing capacity to get incomes in the future (e.g. via increasing education and improving child-care) (Huber and Stephens, 2015). According to Huber and Stephens (2015), all welfare states were generally spending much more on the “consumption” than on the “investment” component. The liberal and the Mediterranean regime countries had the lowest “consumption” spending, whereas the Nordic countries had an advantage against the remaining countries in “investment” component. Meanwhile, many Eastern European countries can be characterized as having very low levels (in both absolute and relative terms) of both types of expenditures. This is despite higher prevalence of poverty, higher social inequality, and lower average incomes than in other welfare regimes (Eurostat, 2019; Skuodis, 2009).

Changes in Welfare State and Life Expectancy The classifications of welfare states provide a plausible framework for identifying possible relationships between different welfare state regimes and national health outcomes. It has been suggested that social policies are powerful instruments in reducing the burden of social determinants of health (Marmot, 2005). The variations in the potential of different welfare state regimes to address these social determinants have been often associated to the degree of social security and its role in reducing health dependence from individual labor market position (Bambra, 2007). Fig. 1 illustrates important variations in female life expectancy at birth and at age 65 across and even within the different welfare state regimes. This figure confirms that although many studies praise the role of universal welfare and equitable policies in the social-democratic Nordic countries, the empirical evidence confirming that these social advantages automatically lead to the corresponding advantages in population health and longevity is inconsistent. First, the outcomes highlighting the advantage of these countries in infant mortality should be treated critically because child mortality at this stage of epidemiological development has a negligible impact on life expectancy. Second, the latest data suggest the worsening international longevity ranking of Sweden (Drefahl et al., 2014) and the persistence of pronounced socio-economic mortality disparities in the region (Mackenbach, 2012, 2017). Although this concerns mainly relative mortality inequalities, it has been shown that absolute mortality inequalities are also increasing (Shkolnikov et al., 2012).This unexpected observation was called the “Nordic puzzle” or “Nordic paradox”. At least partially, it was attributed to the notable compositional changes leading to the shrinkage and marginalization of lower socioeconomic classes, whereas rapidly expanding higher educated and other privileged groups benefited more from overall health improvements (Mackenbach, 2017). This evidence confirms the importance of compositional changes related to the deindustrialization and rapidly expanding high skills and technology-based economy, which pose challenges for social equity even in advanced egalitarian Nordic countries (Esping-Andersen et al., 2002). On the other hand, international comparisons point to a long-standing longevity disadvantage of countries belonging to the formerly communist Eastern European welfare state regime characterized by lower average incomes, higher income inequalities, fragmented social security systems, and overall lower social expenditures (Eurostat, 2019). These countries also show strikingly high socio-economic disparities in mortality and longevity (Mackenbach, 2017). At the same time, some Southern European and Confucian welfare states relying on quite fragmentary or even very small state interventions, but still having strong family-based support mechanisms, display both the world-highest and/or most rapidly improving life expectancies and lowest socio-economic mortality disparities (Fig. 1) (Mackenbach, 2017; Tanaka et al., 2019). Several countries assigned to the liberal welfare regime such as the United Kingdom and (especially) the United States have been recently experiencing a period of stagnation or even a decrease in life expectancy (Ho and Hendi, 2018). Fig. 1 also confirm that the most unfavorable changes concern the United States also showing substantial increases in mortality at working adult ages which are associated with “deaths of despair” due to drugs and suicide (Woolf et al., 2018). It has been shown that the United States “epidemics of midlife mortality” disproportionally affected lower socio-economic groups across all racial groups (Woolf et al., 2018; Avendano

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Fig. 1 Female life expectancy at birth and at age 65 in selected countries representing five different welfare state regimes. From The Human Mortality Database. University of California at Berkeley, USA and Max Planck Institute for Demographic Research, Germany. http://www.mortality.org/ (accessed 12.03.19).

and Kawachi, 2014; Case and Deaton, 2015). In the United Kingdom, a prolonged slow down in life expectancy improvements has been associated to the negative health consequences of austerity policies and cuts in social transfers disproportionally affecting the poorest older people (Hiam et al., 2018). On the other hand, some other liberal welfare countries such as Australia show similar progress in life expectancy as observed in the leading group of the countries (Fig. 1). The situation is also diverse in the ConservativeBismarckian countries such as France, Switzerland, and Germany. Although all these countries show moderate levels of socioeconomic mortality disparities (Mackenbach, 2017), there are important differences in average life expectancy levels with France and Switzerland showing a notable advantage against Germany (Fig. 1). Another important supplementary evidence about the relationships between longevity and welfare state regimes comes from studies examining morbidity and self-perceived health being known predictors of mortality and longevity. For example, the study examining cross-country differences in self-perceived health across 21 countries found that a type of welfare state explained approximately half of the cross-country differentials (Eikemo et al., 2008). The same study suggests that differently from the life expectancy patterns, countries with the social democratic (Nordic) and liberal welfare regimes showed a notable advantage in self-perceived health against the Southern European countries. The results for the Eastern European welfare regime were consistent, confirming the disadvantage in both life expectancy at birth and self-rated health. Interestingly, systematic reviews did not find any significant relationships between social inequalities in various health outcomes and social protection policies (Hillier-Brown et al., 2019).

Complex Pathways Between Welfare State Policies and Individual Health Outcomes An important body of evidence about the potential relationships between the welfare state regime and longevity comes from studies documenting mechanisms relating characteristics of labor markets and related policies, employment, and individual health risks. Although it has been consistently shown that the employed people have significantly lower mortality risk, recent econometric studies challenge this relationship indicating a potential role of selection, i.e., indicating that people who are losing their job differ from those keeping jobs according to a number of unmeasured health characteristics (Avendano and Berkman, 2014). In their review on the role of employment policies on individual health, Avendano and Berkman (2014) highlight the dual effect of such policies. From one side, strong social security systems offering generous income compensation in case of loss of the job may prevent the increased health risks. However, such policies may lead to prolonged unemployed episodes and, consequently, to poorer health outcomes in a longer perspective (Avendano and Berkman, 2014). On the other hand, lacking or very limited social protection in the cases of economic crises and recessions may have a disproportionally negative effect on the unemployed, leading to striking excess in mortality. For example, Lithuania who was one of the hardest-hit countries in the 2008 crisis, showed an increase in mortality differences between the unemployed and employed individuals exceeding the threefold threshold during the post-crisis period 2011–15 (Jasilionis et al., 2019).

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Other important dimensions of employment-related policies concern maternity and retirement (Avendano and Berkman, 2014). The scarce and inconsistent evidence points to the positive effects of maternity leave on mental health and to less extent on physical health (Avendano and Berkman, 2014). The review by Bergqvist et al. (2013) concludes that family benefits and a dual-earner family model are associated with better adult health, lower child mortality, and better protection from ill health for lone mothers. In a similar way, this review also suggests that higher health and social expenditures contribute better average health and lower health inequalities (Bergqvist et al., 2013). Increasing longevity and aging processes force many governments to consider reforming retirement systems, including possible increases in the retirement age. Therefore, possible health consequences of early or (especially) postponed retirement have been addressed in numerous studies. Avendano and Berkman (2014) conclude that there is no evidence that retirement harms psychical health; on the contrary, in the short term, it is associated with better mental health. However, there is still a lack of evidence confirming whether increasing retirement age would eventually lead to poorer mental and overall physical health outcomes (Avendano and Berkman, 2014).

Discussion From a first glance, welfare state concept and related typologies provide a well suited comprehensive framework for studying potential impacts of various welfare state regimes and their components such as social security systems on average longevity and longevity disparities between and within countries. This potential emerges from the fact that many components of social security aim at reducing the burden of ill health and disability (Lundberg, 2009). Theoretically, social policies and welfare state provisions should contribute to further longevity advances via addressing social determinants of health and reducing excess health and mortality in the disadvantaged groups (Marmot, 2005). However, identification of these contributions appears to be a very complicated task because of the complexity of modern welfare systems and their recent changes in response to growing demographic and economic challenges such as population aging, deindustrialization, and economic uncertainties. The findings discussed in this chapter highlight important differences in social transfers and services between different types of welfare state regimes. However, it is also true that the “classical” welfare state regime typologies are no longer valid because of recent “welfare state retrenchment,” in many cases involving important reductions in social transfers and privatization or/and marketization of some services, including social security schemes and health care provision (Eikemo and Bambra, 2008). As a result, the boundaries between different types of welfare systems tend to vanish in the context of the emerging “hybrid” welfare systems with elements from different types of welfare models. Another difficulty to establish a clear pathway between different types of welfare states and related social security systems on one side, and average population health across countries on the other side, is that the proposed classifications of welfare states rely on the main principles which often do not account for specific mechanisms of social transfers and services (Lundberg, 2008). In particular, it is difficult to establish the role of health care provision, which may show substantially different principles within the same type of welfare state regime. Nevertheless, recent life expectancy trends provide interesting insights on specific countries representing certain welfare state regimes. First, although the longevity leaders represent quite a diverse group of countries, there are some indications that the selected Confucian and Southern European welfare states are keeping leadership (together with the conservativeBismarckian France and Switzerland). Interestingly, this spectacular progress resumes and even accelerates in the countries having fragmented social security systems. Taking into that the life expectancy improvements mostly rely on health and mortality improvements at older ages, it is possible that the leading role of these countries can be at least partially explained by the traditional importance of social support from families and strong social networks. Second, the social democratic Sweden and (especially) Denmark as well as some conservative-Bismarckian welfare system countries, including the largest European country Germany, show a slowdown in longevity improvements. The increasingly disadvantaged position of the former longevity vanguard Sweden is mainly attributable to the lack of mortality improvements at older ages which may signal about growing health or even social problems at these ages. The lack of longevity progress in Sweden and Denmark should be considered as a warning sign for the sustainability of social democratic social provision systems in the Nordic region. Third, a striking reversal in life expectancy in the United States as well as a prolonged stagnation in the United Kingdom (the both representing the liberal welfare states) may indicate more fundamental societal problems, at least partially attributable to unfavorable changes in income and social inequalities as well as lacking or declining social support mechanisms in these countries (Avendano and Kawachi, 2014; Case and Deaton, 2015; Hiam et al., 2018). Identification of the relationships between social insurance programs and various health outcomes maybe much more difficult than in the case of corresponding relationships between these programs and other social outcomes such as poverty (Lundberg, 2008). Because comparing the basic principles of different social welfare regimes may provide only very descriptive insights, it has been recommended that future research should focus on the contents, mechanisms, and health impacts of specific programmes such as employment, retirement or childcare provisions (Avendano and Berkman, 2014; Lundberg, 2008). Understanding complex macro-level effects of welfare policies on health and health inequalities holds an important potential for addressing modern public health issues (Lundberg, 2009).

Acknowledgment The study was supported by the Lithuanian Research Council, Grant Nr. S-MIP-17-119.

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Stem Cell Therapy Elena De Falco, Antonella Bordin, and Eleonora Scaccia, Sapienza University of Rome, Latina, Italy Carmela Rita Balistreri, University of Palermo, Palermo, Italy © 2020 Elsevier Inc. All rights reserved.

Introduction Stem Cell Therapy An Overview on Stem Cells Stem Cells as Therapeutic Agents: Limitations and Concerns Progresses and Novel Applications Bio-Nanotechnologies as Support of Stem Cell Therapies: Stem Cell Organoid Engineering Bioprinting and Differentiation of Stem Cells A New Vision in the Application of Stem Cells: Stem Cell Derived Exosomes Conclusions References

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Introduction By 2030, approximately 20% of the population will be aged 65 or older, and age-related diseases (ARD) will represent a very health problem, with the cardiovascular diseases (CVDs), that will result in 40% of all deaths and rank as the leading cause (Edwards, 2012). Consequently, the research of urgent interventions both in preventive measures and biomedicine research is imperative. Some advancements have been achieved in the last years, including primordial prevention based on healthful lifestyle (i.e., Mediterranean diet, lifestyle, and physical activity (Armanios et al., 2015). In addition, advanced procedures, such as for examples the percutaneous coronary intervention and coronary artery bypass grafting in management of coronary artery diseases, having higher prevalence and incidence in the world, have obtained a significant success (Balistreri, 2018). Despite these efforts, there are no effective solutions now, against the ARDs and their complications. In addition, numerous gaps remain between the knowledge of precise cellular and molecular mechanisms involved in the onset and progression of ARDs, and the identification of disease pathways to apply as appropriate biomarkers and targets for new and more efficient therapeutic treatments, that is, personalized therapies. Thus, biomedical community is pursuing new ways in trying to face this imposing challenge. Specifically, the latest discoveries and advanced knowledge in the fields of stem cell biology and their ability to provide a cue for counteracting several diseases are leading numerous researchers to focus their attention on the Regenerative Medicine (RegMed), as possible solutions for ARDs (Balistreri, 2018). However, a critical analysis of the current status of RegMed field appears unfavorable, by evidencing its unproductive application in clinic therapy. Effectively, RegMed is yet to bring about the therapeutic revolution, that it awaited already before its birth. After about two decades of extremely high expectations and often disappointing returns both in the medical as well as in the financial arena, this scientific field reflects the sense of a new era and suggests the feeling of making a fresh start, although many scientists are probably seeking a reorientation. Much of research was industry driven, so that especially in the aftermath of the recent financial meltdown in the last years it has witnessed a biotech asset yard sale. Despite any monetary shortcomings, from a technological point of view there have been great leaps that are yet to find their way to the patient. RegMed is bound to play a major role in our life, because it embodies one of the primordial dreams of mankind, such as: everlasting youth, flying, remote communication and setting foot on the moon. The scientific journals have been the voice of these developments in RegMed from its beginning, and currently reflect the recent scientific advances in this field. Therefore, the idea of our chapter is in describing the advantages, progresses and limitation in this field, that might just be like looking ‘back to the future.’ Thus, the principal message of this chapter stays in suggesting that “we are almost there,” being able to produce tissue replacement ‘off the shelf,’ and soon for everyone in need. However, it currently appearsdliterally spokendthat we can fabricate constructs that ‘look like tissue, smell like tissue and taste like tissue’ but not some that also function equally like one. A continuous evolution in the research and application is yet to bring the long-awaited revolution in the health area. More critically spoken, some researchers and physicians have proclaimed that the time must come to ‘stop tissue engineering and start engineering tissues.’ In order to achieve this goal, these measures are needed: (1) considering the advances and the limitations of this field; (2) re-examining the data obtained and controversies (3) in order to filter them and (4) to put together only the valid parts (5) for constituting a clear puzzle by using standardized research methods and methodologies; (6) this will be useful for pursuing innovative ways through a strong cooperation among scientists, physicians, administrators, and public officials. Obstacles might be diverse, and the road might be hard and long, but the advances obtained might be numerous and offer us greater and unique opportunities to meet the imposing challenge of ARDs.

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Stem Cell Therapy Stem cell therapy represents a new class of medicine, and precisely one of the most crucial approaches of RegMed (see Fig. 1). Ever since their discovery and initial isolation, the scientific community has embraced stem cells as potential candidates for a therapeutic approach to chronic diseases, ARDs, that moves from disease management toward a regenerative framework. However, this strategy is not new, since it has already been successfully applied in the clinic area in the form of organ transplantation. Organ transplantation provides the possibility to replace malfunctioning organs with unscathed donor organs, that can take over the functions and to improve and extend the life’s quality of the patients. However, this approach is severely hindered by the shortage of donor organs, and, therefore, it will never become a viable medical treatment option for most patients. Thus, progression and refinement in terms of both the isolation and culturing procedures of stem cells over recent decades have reopened the door for RegMed approaches, in hope of healing the chronically damaged organs of patients who are on a transplant waiting list (Heidary Rouchi and Mahdavi-Mazdeh, 2015). Regarding stem cell therapy, it needs to stress that it has different features from drug therapy, or other types of RegMed therapies. It is based on cells, and they represent the most complex biopharmaceuticals. Protein or gene therapies are based on relatively simple macromolecules, and they are ideally appropriate to target a single defect, rather than eliciting a complex biological regenerative response (for which stem cells seem to be better suited). Cells are more complex, being formed by different and numerous proteins, and by an entire genome. In addition, they are dynamic in their phenotypes and activities, by interacting with their microenvironment and responding to systemic stressors. These features offer limitations in their application. Upon transplantation, the transcriptome, proteome, and even secretome profile of cells can, indeed, change, thereby varying their functional capacities respect with those observed in vitro upon initial culture expansions. All these observations evidence, on one hand, that cells are unique multidimensional therapeutic treatments well-suited for a RegMed approach. On the other hand, it also stresses that cells are a complex and challenging entity that remain to study and apply (Heidary Rouchi and Mahdavi-Mazdeh, 2015). Accordingly, stem cell therapy shows unique properties when compared with other RegMed approaches or standardized drug treatments. Firstly, it reduces the capacity to discovery an appropriate pharmacokinetics for each type of cell therapy, that is essential for its outcome. Specifically, the methods of administration vary than those for a drug. The preferred drug way is oral administration. For cell therapies, it is not favorable, because cells do not survive in the acid environment of the stomach, and even less so in the intestine. A more appropriate administration way for cell therapies might be into the circulation, by means of an intravenous injection, such as for the hematopoietic stem cells (HSCs) therapy in cases of leukemia treatment (Heidary Rouchi and Mahdavi-Mazdeh, 2015). However, it shows many obstacles prior to the arrival of cells in the specific damaged organ or tissue. Consequently, local strategy might be more advantageous, even if it can be difficult to bring the cells to a preferred location in order to avoid injecting them into a remote region that is too far from the injury or deprived by oxygen and nutrients (Feyen et al., 2016).

Fig. 1 Regenerative medicine. An emerging branch of translational medicine focused on the repair, replacement or regeneration of cells, tissues or organs to restore impaired function resulting from any causes, including congenital defects, diseases, trauma and aging. Stem cells are the cornerstone at the heart of regenerative medicine and might provide the potential solution for human diseases. However, use of stem cells as drugs for diseases, that is stem cell therapy, requires several steps as well described in the picture.

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Furthermore, the pharmacokinetics of cell-based therapies show other difficulties, including: (a) the inability to monitor the biodistribution of stem cells after their administration; (b) the survival of stem cells in the damaged tissues, that is very difficult (cellular therapeutics delivered into ischemic myocardial tissue arrive in a hostile inflammatory milieu, and are therefore susceptible to proapoptotic signaling); and (c) engraftment and integration (in case for example of cardiac stem therapy, engraftment is only the first step toward remuscularization, since subsequent organization and proper tissue integration are critical for the participation of engrafted cardiomyocytes in heart repair) (Feyen et al., 2016). These restrictions have led the researchers to develop delivery strategies to enhance the retention, survival and integration of stem cells. Approaches utilizing pharmacology, genetic manipulation, biological or material incorporation have been implemented to improve these aspects (see below). However, the pharmacokinetic proprieties of cells are not the exclusive aspects to consider for the further improving stem cell therapies, since therapeutic action can also be addressed by modulating the performance of stem cells. All these observations highlight the fact that the early promise of stem cell therapy to repair the damaged organ by injecting different cell types has not yet been satisfied. For improving stem cell therapy, an important feature to consider in the stem cell therapy is the capacity of the injected cells to produce and secrete a pleiotropic repertoire of factors. These factors can influence the cellular micro-environment and thereby help the stressed tissues. As result, stem cell therapy becomes a complex delivery tool for reparative biological drugs. First-generation cells, including bone marrow (BM) stem cells and their secretomes, are mainly aimed at cellular salvage and at stimulating the endogenous repair mechanisms of the damaged organs through pro-angiogenic or pro-survival activities. However, the application of these cells in the clinic area has never achieved the expected level of results. Future studies will need to address the underlying poor pharmacokinetic properties, in order to bolster the effects of these first-generation paracrine therapies. Furthermore, the manipulation of cells to rejuvenate the patients’ own cells or to enhance paracrine action are also exploring. This will lead to the application of stem cell therapy as a complex delivery tool in which the slow release of reparative signals is further enhanced. The paracrine effects will boost endogenous repair mechanisms to maintain organ homeostasis. Overall, a shift from the initial pragmatic delivery approaches toward tailored delivery strategies aimed at improving pharmacokinetics by using pharmacodynamics properties, that will consent their clinical application. However, once optimal strategies are developed, they can be coupled with technologies that have been developed over the last decade of stem cell research. Furthermore, recent clinical trials have helped to train clinicians for the delivery of cells into the organs and lay a foundation for cell therapy work in many medical centers around the world. These advances will help expedite the transition of future cell therapies toward patients. Although cellular therapeutics have failed to survive to their initial hype, careful re-evaluation of their mode of action and steps to address the current pitfalls should help to unlock the vast potential of stem cells, and help them to reach the clinic in a timely fashion. Furthermore, the research community is also focusing its attention on progenitor cells as optimal candidates. Among these, bone marrow (BM)derived endothelial progenitor cells (EPCs) are emerging as candidates for several applications (Feyen et al., 2016).

An Overview on Stem Cells Stem cells and progenitors have been considered as potential candidates for stem cell therapy. For a better understanding of this topic, it briefly reports what it intends for stem cells. Stem cells are defined as undifferentiated cells with the potential to renew themselves, and to differentiate into any other specialized cell of human body, and, therefore (potentially and theoretically), to create any tissues or organs. Under specific conditions, stem cells can, indeed, differentiate into a diverse population of mature and functionally specialized cellular types. To date, different classes of stem cells are recognized. Among these, in the first class, there are the totipotent cells, which have the capacity to differentiate into embryonic and extra embryonic cell types, thereby generating entire organisms, even if this capacity is limited to cells produced by the first few divisions after fertilization. Pluripotent stem cell types are another class. They can differentiate into all embryonic cell types and form ectoderm, endoderm and mesoderm cell lineages, but not into extra embryonic cell types, and thereby they can form all the cell types of an adult organism. Finally, there is the class of adult multipotent/unipotent stem cells, often termed progenitor cells, which can only differentiate into several closely related cell types (Stoltz et al., 2015). Several cellular types have been and are currently investigated and applied in RegMed, including BM-derived mononuclear cells (BM-MNCs), peripheral blood mononuclear cells (PBMCs), mesenchymal stromal cells (MSCs), embryonic stem cells (ESC), induced pluripotent cells (iPSCs), and organ-specific stem cells. Among these cells, ESCs and iPSCs exhibit nearly unlimited potential to differentiate in vitro and in vivo, but their applications are limited by ethical, legal and political concerns, as well as by scientific and clinical issues of safety and efficacy (Stoltz et al., 2015). Therefore, tissue-specific stem cells derived from adults offer alternative approaches that circumvent many of these concerns. However, stem cells for RegMed applications should be consistent with the following criteria (Stoltz et al., 2015): U U U U U U U

Can be found in abundant numbers Can be harvested by a minimally invasive procedure with minimal morbidity Can be differentiated along multiple cell lineage pathways in a controllable and reproducible manner Can be safely and effectively transplanted to either an autologous or allogeneic host Can be produced in accordance with current “Good Manufacturing Practice Guidelines”

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Based on these criteria, alternative and more efficient candidates for RegMed applications are represented by cells of human adipose tissue, that can be collected in large quantities (Lindroos et al., 2011). Human adipose stem cells (ASCs) are an abundant cell source with therapeutic applicability in preclinical studies in diverse fields, due to their ability to be readily expanded and their large capacity to differentiate in vitro in several cell types, from the adipogenic type to osteogenic, chondrogenic and neurogenic varieties. Furthermore, ASCs have been shown to have immune-privilege and to be more genetically stable in long-term culture, when compared with BMSCs. The safety and efficacy of ASCs for tissue regeneration or reconstruction is currently under assessment in clinical trials (Lindroos et al., 2011). The number of trials investigating the efficacy of treating conditions such as Type I and II diabetes, liver cirrhosis and regeneration, fistulas, CVDs, limb ischemia, amyotrophic lateral sclerosis and lipo-dystrophy have risen rapidly, even if a very limited number has been completed (http://clinicaltrials.gov). Furthermore, ASCs are also under examination in clinical case studies for graft-versus-host disease, immunosuppression (rheumatoid arthritis, Crohn’s disease and ulcerous colitis), multiple sclerosis, soft tissue augmentation and bone tissue repair. Clinical bone tissue reconstruction studies using autologous ASCs are also ongoing (Lindroos et al., 2011). Currently, other potential candidates for RegMed cell therapy are emerging, including progenitor cells from BM or other tissue niches. Among these, EPCs are emerging as new therapeutic agents for several age-related diseases. They also represent the most widely studied adult human progenitor cell subpopulation up to now. The interest of the research community on EPCs arises from advances, over the last decade or so, relating to the discovery of postnatal vasculogenesis (called neoangiogenesis), which is brought about by circulating progenitor cells, capable of differentiating into mature blood vessel endothelial cells. Thus, EPCs and their biology constitute a common point of interest for physicians and basic scientists with the goal of translating their research into clinical application by using the innate reparatory mechanisms of the heart and vascular endothelium, as well as of other organs (Balistreri et al., 2015).

Stem Cells as Therapeutic Agents: Limitations and Concerns The clinical application of stem cells as therapeutic agents has a reduced validity limited by different factors: (a) the small number of patients enrolled in the major number of studies, their randomization not blinded, the involvement of few centers, (b) the exact phenotypic profile of cells used for the treatments which is always not indicated or missing, (c) the different administration ways and methods used, and (d) the safety and feasibility of the treatments not proved by long-term follow-up results. Teratoma formation, immunoreactivity, or other negative effects may represent the adverse effects of these treatments. Accordingly, the genetic and epigenetic instabilities of stem cells present a recurring obstacle to progress in RegMed using this approach. Various studies have stated that these instabilities can transform stem cells when transferred in vivo, developing tumors. Previous research has shown that various extrinsic and intrinsic factors can contribute to the stability of stem cells. The extrinsic factors include growth supplements, growth factors, oxygen tension, passage technique, and cryopreservation. Controlling these factors based on previous reports may assist researchers in developing strategies for the production and clinical application of “safe” stem cells. On the other hand, the intrinsic factors can be unpredictable and uncontrollable; therefore, to ensure the successful use of stem cells in regenerative medicine, it is imperative to develop and implement appropriate strategies and technique for culturing stem cells and to confirm the genetic and epigenetic safety of these stem cells before employing them in clinical trials (Stoltz et al., 2015). In addition, there are other limitations in the large-scale clinical use of stem cells and their progenitors, such as EPCs (Lindroos et al., 2011). For example, in the ample number of cases, their progenitors are relatively rare cells, and expansion in enough subpopulations from peripheral blood is hardly possible. Furthermore, in vitro enumeration of progenitor cells for an appropriate quantity for a therapeutic treatment is associated with changes in phenotype and differentiation and risk of cell senescence and it may require artificial cell preactivation or stimulation (Stoltz et al., 2015).

Progresses and Novel Applications To date, stem cells can be considered as a drug and therefore similarly to a pharmacological treatment, as abovementioned. From this point of view, they have been employed for several clinical purposes and mainly in the oncology, cardiovascular and regenerative medicine field (Siciliano et al., 2015). Although, several clinical applications have been tested, not all stem cells have provided the benefits hypothesized. This limitation can be likely ascribable to our poor understanding of the biological interactions between microenvironment and stem cells once injected and to a wide range of negative or positive dynamic changes, which often hamper stem cells to properly engraft, differentiate and function within the tissue (Spaltro et al., 2016). Besides, immune response can severely influence the exogenous treatment with stem cells, although in some body districts such as retina, ESC-derived retinal neurons have been found integrated within the tissue even after 3 months (Chao et al., 2017). The interplay with the recipient’s tissue and the alterations of the stemness is more evident for certain stem cell populations as for MSCs reported to both enhance and suppress cancer progression especially by epithelial-mesenchymal transition process (Gloushankova et al., 2018). The capacity of stem cells to function as a drug or gene carrier has been largely demonstrated in MSCs and mainly for specific clinical use including wound healing, cerebral cancers, bone reconstruction (Wu et al., 2019). Nevertheless, the urgent need to deliver the biological potency of stem cells only where the insult occurs and even if systemically administered, have shifted toward the combination with nanoparticles, synergizing the beneficial effects of both. Organic or synthetic nanoparticles acts as nanocarriers for stem cells or their soluble mediators or protein derived. The small size and the low toxicity of nanoparticles facilitate to decrease the

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potential immunogenic or tumorigenic reactions of stem cells and to empower their function. In this novel technological and always more sophisticated scenario, some stem cell populations are more investigated than others, based on the natural ability to act as carrier such as blood stem cells (Kato et al., 2016). Mesenchymal stem cells are equally and largely employed, due to their phenotypic plasticity, versatility and no induction of teratoma compared to ESCs or iPSCs, as above stressed and evidenced at least so far (Cooper, 2013; Suryaprakash et al., 2019). Although several clinical trials employing MSCs alone, in combination with growth factors, seeded on scaffolds or gene modified, have been tested, the new frontier of the nanotechnologies attempts to address stem cells or their products directly to the site of injury in a more accurate fashion (Sadhukha et al., 2014). To boost the tumortropic ability of MSCs, engineered MSCs and nanocomposites have been integrated and tested in a mouse model of glioblastoma showing high retention ability in the tissue and improved chemotherapeutic drug delivery (Suryaprakash et al., 2019; Wang et al., 2019). The MSC-based cancer tropism has been exploited in other tumors, such as lung cancer, where a similar approach based on a combination of MSCs and loaded nanoparticles with specific cancer drugs avoids the sole entrapment of stem cells within the lung and it increases the suppressive effect on cancer compared to the sole injection of nanoparticles (Wang et al., 2019). In different lung pathologies, the effect of the all trans retinoic acids in the form of solid lipid nanoparticles has been evaluated over the time, demonstrating a comparable efficacy to MSCs (Payne et al., 2019). Metastatic progression has been reduced by gene transfection of MSCs in a model of DNA nanoparticle and spermine pullulan (Payne et al., 2019). The versatility and the chemical composition of nanoparticles have become extremely important to drive stem cell behavior. In fact, if nanoparticles are loaded with drugs or specific molecules, they can be incorporated by stem cells trough endocytosis and once in the tissue, cells can release them over the time in a more physiological fashion. This property has been mainly exploited for MSCs and several antitumoral drugs, demonstrating a better efficacy compared to a mere combination of MSCs and drug in situ (Payne et al., 2019; Levy et al., 2016). The same studies have also highlighted that this approach would not alter MSC stemness. For instance, mesoporous silica nanoparticles (organotic compound) influence the stemness of human melanoma cell line, activating caspase-dependent pathways and modulating stem cell gene expression (Maksimovic-Ivanic et al., 2019). More importantly, stem cell-derived molecules can be also intrinsically considered as drug delivery methods. The combination of gold nanoparticles and X-ray computed tomography has been applied to track the in vivo path of MSC-derived exosomes in the brain area of murine models with cerebral disorders or stroke, highlighting the relevance of proinflammatory signaling to address homing, tissue regeneration and drug delivery in organs more difficult to treat such as the brain (Perets et al., 2019). An even more advanced approach is represented by the stem cellderived membrane coated nanoparticles, which would allow maximizing the paracrine ability of progenitor cells without their direct injection. This strategy based on the stem cell secretome encapsulated in microparticles made of golden, nanogel or different polymers and proteins but with a biological stem cell membrane obtained, would act as a quantum release of soluble mediators in situ. Injection of stem cell-derived membrane coated nanoparticles (for instance endogenous cardiac progenitor cells) in murine model of myocardial infarction, have successfully demonstrated the recovery of the fibrotic scar, a decrease apoptosis and the enhancement of the angiogenic process (Avolio et al., 2014; Li et al., 2012; Luo et al., 2017).

Bio-Nanotechnologies as Support of Stem Cell Therapies: Stem Cell Organoid Engineering Bioprinting and Differentiation of Stem Cells Current strategies employing stem cells in three-dimensional (3D) systems are revealing extremely promising, not only as study models, but mainly as significant tools to better mimic physiological micro-niches as well as pathological scenarios (specifically, oncology and regenerative medicine), often difficult to accurately reproduce in vitro. The need to switch from two (2D) to 3D systems origins from the phenotypic and functional decline observed in stem cell cultures over the time, also hampering the prospect to evaluate the effects due to long-term stimuli. Three dimensional-based approaches seem also to improve metabolism and to enhance gene expression and cell fate, angiogenic secretome and stem cell engraftment in the recipient tissue when transplanted (Kim et al., 2018; Cesarz and Tamama, 2016), strengthening the importance of geometry and spatial arrangement of stem cells and critical to determine cell–cell signaling and interactions. From a biological standpoint, stem cell organoids are currently studied for two main reasons: drug testing and differentiation studies. 3D models employing stem cells can be useful to predict the pharmacological response before a stem cell-based therapy or simply to design the best drug regimen for patients (Mawad et al., 2017; Perkhofer et al., 2018). Stem cell differentiation represents a main gold standard of any clinical treatment. Hence, stem cell-based therapies provide tissue regeneration, only when a proper differentiation program is enough enhanced, and engraftment of progenitor cells in the tissue is achieved in order to restore organ function. The microarchitecture within the 3D system parallel to mechanical stimulation has been demonstrated to improve stem cell fate as reported for human MSCs (Poudineh et al., 2018). Notably, there are still opposite reports on the need to predifferentiate stem cells before assembling into 3D constructs. No difference has been found between in vitro pre-differentiated and undifferentiated stem cells (Gruene et al., 2011). Nevertheless, many reports (on MSCs) have demonstrated that the predifferentiation enhances the efficiency of 3D constructs (Binder et al., 2014), suggesting that the type of commitment required, and the nature of the stem cell population might represent a key issue to consider. A mandatory step of stem cell differentiation, often hampered because of the paucity of the starting material, also requires expansion of progenitors. The 3D systems increase either cell proliferation by decreasing senescence and the chance to expand only selected progenitor fractions which are difficult to isolate and to culture by conventional 2D methods (Underhill and Khetani, 2017). Accordingly, nano-scaffolds of synthetic materials well support stem cell self-renewal, growth and higher purity compared to 2D models especially for HSCs which normally require a considerable number of cells for clinical applications

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(Mehrasa et al., 2014). Additional genetic manipulations of stem cells in the form of organoids are also feasible. Three-D liver cell cultures have been transduced with adenoviruses on microchip platforms aiming to control gene expression of drug metabolism enzymes (Kwon et al., 2014). Genetic modifications are also allowed when stem cells are assembled in 3D organoids. The combination of 3D systems based on ESC spheroids and CRISP/Cas9 technology to knockdown Wtn4, has been recently employed to recapitulate the kidney development in vitro (Tan et al., 2018). Other studies have immobilized hepatocytes-based spheroids on specific microarrays for the evaluation of cytochrome P450 (Fukuda and Nakazawa, 2011). Interestingly, 3D-based organoids have been also employed to increase the differentiation of a progenitor population from a second source of stem cells, as demonstrated for human ESC spheroids directly differentiated into MSCs (Yan et al., 2018). The type of stem cell can also influence the 3D technology. For instance, although iPSCs show an intrinsic ability to generate 3D structures on scaffolds (Hattori, 2014; Lei and Schaffer, 2013), however they are difficult to culture due to their complex cytoarchitecture (Konagaya et al., 2015). Recently, 3D bioprinting-based approaches (which allow to directly mix iPSCs and bioink and fostering a more physiological and enhanced self-assembling) have been developed to facilitate such process, confirming their differentiation toward several phenotypes including the neural, dermal lineage (Gu et al., 2017; Michael et al., 2013). Bioinks vary from natural ECM components (hydrogels, hyaluronic acid) to synthetic fibers (Eswaramoorthy et al., 2019). The bioprinting strategy represents an advancement of the conventional scaffold-based methodology, as it can foster multiple or parallel layer-by-layer stratification of ink and stem cells, therefore better reflecting the different cell layers normally present within a tissue also ameliorating the control of stem cell distribution and in situ differentiation in the scaffold (Gu et al., 2017; Michael et al., 2013; Eswaramoorthy et al., 2019) as demonstrated for ESCs, where even the colony size can be modulated (Dias et al., 2014). More importantly, the 3D bioprinting would also recreate a more physiological differentiation-prone microenvironment in presence of stem cells. Accordingly, bioinks can be preloaded with soluble molecules or alternatively, growth factors and cytokines can be added to the 3D construct-derived media, therefore challenging the whole system before or after its transplantation. Mesenchymal stem cells (precursors of bone and cartilage formation (Siciliano et al., 2015; Spaltro et al., 2016), can be cultured in 3D constructs and differentiated toward the osteogenic and cartilaginous phenotype by adding hydroxyapatite, TGF-b3 or BMP-6 (Siciliano et al., 2015; Spaltro et al., 2016). A further advancement of the 3D bioprinting is based on a laser direct-write, allowing a more controlled design of the size and shape of stem cells during assembling on the constructs and demonstrating that geometry can even influence drug delivery (Michael et al., 2013). Interestingly, the 3D systems allow to combine different biological scenarios: for instance, the investigation and the physical synergy between microenvironments of different origin or stem cells with other non-stem cell adult populations or the testing of a wide range of stimuli including mechanical stretch, extracellular matrix components or metabolic inputs (Gu et al., 2017). The microenvironment generated in 3D systems represents a main determinant of stem cell differentiation. By improving the raw material composition of matrix where stem cells are seeded in, it is possible to split up several signals generated into the microenvironment and to assess them singularly such as reaction of stem cells to stiffness or coculture and soluble mediators (Lei and Schaffer, 2013). Microwell devices made of hydrogels or hard materials have been designed for this purpose and to evaluate the clonal composition of single stem cells in the cultures (Lei and Schaffer, 2013). Besides, organoids represent an interesting method to test the functionality of stem cells, as recently demonstrated by transplanting a new engineered magnetic bioprinting seeded with neural crest-derived MSCs able to differentiate in the salivary gland-like phenotype and to suitable engraft in the tissue without inflammatory or adverse reactions in the recipient (Lei and Schaffer, 2013). Stem cell function can be also verified by coculture 3D systems. The combination of MSCs and endothelial cells have revealed the ability of the stromal population to switch from non-stem cell function with supporting features on angiogenesis to mesodermal differentiation around vessels of the organoid (Lei and Schaffer, 2013).

A New Vision in the Application of Stem Cells: Stem Cell Derived Exosomes Exosomes can be defined as nanosized membrane-bound extracellular vesicles representing a possible carrier of several biological information (Zhang et al., 2019). Exosomes can exert our activity locally where they are produced, playing a key role in cell–cell communication, or even at a distance, reaching faraway areas where they are able to activate a wide range of cells signaling and to influence cellular behavior and to alter tissue metabolism (Phinney and Pittenger, 2017). Both mechanisms implement and represent the foundation of their well-known paracrine effect. For these reasons, exosomes have been considered a great tool to empower regenerative therapy approaches, by including stem cell-derived vesicles, which are currently considered as bioactive component of the stem cells themselves (Khan and Kishore, 2017). Accordingly, exosomes have been isolated from multiple stem cell sources. Specifically, many studies focus on exosomes secreted by bone marrow, umbilical cord, urine, oral mucosa and adipose tissue-derived MSCs and pluripotent stem cells such as ESCs and iPSCs (Xiao et al., 2019). All reports agree that the regenerative potential ascribable to stem cells is mediated by a complex secretome including growth factors, lipids, cytokines, mRNA and microRNAs, where exosomes are recognized as main transporters (Ros¸ca et al., 2018). This heterogenous profile of soluble mediators expressed in the exosomes seems to represent a fundamental feature concerning the regenerative effects for their use in regenerative medicine (Ros¸ca et al., 2018). Accordingly, a more suitable microenvironment would be reproduced, therefore empowering the efficacy of transplanted stem cells, which would condition the recipient’s tissue, as demonstrated in cardiovascular applications where angiogenesis is restored by the indirect support of exosomes (Xiao et al., 2019; Ros¸ca et al., 2018). Besides, the microenvironment conditioned by stem cell-derived micro-vesicles are more appropriate. However, among different type of stem cells the biogenesis of exosomes, which determines their own function and characteristics, cannot be assumed as homogenous, although this requires to be fully explored. Membrane protein and types of nucleic acids have been reported to be specific to stem cell source. For instance, exosomes isolated from bone marrow express Angiotensin-1 and miR21a, whereas those secreted

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by hematopoietic stem cells (HSCs) express tissue factor (CD142) and a different range of mRNAs (Riazifar et al., 2017). Oppositely, both MSC and ESC-derived exosomes equally contain Pax-6, exert regenerative properties and cell plasticity (Ros¸ca et al., 2018; Riazifar et al., 2017). Other studies have highlighted that although ESCs and iPSCs exhibit a starting different genetic profile, however they share a similar array of long non coding-RNAs and miRNAs once differentiated into cardiomyocytes, strengthening the relevance of the degree of the differentiation achieved in culture by pluripotent stem cells rather than their intrinsic genetic profile (Ros¸ca et al., 2018; Riazifar et al., 2017). Although we could question whether a disease-specific exosome profile might exist, many stem cell-derived exosomes are efficient to restore a wide range of functions. Microvesicles obtained from ESCs can endure osteochondral regeneration in a rat model of osteogenic disorder (Ros¸ca et al., 2018; Riazifar et al., 2017), but also to attenuate doxorubicin-induced pyroptosis in muscle cells (Ros¸ca et al., 2018; Riazifar et al., 2017). It has been shown that the intraperitoneal injection in murine ischemic heart of MSC-derived exosomes reduces the infarcted zone, by increasing ATP levels, the activation of the PI3K/Akt pathway and decreasing oxidative stress (Riazifar et al., 2017). Additional and relevant effects of stem cell-derived exosomes have been associated to stem cell differentiation and reprogramming. Embryonic stem cells-derived exosomes can induce both de-differentiation and pluripotency in retinal glial and Müller cells, therefore implementing the retinogenic differentiation in retinal disorders (Ros¸ca et al., 2018; Riazifar et al., 2017). In kidney organogenesis, ESC-derived microenvironment has been reported to act as main regulator of tissue architecture (Ros¸ca et al., 2018) and to switch from malignant to benign cancer phenotype by reprogramming via proteins and RNA (Riazifar et al., 2017). Notably, the efficacy of the stem cell-derived exosomal cargo can be often ascribable to specific mediators. It has been reported that overexpression of exosomal 126-miRNA and miR-181-5p-modified promotes functional recovery after stroke in rats by increased neurogenesis and inhibition of neuroinflammation (Ros¸ca et al., 2018; Riazifar et al., 2017) and prevention of fibrosis via autophagy activation in liver, respectively (Bae et al., 2018). Different and selected ESC-derived miRNAs such as miR-291a3p exert anti-senescent effects in human dermal fibroblasts trough TGF-b receptor 2 pathway and enhance wound healing (Bae et al., 2018), suggesting a protective role. Similarly, HSC-derived miR126 can boost the ESC differentiation in the hematopoietic lineage trough the inhibition of Notch1 pathway (Bae et al., 2018). To date, the employment of exosomes in regenerative medicine can be conceivable as a cell-free therapy, whose foundation is based on two main strategies: (1) exosomes as vehicles of substances; (2) the cargo or the cell membrane of exosomes is modified in order to target specific functions and/or tissues. The abovementioned approaches have been designed because stem cell-derived exosomes act as excellent carriers and therefore they represent a more suitable biocompatible alternative than synthetic vesicles. More importantly, exosomes seem to be well tolerated and nontoxic to the organism when administered, with long half-life properties in systemic circulation and in absence of potential adverse immune effects (Bae et al., 2018). However, different studies have shown that certain types of exosomes express the major histocompatibility complex (MHC), questioning the absence of potential immune reactions (Bae et al., 2018). Intriguingly, hybrid exosomes have been recently engineered to further improve their bio-functionality. Accordingly, studies regarding cellular uptake have shown that the fusion of exosomal membrane with liposomes can modify exosome-cell interaction (Bae et al., 2018). These new approaches represent an alternative modality by which several limitations and risks associated to stem cells might be overcome. Despite this, a deeper understanding of the potency of stem cell-derived exosomes should be implemented, in order to fully exploit stem cell-derived soluble mediators.

Conclusions Although many efforts have been made to clarify the biology of stem cells, additional issues are needed to be solved. Stem cell populations share similar features, such as the ability to proliferate, to differentiate and the paracrine action, therefore altering the microenvironment. Thus, despite the apparent uniformity among stem cell populations, the genetic and protein profile is often dissimilar, as a comparison has proven for iPSCs and ESCs (Balistreri, 2018), therefore suggesting that stem cells are not equal and questioning whether in the next future we might not seek for the unique and best stem cell source for all clinical purposes. For instance, pluripotent stem cells (ESCs and iPSCs) easily but differently reprogram compared to adult stem cells (MSCs, HSCs), therefore this should be considered when used. It is also conceivable that the choice of the best stem cell source depends on the pathological scenario. For instance, bone regeneration can be achieved by employing MSCs, however it might not represent the eligible choice if a bone tumor occurs. Thus, the disease, the tissue involved, the physiology and the intrinsic capacity of the organ to regenerate could eventually dictate the choice of the most suitable stem cell source to employ. Accordingly, tissue rejection still represents a critical issue of ESCs employment, therefore limiting their applicability, but also strengthening the relevance of the microenvironment as a main modulator to address stem cell fate and behavior. To date, we cannot rule out that a multi-combined approach (drug, scaffolds, proteins, genetic modifications) aiming to integrate the regenerative potential of stem cells might provide similar beneficial effects. Both heart and brain are extremely and complex organs with a well acknowledged and restricted regenerative potential and where it is important to restore the function and to instruct stem cells to preserve the tissue in case of future complications or insults. Studies investigating the appropriateness of single or multiple doses of stem cells and whether they are enough to contain the damage within the tissue in the long terms, are urgently needed. Additionally, technical issues as the availability of standardized and optimized protocols for isolation and ex vivo expansion of stem cells must be provided in order to assure reproducibility among clinical applications. The heterogeneity of stem cell populations and the lack of stemness and clonogenic ability thorough in vitro passages is a main technical problem while employing adult progenitors (Stoltz et al., 2015). Pure stem cell-based cultures have not been reproduced yet as well as the differentiation rate into several lineages has not been

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maximized. This aspect reinforces the heterogeneity of the ex vivo cultures, increasing the risk of interference of potential and undesirable populations to prevail after injection. Similarly, ESCs and iPSCs can induce teratomas or malignant transformations due to chromosomal aberrancies (Stoltz et al., 2015; Lindroos et al., 2011), highlighting our current poor knowledge regarding the biology and molecular mechanisms of these cells. Nonetheless, the use of pluripotent stem cells might be limited only to a specific set of high-risk patients and in targeted tissues with severe damages, as demonstrated in age-related macular degeneration (Lindroos et al., 2011). Oncogenic mutation in iPSCs have been described hampering clinical trials (Balistreri, 2018; Stoltz et al., 2015; Lindroos et al., 2011; Balistreri et al., 2015). The manipulation of stem cells by gene therapy, employed to boost the regenerative potential of progenitors, necessarily causes chromatin remodeling. Researchers need to better understand the modality by which epigenetic might influence the genomic stability and the biology of stem cells. As the knowledge on genome regulation gradually improves, a more relevant role of major epigenetic modulators of stem cell identity such as miRNAs and non-coding RNAs is given. The pattern profile of miRNAs significantly varies among iPSCs, ESCs, adult stromal cells and alongside tissue development and reprogramming (Balistreri, 2018; Stoltz et al., 2015; Lindroos et al., 2011; Balistreri et al., 2015). Micro-RNAs play a key role in determining gene expression profile and differentiation as demonstrated in pluripotent stem cells (Balistreri et al., 2015), which remain more unstable and uncontrolled than the adult counterpart. Moreover, in many diseases, non-coding RNAs and epigenetic is already deregulated, therefore potentially conditioning the phenotype, the function and the outcome of the stem cell-based therapy. The genomic instability requires to be deeply investigated, especially in defined type of stem cells like the pluripotent populations, where proto-oncogenes are employed for the reprogramming (Balistreri et al., 2015). Finally, the control of the immune response in the recipient’s tissue requires to be fully explored, specifically when pluripotent stem cells are employed. Induced pluripotent stem cells can alter immune reactions according to the degree of their differentiation state (Balistreri et al., 2015), highlighting the variability of the reprogramming effect even within the same stem cell population. Stem cell-based therapies still represent a valid option for clinical use. However, their clinical relevance will be maximized only when the knowledge regarding the interaction between modified stem cells, patient’s genomic profile and environment will be improved.

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Stochastic Nature of Cellular Aging: The Role of Telomeres
Nikolina Skrobot Vida
cek, Laboratory for Protein Dynamics, Ruder Boskovic Institute, Zagreb, Croatia Ivica Rubelj, Laboratory for Molecular and Cellular Biology, Ruder Boskovic Institute, Zagreb, Croatia © 2020 Elsevier Inc. All rights reserved.

Cell Aging Cell Senescence Persistent Telomere Damage in Non-Cycling Cells Senescence, Immortalization and Carcinogenesis Telomeres Control Normal Cell Aging Mechanisms of Telomere Action in Senescence End-Replication Problem Telomeres and Stochastic Nature of Cellular Aging Extrachromosomal Telomere Circles References

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Cell Aging Aging is defined as a process that results in a gradual reduction in functions of organic systems and disrupted physiology which leads to increased incidence of diseases and eventually to death. The roots of this process is in reduced ability of cells to divide and regenerate tissues. Healthy aging is not considered as a disease and represents a complex process whose exact causes are not yet fully understood. Today we know that telomeres play an important role in aging process both in vitro and in vivo (Harley et al., 1990; Lindsey et al., 1991). Particular attention is paid to examine telomere shortening in vivo. It has been shown that telomeres in liver and other tissues shorten about 36 base pairs per year, but this loss is not linear throughout lifetime (Ishii et al., 2006). Generally, telomeres tend to shorten at accelerated rate in the first few years of life, after which the shortening slows down during childhood and adolescence, but accelerate again in the old age (Frenck Jr et al., 1998; Takubo et al., 2000). While the role of telomere shortening in healthy aging has yet to be fully understood, there are numerous evidence linking telomeres and age-related diseases, such as Alzheimer’s disease (Panossian et al., 2003), coronary artery disease (Ogami et al., 2004), osteoarthritis (Price et al., 2002) and others. In addition to the aforementioned, there are also diseases directly related to telomere shortening caused by abnormal telomerase function such as Dyskeratosis congenita (Mitchell et al., 1999) or mutations in DNA repair genes that are related to telomere processing such as Werner syndrome (Chang et al., 2004) and Hutchinson-Gilford progeria (Huang et al., 2008). All of these are manifested in pathology related to aging, premature aging and early death.

Cell Senescence As proposed by Alexis Carrel in early 1900s (Carrel, 1912), it has believed that cells from multicellular organisms have unlimited capacity for divisions in culture. Leonard Hayflick challenged this misconception in 1961 when he showed that human diploid cells in culture divided limited number of times when they were permanently stopped in G1 phase of the cell cycle (Hayflick and Moorehead, 1961). For human fibroblasts this number ranges from 55 to 65 divisions. Cells that reached their dividing limit, so call Hayflick’s limit (also known as Mortality stage 1) become morphologically and biochemically altered (Reddel, 2000; Shay and Wright, 2000). Senescent cells have increased volume, they are significantly enlarged, they exhibit changes in gene expression, chromatin structure and protein metabolism (Shelton et al., 1999; Trougakos et al., 2006; Zhang et al., 2007). Importantly, senescent cells do not die but remain metabolically active and as such they can be maintained in the culture for years (Matsamura et al., 1979). There are a number of biomarkers for senescent cells in culture or in vivo. Among the most commonly used are detection of lysosomal b-galactosidase activity exclusively associated with senescent cells (SA-b-Gal) (Dimri et al., 1995), detection of a telomere associated DNA damage foci, so-call TIF (telomere dysfunction induced foci) (d’Adda di Fagagna et al., 2003) or the presence of senescence associated heterochromatin foci (Zhang et al., 2007). Two forms of cell aging are distinguished; replicative aging and stress induced premature aging. Olovnikov was first to connect chromosome ends replication and cellular aging in his Theory of Marginotomy (Olovnikov, 1971; Olovnokov, 1973). According to this concept, telomeres as chromosome ends, are shortening with each cell division due to incomplete replication and serve as an internal mechanism that counts cell divisions. When telomeres are shortened to a critical lengths, they can no longer sustain stable conformation when they are recognized as DNA damage by DNA repair machinery. This leads to permanent stop of further cell divisions (Harley et al., 1990; Greider and Blackburn, 1996; Karlseder et al., 2002). Only one nonfunctional telomere is sufficient to induce cellular aging (Hemann et al., 2001). On the other hand, stress induced cell aging can be caused by factors such as DNA damage (von Zglinicki et al., 2005), oxidative stress (von Zglinicku et al., 1995), oncogenes (Serrano et al., 1997) or inappropriate cell culture conditions (Ramirez et al., 2001). Stress induced senescence occurs within few days. Although these two types of senescence share some morphological and biochemical characteristics, the gene

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expression profile shows that there are significant differences between them (Franco et al., 2005). Telomerase expression in replicative senescence allow continuation of cell divisions, but it will have no effect on cells induced in senescence by external stressors (Vaziri and Benchimol, 1998). For cells in replicative senescence, important characteristic is existence of telomeric DNA damage foci, TIFs which contain proteins involved in DNA damage, such as gH2A.X, 53BP1, MDC1, NBS1, while these TIFs do not exist in stress induced senescent cells (Herbig et al., 2004). It is believed that the population of senescent cells is actually heterogeneous and consists of both cell types described above (Herbig et al., 2004; Beausejour et al., 2003). Aging is a complex cellular process whose molecular mechanisms may differ significantly between individual cell lines from the same species and likewise from different species, demonstrated by changed activity of many genes in senescent cells versus young one (Zhang et al., 2003, 2004). However, all aging pathways include tumor suppressor genes p53 and/or pRb in higher mammals (Shay et al., 1991). In senescent cells the p53 protein is phosphorylated and its activity as a transcription factor is enhanced (Herbig et al., 2004). pRb is found in its active hypophosphorylated form in senescence when it binds to E2F transcription factor and thus prevents the transcription of several genes required for cell entry into S phase and transition through cell cycle (Narita et al., 2003). There are two pathways mediated by p53 and pRB, a linear p53-p21-pRb pathway and p16-pRb pathway (Ben-Porath and Weinberg, 2005) (Fig. 1). The main mediator of p53-p21-pRb pathway is p21 protein which is transactivated by p53 and is responsible for cell cycle arrest (Sherr and Roberts, 1999). Protein p21 is inhibitor of several cyclins and cyclin-dependent kinases, including cyclin E/Cdk2 complexes, thus preventing phosphorylation of pRb protein and entrance into cell division. In p16-pRb pathway, p16INK4a protein as a cyclin D/Cdk4.6 complex inhibitor also inhibits phosphorylation of pRb (Lowe and Sherr, 2003). It is primarily induced in different stress situations and it is very active in senescent cells (Alcorta et al., 1996; Palmero et al., 1997). Activation of pRb via p16INK4a is an additional safety mechanism and therefore very important in human cells. Linear p53-p21-pRb pathway of aging is reversible by p53 inactivation, while p16-pRb is irreversible because pRb establishes repressive heterochromatin at sites containing E2F target genes and other growth promoting genes. Once established, such state cannot be reversed by inactivation of p53, pRb or silencing p16 (Beausejour et al., 2003; Narita et al., 2003). p53 activity during aging is mediated by two important pathways. One pathway involves ATM/ATR and Chk1/Chk2 protein kinases. ATM/ATR directly phosphorylates p53, but also Chk1/Chk2 kinases which then additionally phosphorylate p53 and thereby contribute to its stabilization (Herbig et al., 2004; Gire et al., 2004). The second pathway is mediated by the p19ARF protein that activates p53 by its separation of Mdm2 ubiquitin ligase, which prevents proteolytic degradation of p53 (Stott et al., 1998). Like p16INK4a with which shares the same INK4 locus, p19ARF is induced in stressful situations which cause expression of oncoproteins Myc and Ras as well as after ionizing radiation (Lowe and Sherr, 2003). However, its precise role in human cells has not yet been fully explained. We have already stressed that there are few different causes of cell senescence. Gradual telomere shortening with each cell division eventually results in the loss of their t-loop structure so that they are recognized as double-stranded DNA breaks. This activates DNA damage response mechanisms, including activation of ATM/ATR and Chk1/Chk2 proteins, and consequently activation of p53 (d’Adda di Fagagna et al., 2003; Herbig et al., 2004). Linear p53-p21-pRb pathway is the primary mechanism of senescence caused by telomere shortening as response to DNA double strand breaks (DSB). Although the oxidative stress that causes single stranded telomeric DNA breaks (von Zglinicki et al., 2000) also primarily acts via p53-p21-pRb pathway, in some situations p16INK4a can be activated by p38-MAPK protein, a well known member of stress-activated protein kinase family (Iwasa et al., 2003). Normal cells can also enter senescence by p16-pRb pathways in response to inadequate culture conditions (Ramirez et al., 2001) or increased expression of oncogenes, especially Ras oncogene and its downstream effectors. Ras causes parallel

Fig. 1 Cellular aging signal pathways involving p53 and pRb as the main activators of senescence. p53 can activate senescence by activating pRb through p21. In human cells, p53 can activate senescence independently of pRb. Latter one activates senescence by shutting down the transcription of E2F target genes. pRb is activated either by p21, or by the p16INK4a product. Activation of p53 by phosphorylation is performed by the ATM/ATR and Chk1/Chk2 proteins, and by the p19ARF product of the INK4a locus, which sequesters Mdm2 in the nucleolus. Ben-Porath, I. and Weinberg, R.A. (2005). The signals and pathways activating cellular senescence. The International Journal of Biochemistry & Cell Biology 37(5), 961–976.

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activation of p53 and p16INK4a, but p16INK4a is considered to play a more important role in this type of aging (Serrano et al., 1997; Pearson et al., 2000). p38-MAPK proteins play a key role in mediation of Ras induced senescence and activation of p16 INK4a and p53 (Iwasa et al., 2003; Wang et al., 2002).

Persistent Telomere Damage in Non-Cycling Cells It has been reported that telomere damage triggers cellular senescence in post-replicative cells such as cardiomyocytes or neurons. Such senescence develops independently of telomere length, but it is also manifested as persistent DNA damage (Fumagalli et al., 2012). It leads to formation of so called telomere associated foci (TAF) containing proteins of the DNA damage response (DDR). If irradiated, cells in culture show both telomeric DNA and non-telomeric DNA damage but only telomeric DNA damage persists and initiates TAF formation. In cardiomyocytes persistent TAF increase with age regardless of telomere length or TERT activity and can be induced by mitochondrial dysfunction (Anderson et al., 2019). Also, telomeres are favored targets for stress induced damage in vitro and in vivo as shown in the gut and liver of mice. Despite their long telomeres and active telomerase they show an increase in DNA damage foci frequencies in both tissues with age (Hewitt et al., 2012). In addition to replicative senescence, this highlights the relevance of telomeres in stress-related aging of rarely dividing post-mitotic tissues.

Senescence, Immortalization and Carcinogenesis Many tissues of multicellular organisms contain mitotically active cells which enable their maintenance and regeneration. Cell division includes replication of genetic material when errors may occur. Therefore, cells are exposed to various types of damage during life, which if they are not adequately repaired may be a source of mutation and could lead to tumor development. It takes
20–30 divisions in order for a mutation to stabilize in a population of cells. Mutations are mostly recessive and larger number of divisions is required to eliminate wild type alleles from the population. Because of this, normal cells limit their growth by apoptosis or programmed cell death, or by induction of senescence which they need to overcome in order to enter tumorigenesis (Smith and Pereira-Smith, 1996). An example is human mole, which is of benign melanocyte origin and has mutated oncogene BRAF, resulting in senescent phenotype rather than tumor growth (Michaloglou et al., 2005). However, cellular aging is an example of antagonistic pleiotropy, it is beneficial for young organisms but deleterious for old ones (Krtolica et al., 2001). This is a consequence of changes in gene expression of old cells which secrete various proteins in extracellular matrix. These are proteases, protease inhibitors, growth factors, chemokines, factors of angiogenesis and extracellular matrix proteins (Shelton et al., 1999; Zhang et al., 2004; Cristofalo et al., 1998) named senescence associated secretory phenotype (SASP) (Krtolica et al., 2001). SASP disturbs the microenvironment of the surrounding tissues and induces changes in adjacent normal and pre-malignant cells in which may trigger malignant transformation (Krtolica et al., 2001). As already mentioned, cell aging is mediated by tumor suppressor genes p53 and pRb and their effectors. Their mutations are most common among all tumors. In order to overcome cellular aging, both p53 and pRb must be inactivated (Hara et al., 1991). Cells in which p53 is inactivated by viral oncoproteins (such as E6 proteins of human papillomavirus, E1B adenovirus protein), mutations or if it is spontaneously lost as in Li-Fraumeni syndrome, may initially have extended replicative capability but they eventually enter senescence (Bond et al., 1994; Rogan et al., 1995). The same was observed in cells with inhibited expression of p16INK4a gene due to methylation of CpG islands and in cells where pRB was inhibited by E7 oncoprotein of human papillomavirus (Bond et al., 1999; Huschtscha and Reddel, 1999). Cells that are expressing viral oncoproteins which inactivate both p53 and pRb (such as SV40 large T antigen) have an extended number of divisions that ultimately lead to unstable condition called a “crisis” (Girardi et al., 1965; Rubelj et al., 2002) (Fig. 2). The crisis occur because cells, due to inactivation of p53 and pRb signaling pathways, continue to divide despite too short telomeres when they are no longer able to protect chromosome ends from DNA repair mechanisms. Telomeres are than recognized as double-stranded DNA breaks which activates DNA damage repair proteins such as ATM and Ku which engage homologous recombination or non-homologous chromosome end joining which consequently leads to cell instability. The cell population then enters second proliferative obstacle or Mortality stage 2 (M2) known as crisis (Wright and Shay, 2000; Simon and Blackburn, 2002). Crisis is characterized by ultra short telomeres, chromosome ends fusions, anaphase bridges and massive apoptosis (Shay and Wright, 2005; Wright and Shay, 1992). Only about 1 out of 107 cells in crisis survive and start clonal growth as immortal subpopulation (Huschtscha and Holliday, 1983), most often due to spontaneous re-activation of telomerase (Halvorsen et al., 1999). The introduction of telomerase at any stage prior to cellular aging or crisis results in direct immortalization but these cells than retain a stable genome (Halvorsen et al., 1999; Counter et al., 1998; Zhu et al., 1999). On the other hand, clones that exit crisis and do not activate telomerase, but rather induce recombination driven, so call alternative lengthening of telomeres (ALT) mechanism have unstable telomeres subject to large variations in lengths and sudden extensions and shortenings are observed (Grogelny et al., 2001; Bryan et al., 1997). Normal cells immortalized with telomerase have infinite division capacity and their telomeres are stabilized at a constant length, as demonstrated by the introduction of hTERT subunit into normal human fibroblasts and epithelial cells (Bodnar et al., 1998). They can be maintained in culture for a long period of time and serve as a good model for studies in normal cell phenotype background because they have a gene profile very similar to normal untransformed cells, they maintain normal karyotype, contact inhibition and react to growth stimulation or inhibition in a manner of normal cells (Zhu et al., 1999).

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senescence Fig. 2 The role of p53 and pRb in replicative aging, crisis and immortalization. A sequence of events after the introduction of SV40 Tg into normal culture. SV40 Tg inhibits p53 and pRB, percentage of cycling cells increase resulting in the increase of the culture growth rate and population doublings (dashed line). This is perceived as the “extended lifespan” after which cells enter crisis. Occasionally, some cells escape crisis and become immortalized. Rubelj, I., Huzak, M., Brdar, B., and Pereira-Smith, O.M. (2002). A single-stage mechanism controls replicative senescence through Sudden Senescence Syndrome. Biogerontology 3(4), 213–222.

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Fig. 3 Steps in in vitro normal human cell transformation. Introduction of SV40 Large T and small t antigens, thus functionally inactivating p53, pRb, and PP2A in combination with introduced oncogenic H-Ras and the hTERT catalytic component of the telomerase results in anchorageindependent growth with the capacity for tumor formation in immunocompromised mice. Stewart, S.A. and Weinberg, R.A. (2006). Telomeres: Cancer to human aging. Annual Review of Cell and Developmental Biology 22, 531–557.

Expression of hTERT subunit in normal cells is not sufficient for malignant transformation (Jiang et al., 1999; Morales et al., 1999). Carcinogenesis is a multi-step process that requires 4–6 genetic changes to produce tumor cell (Armitage and Doll, 2004), these includes oncogene(s) activation, tumor suppressors inactivation and continuous cell divisions (Hahn and Weinberg, 2002). These changes in gene expression provide cells with all prerequisite for transformation, such as constant growth signaling, insensitivity to growth inhibitors, resistance to apoptosis, ability for (neo)angiogenesis and metastases. As a good example are human fibroblasts transduced with the SV40 virus. Inactivation of p53 and pRb tumor suppressor genes via SV40 large T antigen, suppression of protein phosphatase 2A function due to expression of SV40 small t antigen, mitogenic stimulation as a result of expression of H-Ras oncogene and immortalization due to telomerase expression, all together result with transformed human cell (Hahn and Weinberg, 2002; Stewart and Weinberg, 2006) (Fig. 3).

Telomeres Control Normal Cell Aging The beginnings of telomere research started in 1930’s when Barbara McClintoc, working on corn (McClintoc, 1939), and Herrmann Muller, working on fruit flies (Muller, 1938), suggested that the chromosome ends have a special structure that protects them from fusion and breaks, and thus maintains their stability. Muller called these structures telomeres from the Greek word “telos,” meaning end and “meros,” meaning part.

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A major breakthrough in telomere research has mainly been attributed to the Nobel Prize winners, Elizabeth Blackburn who has shown that telomeres in Tetrahymena pyriformis consist of long repetitive sequences (Blackburn and Gall, 1978) and, at the time her doctoral student, Carol Greider who isolated the enzyme telomerase responsible for maintenance and extension of telomeres (Greider and Blackburn, 1985). These discoveries provided insights into some fundamental questions in biology and opened a new field in still expending biological research.

Mechanisms of Telomere Action in Senescence Cells of multicellular organisms carry large genomes that are organized in the form of linear chromosomes, which enables accurate chromosome separation during mitosis and crossing over during meiosis. However, the ends of liner chromosomes are susceptible to fusions and chromosomal rearrangements which causes genetic instability and may be detrimental to cells. Elizabeth Blackburn was first to demonstrate that the ends of linear chromosomes consist of long repetitive sequences rich in guanins. Ten years later, Moyzis showed that telomeres in humans and other vertebrates consist of repetitive hexanucleotides (TTAGGG)n (Moyzis et al., 1988). In the living world there are different types of telomeric DNAs that are evolutionary conserved (Meyne et al., 1989). In humans, telomere repeats are on average 4 to 15 kilobases long (de Lange et al., 1990) depending on the type of tissue from which cells are isolated and the age of the donor. There are also large differences between individual chromosomes within a cell regarding telomere lengths and chromosome 17p have the shortest one (Lansdorp et al., 1996; Baird et al., 2003; Martens et al., 1998). Telomeres are organized in the form of a double stranded DNA with a 30 single stranded G rich overhang which varies between 150 and 300 nucleotides in length (Makarov et al., 1997). Electron microscopy has shown that long telomeres form the so-called telomeric loop (t-loop), in the way that the 30 single-stranded overhangs invades telomere/subtelomere border region where they are fixed in the displacement loop (D-loop) (Rubelj and Vondracek, 1999; Greider, 1999; Griffith et al., 1999) (Fig. 4). This way telomere is protected from degradation and detection by DNA repair mechanisms which prevents various chromosomal aberrations such as deletions, translocations, chromosome fusions etc. (Blackburn, 1991). The existence of t-loops has been found in other organisms as well such as Trypanosoma Brucei, Oxytricha fallax and Pisum sativum (Munoz-Jordan et al., 2001; Cesare et al., 2003). The whole loop structure is additionally stabilized by a protein complex called shelterin (de Lange, 2005). Shelterin consists of six proteins, three of which are directly bound to telomere sequences; TRF1, TRF2 and Pot1, while TIN2, TPP1 and RAP1 interact with them. TRF1 (Telomeric repeat binding factor 1) and TRF2 (Telomeric repeat binding factor 2) are paralogs (Broccoli et al., 1997). They bind double-stranded TTAGGG sequences and play main role in t-loop formation and its stabilization (Bianchi et al., 1997). Pot1 binds 30 single-stranded telomere sequences and has a dual role on telomeres. It protects telomere 30 single strand overhang from being recognized as a DNA damage and thus plays an important role in stabilization of the t-loop structure, and in some cases enables action of telomerase on t-loop (Raynaud et al., 2008).

End-Replication Problem In normal somatic cells, telomeres are shortened with each cell division and this phenomenon is the consequence of incomplete DNA replication at the end of linear chromosomes (Olovnikov, 1971). Telomeres are shortened in the S phase of the cell cycle due to the inability of DNA polymerase to start DNA synthesis de novo. To begin DNA replication, the DNA polymerase needs an RNA

Fig. 4 Visualization of human t-loop in HeLa cells by electron microscopy. Griffith, J.D., Comeau, L., Rosenfield, S., Stansel, R.M., Bianchi, A., Moss, H., and de Lange, T. (1999). Mammalian telomeres end in a large duplex loop. Cell 97, 503–514.

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additional processing of the leading strand Fig. 5 Telomere shortening during DNA replication in normal somatic cells. At lagging telomere there is incomplete 50 strand replication. At leading telomere additional processing of the 50 strand occurs. Martincic Spoljaric, A., Rubelj, I., and Huzak, M. (2019). Mathematical model and computer simulations of telomere loss. Journal of Theoretical Biology 465, 78–89.

primer. In this way 50 / 30 leading strand and lagging strand are formed (Reddel, 2000). At the end of the synthesis, the gaps between the newly synthesized fragments of the lagging strand are filled by DNA polymerase I which also removes the RNA primers, and the final ligation of fragments is performed by DNA ligase. Since the DNA polymerase adds nucleotides only in the 50 / 30 direction, the 50 end of the lagging strand remains empty after removal the terminal RNA primer. Telomeres in human fibroblasts have been shown to shorten on average about 63 base pairs with each cell division (Harley et al., 1990). In order for both ends of the chromosome to have a 30 single-stranded extension necessary to form t-loops, 50 exonuclear activity is employed (Makarov et al., 1997) (Fig. 5). 30 single strand protruding end of the leading chain formed by 50 end processing is by half to one third shorter than the 30 protruding end of the lagging strand (Chai et al., 2006). Formation of telomere ends is strictly regulated so that C rich strands end with a specific nucleotide within hexanucleotide telomere repeat (Sfeir et al., 2005). So, telomeres are shortened at each cell division by combination of incomplete replication of chromosome ends and subsequent enzymatic processing of 50 ends (Wu et al., 2012). When telomeres reach critical lengths when they can no longer form t-loops, either cellular aging or apoptosis occurs (Karlseder et al., 1999, 2002).

Telomeres and Stochastic Nature of Cellular Aging Telomere shortening and occurrence of cellular aging is consistent with the observed gradual decline of cell culture growth potential (Smith and Hayflick, 1974). However, gradual telomere shortening could not explain the experiment performed by Smith and Whitney 40 years ago (Smith and Whitney, 1980). They started monoclonal culture of IMR90 cells and at three points during their growth they isolated 200 subclones each time. Than they followed all subclone’s remaining population doublings. Surprisingly, subclones showed a very different dividing potential in the form of strict bimodal distribution. With increasing number of divisions of the culture, peak of subclones with higher dividing potential declined while peak of subclones with lower dividing potential increased. At the end all subclones ceased further divisions. In another experiment, differences in the proliferative potential of cells arising from the same mitosis demonstrated great variety of differences in dividing potentials between them. Each sister cell could make anywhere between 0 and  8 population doublings in completely random fashion. In order to explain this phenomenon, a theoretical model of sudden and stochastic deletion of telomeres, so call Abrupt Telomere Shortening (ATS) is proposed. This abrupt shortening is a consequence of intraalelic recombination resulting from resolution of Holliday’s structure at the border of the telomere/subtelomere region. Model predicts increased frequency of ATS as telomere gradual shortening progresses (Fig. 6). As a result of this recombination, extra short telomere and extra-chromosomal circular telomeric DNA molecule are produced (Rubelj and Vondracek, 1999). Indeed the existence of very short telomeres in individual cells, not consisted with exclusive gradual shortening model, has been demonstrated in coming years thanks to the development of new experimental methods. Telomere PNA-FISH (Peptide Nucleic Acid-Fluorescent in Situ Hybridization) revealed that in rare cases the ends of some chromosomes did not show a telomere fluorescent signal (Callen et al., 2002). Furthermore, individual telomere PCR length analysis using so call STELA technique, showed the existence of very short telomeres at the ends of some chromosomes (Baird et al., 2003). Various mechanisms were suggested that could explain the deletion of a large portion of telomere repeats. One of the candidates is sister chromatid exchange which occurs 1600 times more frequently on telomeres than elsewhere in the human genome (Rudd et al., 2007). Also, telomere repetitive sequence may pose a problem for DNA replication machinery (Ohki and Ishikawa, 2004) in a way that telomere sequences can create secondary structures, such as G-quadruplex (Neidele and Parkinson, 2003)

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Circular telomere repeats Fig. 6 Model of Abrupt Telomere Shortening and t-circle formation. t-loop formation is stabilized by specific telomere binding proteins. Gradual telomere shortening occurs as a consequence of the inability of DNA polymerase to replicate ends of chromosomal DNA as well as specific exonuclease degradation of the 50 strand to create 30 single strand protruding end at telomere. When telomere reaches its critical length it switches from stable to unstable conformation, which can provoke subsequent recombination event (between dashed lines) which results in a deletion of distal repeats through circularization. Abrupt shortening could occur at any telomere in the cell. Ferenac, M., Polancec, D., Huzak, M., Pereira-Smith, O.M., Rubelj, I. (2005). Early-senescing human skin fibroblasts do not demonstrate accelerated telomere shortening. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 60, 820–829.

which could make replication difficult. If these structures are not repaired by recombination, a stall of replication fork occur, which can result in random telomere deletion (Lansdorp, 2005). A stall of replication fork may also occur at sites of DNA damage within a telomeric sequence caused by various factors, such as UV and ionizing radiation or oxidative stress. G rich telomere strand is particularly susceptible to oxidative stress (Oikawa and Kawanishi, 1999) which causes a single strand DNA nicks (Petersen et al., 1998). This may result in telomere deletions. Anyway, one of the most widely accepted mechanisms of random telomere deletions is ATS (Rubelj and Vondracek, 1999).

Extrachromosomal Telomere Circles Apart from human, the presence of t-circles is confirmed in cells of different other organisms. In the yeast Candida parapsilosis, they serve as a rolling cycle in DNA synthesis, product of which will later be used as a substrate for recombinational extension of telomeres

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(Tomaska et al., 2000; Nosek et al., 2005). t-circles were also found in other yeast species (Cesare et al., 2008) and in plant Arabidopsis thaliana that has mutated Ku70/Ku80 proteins involved in DNA repair (Zellinger et al., 2007). Interestingly, there exists a large number of t-circles in Xenopus laevis embrional cells, while their number declines drastically in adult individuals (Cohen and Mechali, 2002). It is considered that t-circles in this species participate in the maintenance of telomeres at early-stage of development. Telomeric circles have also been shown in a large number of human cells, especially those that maintain their telomeres by ALT mechanism (Cesare and Griffith, 2004). It was suggested that t-circles in these cells serve as a part of the mechanism for the synthesis of telomeric DNA, as it was shown in yeast, but further research revealed that they are not necessary for survival of ALT cells (Compton et al., 2007). The existence of t-circles has recently been demonstrated in telomerase-positive cells as well as in cells with additional overexpression of telomerase where telomeres were extended even further (Pickett et al., 2009). As an explanation for the existence of t-circles in these cells, the mechanism of “trimming ends” is suggested. It argues that too long telomeres are trimmed to a certain shorter but more stable lengths resulting with extrachromosomal circular telomeric DNA molecules as by-products (Pickett et al., 2009). It is believed that telomeric trimming act as negative telomere length regulation in ALT cells. A similar process was also observed in the mutated yeast Saccharomyces cerevisiae in which very long telomeres shortened rapidly, so called telomere rapid deletion (TRD) (Cesare et al., 2008; Li and Lustig, 1996). The presence of t-circles is demonstrated in human cells that carry mutations for certain proteins important for telomere function such as TRF2 (Wang et al., 2004), Ku86 (Wang et al., 2009), WRN (Li et al., 2008), ORC2 (Deng et al., 2007), NBS1 and Xrcc3 (Compton et al., 2007). Although there was no direct evidence for the existence of t-circles in normal human cells, sudden and stochastic appearance of senescent cells, even in a young cultures, suggests this possibility (Ferenac et al., 2005). Subsequent studies confirmed important structural or functional features of the model (Griffith et al., 1999; Wang et al., 2004) but convincing evidence for its presence in normal cycling cells has been missing. In 2010 the presence of t-circles has been confirmed in normal human skin and lung fibroblasts, MJ90 and IMR90 respectively (Vidacek et al., 2010). Abrupt telomere shortening provides a plausible explanation for quick generation of heterogeneity in PDs potential among clonal cell culture. Indeed, catastrophic telomere deletion can cause rapid onset of senescence even in young cells with long telomeres. Vidacek and co-workers isolated and analyzed extrachromosomal circular telomere DNAs from normal human fibroblasts at different PDs and used quantitative PNA-FISH (Q-FISH) method to analyze differences in PNA-FISH signals among their sister telomeres. Obtained results suggests revision of the theoretical ATS mechanism in senescing cultures, demonstrating that this is not predominantly a single-step process, although single loss of (nearly) all telomere repeats cannot be excluded. Most frequently telomeres loose
2 kb of repeats allowing possibility that more than one abrupt shortening can occur at single telomere in multi-step fashion during consecutive cell divisions. This explain a hallmark of cell senescence, a high stochasticity, where individual cells enter senescence in a completely random and stochastic fashion. A mathematical modeling and computational simulations of telomere dynamics are often used to explain this stochastic nature of cell aging. Models published thus far were based on the molecular mechanisms of telomere biology and how they dictate the dynamics of cell culture proliferation. In recent work an advanced model of telomere controlled cell senescence based on multi-step abrupt telomere shortening has been proposed which explain some important but thus far overlooked aspects of cell senescence (Martincic Spoljaric et al., 2019). Model was tested by simulating not only the proliferative potential of individual subclones but also, for the first time, twosister experiment originally conducted by Smith and Whitney in 1980. Obtained computational simulations matched well with experimental results. It appears obvious that abrupt telomere shortening contributes to generation of endogenous heterogeneity in telomere lengths and consequently stochasticity of cell senescence, thus it plays an important role in gradual accumulation of senescent cells in vitro as well as in vivo ensuring gradual progression of the aging process at the organismal level. However, we need to mention that in return, influence of cell growth conditions on telomere dynamics has been recognized (Nanic et al., 2018). These includes contact inhibition, gradual accumulation of non-dividing cells and other cell culture maintenance factors, thanks to which a rapid generation of cell subpopulations undergoing various divisions within 3 to 7 days in growing cultures has been observed. Differences in number of divisions among individual cells due to cell culture conditions guarantee a strong impact on well known telomere length heterogeneity.

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Stress Response Pathways Sumangala Bhattacharya and Suresh IS Rattan, Aarhus University, Aarhus, Denmark © 2020 Elsevier Inc. All rights reserved.

Introduction Autophagy (AP) DNA Damage Response (DDR) Energy Stress Response (ESR) Heat Shock Response (HSR) Hypoxia-Induced Stress Response (HISR) Inflammatory Stress Response (ISR) Oxidative Stress Response (OSR) Unfolded Protein Response (UPR) Conclusions References

282 282 284 284 285 286 286 287 287 288 288

Introduction All living systems have the ability to respond, counteract, and adapt to internal and external sources of disturbance. This ability is traditionally termed as homeostasis, which is a misleading term since there is little or no constancy in living systems. Rather it is the dynamic equilibrium of continuous changes and remodeling that determines survival, and for which the term homeodynamics (Yates, 1994) is better suited to expound the continuity of growth, development and aging. This term has been further modified to homeodynamic space as indicative of the overall survival ability of a biological system (Rattan, 2012). One of the crucial components of the homeodynamic space is the stress response (SR), by virtue of which a living system is able to sense disturbance, and initiates a series of events for maintenance, repair, adaptation, remodeling and survival of the organism (Rattan, 2012). Here we provide a brief and integrated synopsis of the key molecular SR pathways that are well characterized in humans and other eukaryotes. These pathways can be considered as the primary SR pathways underlying one of the main characteristics of homeodynamics and homeodynamic space (Bhattacharya and Rattan, 2019). Other higher-level stress responses that involve the sympathetic adrenomedullary system (SAM) for the immediate response, and the hypothalamic pituitary adrenal axis (HPX) for the persistent response are beyond the scope of this article. Starting from the exposure to a stressor, SR can be elucidated in five conceptual steps: (1) stress-induced disturbance in the homeodynamics; (2) activation of signaling pathways to initiate SR; (3) activation of SR pathway-mediated effector responses; (4) restoration of homeodynamics; and (5) enhanced adaptive ability (Bhattacharya and Rattan, 2019). These steps comprise both the immediate and delayed SR. Immediate SR can last for from a few seconds to several hours, and generally involves receptor-mediated intracellular signaling during the period of exposure to stressors. The delayed response comprises the involvement of modulators and downstream effectors even after the original source of disturbance is removed (Bhattacharya and Rattan, 2019). Table 1 gives a summary of the primary SR arranged in an alphabetical order, along with examples of major stress inducers, markers of early and late responses, and their molecular mediators. A brief discussion of these SR is given below.

Autophagy (AP) Eukaryotic cells respond to nutritional deficiency mainly by inducing autophagy (AP), also known as the nutritional stress response (NSR), which serves as the primary SR pathway (Ryter and Choi, 2013). AP is a mechanism by which cytoplasmic components are preferentially digested by the cell to produce new building blocks, and/or to produce energy during nutrient deprivation. There are three major types of AP, namely macro-, micro- and chaperone-related AP (Galluzzi et al., 2017), of which only macro AP will be discussed here. The specific removal of damaged or excess mitochondria by micro- or macroautophagy is also known as mitophagy (Galluzzi et al., 2017). As discussed in detail in (Bhattacharya and Rattan, 2019), a characteristic double membraned vesicle called autophagosome is formed during AP, which engulfs cytosolic particles and delivers them to the lysosome for degradation. Lysosomal and proteosomal degradation-related AP of cytosolic constituents is a constitutive process, which actively recycles cellular debris. Nevertheless, a boost in AP and lysosomal degradation is observed when the cell experiences a lack of nutrients (amino acids, sugars, and nucleotides), or if there is an increase in the accumulation of damaged/aggregated proteins, modified/non-functional organelles and macromolecules or even bacteria, that the cell needs to degrade or destroy. AP is regulated by the major energy-sensing proteins mTORC1 (mammalian target of rapamycin (mTOR) complex 1) and AMPK (AMP kinase). AMPK directly inhibits mTORC1 (a serine/threonine kinase, promoting anabolic processes), to reduce energy use

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Stress Response Pathways Table 1

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Primary molecular stress response pathways, their inducers and mediators.

Stress response

Inducers

Early response

Late response

Mediators

Autophagy (AP) or nutritional stress response (NSR)

Nutritional inadequacy

Autophagosome formation and lysosomal digestion

AMPK, autophagy-related proteins

DNA damage response (DDR)

Radiation, free-radicals (ROS, RNS)

Activation of cell cycle checkpoint pathways

p53, mortalin/PBP74, DNA repair enzymes

Energy stress response (ESR)

Energy deficit (low ATP/ AMP or NADþ/NADH) ratio

AMPK activation, mTORC1 inhibition, dephosphorylation of ULK1/2, Atg13 ATM and ATR recruitment to double strand- and single strand-breaks, respectively AMPK activation, deacetylation of PGC-1a, FOXO

AMPK, sirtuins

Heat shock response (HSR)

Heat, exercise, denatured proteins, heavy metals, antibiotics

Inhibition of anabolic pathways, activation of catabolic pathways; increased mitochondrial biogenesis Transcription and translation of HSP

Hypoxia-induced stress response (HISR)

Low oxygen levels

Inflammatory stress response (ISR)

Pathogens, allergens, injuries

Oxidative stress response (OSR)

Pro-oxidants, free-radicals (ROS, RNS)

Unfolded protein response (UPR)

Unfolded/misfolded proteins in ER

Heterotrimerisation of HSF1, nuclear translocation and binding to HSE in the promoters of HSP genes Inhibition of HIFa degradation, nuclear translocation, binding to HIF-b, and later to HRE Chemokine release, activation of cell-surface receptors like TNF-a, IL-1 and nuclear translocation of NF-kb Nrf2 release from Keap1, stabilization, nuclear translocation, binding to ARE Activation of ER stress sensors (IRE1, ATF6, PERK)

Chaperones (HSP), co-chaperones (HOP), proteases, proteasome

Induction of HIF-inducible genes

Erythropoetin, HO-1, iNOS, VEGF

Induction of genes involved in cell survival, angiogenesis, tumor progression

Cytokines, pro-/antiapoptotic enzymes (IL-2, IL-6, Bax, Bcl-2)

Transcription and translation of antioxidative genes

Antioxidant gene products (HO-1, GST, SOD)

Induction of chaperones, pro/anti-apoptotic genes

Chaperones (GRP78, GRP94), HSP40-type cochaperones

Abbreviations: AMPK, AMP-activated protein kinase; ARE, antioxidant response elements; ATF6, activating transcription factor 6; Atg13, autophagy-related protein 13; ATM, Ataxiatelangiectasia-mutated; ATR, Ataxia-telangiectasia and Rad 3-related; Bax, Bcl-2-associated X protein; Bcl2, B-cell lymphoma 2; FOXO, forkhead box protein; GRP78/94, glucoseregulated binding protein 78/94; GST, glutathione S-transferase; HIF-a/b, hypoxia inducible factor-a/b; HO-1, heme oxygenase-1; HOP, Hsp70/Hsp90 organizing protein; HRE, HIF responsive elements; HSE, heat shock element; HSF1, heat shock factor 1; HSP, heat shock proteins; IL-1/2/6, interleukin-1/2/6; iNOS, inducible nitric oxide synthase; IRE1, inositol-requiring enzyme 1; Keap1, Kelch-like enoyl-CoA hydratase-associated protein 1; mTORC1, mammalian target of rapamycin complex 1; NF-kb, nuclear factor kappa-lightchain-enhancer of activated B cells; Nrf2, nuclear factor erythroid-2 related factor 2; PBP74, peptide-binding protein 74; PERK, protein kinase-like ER kinase; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD, superoxide dismutase; TNF-a, tumor necrosis factor-a; VEGF, vascular endothelial growth factor. Modified from Bhattacharya S, Rattan SIS (2019) Primary stress response pathways for pre-conditioning and physiological hormesis. In: Rattan SIS and Kyriazis M (eds.) The Science of hormesis in health and longevity, pp. 35–54. UK: Academic Press.

and enhance macromolecular breakdown and recycling in energy depleted cells (Gwinn et al., 2008). In mammals, mTORC1 keeps ULK1/2 and Atg13 proteins in a phosphorylated state, which inhibits the formation of the AP complex under nutritionally abundant conditions (Hosokawa et al., 2009). Under conditions of nutrient deficiency ULK1/2 and Atg13 are rapidly dephosphorylated activating the kinase activity of ULK1/2, which then undergoes autophosphorylation and phosphorylates Atg13, and FIP200. This complex is now ready to initiate the formation of the pre-autophagosome or the phagophore. A number of AP-related proteins in mammals, such as class III PI3K, Vps15, and Beclin1 are involved in phagophore biogenesis, initiated out of either the endoplasmic reticulum (ER) membrane or the intermediate compartments between the ER and Golgi apparatus (Ge et al., 2014). Further expansion of the phagophore involves a specific group of AP proteins (Atg3, Atg5, Atg7, Atg12, Atg16L1) together with the WIPI proteins targeting LC3 (microtubule associated protein 1 light chain 3, a constitutively expressed cytosolic protein) to the phagophore membrane. LC3 is then conjugated to phosphatidylethanolamine in the membrane following a reaction known as the LC3 lipidation, forming LC3II, which enables the phagophore to close to form a mature autophagosome and fuse with the lysosomal membrane (Wild et al., 2014). The docking and fusion of the autophagosome into the lysosome is facilitated by the SNARE protein complex and Rab7 incorporated into the outer membrane of these vesicles, which finally lead to the release of the sequestered cytosolic macromolecules for lysosomal degradation and recycling. With respect to aging, basal levels of autophagy are reported to increase in serially passaged senescent cells in vitro, which could be a sign of increased intracellular stress in terms of reduced availability of nutritional components during aging (Ryter and Choi,

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2013; Demirovic et al., 2015). However, the inducibility of autophagy in old cells and organisms, when exposed to additional nutritional stress, is significantly reduced, and can lead to excessive cell death and associated consequences (Terman et al., 2007; Pyo et al., 2013).

DNA Damage Response (DDR) DNA damage recognition and signaling are the pre-requisite of DNA damage response (DDR), leading to DNA repair (Fleck and Nielsen, 2004). Different kinds of DNA damage bring into play specific sets of DNA repair mechanisms, although many components of the pathways involved can overlap. Commonly known DNA repair pathways include mismatch repair, base-excision repair, nucleotide-excision repair, repair for DNA single-strand breaks (SSB) and double-strand breaks (DSB). Sensors of DNA damage are also specific to the type of damage. For example, DNA glycosylases act as sensors for base excision repair; the signaling protein kinase ATR (Ataxia-telangiectasia and Rad 3-related) detects the formation of DNA single strand breaks (SSBs); and the MutS homologues MSH2, MSH3 and MSH6 form heterodimers (MSH2-MSH6 and MSH2-MSH3) to recognize the disparity caused by the formation of insertion/deletion loops or base-base mismatches (Jiricny, 2006). DSB are considered most hazardous for the organism and are generally repaired by non-homologous end joining (NHEJ), where Ku protein acts as the sensor and binds to specific protein kinases, leading to the joining of the broken strands (Rulten and Grundy, 2017). Another way of repairing DSB is via homologous recombination (HR), where DNA breaks are detected by the MRN-complex. Detection is normally followed by the induction of transcription factors that lead to an increased level of enzymes, speeding up DNA repair. In eukaryotes, ATM (ataxia-telangiectasia-mutated) and ATR (ataxia-telangiectasia-mutated and Rad3-related) signaling proteins are the key players regulating DNA damage and repair. Both are members of class IV phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family (Awasthi et al., 2015). They act as serine (S)/threonine (T) kinases, phosphorylating S and/or T (followed by glutamine (Q) residues) in downstream proteins. Both ATM and ATR activate cell cycle checkpoint pathways, leading to cell cycle arrest ensuring time for DNA damage repair. However, ATM and ATR are recruited by co-factors that are specific to particular types of DNA damage. ATM is specifically involved in DNA double strand break repair, while ATR plays a more regular role in the repair of stalled replication forks and maintenance of genome integrity (Awasthi et al., 2015). DSB are repaired using two major pathways: NHEJ and HR DSB are repaired using two major pathways: NHEJ and HR (Bhattacharya and Rattan, 2019). DSB are detected by the MRN complex (MRE11-RAD50-NBS1 [MRE11: meiotic recombinase 11, NBS1: nijmegan breakage syndrome1 protein]), the binding of which triggers a signaling cascade resulting in the transcription of a variety of genes responsible for DNA repair (Lamarche et al., 2010). Upon binding to the DSB, the NBS1 protein in the MRN complex changes its conformation, promoting the binding, autophosphorylation and activation of the S/T kinase, ATM. Activated ATM then phosphorylates the S139 residue on histone H2AX (belonging to the H2A family of histones) leading to a significant conformational change. An amplification of signaling takes place at this point, when a single ATM phosphorylates several H2AX. S139 phosphorylated H2AX, also known as ɤH2AX now recruits and activates another S/T kinase Chk2 (checkpoint kinase 2). Chk2 phosphorylates the inhibitory protein Mdm2 (murine double minute 2) releasing p53. Under normal conditions, p53 is found in its inactive state in the cytoplasm bound to Mdm2. Eventually, ATM and Chk2 both take part in the phosphorylation of p53, in two different S residues, changing its conformation in the Mdm2-binding region. Activated p53 now released into the cytoplasm forms tetramers and binds to the promoter region of several genes involved in DNA repair, acting as a transcription factor upregulating their transcription and expression. Simultaneously p53 down regulates the genes involved in cell cycle progression, which increases the time available for DNA repair (Lamarche et al., 2010). In NHEJ, the double strand breaks are primarily detected by Ku protein (Ku70-Ku80 heterodimer) (Chang et al., 2016), which then recruits the DNA protein kinase catalytic subunits (DNAPKcs), forming Ku-DNA-PK complex surrounding the broken strands; whereas in HR (also known as the Holliday junctions), the sister chromatids are used as templates to copy the missing bases. Therefore, HR normally occurs in the S and G2 phases of the cell cycle where sister chromatids are present in the same nucleus (Chang et al., 2016). DDR is one of the crucial SR pathways for survival and health. With respect to aging, a progressive decline in the extent and efficiency of both the global- and the gene-specific repair is reported for almost all aging systems studied so far (Lombard et al., 2005; Vijg, 2008; Sanchez-Flores et al., 2017). Thus, a declining DDR is a major contributor to the shrinkage of the homeodynamic space during aging (Rattan, 2008).

Energy Stress Response (ESR) Reduction in cellular energy levels is marked by a shift in AMP/ATP ratio and NADþ/NADH ratio (Hardie and Lin, 2017). AMP, ADP, ATP, NADþ, NADH are energy molecules that act as cellular currencies, used for spending and harvesting energy through various reactions involved in biochemical processes. An increase in AMP/ATP and NADþ/NADH ratio indicates a low-energy state, which triggers a counter response to neutralize the energy deficit, and is known as the ESR. A rise in AMP can be caused by energy demanding physical exercise, calorie restrictions, malfunctioning of cellular glucose uptake etc. AMPK (AMP-activated protein kinase), a heterotrimer of catalytic a-, and regulatory b- and g-subunits, is the master regulator of cellular energy balance. It integrates several metabolic cues and controls many crucial biochemical pathways primarily to maintain energy homeodynamics. AMPK is activated by phosphorylation at thr172, by the following kinases: tumor suppressor protein LKB1 (liver kinase B1),

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CAMKK2 (Ca2 þ/calmodulin-activated kinase kinase 2) and Tak1 (TGF-b activated kinase 1). Once activated AMPK inhibits anabolic pathways like lipid biosynthesis, energy consuming protein synthesis, glycogen synthesis etc. and activates several catabolic processes like glycolysis, glucose uptake and mitochondrial biogenesis, to restore energy balance (Hardie and Lin, 2017). Another major group of pathways involved in ESR is controlled by a class of seven NADþ–dependant deacylases, called sirtuins (SIRT) (Morris, 2013; Grabowska et al., 2017). They differ in their intracellular localisation, and regulate different biochemical pathways. SIRT1 and 6 reside in the nucleus, SIRT2 in the cytoplasm, SIRT3, 4 and 5 in the mitochondria and SIRT7 in the nucleolus. All the SIRTs are deacylases, although some of them might have additional enzymatic roles. SIRT1 and 2 are primarily deacetylases, SIRT 4 and 5 mainly function as mono-ADP-ribosyl transferases, whereas SIRT3 and 6 are equally capable of both activities. A rise in intracellular NADþ concentration, following physical exercise, calorie restriction and fasting activates SIRT1, which then regulates several metabolic pathways by deacetylation of its target proteins. These proteins include histones, nuclear receptors, transcriptional coactivator: peroxisome proliferator-activated receptordg coactivator 1a (PGC-1a), forkhead box (FOXO) transcription factors and peroxisome proliferator-activated receptor-a (PPAR-a). Deacetylation of PGC-1a and FOXO transcription factors leads to enhanced mitochondrial respiration, catabolic breakdown of lipids, transcription of target genes regulating stress resistance and apoptosis (Canto and Auwerx, 2012; Gross et al., 2008). On the other hand, SIRT1 counteracts inflammation by negative regulation of NF-kB. Taken together, SIRT-mediated ESR involves regulation of metabolic and stress-related biochemical processes leading to an increase in AP, stress resistance, glucose uptake, adiponectin secretion, oxidation of fatty acids, gluconeogenesis, insulin secretion and a decrease in inflammation and biosynthesis of lipids. Regulation of these processes via SIRTs have major implications on management of metabolic disorder and age-related ailments (Morris, 2013). During fasting or calorie restriction, the AMPK- and SIRT-regulated pathways work in harmony to mediate ESR. For example, with the increase in AMP/ATP and NADþ/NADH ratio, both AMPK and SIRT1 get activated, leading to phosphorylation and activation of PGC-1a by AMPK. This makes PGC-1a available to SIRT1 mediated deacetylation (Canto and Auwerx, 2012; Gross et al., 2008). AMPK activation occurs immediately after energy stress, whereas SIRT activation ensues as a delayed response that can take a few hours. ESR becomes less efficient with age, and is correlated with the reduction in the amount and activity of various SIRTs (Grabowska et al., 2017; Haigis and Yankner, 2010; Giblin et al., 2014). That is why activating SIRTs and supplementing with NAD are reported to have aging modulatory and longevity enhancing effects (Grabowska et al., 2017; Pajk et al., 2017).

Heat Shock Response (HSR) HSR is one of the most widely studied and evolutionarily well-conserved SR mediated primarily by the heat shock proteins (HSP) (Verbeke et al., 2001). Almost all HSPs are molecular chaperones that assist other misfolded or aggregated proteins to fold properly, helping them to regain their conformation and functionality. A wide range of conditions such as temperature shock, hypoxia, oxidative stress, nutritional deprivation, exercise, heavy metals, ethanol and others, can increase the load of misfolded and aggregated proteins in the cell, which then initiate HSR. The first step in HSR is the activation of specific transcription factors called heat shock factors (HSF) and their translocation from cytoplasm to the nucleus. HSFs bind to specific DNA sequences known as heat shock elements (HSE), located in the promoter region of HSP genes, and are responsible for the assembly of the transcription machinery, and eventually the expression of HSPs (Verbeke et al., 2001). Accumulation of denatured and poly-ubiquitinated proteins in the cytosol activates HSFs, some of which are constitutively expressed in almost all cell types (Verbeke et al., 2001). There are at least 5 HSF involved in HSR, but the most extensively studied is HSF1, which is constitutively expressed in cells and is present in both cytoplasm and nucleus, although more abundantly in the former. It exists as a non-DNA-binding inactive monomer capped and blocked by HSPs like HSP70, HSP90 and other chaperones like HSc70 (constitutively expressed HSP70) and TRiC (TCP1 ring complex) (Neef et al., 2014). These chaperones maintain HSF1 in an inactive state until the cell encounters stress that causes protein denaturation and aggregation, requiring the involvement of these chaperones for protein homeostasis. As soon as the chaperones leave to participate in protein refolding, HSF1 monomers trimerise with the help of hydrophobic interactions between their three N-terminal and one C-terminal leucine zipper domains (LZDs), forming a three-stranded coiled coil. Under unstressed conditions, the oligomerisation is inhibited by intramolecular interaction between the hydrophobic LZDs of HSF1. HSF1 protein has a nuclear localisation sequence (NLS), necessary for its nuclear import. However, when in cytosol the NLS of HSF1 remains hidden due to the above-mentioned monomeric LZD interactions. Under stressful conditions, this interaction is replaced by an intermolecular interaction between the same LZDs of three HSF1 molecules, exposing the NLS, facilitating its nuclear translocation. It is upon trimerisation, that HSF1 moves into the nucleus and binds to the HSE, driving the expression of HSPs. Furthermore, post-translational modifications like sumoylation, acetylation and phosphorylation, especially in the regulatory domain (RD) and DNA-binding domain (DBD) play a vital role in regulation of HSF1 transactivation and attenuation of SR (Bhattacharya and Rattan, 2019). There are six families of HSP reported in the literature, and most commonly, their nomenclature reflects their molecular weight (for example HSP100, HSP90, and HSP70). The most studied function of HSP is the restoration of aggregated and misfolded proteins during cellular stress, and prevention of apoptosis. HSPs achieve this goal by interacting with the incorrectly folded proteins, assisting them towards correct interactions within their own amino acid backbone (and side-chains), thereby restoring their native conformation and hence functionality (Westerheide et al., 2012). Co-chaperones like HOP (Hsp70/Hsp90 organizing protein) play a crucial role in achieving this goal. Other than being cyto-protective, HSPs have been attributed with immunostimulatory functions, and their presence has been detected in the plasma membrane and the extracellular space. HSPs do not have a signaling peptide to assist in membrane translocation. Hence, it is possible that these proteins are carried to the plasma

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membrane by other proteins having membrane localisation signals. During stress, these proteins are delivered into the extra-cellular space, where they are found to function as chaperokines. Age-related decline in the induction of HSR is well-established in model systems and in humans (Verbeke et al., 2001; Singh et al., 2006). However, the basal levels of some HSP becomes elevated during aging, which is indicative of the increased levels of intrinsic stress involving protein denaturation (Njemini et al., 2007).

Hypoxia-Induced Stress Response (HISR) Hypoxia or a lack of oxygen can be as stressful and damaging to an organism as its excess. HISR in mammals is regulated by transcription factors called hypoxia-inducible factors (HIF) (Maxwell, 2005). HIF belong to a large family of transcription factors having a relatively simple structure made up of a helix-loop-helix region and a PAS domain. The regulatory a-subunit is oxygen sensitive and mediates hypoxic response, whereas the b-subunit is constitutively expressed and maintained at a stable concentration in the cell. There are three mammalian isoforms of the a-subunit, namely HIF1a, HIF2a, and HIF3a or IPAS. HIF-1a is ubiquitously expressed. However, it is continuously degraded in the proteasomes followed by poly-ubiquitination via von Hippel-Lindau protein (pVHL) ubiquitin ligase complex, giving it a half-life of about 5 min. The HIF-a subunit has conserved prolyl and asparaginyl residues, which play pivotal role in the regulation of HIF1a/2a. Under normal oxygenated conditions, prolyl hydroxylase domain containing enzymes (PHD), belonging to a large family of Fe(II) and 2-oxoglutarate dependant oxygenases, hydroxylates at least one of the two critical proline residues (Pro402 and Pro564) of HIFa subunit, creating binding sites for pVHL, which causes its poly-ubiquitination and degradation (Bhattacharya and Rattan, 2019). PHDs use oxygen as a cosubstrate and are therefore dependent on well-oxygenated conditions for their activity. In the absence of adequate amount of oxygen, they are incapable of hydroxylating the proline residue(s), thereby stopping the degradation of the a-subunit, leading to an increase in its concentration in the cytosol. During hypoxia, when the a-subunit is stabilized, it translocates into the nucleus and forms a heterodimer with the HIFb subunit. HIFab then binds to gene sequences called HIF responsive elements (HRE) ahead of promoters of hypoxia inducible genes, and recruits coactivator proteins like p300, CBP (CREB binding protein), SRC-1 (steroid receptor coactivator-1) or transcriptional intermediary factor-2. This HIFab/co-activator complex is transcriptionally active, and capable of facilitating HISR (Majmundar et al., 2010). HIF induces transcription of those genes that can counterbalance the effects of hypoxia. HISR becomes less efficient during aging and the sensitivity of old cells and organs, specially the brain, to hypoxia is increased (Kagias et al., 2012; Leontieva and Blagosklonny, 2012). That is why even the beneficial effects of physical exercise, which depend on appropriate HISR are significantly reduced with age (Radak et al., 2008).

Inflammatory Stress Response (ISR) Inflammation is a hugely complex response of the immune system against infectious pathogens or external irritants, where the organism tries to destroy the damaged cells or tissues affected by and containing the pathogen (Frasca and Blomberg, 2016). When the defense barriers of an organism is breached by a foreign object, be it virus or bacteria or a sharp pin, the damaged cells start releasing small molecule chemical messengers known as chemokines to activate the immune system. Molecules and degraded/ intact proteins from the foreign organism can also trigger host immune response. Not only foreign components, ISR can also be triggered by tissue dysfunction, ROS and physiological stress (Padgett and Glaser, 2003; Chovatiya and Medzhitov, 2014). Cells participating in ISR, for example, macrophages, neutrophils, lymphocytes, monocytes, dendritic cells, T-lymphocytes, B-lymphocytes, natural killer cells and mast cells interact with each other by releasing lipid or protein messenger molecules like prostaglandin and cytokines. However, majority of the inflammatory and immune response is achieved by the activation of the fast-acting transcription factor NF-kB. Mammals have five different NF-kB proteins (RelA, RelB, c-Rel, NF-kB1, and NF-kB2) which form homo/heterodimers with each other, and are capable of inducing transcription of a specific set of genes, based on the combination (Kriete and Mayo, 2009; Smale, 2012). In unstressed cells and uninfected conditions, the NF-kB dimer remains tightly bound to inhibitory protein IkB (inhibitor of kappa B), which restricts the transcription factor in the cytosol and inhibit its nuclear import. Binding of cytokines, antigens and pro-inflammatory messenger molecules to cell-surface receptors e.g., TNF-a (tumor necrosis factor-a) receptors, interleukin-1 receptor (IL-1R), antigen receptors and toll like receptors (TLRs), initiates a signaling cascade, which leads to the phosphorylation of two serine residues on IkB by a serine/threonine kinase called IkB kinase (IKK). This promotes ubiquitination and degradation of IkB, which then exposes a nuclear translocation signal on the released NF-kB, facilitating its nuclear import (Bhattacharya and Rattan, 2019). Pro-inflammatory ligands triggering the release of NF-kB could be TNF-a, Interleukin 1 (IL-1) and lipopolysaccharides (LPS). In the nucleus, NF-kB induces the transcription of over 150 target genes, promoting the expression of pro-survival cytokines and chemokines, such as IL-2, IL-6, lymphotoxin-a, TNF-a; receptor proteins involved in immune defense (CD40, CD98, TNF receptor); other sell surface receptors (epidermal growth factor or EGF receptor, bradykinin B1 receptor); pro- as well as anti-apoptotic factors (Bax, Caspase-11, Bcl-xL, Bcl-2), its own inhibitor IkB, and adhesion proteins (intercellular adhesion molecule 1 or ICAM-1, fibronectin) (Mussbacher et al., 2019). It is important to note that NF-kB induces the transcription of its own inhibitor, ensuring that the ISR is transient and not continuous.

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Aging is often characterized as inflammaging, due to chronically activated ISR (Fulop et al., 2018). However, inflammaging is also accompanied by immonosenescence manifested as reduced and inefficient response to novel stress due to infections and other antigens (Fulop et al., 2018).

Oxidative Stress Response (OSR) Reactive oxygen species (ROS), reactive nitrogen species (RNS) and other electrophilic molecules, collectively known as free radicals, are produced as a result of numerous metabolic biochemical reactions that are carried out within the cells, primarily in the mitochondria (Balaban et al., 2005). OSR is mainly regulated by the transcription factor Nrf2 (nuclear factor erythroid-2 related factor 2) and ARE (antioxidant response elements), a 16 base pair long consensus sequence present in the promoter region of genes encoding proteins that mediate OSR. Nrf2 is constitutively expressed in cells and is kept in the cytosol by binding with Keap1 (Kelch-like enoyl-CoA hydratase-associated protein 1). Keap1 is a cysteine rich protein, with numerous side-chain sulfhydryl groups, which interact with the excess ROS and other electrophilic components in the cytosol, during oxidative stress, disrupting the interactions between Nrf2 and Keap1 (Tebay et al., 2015). Nrf2 contains signal peptides for both nuclear localisation and nuclear export. After its release from Keap1, the transcription factor gets phosphorylated at Ser40, forms heterodimers with a set of small musculoaponeurotic fibrosarcoma (Maf) proteins and moves to the nucleus. The activity of Nrf2 can be regulated by phosphorylation at different sites, and the interaction with Mafs covers the nuclear export signal facilitating its entry into the nucleus. Here it binds specifically to the AREs or electrophile response elements (EpREs) in the promoter region of genes whose protein products take part in anti-oxidative, radical scavenging reactions and cyto-protective phase II detoxification in cells (Tebay et al., 2015). Some of the main examples of the anti-oxidative protein products are enzymes like NAD(P)H:quinone oxidoreductase-1 (NQO1), thioredoxin (TXN), thioredoxin reductase (TXNRD), heme oxygenase-1 (HO-1), superoxide dismutase (SOD), sulfiredoxin (SRXN), glutathione S-transferase (GST), glutathione reductase (GR), peroxiredoxin sulfotransferase and UDP-glucuronyl transferase (Smith et al., 2016). The inducibility of OSR is decreased during aging (Liguori et al., 2018; Pomatto and Davies, 2018), and as a consequence, the harmful effects of ROS and other oxidative-damage inducing agents become more severe in old age.

Unfolded Protein Response (UPR) Endoplasmic reticulum (ER) is the cellular organelle responsible for proper folding of transmembrane or secreted proteins. After being produced by the ribosomes, proteins enter the ER lumen, where they are assembled before they are transported out to other organelles, placed in the plasma membrane or exported out of the cell. ER enforces strict quality control, so that only correctly folded proteins are allowed to exit the organelle. Proteins that do not fold properly are packed in vesicles and exported to proteasomes for degradation. An accumulation of unfolded proteins in the ER lumen, induced by oxidative stress, hypoxia, toxins, viral infections etc. triggers a SR called the UPR or ER stress response (Pomatto and Davies, 2018; Walter and Ron, 2011). During UPR, an expansion of ER membrane is initiated, to accommodate the incorporation of a large number of newly synthesized proteins that assist in the correct folding of the misfolded ER proteins. Three major ER stress sensors are known: inositol-requiring enzyme-1 (IRE1), activating transcription factor-6 (ATF6), and double-stranded RNA-activated protein kinase-like ER kinase (PERK). The general theme of sensing ER stress by all three sensors is via a transmembrane protein embedded in the ER membrane (ERM), which transmits the signal of ER stress to the cytosol. In the absence of ER stress, a molecular chaperone GRP78 (glucose regulated binding protein 78, also known as BiP), binds to and inhibits the transmembrane sensors (Li et al., 2008). With the accumulation of proteins in the ER lumen, GRP78 dissociates from these sensors and UPR is activated. Both paralogs of IRE1, IRE1a and IRE1b are bi-functional transmembrane proteins, having cytosolic kinase and endoribonuclease domains; whereas its luminal domain (that is present in the ER lumen, on the other side of the ERM) bind to unfolded proteins during ER stress. When the luminal domain binds to unfolded proteins, IRE1 is activated by lateral oligomerisation in the ERM, leading to trans-autophosphorylation (Korennykh et al., 2009). The endoribonuclease domain of active IRE1 cleaves the intron out of XBP1 (X-box binding protein 1) mRNA, the exons are joined to form the spliced mRNA, which is then translated into active XBP1 protein. The transcription factor XBP1 binds directly to the ERSE (endoplasmic reticulum stress element) and induces the transcription of the genes encoding ER folding machinery. An immediate response during UPR is obtained via ATF6 activation. The transcription factor ATF6 is synthesized as a transmembrane protein having a large luminal domain that resides in the ER, and a relatively small cytosolic domain. When there is predomination of unfolded proteins in the ER, ATF6 buds off the ERM in a vesicle, and reaches the Golgi apparatus. Here its luminal and transmembrane domain is cleaved off by the S1P and S2P (site 1 and site 2 proteases). The released cytosolic part then moves to the nucleus and transcribes ER stress responsive genes involved in the correct folding of the proteins stranded in the ER lumen. Some of the target proteins of ATF6 are molecular chaperones of the HSP70 family (GRP78), HSP90 family (GRP94) (Li et al., 2008). Another dimension of UPR is the protein kinase PERK located in the ER membrane (Romine and Wiseman, 2019). During ER stress, it dimerises and undergoes autophosphorylation. Additionally, it inhibits the ubiquitously expressed eIF2a (eukaryotic initiation factor 2a) by phosphorylating it at ser51 which resulting in an overall reduced rate of mRNA translation and protein synthesis, therefore minimizing ER load. During excessive ER stress, ATF4 induces the transcription of CHOP (C/EBP homologous protein),

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which regulates the downstream proteins of the Bcl-2 (Beta cell lymphoma 2) family and GADD34 (growth arrest and DNA damage-inducible gene 34) leading to growth arrest and apoptosis. As in the case of other stress responses, UPR inducibility also declines with age while the basal levels of UPR seem to become constitutively upregulated (Seli et al., 2019).

Conclusions SR pathways discussed here comprise the main molecular repertoire of an organism to maintain stability in a dynamic and interactive manner. Table 1 gives a summary of the primary intracellular SR pathways, along with examples of stressors, early responses, late responses and molecular mediators and effector molecules of responses. Other higher order responses such as apoptosis, release of stress hormones, immunological reactions and thermoregulation, add to the complexity of the overall homeodynamic space of a living system. Not all pathways of SR respond to every stressor, and although there may be some overlap, generally SR are quite stressor-specific. However, these pathways, although start off with very specific enzymatic steps that carry the response forward, can diverge at the level of effector molecules and overlap with downstream effectors of other SRP (Bhattacharya and Rattan, 2019). Each of these SR pathways can involve both initial and late biochemistry, typically designated as the immediate and the late response. Here, initial response is mediated by a set of biomolecules in the cell belonging to one particular SR pathway, whereas the later stage response might involve a different set of effector molecules and may overlap with a different SR pathway. Exposure to multiple stressors simultaneously or within a short interval, can trigger a network of individual and overlapping SR. Therefore, to understand SR in its entirety, a simultaneous analysis of all the SR pathways is necessary (Demirovic and Rattan, 2013; Rattan et al., 2018). It is important to establish a complete SRP under a given framework of age, health and disease status before, during and after exposure to single/multiple stressors (Demirovic and Rattan, 2013; Rattan et al., 2018). A consolidated SR can be triggered by stressors like fasting, calorie restriction, exercise, heat shock, pro-oxidants, hypoxia and other hormetins, which can have hormetic health benefits at cellular and organismal levels during aging (Rattan, 2014).

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Strokeq Muhammad U Farooq, Christopher Goshgarian, Bradley Haveman Gould, and Amy Groenhout, Mercy Health Hauenstein Neurosciences, Grand Rapids, MI, United States Philip B Gorelick, Michigan State University College of Human Medicine, East Lansing, MI, United States; and Mercy Health Hauenstein Neurosciences, Grand Rapids, MI, United States © 2020 Elsevier Inc. All rights reserved. This article is an update of P.B. Gorelick, V. Shanmugam, A.K. Pajeau, Stroke, Editor(s): James E. Birren, Encyclopedia of Gerontology (Second Edition), Elsevier, 2007, Pages 565–574, ISBN 9780123708700, https://doi.org/10.1016/B0-12-370870-2/00181-5.

Introduction Stroke Classification Clinical Implications for Primary Care Practice Primary Stroke Prevention Secondary (Recurrent) Stroke Prevention Neuroimaging in Stroke Acute Ischemic Stroke Management Prehospital Phase ED Phase Neuroimging Phase Administration of IV t-PA and Blood Pressure Control Evidence to Support IV t-PA Administration, Thrombectomy and Late Time Windows of Treatment for AIS Role of Stroke Units in Improving Stroke Care Systems of Care in Stroke Management: Nursing Perspective Conclusion Addendum References Further Reading Relevant Websites

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Glossary Atrial fibrillation Irregular and often rapid heart rate associated with an increase in the risk of stroke. Apolipoprotein Apolipoproteins are proteins that bind lipids to form lipoproteins. They transport lipids through the lymphatic and circulatory systems. Cryptogenic stroke A type of stroke of uncertain etiology or origin. Cerebral blood flow (CBF) Is the blood supply to the brain in a given period of time. In an adult, cerebral blood flow is typically 750 mL per minute or 15% of the cardiac output. Cerebral blood volume (CBV) Is the volume of blood in a given amount of brain tissue, most commonly measured as milliliters of blood per 100 g of brain tissue. Carotid endarterectomy Surgical procedure to open or clean the carotid artery of atherosclerotic plaque with the goal of stroke prevention. Embolic stroke Stroke that occurs if a blood clot that forms elsewhere in the body breaks loose and travels to the brain via the bloodstream and blocks a blood vessel. Common sources are the roughened wall of an atherosclerotic artery or a damaged cardiac heart valve or source such as atrial fibrillation. Lipohyalinosis Cerebral small vessel disease affecting the small arteries, arterioles or capillaries in the brain. Originally defined by C. Miller Fisher as “segmental arteriolar wall disorganization,” it is characterized by vessel wall thickening and a resultant reduction in luminal diameter due to lipid deposition and hyaline change in the wall of the small artery. Metabolic Syndrome Clustering of at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides and low high-density lipoprotein (HDL) levels. Mean transient time (MTT) Average time, in seconds, that red blood cells spend within a determinate volume of capillary circulation. It is expressed by the formula: MTT ¼ cerebral blood volume (CBV)/cerebral blood flow (CBF).

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Change History: January 2019. PB Gorelick, V Shanmugam and AK Pajeau updated the text and references.

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Mechanical thrombectomy Emergency procedure used to remove a blood clot from a cerebral blood vessel using devices such as stent retrievers or suction devices. Thrombolysis or thrombolytic therapy Pharmacological treatment to dissolve a blood clot in a blood vessel to restore blood flow to tissues.

Abbreviations AHA/ASA American Heart Association/American Stroke Association AIS Acute Ischemic Stroke ASCVD Atherosclerotic cardiovascular disease CBF Cerebral blood flow CBV Cerebral blood volume CVA Cerebrovascular accident CEA Carotid endarterectomy CT Computerized tomography CTA CT angiography CTP CT perfusion DWI Diffusion weighted image EMS Emergency medical services FAST Face, arm, speech, time ICH Intracerebral hemorrhage LKW Last known well LVO Large vessel occlusion MCA Middle cerebral artery MRI Magnetic resonance imaging MTT Mean transient time NIHSS National Institute of Health Stroke Scale PFO Patent foramen ovale RCT Randomized controlled trials IV t-PA Intravenous tissue plasminogen activator TIA Transient Ischemic Attack

Introduction Diagnosis, prevention and treatment of stroke has substantially evolved over the past several decades. Stroke is one of the most common disabling and lethal diseases of adult life, but is not a chance or random event as the moniker “cerebrovascular accident” (CVA) would lead one to believe (Wolf et al., 1983). Stroke is not an accident but rather is linked to precursors or risks many of which can be prevented or treated to successfully lessen the frequency of stroke (Stroke Prevention, 2005). A prime example of a factor closely linked to stroke and for which treatment of the factor significantly reduces the occurrence of stroke is hypertension. Treatment of hypertension may reduce the risk of stroke by about a third or more. Because hypertension is so prevalent in many communities, is highly associated with stroke, and is modifiable, it is considered a “crown jewel” of stroke prevention (Gorelick, 2002). Beyond stroke prevention there has been an explosion of advances in acute stroke diagnosis and treatment. Adoption of computer-driven software programs has led to the measurement of blood flow, blood volume, and infarct volume to assist in the proper selection of patients for mechanical thrombectomy and intravenous thrombolytic administration (Nogueira et al., 2018a; Albers et al., 2018a). At one time we were limited to no major acute ischemic stroke therapies, whereas now acute stroke interventions have been extended from a 0–3 h window after acute ischemic stroke onset to a 24-h time window. In this article we provide evidence-based guidance to the prevention, diagnosis, treatment and nursing management of ischemic stroke according to American Heart Association/American Stroke Association (AHA/ASA) recommendations.

Stroke Classification An initial step to assure a proper diagnosis of stroke is completion of an adequate neurological history and physical examination by a well-trained health care team member. Neurological history and physical examination coupled with appropriate

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neuroimaging diagnostic studies are key elements to arrive at a correct stroke subtype diagnosis. Stroke classification is important as stroke prevention and treatment recommendations are guided initially by identification of stroke subtype. In the 1970s and 1980s a number of organized efforts, largely through the use of regional stroke registries, were carried out to study and classify stroke subtype (Caplan, 2000). A detailed review of these efforts is beyond the scope of this article and is discussed by Caplan elsewhere (Caplan, 2000). In the United States (US), modern, select stroke registries furthered our knowledge about stroke classification and included such programs as the Harvard Stroke Registry (Mohr et al., 1978), Michael Reese Stroke Registry (Caplan et al., 1983), Stroke Data Bank (Foulkes et al., 1988), and others (Caplan, 2000). Later, the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) stroke classification system was developed (Adams et al., 1993). The latter classification system has been widely used in clinical trials. Since the development of the TOAST stroke classification system, other systems such as ASCO (A ¼ atherosclerosis, S ¼ small vessel disease, C ¼ cardiac source embolism, and O ¼ other cause) and causative classification of stroke (CSS) have surfaced for use in research studies (Arsava et al., 2017). The reader is referred to a review of variation in the predictive validity of these classification systems (Arsava et al., 2017).

Clinical Implications for Primary Care Practice The primary care practitioner should have familiarity with stroke classification systems and how to apply them in practice. For example, it is important to be able to identify acute large artery occlusive ischemic stroke as such patients may be candidates for mechanical thrombectomy to remove a thrombus underlying acute ischemic stroke (AIS) (Nogueira et al., 2018a; Albers et al., 2018a). Furthermore, certain race-ethnic groups may be more prone to certain stroke subtypes and such knowledge may be useful. A recent meta-analysis and systematic review of the distribution of ischemic stroke subtypes showed that there may be heterogeneity of ischemic stroke subtypes in different populations. Cardioembolism was the leading cause of stroke among Caucasians, large artery atherosclerosis was common among Asians, and small vessel disease was common among African Americans and Hispanics (Ornello et al., 2018). Stroke is divided into ischemic and hemorrhagic subtypes (see Table 1). Hemorrhagic stroke makes up about 10%–20% of stroke and may be subdivided into intraparenchymal hemorrhage and subarachnoid hemorrhage. The focus of this article, ischemic stroke, comprises approximately 80%–90% of all strokes and may be subdivided into large artery atherosclerosis (high-grade occlusive disease and artery-to-artery embolism), small vessel (e.g., lacunar) disease, cardioembolism, nonatherosclerotic stroke, and cryptogenic stroke (Gorelick and Ruland, 2010). The ischemic stroke subtypes are defined in Table 1. Large artery atherosclerotic stroke occurs when there is a low flow state due to high-grade intra- or extracranial large artery occlusive disease (e.g.,  70% stenosis of the extracranial carotid artery) or atherosclerotic plaque debris causing downstream artery-to-artery embolism with occlusion of distal cerebral arteries. Small vessel or lacunar disease results when arteries that may measure only several 100 mm in diameter undergo arteriopathic changes such as lipohyalinosis or fibrinoid change, are affected by microatheroma at their orifice from a large parent artery that has atherosclerosis, or are affected by microembolism. Cardioembolism is associated with atrial fibrillation or some other high-risk cardioembolic source (e.g., acute myocardial infarction or heart failure with significant left ventricular dysfunction). Nonatherosclerotic stroke is caused by nonconventional conditions such as sickle cell disease, thrombophilic states, and strokes associated with infections. Finally, cryptogenic stroke occurs when there is no cause of stroke that can be identified. In some cases, however, a cause for stroke cannot be identified as diagnostic study is lacking.

Table 1

Classification of stroke by stroke subtype (Gorelick and Ruland, 2010)

Ischemic Stroke 1. Large artery atherosclerosis: high-grade stenosis of a large extracranial artery (e.g., internal carotid artery) or intracranial artery (e.g., middle cerebral or basilar artery) causing a low flow state or an atherosclerotic plaque causing artery-to-artery embolism and downstream embolism. 2. Small vessel or lacunar disease: small deep infarcts resulting from deep penetrating artery arteriopathy (e.g., due to lipohyalinosis or fibrinoid change), microatheroma from originating from parent large artery atherosclerosis, or microembolism. 3. Cardioembolism: secondary to cardiac disease such as atrial fibrillation and myocardial infarction or chronic heart failure with significant left ventricular dysfunction. 4. Nonatherosclerotic: secondary to nonconventional causes of stroke such as thrombophilic disorders, vasculitis, infections, and dissection of cerebral arteries. 5. Cryptogenic: none of the above causes for stroke is identified.a Hemorrhagic Stroke 1. Intraparenchymal (when deep in the brain [e.g., putamen, thalamus, cerebellum] is often times due to hypertension and when in a lobar location [frontal, parietal, temporal or occipital lobe] is often times secondary to amyloid angiopathy/cerebral microbleeds) 2. Subarachnoid (often times caused by rupture of a brain aneurysm a A cause for stroke may not be obvious when there is limited stroke diagnostic study. In such a case the cause of stroke may best be considered stroke of uncertain etiology, as diagnostic study is incomplete (Adams et al., 1993).

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Primary Stroke Prevention About 90% of ischemic stroke is attributed to 10 cardiovascular risks which include hypertension, current smoking, elevated waistto-hip ratio, poor diet, lack of exercise, diabetes mellitus, alcohol intake, stress and depression, cardiac disease, and apolipoprotein B to A1 ratio (Testai and Gorelick, 2012). In the absence of such risks or when there is a healthy lifestyle and stroke risk profile, the risk of stroke may be reduced up to  80%. In practice there are two main approaches to stroke prevention: the population or mass approach and the high-risk approach (Gorelick, 2009). The former approach relies on shifting the population risk to a more favorable profile by enacting global health education, legislation, and economic measures to reduce or lessen exposure to unhealthy risks in a population. The high-risk approach focuses on screening individuals such as in an individual provider practice to seek those at high risk and then aggressively modify the risks by advocating lifestyle change and by administration of medication (Gorelick, 2009). The population and high-risk approaches are complementary strategies to reduce disease burden. Hypertension is a major target for stroke prevention as it has a high population attributable risk (PAR), is modifiable, and there is substantial clinical trial evidence to support reduction of stroke when blood pressure is lowered (Testai and Gorelick, 2012; Gorelick, 2009). Hypertension has a continuous relationship to stroke with stroke risk beginning with blood pressure as low as 115/75 mmHg according to observational epidemiological studies (Gorelick, 2009). Furthermore, raised blood pressure often times occurs in the company of other cardiovascular risks such as hyperglycemia, overweight/obesity and lipid abnormalities as part of a metabolic syndrome complex. A 2014 AHA/ASA stroke-specific guidance statement had the following first stroke prevention recommendations in relation to blood pressure: (1) Regular blood pressure screening; (2) Promotion of lifestyle modification; (3) Blood pressure lowering to a target of < 140/90 mmHg and administration of antihypertensive medication if blood pressure level is  140/90 mmHg; (4) Lowering of blood pressure is favored over a specific class of antihypertensive agent, unless there is a compelling indication to use a certain blood pressure lowering agent; and (5) Self-monitoring of blood pressure to improve blood pressure control (Meschia et al., 2014). Based on a 2017 guidance statement endorsed by AHA/ASA, the target blood pressure goal for cardiovascular prevention is modified to < 130/80 mmHg for the following patient groups: (1) Presence of cardiovascular disease or 10-year atherosclerotic cardiovascular (ASCVD) risk  10%; (2) No clinical cardiovascular disease and 10-year ASCVD risk < 10%; and (3) Older persons 65 years of age or older, noninstitutionalized, ambulatory, and community dwelling (Whelton et al., 2017). According to the latter guideline, initial antihypertensive drug therapy may include thiazide diuretics, calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers. Of further note, it is shown that beta-blocker drugs are less effective than diuretics for prevention of stroke and cardiovascular disease (Whelton et al., 2017). In addition, for those with stage 1 hypertension (systolic blood pressure 130–139 mmHg or diastolic blood pressure 80–89 mmHg), mono-antihypertensive therapy is reasonable. Whereas for those with stage 2 hypertension (systolic blood pressure  140 mmHg or diastolic blood pressure  90 mmHg) and an average blood pressure > 20/10 mmHg above the target goal, two first-line agents from different blood pressure lowering classes are recommended for administration (Whelton et al., 2017). In addition to management of high blood pressure the 2014 AHA/ASA guidance statement addresses goals for management of other well-documented and modifiable risk factors for first stroke prevention (Meschia et al., 2014). The factors include physical inactivity, dyslipidemia, diet and nutrition, obesity, diabetes, cigarette smoking, atrial fibrillation, asymptomatic carotid artery stenosis, and other factors. Table 2 provides a summary of recommendations for management of select modifiable factors for first stroke prevention according to 2014 AHA/ASA guidance (Meschia et al., 2014).

Secondary (Recurrent) Stroke Prevention After an initial ischemic stroke or transient ischemic attack, the annual risk for a recurrent ischemic event is approximately 3%–4% (Kernan et al., 2014). Cumulative ischemic strokes result in increased morbidity and mortality, suggesting clinicians take measures to mitigate stroke risk after a sentinel ischemic event. The 2014 ASA/AHA guidelines for the prevention of stroke in patients with stroke and transient ischemic attack offer a multipronged approach to secondary stroke prevention (Kernan et al., 2014). Based on these guidelines, blood pressure therapy is recommended several days after ischemic stroke for patients with established systolic blood pressure  140 mmHg or diastolic blood pressure  90 mmHg, with a reasonable goal of systolic blood pressure < 140 mmHg and diastolic pressure < 90 mmHg (Wolf et al., 1983). For patients with small vessel lacunar strokes, it is reasonable to target a lower systolic blood pressure of < 130 mmHg (Kernan et al., 2014). Dyslipidemia is another significant vascular risk factor, and the guidelines suggest statin therapy with lipid-lowering effects for patients with ischemic stroke or TIA attributed to atherosclerosis, noting a lower level of evidence for this approach when LDLC < 100 mg/dL as compared to  100 mg/dL (Kernan et al., 2014). The 2013 ACC/AHA cholesterol guidelines suggest use of a high intensity statin when age is  75 and a moderate intensity statin when age is > 75 (Stone et al., 2014). An additional target for vascular risk factor optimization is glycemic control. Keeping in mind that factors such as an acute illness can interfere with the diagnostic sensitivity and specificity for fasting glucose levels or an oral glucose tolerance test as a diagnostic test for diabetes mellitus, the 2014 ASA/AHA guidelines favor use of HgbA1c as a screening test in the poststroke period (Kernan et al., 2014). A goal of HgbA1c < 6.5% is considered, keeping in mind the need for safety and risk of hypoglycemia (Kernan et al., 2014).

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Stroke 2014 American Heart Association/American Stroke Association stroke-specific recommendations for management of select welldocumented and modifiable risk factors for first stroke prevention (Meschia et al., 2014)

Risk factor and management recommendation (see text for discussion of management of hypertension) 1. Physical Inactivity: for healthy adults, perform moderate to vigorous intensity aerobic exercise for 40 min/day, 3–4 times/week. 2. Dyslipidemia: for those with a high 10-year risk for cardiovascular events, lifestyle changes and treatment with a statin agent; niacin may be considered for persons with low HDL-cholesterol or elevated Lp(a) but may increase risk of myopathy; fibric acid may be considered if there is hypertriglyceridemia; and nonstatin lipid lowering agents (e.g., fibric acid derivatives, bile salt sequestrants, niacin, and ezetimibe) may be considered for those who cannot tolerate statins (latter agents may not reduce stroke risk). 3. Diet and nutrition: reduce sodium intake, DASH-style diet (fruits, vegetables, and low-fat dairy sources and reduced saturated fat), diet rich in fruits and vegetables (high in potassium), and Mediterranean diet supplemented with nuts may be considered. 4. Obesity and body fat distribution: for overweight and obese weight reduction recommended to lower blood pressure and reduce stroke risk. 5. Diabetes mellitus: blood pressure control (target: 70% stenosis of the internal carotid artery if major perioperative risk is 25) (Hacke et al., 2008). Initially, exclusions to IV t-PA were similar to many of the exclusion based on the original NINDS trial. In 2015, IV t-PA (Alteplase) underwent a label change with removal of many of the prior exclusions. The readers are directed to ASA/AHA 2018 guidelines for management of acute ischemic stroke, Table 6, for a full list of eligibility recommendations for IV t-PA (Powers et al., 2018). IV t-PA is dosed based on patient’s weight (0.9 mg/Kg with a maximum dose of 90 mg) and administered over 60 min with initial 10% of the dose given as a bolus over 1 min.

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Now that the decision to administer or forgo IV t-PA has been made, a noninvasive intracranial vascular study is recommended in order to identify evidence of large vessel occlusion/intracranial thrombus (Powers et al., 2018). Timing remains of critical importance to good neurological outcomes and therefore as little delay as possible is stressed when completing intracranial imaging. In fact, intracranial imaging should be pursued as soon as the IV t-PA bolus is completed or while the IV t-PA infusion is being administered. The authors recommend a CTA of head with contrast as our preferred imaging modality due to the sensitivity of identifying thrombus and the speed in which this test can be accomplished. AHA/ASA guidelines recommend mechanical thrombectomy with a stent retriever if the following criteria are met: (1) prestroke mRS of 0 to 1; (2) occlusion of ICA or MCA segment 1; (3)  18 years of age; (4) NIHSS  6; and groin puncture within 6 h of symptom onset (Powers et al., 2018). A meta-analysis of five randomized controlled thrombectomy trials demonstrated endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted odd ratio 2.49, 95% CI 1.76– 3.53; P < .0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on the modified Rankin Scale for one patient was 2.6 (Goyal et al., 2016). Patients who have large vessel anterior circulation occlusion within 6–24 h of LKW may be eligible for mechanical thrombectomy, but only when advanced imaging and other eligibility criteria from randomized controlled trials are strictly applied as mentioned in the neuroimaging section (Powers et al., 2018). This necessitates the need for additional imaging modalities, such as CT perfusion with Rapid software, which can help better define the ischemic penumbra as discussed previously. Both the DAWN trial and DEFUSE 3 trial demonstrated significant benefit with the use of mechanical thrombectomy beyond 6 h of LKW for selected patients with anterior circulation large vessel occlusions. The DAWN trial selected patients up to 24 h from LKW by using a combination of NIHSS and imaging findings on CT perfusion or DW-MRI. This trial demonstrated an overall benefit in functional outcome at 90 days in the thrombectomy group (modified Rankin Scale score 0–2, 49% versus 13%; adjusted difference, 33%; 95% CI, 21–44) (Nogueira et al., 2018b). The DEFUSE 3 trial used perfusion-core mismatch and maximum core size as imaging criteria to select patients from 6 to 16 h of LKW for mechanical thrombectomy. DEFUSE 3 also showed significant benefit at 90 days (modified Rankin Scale score 0–2, 44.6% versus 16.7%; RR, 2.67; 95% CI, 1.60–4.48; P < .0001) (Albers et al., 2018b). Thus, these are now available acute stroke interventions, which can extend up to 24 h from the onset of stroke or LKW, having profound effects on morbidity.

Role of Stroke Units in Improving Stroke Care A stroke unit is characterized by a specialized, geographically defined, hospital unit managed by an experienced stroke team and is one of the most important advances in the management of acute stroke patients as it has been shown to reduce stroke death and dependency. Therefore, AHA/ASA, Canadian and European guidelines recommend that all hospitalized stroke patients be treated in stroke units to facilitate better outcomes (Powers et al., 2018; Hebert et al., 2016; European Stroke Organization (ESO) Executive Committee; ESO Writing Committee, 2008). One of the key components of a stroke unit is a designated area and each country defines its own standards of care, human resources, and such facilities, but a multidisciplinary and interprofessional stroke team working in a stroke unit may be comprised of physicians, nurses, a physiatrist, physical, occupational and speech therapists, clinical nutritionist, neuropsychologist and social workers dedicated to the management of stroke patients. It is also recommended that stroke teams include hospital pharmacists to promote patient safety, medication reconciliation, provide education to the team, patients and their families regarding medications including side effects, drug interactions and adherence to medications for secondary stroke prevention. Other important members of this stroke team may include discharge planners or case managers and palliative care specialists. The interprofessional team should assess patients within 48 h of admission to the hospital and establish a management plan. A globally accepted standard of care is ideal, however, stroke units may function differently according to country-specific guidance (Powers et al., 2018; Hebert et al., 2016; Chiu et al., 2007; Shultis et al., 2010). A stroke unit provides initial comprehensive medical care by the above mentioned interprofessional team, mostly during the first 7–10 days (or fewer days) following a stroke. It is recommended that stroke patients be placed in a stroke unit within 3–6 h of presentation to the ED, and the interprofessional team assesses stroke patients and map out a management plan within 24 h. It is recommended that standard and valid assessment tools such as written protocols and order sets/algorithms are used to evaluate stroke patients for acute management and rehabilitation. For example, introduction of a standardized dysphagia screening tool in a stroke unit as a part of an admission order set may help reduce the rates of in-hospital pneumonia. It is now well-established that stroke units are cost effective and patients who receive stroke unit care are more likely to survive and regain independence compared to patients who receive less organized forms of stroke care (Powers et al., 2018; Hebert et al., 2016; European Stroke Organization (ESO) Executive Committee; ESO Writing Committee, 2008; Chiu et al., 2007; Shultis et al., 2010; Stroke Unit Trialists Collaboration, 2013; Martino et al., 2009). Besides acute management, the stroke team should assess other components of patient care including dysphagia, mobility, functional assessment, nutrition, bowel and bladder function, skin care, discharge planning, and deep venous thrombosis prophylaxis. One should not forget about addressing mood and cognition of the stroke patients (e.g., poststroke fatigue and depression). Another important aspect of care is assessment of functional status and postacute stroke rehabilitation needs. All these components of clinical and supportive care should occur within the first 72 h poststroke (Powers et al., 2018; Hebert et al., 2016; Stroke Unit Trialists Collaboration, 2013). Key components and functions of a stroke unit and important time lines are summarized in Table 4.

Stroke Table 4

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Key components and functions of stroke units and important time frames for patient care in stroke units (Powers et al., 2018; Hebert et al., 2016; European Stroke Organization (ESO) Executive Committee; ESO Writing Committee, 2008; Chiu et al., 2007; Shultis et al., 2010; Stroke Unit Trialists Collaboration, 2013; Martino et al., 2009) Key components, functions and timeframes for stroke units

Physical location Multidisciplinary and interprofessional team in stroke unit

Spectrum of patient care in stroke unit

Designated and geographically defined unit in hospital Physicians, pharmacists, nurses, physiatrist, physical, occupational and speech therapists, clinical nutritionist, neuropsychologist, social workers, discharge planners, case managers and palliative care specialists acute management, dysphagia, mobility, and functional assessment, nutrition, bowel and bladder function, skin care, deep venous thrombosis prophylaxis, mood and cognition assessment, and review of rehabilitation needs and discharge planning

- Patient should arrive in the unit within 3–6 h of presentation to the ED - Patient will stay for the first 7–10 days (or fewer days) following a stroke Initial assessment and management plan should be addressed by the team members within the first 24 h of patient arrival to the stroke unit these aspects of patient care should be addressed within the first 72 h after stroke

Various randomized controlled trials and meta-analysis have shown the benefits of stroke units in reducing mortality and morbidity in stroke patients. In a Cochrane Review, the Stroke Unit Trialists’ Collaboration identified 28 randomized and quasirandomized trials (n ¼ 5855) comparing stroke unit care with alternative, less organized care (e.g., an acute medical ward) (Stroke Unit Trialists Collaboration, 2013). Compared to less organized forms of care, stroke unit care was associated with a significant reduction in the odds of death (P ¼ .005), death or institutionalization (P ¼ .0003) and death or dependency (P ¼ .0007) at a median follow-up period of 1 year. Based on the results from other trials, it was reported that the benefits of stroke unit care are maintained for periods up to 5 and 10 years poststroke regardless of sex, age or stroke severity (Stroke Unit Trialists Collaboration, 2013). Another study investigated the differential impact of stroke unit care on four subtypes of ischemic stroke (cardioembolic, large artery disease, small vessel disease or other). It was reported that stroke unit care was associated with reduced 30-day mortality across all subtypes (Saposnik et al., 2011). In spite of the well-established benefits of stroke units in outcomes for stroke patients, a significant proportion of stroke patients do not receive care in stroke units. There is a need to establish stroke units both in tertiary care centers and community hospitals to improve survival of stroke patients and increase the proportion of stroke patients going home after discharge from the hospital. Moreover, benefits of stroke units in tertiary care hospitals also extend to smaller community hospitals with limited resources (Langhorne et al., 2012; Tamm et al., 2014). Establishing stroke units is a major component of optimizing stroke care, improving patient outcomes and reducing cost in the management of this particular patient population. Therefore, resources and efforts should be dedicated to organizing stroke care by establishing stroke units globally.

Systems of Care in Stroke Management: Nursing Perspective A stroke system of care is one that systematically coordinates and organizes stroke care to ensure that each patient receives the right care at the right time. A stroke system of care should use organized approaches to optimize acute and subacute care. Prompt delivery of care is essential within each facility to provide and meet all treatment needs of the acute stroke patient. We are able to save lives through coordinated and integrative systems that involve primary prevention, community education, EMS, acute care and rehabilitation. All hospitals caring for stroke patients within a stroke system of care should develop, adopt, and adhere to care protocols that reflect current care guidelines as established by national and international professional organizations (Powers et al., 2018). So what does a good stroke system of care look like? Stroke systems of care need to have an intense community based primary prevention education led by skilled individuals who share in the passion of stroke prevention. The community needs to understand personal risk factors for stroke such as hypertension, atrial fibrillation and the treatment that is needed to prevent stroke from occurring. They must also be able to recognize the signs and symptoms of stroke via the educational acronym of FAST (face, arm, speech and time). FAST has now been expanded to become BEFAST to add symptoms of balance and eye symptoms to better reflect the occurrence of strokes in the brainstem and cerebellum. Advanced hospital notification is a key to attaining rapid patient evaluation. This starts with a single call activation followed by carrying out guidelines related to stroke care. Several studies have shown that prehospital notification by EMS reduces door to imaging and door to needle times (Higashida et al., 2013). EMS personnel should begin with the initial management of stroke patients in the field. Activation of the “9-1-1 like system” by patients or other members of the public is strongly recommended. 9-1-1 dispatchers should always make stroke a priority. Multiple studies show that “time is brain” and a stroke system of care should

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strive to reduce any time delays (Saver, 2006; Higashida et al., 2013). Facilities caring for stroke patients should strive for seamless stroke systems of care that starts with rapid symptom recognition, notification through contact of 9-1-1, proper triage and transport to the nearest center with the most appropriate level of care. Stroke patients require careful clinical neurological nursing assessment, which includes precise hand offs that ensure safe and efficient patient care from one department to another. The NIHSS is a formal stroke scale that can be performed rapidly and has demonstrated utility, accuracy and reliability when used by qualified healthcare providers (Hinkle, 2014). This scale helps quantify the degree of neurological deficit and the objective measurement of changing clinical status. Having a core group of highly trained nurses that are certified in stroke care as well as utilization of the NIHSS ensures the best detection for neurological change. Lastly, healthcare institutions should organize a multidisciplinary quality improvement committee to review and monitor stroke care quality benchmarks, indicators, evidence based practices, and outcomes. The formation of a clinical process improvement team and the establishment of a stroke care data bank are helpful for such quality of care assurances. The data repository can be used to identify gaps or disparities in quality stroke care. Once the gaps have been identified, specific interventions can be initiated to address these gaps or disparities (Powers et al., 2018).

Conclusion Stroke is a major cause of death and disability worldwide. Stroke risk factor control is important for reducing mortality and morbidity from this lethal disease. Primary care physicians having familiarity with stroke mechanisms and risk factors can play a key role in the fight against stroke. Furthermore, acute stroke management has significantly changed in recent years. Brain imaging plays an essential role in diagnosis and identification of the proper stroke mechanism which helps not only in making therapeutic decisions about neurointervention in select patients up to 24 h but also helps in the selection of treatments for secondary stroke prevention. There is realization in the medical community that organized stroke care with involvement of EMS, nursing staff, mobile stroke units, emergency department physicians, stroke neurologists, stroke units with an interdisciplinary team is the best approach to optimal recovery and better outcomes after stroke.

Addendum Since the submission of this chapter, portions of the American Heart Association/American Stroke Association guidelines for the management of acute ischemic stroke (Powers et al, 2018) have been temporarily withdrawn and are undergoing revision. The portions which have been withdrawn include parts or all of sections: 1.3 EMS Systems Recommendation 4, Section 1.4 Hospital Stroke Capabilities Recommendation 1, 1.6 Telemedicine Recommendation 3, 2.2 Brain Imaging Recommendation 11, 3.2 Blood Pressure Recommendation 3, 4.3 Blood Pressure Recommendation 2, 4.6 Dysphagia Recommendation 1, and 6.0 all subsections (please see the reference below). We anticipate that the revised acute ischemic stroke guidance paper by Powers et al will become available some time in 2019. Reference: Correction to: 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association Originally published on June 1, 2018 https://doi.org/10.1161/STR.000000000 0000172Stroke. 2018;49:e233–e234 This article provides corrections for the following publication: 10.1161/STR.0000000000000158 (Stroke. 2018;49:e46–e99)

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Further Reading Schwamm, L.H., Pancioli, A., Acker 3rd, J.E., et al., 2005. American Stroke Association’s task force on the development of stroke systems. Recommendations for the establishment of stroke systems of care: Recommendations from the American Stroke Association’s task force on the development of stroke systems. Circulation 111, 1078–1091.

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Relevant Websites http://www.stroke.org/. http://www.heart.org/HEARTORG/. https://eso-stroke.org/. http://www.strokeassociation.org/STROKEORG. https://www.webmd.com/stroke/default.htm. https://www.womenshealth.gov/heart-disease-and-stroke. https://www.nhs.uk/conditions/stroke/. http://www.strokensw.org.au/. http://www.world-stroke.org/. https://www.strokeawareness.com.

Suicide Annalisa Anastasiaa, Marco Solmib, and Michele Fornaroa, a Neuroscience, Reproductive Science, and Dental Science, Section of Psychiatry, University School of Medicine Federico II, Naples, Italy; and b Neurosciences Department, Section of Psychiatry, University of Padua, Padua, Italy © 2020 Elsevier Inc. All rights reserved.

Introduction Epidemiology Risk Factors Essential Neurobiology Late-Life Depression Dementia Assessment Rating Scales Neuroimaging Prevention: Primary, Secondary and Tertiary Interventions Primary Care Setting and Special Settings Evidence-Based Treatment and International Guidelines References Further Reading Relevant Website

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Introduction Both completed suicide and suicidal attempts (herein altogether referred to as: “suicidal behavior”) represent major public health concerns and leading causes of injury and death. The World Health Organization (WHO) defines suicide as “the act of deliberately killing oneself,” an act potentially occurring at any age, including the elderly across different ethnicities and societies (http://www.who.int/mental_health/prevention/suicide/ suicideprevent/en/). Older adults constitute the fastest growing population segment worldwide. Older adults have a higher risk of suicide than other age groups, with men being at higher risk than women (Okolie et al., 2017). Older adults may be less communicative about their suicidal thoughts; the attempts they may make may be more violent, carefully planned, and “successful,” but also insidious and “indirect” (e.g., by indirect food refusal or non-adherence to therapy) (Canetto and Birren, 2007). Suicidal behavior may associate with depression, dementia, and other physical illness, functional limitation, disruption of social ties (Duberstein et al., 2004; Conwell et al., 2002). The prevention of suicide may either apply to the prevention of the act first ever in life (“primary prevention”), the prevention of the recurrence of suicidal behavior (“secondary prevention”), or its long-term consequences (“tertiary prevention”) (Sher, 2004). The present chapter aims at summarizing the essential epidemiology of suicide in the old age, alongside with an overview of the evidence-based management from a multi-diagnostic standpoint.

Epidemiology In most countries censored by the WHO – Mental Health, Suicide Prevention section (SUPRE) the rates of suicides peak highest among senior women or men (http://www.who.int/mental_health/prevention/suicide/suicideprevent/en/). Based on the mortality and population data from the Centers for Disease Control and Prevention’s (CDC). National Center for Health Statistics 1999–2014 (Curtin et al., 2016a), suicide rates in the US increased by 24%, for both males and females across people aged 10–74 years old (Curtin et al., 2016b). In contrast to other age groups, the rates of suicide among men aged 75 years old and over decreased within the period 1999–2014 (42.4% vs. 38.8% per 100,000 inhabitants among special groups); similarly, the rates of suicide among women aged 75 years or older decreased by 11%, from 4.5% to 4.0% per 100,000. When compared to younger age groups, only men had the highest rates of suicide overall (Curtin et al., 2016b), peaking higher among US men of European descent than indigenous, Latino, or Asian/Pacific men, being lowest among senior men of African descent (Canetto, 2017). Besides the US, Shah et al. (2007) outlined a wide cross-national variation in elderly suicide rates in the elderly, with rates lowest in the Caribbean, Central American and Arabic countries, and the highest in central and eastern European, some oriental and some west European countries. Also, suicide rates were higher in men compared to women for both the age-bands 75 þ years (highest rates) and 65–74 years (Shah et al., 2007).

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The final reader is encouraged to seek for periodically updated suicide rates per 100,000 population adjusted for i) specific country; ii) sex (male, female, both sexes); data release (up to the year 2016 at writing time), age group (e.g., 60–69 vs. 70–79 vs. 80þ years old) at the following WHO publicly available website: http://apps.who.int/gho/data/node.main. MHSUICIDE10YEARAGEGROUPS?lang¼en.

Risk Factors There is a broad medical and psychosocial literature covering the potential risks for suicide in the elderly. Many hypotheses have been likewise advocated (Wiktorsson et al., 2010; Harwood et al., 2000). Sadly, no specific risk factors yield an “acceptable” predictive value. Among others, the following risk factors have been recognized, and are summarized in Table 1. Older adults who commit suicide are likely to be men, often living alone or isolated, unmarried or widowed, with low educational level, higher financial difficulties, and lower levels of perceived social support (Cohen et al., 2009; Harrison et al., 2010; Rowe et al., 2006; Duberstein et al., 1998; Szanto et al., 1997). Functional limitation due to medical illnesses (e.g., cardiovascular disease, stroke, dementia, chronic pain, cancer) in combination with likely inevitable polypharmacy complete and complicate this dramatic frame (Alexopoulos, 2005; Conwell et al., 1990; Juurlink et al., 2004; Carlsten and Waern, 2009). All this seems to contribute and lead to a depressive condition which constitutes the inauspicious ground for the occurrence of suicide (please refer to the section of late-life depression). In this regard, current depressive illnesses, history of psychiatric illness, narcissistic personality, alcohol/substance use disorder, and previous suicide attempts play an essential role in determining the risk of suicide (Heisel et al., 2007). Moreover, non-fatal selfharm, with or without suicide intent, seems to be one the strongest predictors of suicide, and the older the person who has selfharmed, the higher the risk for subsequent suicide (Owens et al., 2005; Murphy et al., 2012). Noteworthy, suicide attempts in the elderly are usually less evident than the ones made by younger individuals, the suicidal acts mad by old aged individuals are well-determined, being more lethal (Conwell et al., 2002; Dombrovski et al., 2008a).

Essential Neurobiology The neurobiology of suicide in the elderly is yet to be fully elucidated. However, neuroendocrine alterations are relatively common findings. The HPA dysregulation has been associated with increased suicide risk. Elderly depressed patients who went on to commit suicide all failed the dexamethasone suppression test (Jokinen and Nordström, 2008). Similarly, neurocognitive correlates of suicidality in the elderly have been documented. Cognitive impairment has been associated with increased passive and active suicidal ideation in the elderly. More specifically, impairment in executive function, memory, and attention, was associated with suicidal ideation. The cognitive impairments have also been linked to poor decision-making seen in suicidality (Ayalon et al., 2007; Dombrovski et al., 2008b). Elderly suicide attempters had impaired reward/punishment learning characterized by an inability to learn from experience (Dombrovski et al., 2010). Overall, post-mortem studies and molecular research deserves additional efforts.

Late-Life Depression A significant proportion of patients may experience their first depressive episode in old age (Blazer and Hybels, 2005). Late-life depression can lead to an increase in morbidity and mortality through an unhealthy lifestyle and non-adherence to prescribed treatment for somatic comorbidities (Vancampfort et al., 2018), with inflated risk for suicide especially among old-age depressed suffering depression with psychotic features (Sözeri-Varma, 2012; Cole and Dendukuri, 2003; Henderson et al., 1998). Late-onset depression is closely associated with physical illness; it is common for disabled elderly as occurs with cardiac Table 1

Major risk factors for suicide in the elderly

Socio-demographic risk factors Clinical risk factors Psychological risk factors Iatrogenic risk factors

Male sex, low educational level, unmarried condition, living alone or isolation, loss of a spouse/complicated bereavement, financial difficulties. Depressive illness, history of psychiatric illness or previous suicidal attempt, physical/medical illness (cardiovascular disease, stroke, dementia, cancer, chronic pain, and other disease leading to a functional limitation), alcohol/substance use disorder, non-fatal self-harm. Lower levels of perceived social support; narcissistic personality Depressive symptoms induced by medication such as analgesics, antiepileptic agents, anti-hypertensive agents, cancer and chemotherapeutic agents, hormones, and steroids and central nervous system (CNS) drugs including antipsychotics, anxiolytics, anti-Parkinsonian drugs; antidepressant drugs (controversial role), hypnotics, sedatives, polypharmacy.

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illness, stroke, fractured hip, arthritis (Vancampfort et al., 2018; Erlangsen et al., 2015; Webb et al., 2012; Moylan and Binder, 2007). Use of medications for medical problems often generate adverse effects and complicates the diagnosis of depression. Also, medical illness may mimic depression, and depression may mimic medical illness. Neurological disorders also complicate the diagnosis. For example, depression is both a risk factor and a prodromal sign of dementia (Vilalta-Franch et al., 2006). Alzheimer disease is the most frequent cause of dementia and has been reported as a predictor for suicidal behavior even if it seems that the risk concerns a subgroup in which hopelessness and prior suicide attempts may be identified (Hill et al., 1988). Alzheimer’s related neuropathological changes are commonly found in the brain of older people (Rubio et al., 2001; Enache et al., 2011). The rates of depression in subcortical dementia seem to exceed the 20% rates usually documented for Alzheimer disease (Byers and Yaffe, 2011). Executive functions, in particular, decision making and cognitive inhibition, seems to be more impaired in depressed elderly with a history of suicide attempts compared to those without such a history (Richard-Devantoy et al., 2013). However, abnormalities of frontal-limbic circuits from functional magnetic resonance imaging (fMRI) data seem to be involved in suicide vulnerability in the elderly independently of any associated psychopathological conditions including depression (Richard-Devantoy et al., 2013).

Dementia Neurological disorders often complicated the diagnosis of depression even in the elderly. This latter issue is a compelling issue considering that the risk for depression in the post-stroke period is high, with 25% to 50% developing depression within two years of the event (Carota et al., 2005). Alzheimer disease carries an increased risk of depression. Approximately 20%–30% either preceding or co-occurring with the time of the diagnosis of depression. Delusions are also prominent in depression associated with dementia (Olin et al., 2002). While seniors newly diagnosed with dementia may have a higher risk for suicide compared to age-matched controls, chances are that the most chronic and severe cases of dementia may rarely commit suicide, possibly due to inability to plan and to act a suicidal behavior following major cortical degeneration leading to serious cognitive impairment and deterioration of the executive functions (Conejero et al., 2018). Recent research confirms the association of depression with an increased risk of developing late-onset Alzheimer disease (VilaltaFranch et al., 2006). Up to 50% of patients with Parkinsons diseases develop depression or they have a history of depression with anxiety, persistent depressive disorder, or frontal-lobe dysfunction (Ravina et al., 2007). Degeneration of the subcortical nuclei (especially the Raphe nuclei) is related to the development of the Parkinson disease, and may account for increased risk for suicidality in elderly (Huot et al., 2011).

Assessment Rating Scales The assessment of suicide potential in the elderly depends on the specific risks detected for a given patient. Elderly patients with depression may be screened using the Hamilton Depression Rating Scale (HAM-D) (Hamilton, 1960), which includes an item assessing “suicide.” The Beck Depression Inventory (BDI) likewise includes a specific question about suicide (Beck and Beamesderfer, 1974). The Interestingly, while the HAM-D is a hetero-administered questionnaire, the BDRS is a self-administered one. The Geriatric Depression Scale (GDS) has specifically developed for use in the geriatric population, and it includes 30 items vouched by the caregiver as necessary (Yesavage et al., 1982); the 1986 shorter version consists of 15 items (Sheikh and Yesavage, 1986). Although the GDS lacks a specific item questioning the about suicide ideation or attempts, it proved to be effective in detecting varying degrees of suicide risk (Heisel et al., 2005), especially among eldest people (aged 75þ years) (Cheng et al., 2010). The SLAP interview protocol has been specifically developed for older people who expressed their suicidal intent. The SLAP acronym stands for the specificity of the suicide plan, the lethality of the means, availability of the means, and proximity of the rescuers (Mitty and Flores, 2008). The Patient Health Questionnaire 9-item version (PHQ-9) (Forkmann et al., 2013) and the Mini-Mental State Evaluation (MMSE) should be likewise submitted to old-age patients regardless a positive personal or family history for suicide, especially when sudden suicide attempt is concerned (Keilp et al., 2001) since cognitive functioning is a core moderator of suicide risks besides the underlying depression (Upadhyaya et al., 1999).

Neuroimaging Even when major risk factors or previous suicide attempts ascertained, the structural neuroimaging findings may be completely normal in old age people with late-life depression. However, declined meso-temporal volumes (hippocampus and amygdala), sub-cortical white matter lesions (leading to the vascular hypothesis of depression), or reduced volumes of frontal-striatal structures are common findings among old age depressed (Alexopoulos, 2005; Baldwin and O’Brien, 2002).

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Prevention: Primary, Secondary and Tertiary Interventions The specific factors discussed above make suicide prevention in older adults a difficult task. Primary care has an essential role in the detection and management of depression in the elderly. A recent systematic review on the topic (Okolie et al., 2017) found that effective interventions were multifaceted primary care-based depression screening and management program; treatment interventions (pharmacotherapy and psychotherapy); telephone counseling for vulnerable older adults; community-based programs incorporating education, gatekeeper training, depression screening, group activities, and referral for treatment (Lapierre et al., 2011).

Primary Care Setting and Special Settings Mental health setting is common locations for suicidal assessments. Unfortunately, a large number of elderly patients will not use mental health facilities. Instead, older patients will most likely seek primary care, as depression may onset in the old age. Since up to 76% of old-aged patients who turn out to commit suicide had previous medical contact with their general practitioners within one month of their suicide (Conwell and Duberstein, 2001; Conwell and Thompson, 2008), the primary care setting plays a crucial role in the detection and the prevention of suicide in the elderly. Roughly, 20% of old age people who commit suicide visited a physician within 24 hours of their death, or they met with a doctor within one week of subsequent suicide in up to 41% of the cases (Conwell and Duberstein, 2001; Conwell and Thompson, 2008). The PROSPECT study (Prevention of Suicide in Primary Care Elderly: Collaborative Trial) showed a significant reduction in suicidal ideation when tailored-treatment guidelines were used in a primary care setting compared to treatment as usual (Bruce et al., 2004). The IMPACT study (Improving Mood: Promoting Access to Collaborative Treatment). The use of a problem-solving approach lowered suicidal ideation as early as six months and as late as 24 months after an intervention involving problem-solving treatment (Unützer et al., 2006). Relocating the elder patient into a special setting (e.i. an assisted facility, living facilities, assisted living facilities, and long-term care facilities) may allow for effective management of old-age suicidal patients by promoting approaches addressing issues such as copying, enhancing social networks, decreasing access to lethal means, and promoting engagement in positive activities (Oyama et al., 2005; Podgorski et al., 2010). Finally, optimal prevention should include an accurate medical history, focusing on previous psychiatric diagnosis, especially suicidal behavior; sleep disturbances, and memory complaints. Possible positive family history for mood disorders, dementia, and suicide are also clinically relevant matters, as the non-somatic disease is.

Evidence-Based Treatment and International Guidelines When it comes to the pharmacological management of suicidal depression in the elderly, one should bear in mind that the old-aged may have a declined protein-binding and that the pharmacokinetics may differ from the one expected for the young adult. Receptor sensitivity likewise may vary compared to the younger adult, therefore accounting for higher sensitivity to side effects. Drugs with fewer side-effects should be promoted striving at monotherapy and low dose (Wiese, 2011; Reynolds et al., 2006; Espinoza et al., 2015). Potentially harmful drugs in the elderly should be carefully accounted especially in people with suicidal behavior and concurrent polypharmacy (Fick et al., 2015). The use of antidepressant drugs in the treatment of late-life depression is widely accepted in the clinical practice; however, controversies surround such approach since the antidepressant drugs have been linked to an increased risk for suicide in a subset of depressed geriatric patients, as it may occur in the young adults (Crumpacker, 2008; KoKoAung et al., 2015). While the Selective Serotonin Reuptake Inhibitors (SSRIs) represent the most widely prescribed antidepressant drugs in the elderly, refractory cases may require a switch to newer generation antidepressants such as the SerotoninNorepinephrine Reuptake Inhibitors (SNIRs), or the older, yet often regarded as more effective, Tricyclic Antidepressant drugs (TCAs) (Mulsant et al., 2014). Augmentation strategies with lithium or Second Generation Antipsychotics (SGAs) may be attempted in case of antidepressant refractoriness (Cooper et al., 2011; Frank, 2014). Not all the risk factors could be managed or prevented. Therefore, and optimal management should account for intervention targeting the modifiable risk factors besides the pharmacological interventions, and cognitive behavioral therapy (CBT) or interpersonal therapy (IPT) should be delivered especially to those patients with sufficient “cognitive reserve” (Wilson et al., 2008; Gould et al., 2012). Ideally, one should strive at promoting the social inclusion of the suffering elder, and promote an alliance with tertiary care services, in line with the recommendations made by most recent international guidelines on the matter (Cleare et al., 2015; Avasthi and Grover, 2018). However, in some instances, additional interventions may be recommended, including, but not necessarily limited to, physical, psychiatric treatment (electroconvulsive therapy in the early phase of high-risk patients for suicide) (Alexopoulos et al., 2001), associated with general medical treatments and physiotherapy (Cleare et al., 2015).

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Moylan, K.C., Binder, E.F., 2007. Falls in older adults: risk assessment, management and prevention. Am. J. Med. 120 (6), 493 e1–e6. Mulsant, B.H., Blumberger, D.M., Ismail, Z., Rabheru, K., Rapoport, M.J., 2014. A systematic approach to pharmacotherapy for geriatric major depression. Clin. Geriatr. Med. 30 (3), 517–534. Murphy, E., Kapur, N., Webb, R., Purandare, N., Hawton, K., Bergen, H., et al., 2012. Risk factors for repetition and suicide following self-harm in older adults: multicentre cohort study. Br. J. Psychiatry 200 (5), 399–404. Okolie, C., Dennis, M., Simon Thomas, E., John, A., 2017. A systematic review of interventions to prevent suicidal behaviors and reduce suicidal ideation in older people. Int. Psychogeriatr. 29 (11), 1801–1824. Olin, J.T., Katz, I.R., Meyers, B.S., Schneider, L.S., Lebowitz, B.D., 2002. Provisional diagnostic criteria for depression of Alzheimer disease: rationale and background. Am. J. Geriatr. Psychiatry 10 (2), 129–141. 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Further Reading Canetto, S.S.J.M., 2017. Masculinities. Suicide: Why Are Older Men so Vulnerable? 20 (1), 49–70. Okolie, C., Dennis, M., Simon Thomas, E., John, A., 2017. A systematic review of interventions to prevent suicidal behaviors and reduce suicidal ideation in older people. Int. Psychogeriatr. 29 (11), 1801–1824. Panel, A.G.S.B.C.U.E., Fick, D.M., Semla, T.P., Beizer, J., Brandt, N., Dombrowski, R., et al., 2015. American Geriatrics Society 2015 updated Beers criteria for potentially inappropriate medication use in older adults. J. Am. Geriatr. Soc. 63 (11), 2227–2246. The PROSPECT study, Bruce, M.L., Ten Have, T.R., Reynolds III, C.F., Katz, I.I., Schulberg, H.C., Mulsant, B.H., et al., 2004. Reducing suicidal ideation and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA 291 (9), 1081–1091. The IMPACT study, Unützer, J., Tang, L., Oishi, S., Katon, W., Williams Jr., J.W., Hunkeler, E., et al., 2006. Reducing suicidal ideation in depressed older primary care patients. J. Am. Geriatr. Soc. 54 (10), 1550–1556.

Relevant Website The World Health Organization report on suicide: the website provides updates on the topic. https://www.who.int/news-room/fact-sheets/detail/suicide.

Supplements (Vitamins, Minerals, and Micronutrients) Joanna Chłopicka and Paweł Pasko, Jagiellonian University Medical College, Kraków, Poland © 2020 Elsevier Inc. All rights reserved.

Vitamins Fat-Soluble Vitamins Vitamin A Vitamin D Vitamin E Vitamin K Water Soluble Vitamin Vitamin B1 (thiamine) Vitamin B2 (riboflavin) Vitamin B3 (niacin: i.e., nicotinic acid and nicotinamide) Vitamin B6 (pyridoxal, pyridoxamine, and pyridoxine) Folic acid Vitamin B12 Vitamin C (ascorbic acid) Multivitamin Supplements Omega 3 Omega 3 and Cognitive Function Omega-3 and Inflammation and Depression Minerals Calcium Osteoporosis Cardiovascular diseases Magnesium Potassium Iron Zinc, Copper, and Selenium References

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Vitamins Fat-Soluble Vitamins Requirements related to fat-soluble vitamins intake in old age do not particularly differ from the ones for adults, but we have to consider that the body vitamin deposits might have been filled up; hence, on the one hand, vitamin needs may be reduced, though, on the other, the latter can be also increased by altered physiological processes. Concerning the fat-soluble vitamins, reduced fat absorption, decreased vitamin storage capacity of the liver and/or absorption disorders in the intestines, it all may lead to fat-soluble vitamin deficiencies. Many authors have shown that A, D, E, or K vitamin deficiency in elders occurs very seldom for a normal diet; however, to avoid osteoporosis and an increased risk of bone fractures in aging people the greatest attention should be paid to interrelated vitamin D and calcium requirements.

Vitamin A Vitamin A deficiency in older people is mainly associated with a defective immune response to infection and reduced antioxidant protection. Recent review reports not only show the intakes of those vitamins to fall below the recommended nutrient intake (RNI), that is, RNI, 600 mg/day, proposed for the elderly (65 þ years) for only a small percent of elderly people, but also confirmed vitamin A intake in this age group to be often much higher than the suggested level. Reports on associations between vitamin A intake, serum retinol concentrations, as well as bone health and mineral density, or fracture, seem rather controversial. Epidemiological studies have shown increased fracture risk at high intakes and serum concentrations of retinol. Research carried out among older Norwegians by Holvik et al. (2015) has shown neither risk of hip fracture to be associated with high serum retinol levels, nor safety of the fish oil supplementation containing both vitamins A and D. No increase in risk of hip fracture at high serum retinol concentrations in community-dwelling older Norwegians: the Norwegian Epidemiologic Osteoporosis Studies. Retinol and carotenoids (provitamin A) may support a chemo-preventive role in estrogen-dependent cancers, often occurring in postmenopausal women because (Maggio et al., 2015) showed that b-carotene levels were inversely associated with estradiol levels in older women. Research to determine whether carotenoids consumed as supplements are beneficial for older people remains to be carried out. Similarly,

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association between the use of carotenoid supplements by older people and their cognitive and physical health appears likely, even though investigation to date is limited. Vitamin A has been considered an antioxidant compound, displaying affinity to fat, and therefore it can play a role in protecting the central nervous system. Plasma or cerebrospinal fluid concentrations of b-carotene and vitamin A have been described to be lower in Alzheimer’s disease (AD) patients, and these components have been clinically shown to slow the progression of dementia. Unfortunately, so far, the studies on the effect of pro-vitamin A and vitamin A supplementation on the development of Alzheimer’s disease especially in older people are rather scarce. Fortes et al. (1998) in doubleblind, randomized control trial determined the supplementation with vitamin A (800 mg retinol palmitate), zinc (25 mg zinc sulfate), or both, to improve the cell-mediated immune response in older population. Supplementation with zinc improved immunological parameters, that is, CD4 þ DRþ T-cells, cytotoxic T-lymphocytes, whereas for the supplemented vitamin A the opposite results were obtained. These results indicate that vitamin A supplementation had a harmful effect on reducing cell-mediated immune response, though the findings require further research for the conclusion to show its clinical significance.

Vitamin D Vitamin D insufficiency/deficiency is highly prevalent in older adults aged 65 years and above, and it can be associated with a number of diseases such as decreased muscle strength and mobility (lower physical performance), osteomalacia and bone fractures, brain changes and depression/dementia or cognitive impairment, cardiovascular disease, and last but not least hypertension. The greatest useful indicator of vitamin D status is serum 25-hydroxyvitamin D [25(OH)D] level, which tends to decline with age, as a result of diminished dietary intake and decreased cutaneous synthesis of that vitamin. The Institute of Medicine (IOM) published dietary strategies concerning vitamin D supplementation for individuals, up to 70 years of age, who are suggested to consume 600 IU (15 mg) of vitamin D daily and 800 IU (20 mg) for people older than 70 (Ross et al., 2011). Approval for optimum vitamin D requirement of older adults to effect a serum [25(OH)D] level of 75 nmoL/L (30 ng/mL) is 20–25 mg/day (800 to 1000 IU/day). Additionally, elderly people with obesity or who have malabsorption or/and osteoporosis should intake 2000 IU (50 mg) vitamin D per day. Oral supplementation with vitamin D is suggested for older adults to maintain a sufficient mean serum 25(OH)D concentration, particularly supplementation with vitamin D2 or D3. Vaes et al. (2018) investigated the dose–response effects of supplementation with calcifediol and assessed the dose which resulted in mean serum 25(OH)D3 concentrations between 75 and 100 nmol/L. Supplementation with 20 mg vitamin D3 increased 25(OH) D3 concentrations toward 70 nmol/L within 16 weeks. The authors found a steady state (between 84 and 89 nmol/L) with serum 25(OH)D3 levels after 12 weeks of supplementation. A daily dose of 10 mg calcifediol allows mean serum 25(OH)D3 levels in elderly people between 75 and 100 nmol/L; additionally no cases of hypercalcemia were observed in participants during the study period. The authors suggested calcifediol supplementation to be safe and quickly elevate serum 25(OH)D3 concentrations, hence helpful in improving vitamin D status in elderly people. Vitamin D status (serum 25(OH)D) with the cognitive decline rates for older people considered has been defined as deficient, insufficient, adequate, or high for < 12 ng/mL, 12 to < 20 ng/mL, 20 to < 50 ng/mL, 50 ng/mL or higher, respectively (Miller et al., 2015). American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults concluded that a serum 25(OH)D concentration of 30 ng/mL (75 nmol/L) is the level at which the risk of bone fracture and falls is the lowest. Vitamin D and bone health/fracture prevention Aleteng et al. (2017) considered for the whole population of elderly individuals living in Shanghai the optimal 25(OH)D serum concentration of 55 nmol/L, the highest bone mineral density at lumbar spine (L1-L4), and total hip as 53 nmol/L and 75 nmol/ L, respectively. These levels were sufficient to keep the bone in good health and metabolic status. Meta-analysis and randomized controlled trials of calcium plus vitamin D supplementation (800 IU/day) carried by Weaver et al. (2016) showed statistically significant reduction in risk for total and hip fractures by 15% and 30%, respectively, in elderly populations. Hin et al. (2017) assessed the effects of daily supplementation with vitamin D3 4000 IU (100 mg), 2000 IU (50 mg), or placebo on prevention of fractures in older people and they confirmed that doses of 4000 IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with the lowest disease and mortality risks in the older people population. This dose (4000 IU) ought to be verified in future trials to confirm fracture prevention. The result of meta-analysis of 33 randomized clinical trials with 51,145 participants dealing with effectiveness of elderly population supplementation with calcium, vitamin D, or both, compared to no treatment, was found not to be related with a lower risk of fractures among older adults. To update the suggestion for benefits or harms of vitamin D supplementation of older population Kahwati et al. (2018) reviewed the results obtained from randomized clinical trials dealing with supplementation with vitamin D, calcium, for the primary prevention of fractures in older subjects. Conclusions of their study they are like that vitamin D supplementation alone or with calcium was not associated with reduced fracture incidence among elderly subjects but unfortunately may be related with an rise in the incidence of kidney stones. US Preventive Services Task Force (USPSTF) found inadequate evidence to estimate the benefits of vitamin D, calcium, or their combined supplementation, to prevent fractures and the benefits of doses > 400 IU for vitamin D, or > 1000 mg for calcium, to prevent fractures in older people including postmenopausal women. Adequate evidence was found in relation to the possible association between supplementation with vitamin D and calcium, with the increased incidence of kidney stones. The USPSTF concluded the current evidence to be insufficient to assess the balance of the benefits and harms of daily vitamin D supplementation at doses > 4000 IU and calcium doses > 1000 mg for the primary prevention of fractures in postmenopausal women (Moyer, 2013).

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Vitamin D and muscle strength and mobility It has been proposed that vitamin D supplementation is significant for keeping or improving muscle strength and mobility in older adults. Nevertheless, in 2017 no improvement in muscle strength and significant improvement of mobility in elderly persons following vitamin D supplementation were observed. Article by Muir and Montero-Odasso (2011) provided a systematic review and meta-analysis concerning the effect of vitamin D supplementation on muscle strength, gait, and balance in older adults (over 60) without an exercise intervention. They found vitamin D supplementation at daily doses of 800 to 1000 IU to reliably confirm beneficial effects on strength muscle and balance though no effect on gait in older people was observed. Similar research related to the effect of supplementation with vitamin D on fall prevention among two groups of elderly women was carried out by Uusi-Rasi et al. (2015). Their research divided the study group into women who did physical exercise and those who did not, as the risk of fall is multifactorial, and the most effective agent for fall prevention in older adults is the regular exercise. The results obtained in their study indicated that supplementation with vitamin D slightly increased bone density and only in connection with enhanced physical activity the reduced rate of falling in population of elderly women was found. In older people with obesity a decreased bioavailability of circulating 25(OH)D is confirmed, and additionally low vitamin D status may stimulate adipogenesis. The objective of over 5-year long study carried out by Scott et al. (2015) was to investigate the interaction between 25(OH)D and physical activity status on keeping the body composition and muscle function in volunteers aged 50 years or older. High vitamin D and physical activity status are independently associated with smaller gains in body fat while aging, whereas improved body composition and muscle function are found in older adults. Physical activity-related declines in body fat storage while aging showed a greater impact on this occurrence than a direct effect of vitamin D. Under the double-blind, placebo-controlled clinical trial carried out by Cangussu et al. (2015) the effect of supplementation with vitamin D3 in the amount of 1000 IU/day alone on the muscle function was investigated in the population of postmenopausal women aged 50–65 years. It has been shown for this studied group of women with hypovitaminosis D that such supplementation provides a significant protecting factor against sarcopenia and causes significant increase in muscle strength; besides, it influenced the stoppage and control of progressive loss of lean mass. The annual oral administration of 500,000 IU cholecalciferol was concluded to increase risk of falls and bone fractures in older women, and vitamin D was confirmed to be associated with significantly increased risk of hip fractures. The results obtained in the metaanalysis of high dose, intermittent vitamin D supplementation among older adults provided by Zheng et al. (2015) disproved several relationships to exist. Namely, high dose, intermittent vitamin D therapy did not decrease all-cause mortality among older adults. Similarly, high-dose vitamin D may not have any favorable effect on the general health in preventing overall mortality; the effect dealing with fractures or falls among older adults was likely to be neutral. Nevertheless, high levels, > 50 nmol/L, in serum of vitamin D (25(OH)D) may have a deleterious effect on falls. Under a randomized, placebo-controlled trial including people aged 65 years or older Hin et al. (2017) compared the effects of an annual, daily treatment with vitamin D3 4000 IU (100 mg), and 2000 IU (50 mg), or placebo, on biochemical markers and vitamin D status, as well as on prevention of fractures and other effects. Their results confirmed that daily 4000 IU vitamin D3 supplementation is required to achieve blood levels associated with the lowest risks of mortality and diseases; thus this dosage should be tested under further trials on fracture prevention; moreover, it should be recommended to older people for this disease prevention. Doses of 4000 IU (100 mg) vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with the lowest disease and mortality risk under observational studies, and the level shall be recommended to older subjects. Vitamin D and neuroplasticity The purpose of the study (10-week double-blinded, placebo-controlled randomized trial) carried out by Pirotta et al. (2015) was to examine the effects of vitamin D supplementation on neuroplasticity, serum brain-derived neurotrophic factor (BDNF), and muscle strength in elderly adults. The study group with serum 25(OH)D concentrations 25–60 nmol/L was either randomized to 2000 IU/day vitamin D3 group, or matched with the placebo group. After 10 weeks, the mean 25(OH)D levels increased from 46 to 81 nmol/L in the vitamin D group (2000 IU/day), whereas no changes were observed in the placebo group. Vitamin D treatment alone was linked to a decrease in corticospinal excitability and intracortical inhibition, but such alterations were not significantly different from the placebo group. The results of the studies proved that daily supplementation with 2000 IU vitamin D3 over 10 weeks had no significant effect on neuroplasticity in older people compared to placebo. Additionally, for the vitamin D group a significant, that is, 8%–11%, increase in muscle strength was found, though no effect of vitamin D on the efficacy of neural transmission and neuroplasticity or BDNF was detected. Vitamin D and dementia/cognitive decline Vitamin D has been considered as an important factor for maintaining cognitive function in old age. Under 18-year follow-up study in community-living old men, Olsson et al. (2017) examined the association of mean concentrations plasma 25(OH)D (mean  SD was equal to 68.7  19.1 nmol/L) with incident dementia and cognitive impairment. The results from longitudinal studies show that there is no association between baseline vitamin D status and a long-term risk of dementia or cognitive impairment in older men under examination. The results of studies on the effects of hypovitaminosis D on brain changes and dementia are contradictory, yet in older adults aged 65 years and above this condition is highly prevalent. The impact of low level of vitamin D on dementia has been confirmed, but there is no conclusive evidence that such deficiency causes Alzheimer’s disease. Similar observations and suggestions can be found in works by Feart et al. (2017) who examined a population of 916 participants, aged 65 years and above, for up to 12 years searching for connections between hypovitaminosis D and a cognitive decline, risk of dementia and

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Alzheimer’s disease. The results from this large, prospective study showed that adequate vitamin D status in elderly can slow down the development of cognitive disorders and contribute to the delay in developing Alzheimer’s disease. Miller et al. (2015) assessed associations between vitamin D level and cognitive function in a group of ethnically diverse elderly subjects. Longitudinal cohort study covered 382 participants; after measuring the serum vitamin D concentration the group was divided into subgroups and defined following the status of the subjects as deficient (less than12ng/mL), insufficient (12 to < 20 ng/mL), adequate (20 to < 50 ng/mL), and high (50 ng/mL or higher). Cognitive functions were assessed with the Spanish and English Neuropsychological Assessment Scales. The conclusions demonstrated vitamin D status to be associated neither with a cognitive decline, nor with failure in semantic memory or visuospatial ability of older people. However, low status of vitamin D was associated with accelerated, significantly faster decline in cognitive function domains in ethnically diverse older adults; African American and Hispanic individuals are more likely to have insufficient or deficient vitamin D status. Vitamin D and depression The result of vitamin D supplementation on depression management in older adults was investigated in a randomized clinical trial by Alavi et al. (2018). Seventy-eight older adults, aged over 60 years, with moderate to severe depression participated in the research and received 50,000 IU vitamin D3 or placebo weekly over 8 weeks. In vitamin D group the mean concentration of 25(OH)D3 was found to reach 22.57  6.2 ng/mL, whereas following the supplementation it increased to 43.48  9.5 ng/mL; in the placebo group the relevant concentration of 21.2  5.8 ng/mL was found and it increased to 25.9  15.3 ng/mL. The multiple regression analysis showed that vitamin D supplementation can improve the depression score in persons aged 60 and older. A similar survey (randomized, double-blind, placebo-controlled clinical trial) was carried out by de Koning et al. (2015). They examined the effect of a daily supplementation of vitamin D in the dose of 1200 IU/day to elderly people, aged 60–80 years, versus administered placebo, on the depressive symptoms and physical functioning. The obtained results indicated that such supplementation to older individuals is quite effective in reducing depressive symptoms, and it can also improve participants’ physical functioning. Vitamin D and cancer In a 4-year, randomized clinical trial, double-blind, placebo-controlled, made by Lappe et al. (2017) the effect of vitamin D and calcium supplementation on cancer incidence in older women, as evidence suggests that insufficient vitamin D status may increase the risk of cancer. The studied group received vitamin D3 in the dose of 2000 IU/day, and calcium in the amount of 1500 mg/day. The primary outcome was the incidence of all types of cancers, excluding nonmelanoma skin cancers. They concluded that among healthy postmenopausal older women with a mean serum 25(OH)D concentrations of 32.8 ng/mL, who were additionally supplemented with calcium, a significantly lower risk of all types of cancers under 4 years’ observation was not observed, compared to the placebo group.

Vitamin E Vitamin E and antioxidant status Vitamin E is a fat-soluble compound, which is a mixture of tocopherols and tocotrienols characterized with the antioxidant power that have been shown to protect the cell membranes against damage affected by free radicals, and are known to prevent degenerative diseases. Studies concerning human vitamin E supplementation are usually limited to a-tocopherol (a-TF). The survey conducted by Nor Azman et al. (2018) aimed at comparing the effects of tocotrienol-rich fraction (TRF) with a-tocopherol (a-TF) on the antioxidant status of healthy subjects, aged between 50 and 55 years. After 6 months of supplementation they determined activity of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase, as well as concentrations of the reduced and oxidized glutathione. The obtained results found catalase and glutathione peroxidase to be unaffected by TRF and a-TF; only superoxide dismutase activity was observed to increase following half-year supplementation in females compared to males. Tocopherol-rich fraction and a-tocopherol showed similar effects to the antioxidant levels of older adults. Goon et al. (2017) also studied the influence of supplementation with a-tocopherol and tocotrienol-rich fraction on the plasma vitamin D concentration in both males and females over 6 months investigation. Vitamin D concentration in male subjects was significantly higher compared to female subjects in the groups supplemented with a-TF tocotrienol-rich fraction. It was attributed to the different supplementation effects and found to depend both on the gender and the form of vitamin E. The effects were different from a-TF in reducing oxidative stress markers, and vitamin D levels with a more marked effect in female. Taking into account the primary role of vitamin E as the antioxidant function scavenging harmful free radicals, and the evidence that they may contribute to cognitive impairment including Alzheimer’s disease, no substantial evidence was found for vitamin E supplementation to have a beneficial effect on slowing down the cognitive damage. Vitamin E and sarcopenia While aging, skeletal muscle disorders and muscle loss of strength and mass (sarcopenia) often occur. Such a state induces chronic inflammation, with increased oxidative stress and mitochondrial dysfunction. Vitamin E (tocopherols and tocotrienols) may have a beneficial effect on the oxidant stress and display antiinflammatory capabilities, which may alleviate age-associated skeletal dysfunction and enhance muscle regeneration in older persons. Limited number of human observational studies reveals positive associations between serum tocopherol level and muscle strength. Further research should consider such observations and underlying association between vitamin E supplementation to elderly populations, their muscle strength, mass and physical performance (Chung et al., 2018).

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Vitamin E and cognitive impairment Since vitamin E has antioxidant properties, and free radicals may cause cognitive impairment including Alzheimer’s disease (AD), Farina et al. (2012) have assessed the efficacy of vitamin E supplementation on AD treatment and its capability to correct mild cognitive damage. According to their results supplementation of vitamin E in the amount of 800 IU/day, or 2000 IU/day, no statistically significant differences were found between the vitamin group and the placebo one, in progressing AD and cognitive impairment, which provides the evidence that vitamin E does not affect the treatment for such diseases.

Vitamin K Research has shown that insufficient intake of vitamin K may be linked with conditions associated with abnormal calcification such as bone health, osteoarthritis, cognitive functions, and even coronary artery health, particularly in elderly population. Vitamin K and bone health Booth et al. (2008) determined the role of phylloquinone supplementation on preventing bone loss in men and women. Over 3 years the influence of phylloquinone (500 mg/day) supplementation on changes in bone mineral density (femoral neck bone) was observed in elderly (60–80 year) men and women in a population where no shortages of calcium and vitamin D were found. Mineral density of femoral neck, spine (L2–L4), and bone turnover was measured every 6–12 months. Differences neither in bone mineral density nor in other biochemical measures were recorded, though for the group where the phylloquinone supplement was received a significantly higher phylloquinone level was found; still, no additional benefits to bone health or risk of fractures were concluded. The current evidence from randomized, controlled trials is not powerfully supportive of vitamin K supplementation for the committed improvement in bone health in elderly population. The efficacy of vitamin K supplementation in reducing agerelated bone loss to be a questionable, as the evidence for vitamin K supplementation in older adults is mixed, although observational study had shown associations between vitamin K intake and lower risk of fractures in older subjects. The adequate intake of vitamin K affects the proper bone condition, and investigational data suggest that insufficient intake of vitamin K may be associated with the increased risk of fracture. Cockayne et al. (2006) assessed whether oral vitamin K (phytonadione and menaquinone-4) supplementation can reduce bone loss and prevent fractures, and show antiosteoporotic properties. So far a routine supplementation has not been recommended, as it cannot be introduced until such results are confirmed for a large population. Currently the evidence is too scarce to recommend the use of vitamin K supplements in order to prevent bone loss, fractures, or osteoarthritis in postmenopausal women. Vitamin K and cognitive function In addition to the features described above, vitamin K could play a role in cognition, especially in aging. Presse et al. (2013), using data from the Québec Longitudinal Study on Nutrition and Successful Aging, conducted a survey to examine the relations between vitamin K status in men and women aged 70–85 years, measured as serum phylloquinone concentrations, and the performance in verbal and nonverbal episodic memory, executive functions, as well as in the processing speed. No associations were found between nonverbal episodic memory, executive functions, and processing speed set against serum phylloquinone levels. Vitamin K and coronary artery calcification Vitamin K seems to play a preventive role against coronary artery calcification though due to these properties it can be also considered as an independent predictor of cardiovascular disease. The aim of the study performed by Shea et al. (2009) was to determine the effect of phylloquinone (vitamin K1) supplementation on coronary artery calcification development in older men and women. The revision lasted 3 years and covered 388 healthy men and postmenopausal women; the subjects received 500 mg phylloquinone/ day. It was concluded that phylloquinone supplementation slows the progression of coronary artery calcification in healthy older adults with preexisting state. The data require further research as the mechanism of action is not explained.

Water Soluble Vitamin Vitamin B1 (thiamine) Poor nutrition often occurring in older people can be a factor in deficiency of vitamin B1, thiamine derivative (thiamine diphosphate) and serves as a cofactor for several enzymes significant for the biosynthesis of a number of cell constituents. The main manifestations of thiamine deficiency in old persons implicate the cardiovascular (heart failure) and nervous systems (peripheral neuropathy, cognitive impairment, depression) disorders. Vitamin B1 and mental health Thiamine has been postulated to play a significant role in mental health for example, depression. Zhang et al. (2013) determined associations between thiamine status in older Chinese adults and their appearing depressive symptoms. Concentrations of free thiamine and its phosphate esters were measured in 1587 Chinese men and women aged 50–70 years; the result was correlated with depressive symptoms (depression scale). Higher prevalence of depressive symptoms was found in people with lower concentrations of erythrocyte thiamine biomarkers. The results of these studies suggest a relationship to exist between the thiamine deficiency and depressive symptoms among older adults.

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The aim of this cross-sectional study was to investigate the association between dietary intakes, specifically for thiamine and protein, with cognitive deficits (e.g., depressive symptoms) in older adults aged  60 years. No significant association was found between thiamine or protein and the cognitive functions in elderly people under examination (Koh et al. 2015).

Vitamin B2 (riboflavin) Riboflavin plays a significant role in the metabolism of carbohydrates, proteins, and lipids, as well as in antioxidant processes. It affects the proper condition of the skin and epithelium. Deficiency may lead to inflammation of mouth, eyes, and gastrointestinal tract. It was shown that deficiencies in riboflavin in older adults were linked with poor cognitive outcomes. Vitamins B2 and B12 and folate interact synergistically helping in declined plasma homocysteine levels, which is important in preventing heart disease (e.g., atherosclerosis). Vitamin B2 and plasma homocysteine level McKinley et al. (2002) determined the effect of riboflavin supplementation on plasma homocysteine in older healthy adult population in a double-blind, randomized, placebo-controlled trial. Riboflavin status was rated either by determining the levels in erythrocytes or by measuring glutathione reductase activity. During 12-week intervention elderly subjects received riboflavin in the amount of 1.6 mg/day; after this period riboflavin supplementation was found to significantly improve riboflavin status in elders, but plasma homocysteine concentrations remained unaffected even in subjects with low vitamin B2 levels. Similar studies have been undertaken by other authors (Tavares et al., 2009) with a different dose of vitamin B2 (10 mg/day) used for 28 days’ supplementation of individuals aged between 60 and 94 years. In the examined group researchers found that 10 mg/day oral vitamin B2 supplementation observed a reduction in plasma homocysteine concentrations, particularly in older subject with low riboflavin status.

Vitamin B3 (niacin: i.e., nicotinic acid and nicotinamide)

The review reported studies on biological effects associated with NAD(P)þ, NADþ metabolism, and the influence of these agents on cell, tissue, and aging, as well as development of diseases associated with age, such as cancer or neurodegeneration. Vitamin B3 functions in energy metabolism and DNA repair pathways and it is connected with effects influencing aging processes. It also plays very important roles in maintaining and regulating cellular redox state; therefore researchers consider the vitamin to take a central place in the aging processes (Xu and Sauve, 2010). Vitamin B3 and blood pressure Advancing age is the main risk factor for the development of cardiovascular disease, and use of NADþ precursors to enlarge NADþ bioavailability has been proposed as a plan for improving cardiovascular functions in an aging population, as cellular bioavailability of NADþ and the related metabolites decline in animals and in humans during normal aging process. Martens et al. (2018) found that NADþ precursor vitamin, nicotinamide riboside, is well tolerated and effectively stimulates NADþ metabolism in healthy older adults, and that it has a potential property in reducing blood pressure and arterial stiffness in this group. Supplementation of nicotinic acid or nicotinamide can be helpful in delaying aging processes and maintaining health in elderly. Of course future clinical trials should assess the potential benefits of vitamin B3 for reducing blood pressure and arterial health in old persons.

Vitamin B6 (pyridoxal, pyridoxamine, and pyridoxine) The aim of the study by McKinley et al. (2001) was to investigate the effect of low-dose vitamin B6 supplementation on fasting total homocysteine levels in healthy elderly persons with deficiencies of folate and riboflavin. Older adults, aged 63–80 years, were supplemented with a 1.6 mg/day dose of vitamin B6 for 12 weeks, and with folic acid (400 mg/day) and riboflavin (1.6 mg/day). This low-dose vitamin B6 successfully lowered fasting plasma homocysteine. To prevent and treat hyperhomocysteinemia in elderly subjects we should include vitamin B6 supplement. Ford et al. (2010) investigated in a randomized, double-blind controlled clinical trial whether over 2 years supplementation with vitamins B12, B6, and folic acid improves cognitive function in 75 years older men. Results showed that daily supplementation of vitamin B6, B12, and folic acid does not benefit cognitive function in older men.

Folic acid In elderly people age-related hearing loss was observed, and additionally low folate status has been connected with poor hearing. Therefore, Durga et al. (2007) aimed to determine whether daily folic acid supplementation (800 mg) for 3 years can slow hearing injury in older adults. Folic acid supplementation slowed the decline in hearing the speech frequencies though it did not affect the decline in hearing high frequencies.

Vitamin B12 Vitamin B12 and cognitive function The prevalence of vitamin B12 deficiency is relatively common in older people and it is known that this condition leads to neurologic and cognitive outcomes. Investigation whether vitamin B12 supplementation can be beneficial for neurologic and cognitive function in older people was conducted by Dangour et al. (2015) during a double-blind, randomized, placebo-controlled trial. The participants aged  75 years (serum vitamin B12 concentrations: 107–210 pmol/L) received 1 mg crystalline vitamin B12 for a year, and then their peripheral and central motor and sensory nerve conduction was studied. Conclusions of the examination

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fail to support the hypothesis that B12 deficiency has healthy effects on neurologic or cognitive function in older age. Miles et al. (2017) conducted experiment likewise and confirmed no evidence for efficacy of supplementation with vitamin B12 to support neurological function in elderly population. Therefore, currently the evidence for recommending vitamin B12 supplementation to older people seems insufficient, and marginal support exists for vitamin B12 status to enhance neurologic functions. Just contrary were the results obtained by Sánchez et al. (2011) who examined people aged 70–79 supplemented with 1 mg of vitamin B12 over 18 months. The study confirmed that such proceedings may contribute to preserving neurophysiologic and cognitive function in older people.

Vitamin C (ascorbic acid) Vecchio et al. (2016) estimated the public health impact that vitamin supplementations may have in terms of cardiovascular events risk reduction on elderly population. Only for vitamin C, in the amount higher than 400 mg/day a significant reduction in risk of cardiovascular diseases following supplementation of elderly population was observed. Trinity et al. (2016) studied whether ascorbic acid improves brachial artery vasodilation while handgrip exercising older people. This investigation confirmed evidence for vitamin C to improve endothelial vascular function during progressive handgrip exercise; it was found to be NO-dependent mechanism. The effects of vitamin C and E supplementation on changes in muscle mass (lean mass and muscle thickness) and strength during 12 weeks of strength training in males aged 60–81 years were examined. Participants received 500 mg of vitamin C and 117.5 mg vitamin E before and after training. Vitamin C supplementation was beneficial for muscular adaptation during forte training in old men (Bjørnsen et al., 2016).

Multivitamin Supplements Gupta et al. (2017) evaluated the association between severity of periodontitis in older women, and use of multivitamin supplements. They found that bleeding on probing and fracture risk assessment tool score are significantly associated with multivitamin supplement intake. Research results have shown that there is no relationship between multivitamin use and the severity of periodontal disease. Harris et al. (2016) investigated during 16 weeks the influence of multivitamin supplementation on healthy females aged  50, and males aged 50–65 years, on their brachial blood pressure. No effects of multivitamin supplementation were observed in either males or females on the central blood pressure. Similar investigation performed by Tabei et al. (2015) aimed to tact the effect of multivitamin complex supplementation on mood disorder, anxiety, and depression in elderly, aged over 60 years, with mild depression. For 12 weeks the subjects received multivitamin complex tablet, and then depression scores were evaluated. The results did not confirm taking multivitamin complex to have a positive influence on depression, mood disorders, and anxiety, but it increased elderly appetite resulting in their increased energy intake.

Omega 3 Omega 3 and Cognitive Function The aim of the study conducted by Baleztena et al. (2018) was to evaluate the effect of a one-year multinutrient supplementation rich in n-3 PUFA on the cognitive function in elderly population ( 75 years) without or with mild cognitive impairment. Supplementation with n-3 PUFA did not show any amelioration in the global cognitive function in older people, with the exception of memory loss, where a small improvement was observed. Andrieu et al. (2017) tested the effect of 36 months omega 3 polyunsaturated fatty acid supplementation (daily dose consisted of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid) on cognitive decline in nondemented, aged 70 years or older. There were no significant differences in 3-year cognitive decline between the intervention groups and the placebo group. D’ascoli et al. (2016) were searching for a link between serum long-chain and the cognitive functioning in older men and women. They found statistically significant associations between higher serum omega-3 PUFA levels and better performance on neuropsychological tests.

Omega-3 and Inflammation and Depression Kiecolt-Glaser et al. (2012) observed during a randomized, placebo-controlled, double-blind 4-month trial the association between lower levels of omega-3 fatty acids and inflammation and depression in healthy middle-aged and older adults. Serum interleukin-6 (IL-6) decreased by 10% in low-dose omega-3 groups, and changes in serum tumor necrosis factor alpha, compared to a 12% increase in the control group. Depressive symptoms did not change significantly in response to supplementation with omega-3 fatty acids. Lai et al. (2016), in their research, aimed at confirming hypothesis that inflammatory markers interleukin (IL)-6 and Creactive protein (CRP) antioxidant and fatty acid intakes are associated with depression in adults aged 55–85 years. Omega-3 polyunsaturated fat was inversely related with depression only in men. IL-CRP significantly mediated the relationship between total fat, saturated fat, and monounsaturated fat intakes and depression in women, and saturated fat intake and depression in men. This conclusion indicates that a possible relationship between fatty acid intake and depression is partially mediated by inflammatory indicators. A review which synthesized the effects of supplementation with n-3 PUFAs on reducing depressive symptoms among older adults (aged 60 and above) was carried out by Bai et al. (2018). The whole treatment effects of n-3 PUFA supplements

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decreasing depressive symptoms in older adults were not statistically significant. This study conducted meta-analyses to provide a critical evidence concerning the potential benefits of omega-3 fatty acids in elderly patients, aged over 65, with depression. The analysis was conducted to provide evidence for the clinical application of omega-3 fatty acids in the treatment of depressive symptoms of elderly subjects older than 65 years. The obtained results were divided into two groups, namely a well-being mental health group and a depressive group. For the first group no statistically significant effect of n-3 PUFA supplementation on the score of depressed mood was recorded related to placebo. For the second group a meaningful effect of n-3 PUFA supplementation on the depressed mood, compared with placebo, was found. It shall be stressed that this review demonstrated omega-3 fatty acids to be effective in supporting treatment of depression, though the most optimal benefits of omega-3 fatty acid supplementation were found to be significant only in the elderly patients with already existing, mild to moderate depression (Bae and Kim, 2018).

Minerals Calcium Osteoporosis It is known that calcium supplementation reduces osteoporotic fractures. A meta-analysis performed by Tang et al. (2007) included 29 randomized trials (n ¼ 63,897) in which calcium, either alone or in combination with vitamin D, was used to prevent fracture and osteoporotic bone loss. The main outcomes of the meta-analysis were fractures of all types and percentage change of bone mineral density from baseline. The obtained evidence supported the use of calcium supplements, alone or in combination with vitamin D, in the preventive treatment of osteoporosis in people aged 50 years or older. For achieving the best therapeutic effect, 1200 mg of calcium was recommended as a minimum dose. In addition, Boonen et al. (2007) indicated that oral vitamin D can reduce the risk of hip fractures only when it is used in combination with calcium. A meta-analysis by Reid et al. (2008) suggested that total number of fractures was reduced when calcium was used with vitamin D. However, this trial of calcium monotherapy involving a total of 5500 women showed adverse trends in the number of hip fractures. The observational data from the Study of Osteoporotic Fractures showed a similar increase in the risk of hip fractures associated with calcium use. The authors of the study supposed that reduced periosteal expansion in women using calcium supplements might account for the differences in the efficacy of calcium in preventing hip fractures. The findings of the study indicated that high calcium intake is not appropriate to reduce the risk of hip fracture in older women. A study showed that combined vitamin D and calcium supplementation can reduce the risk of fractures, but the fracture-preventing effect may be insignificant among community-dwelling older adults than among institutionalized elderly persons. Additionally, another study proved that combined calcium and vitamin D supplementation is superior to supplementation of calcium alone in reducing the number of falls and improving muscle function in community-dwelling older individuals (Pfeifer et al., 2009).

Cardiovascular diseases Calcium supplements are commonly used by people over the age of 50 years. Many investigations suggest that high intake of calcium might protect against vascular diseases, but there is also evidence indicating rise in some vascular risk factors with increased calcium intake. In a meta-analysis of randomized, double-blind, placebo-controlled trials, including a total of 12,000 participants (mean age at baseline, > 40 years) who were administered elemental calcium at a dose of  500 mg/day, Bolland et al. (2010) reported that calcium supplements increased the risk of myocardial infarction by about 30%. In the Women’s Health Initiative Calcium/Vitamin D Supplementation Study, a 7-year, randomized, placebo-controlled trial, in which 36,282 postmenopausal women were administered 1 g calcium and 400 IU vitamin D daily, showed that calcium supplements, alone or with vitamin D, modestly increased the risk of myocardial infarction. In healthy postmenopausal women, calcium supplementation was associated with increase in the rates of cardiovascular events. In contrast, another meta-analysis showed that supplementation with 1 g calcium per day significantly reduced systolic (SBP) and diastolic blood pressure (DBP) by 2 mmHg and 1 mmHg, respectively, especially in population with a low (< 800 mg/ 24 hours) habitual intake of calcium (van Mierlo et al. 2006). The negative effect of calcium supplements on the cardiovascular system, taken together with their possible adverse effect on the incidence of hip fractures, especially in women, suggests that the use of calcium supplements for the prevention and treatment of osteoporosis should be reassessed. On the other hand, calcium supplements have been shown to significantly lower the risk of mortality in older women (Mursu et al. 2011).

Magnesium In the Iowa Women’s Health Study, Mursu et al. (2011) assessed the use of vitamin and mineral supplements in relation to total mortality in 38,772 older women whose mean age was 61.6 years, and found that the use of magnesium supplements was associated with an increased risk of total mortality (3.6%) compared to no supplementation. However, some special indications for magnesium supplementation in older people should be considered. There is limited research concerning magnesium supplementation in people with diabetes. A meta-analysis provided evidence that magnesium intake is significantly inversely associated with the risk of type 2 diabetes in a dose–response manner (Dong et al., 2011). A recent study also showed that supplementation of this essential element has a beneficial role and improves glucose parameters in people with diabetes, while improving insulin-sensitivity parameters in those at high risk of diabetes (Veronese et al., 2016). In addition, Simental-Mendía et al. (2016) confirmed that

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supplementation of magnesium for 4 months significantly improved the Homeostatic Model AssessmentdInsulin Resistance (HOMA-IR) index and fasting glucose in both diabetic and nondiabetic subjects. Barragán-Rodríguez et al. (2008) evaluated the efficacy of oral supplementation of magnesium, with magnesium chloride (450 mg of elemental magnesium), in the treatment of newly diagnosed depression in the elderly with type 2 diabetes and hypomagnesemia at 12 weeks. They found that supplementation was as effective in the treatment of depressed elderly as daily treatment with imipramine 50 mg. Additionally, magnesiumcontaining supplements may hold promise for the treatment of anxiety and anxiety-related disorders, but more research is needed before these products can be recommended to patients (Lakhan and Vieira, 2010). The inconclusive evidence regarding the effect of magnesium supplementation on blood pressure (SBP and DBP) was evaluated in a meta-analysis (Kass et al. 2012). The mean age of individuals taking magnesium supplements in the included trials was 50.1 years, with the dose of elemental magnesium supplement being in the range of 120–973 mg (mean dose, 410 mg). Although not all individual trials showed a significant decrease in blood pressure, combining the results of all trials, a reduction in SBP of 3–4 mmHg and DBP of 2–3 mmHg was noted. Thus, magnesium supplementation appears to be associated with a small but clinically significant reduction in blood pressure, and this effect is worth noting for conducting future prospective randomized trials, particularly on the prehypertensive population. Magnesium supplementation can reduce the incidence of arrhythmias, which often occurs following cardiac surgery. A study showed that administration of prophylactic magnesium reduced the risk of supraventricular arrhythmias after cardiac surgery by 23% (atrial fibrillation by 29%) and of ventricular arrhythmias by 48%. However, the supplementation showed no notable benefit with respect to length of hospitalization, incidence of myocardial infarction, or mortality (Shiga et al., 2004).

Potassium A meta-analysis by Whelton et al. (1997) assessing the effects of oral potassium supplementation on blood pressure in humans (33 randomized controlled trials, 2609 participants) indicated that potassium supplementation was associated with a significant reduction of SBP and DBP by 3.11 mmHg and 1.97 mmHg, respectively. The effects of supplementation seemed to be higher in trials in which patients were concurrently exposed to a high dose of sodium. Thus, increased potassium intake can be recommended for the prevention and treatment of hypertension, especially in those who are unable to reduce their intake of sodium. Aburto et al. (2013) also showed that increased potassium intake reduced blood pressure in adults. However, this effect was observed only in people with hypertension and not in those without hypertension. Moreover, potassium intake was not found to have any significant adverse effect on renal function, level of blood lipids, or catecholamine concentration in adults. On the other hand, a statistically significant association was seen between potassium intake and risk of incident stroke (24%). However, the associations between potassium intake and incident cardiovascular disease (CVD) or coronary heart disease were not statistically significant. The authors suggested that increased potassium intake is potentially beneficial to most people without impaired renal handling of potassium for the control of blood pressure and prevention of stroke.

Iron The Iowa Women’s Health Study assessed the use of iron supplements in relation to total mortality in older women. The authors found that women who used this essential element were strongly and dose dependently associated with an increased risk of total mortality compared to those who were not using supplements. In addition, iron supplementation was related to an increased risk of future mortality, even 19 years later, in women free of CVDs, diabetes mellitus, and cancer. In some studies, high iron stores, measured as serum ferritin, have been found to be related to increased risk of CVD. Iron is also suggested to catalyze reactions that produce oxidants and promote oxidative stress. Iron deposition in the brain had also been associated with common neurodegenerative diseases that affect the elderly (Stankiewicz and Brass, 2009). On the other hand, some current reports indicate high risk of anemia in elderly patients, with men having higher rates of risk than women. The incidence of anemia rises with age, and a notable increase in the incidence is seen in the oldest patients ( 85 years). Anemia is associated with symptoms like weakness and fatigue which may increase falls and depression, and in severe cases, can lead to congestive heart failure (Beghé et al., 2004). However, limited evidence supports any benefit from mineral (iron) supplementation for the prevention of CVD (Fortmann et al., 2013). The results of a case-control study by Beghé et al. (2004) suggested the relationship between anemia and cognition, and Alzheimer’s disease was twice as prevalent in older people with anemia. Peters et al. (2008) performed a systematic review of three studies and found that patients with anemia had double the risk of dementia, and confirmed that elderly persons with mild anemia had significantly worse cognition, function, mood, and quality of life. Many chronic diseases, major injuries, and surgeries can cause anemia which is treated with supplemental iron, despite observational studies suggesting that it can be ineffective in elderly people. A meta-analysis by Tay and Soiza (2015) showed that oral iron supplementation increased hemoglobin levels more than placebo or no treatment after 4–6 weeks. However, there were no statistically significant differences in adverse effects, length of hospitalization, or mortality, and the authors concluded that it is unclear whether iron supplementation will result in tangible health benefits.

Zinc, Copper, and Selenium Mursu et al. (2011) also assessed the use of trace elements like zinc and copper in relation to total mortality in older women in the Iowa Women’s Health Study and showed that zinc supplements increased the risk of total mortality by 3% and copper

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supplements by 18% compared to no supplementation. It is known that copper induces excessive production of damaging reactive oxygen species through Fenton chemistry, and thus may contribute to many aging-related diseases such as atherosclerosis, Alzheimer’s disease, Parkinson’s diseases, diabetes, and also inflammation, fibrosis, and autoimmunity (Brewer, 2007). In the Age-Related Eye Disease Study, a total of 2166 elderly persons were randomly assigned to receive any of the following treatments daily: antioxidants, zinc, and copper (zinc, 80 mg; cupric oxide, 2 mg); antioxidants plus zinc or copper; or placebo. A cognitive battery was administered to the participants after a median of 6.9 years of treatment, and the groups were not found to differ on any of the used cognitive tests. Thus, these results did not support a beneficial or harmful effect of zinc and copper on cognition in older adults (Yaffe et al., 2004). Currently, increasing interest is being shown in the use of mineral supplements especially zinc and selenium, with the hope of preventing and reducing infections in the elderly population. Girodon et al. (1999) determined the effects of long-term daily supplementation of zinc and selenium (zinc sulfate and selenium sulfide, providing 20 mg of zinc and 100 mg of selenium, respectively) on immunity and the incidence of infections in 725 institutionalized elderly patients (> 65 years) from 25 geriatric centers in France. Low-dose supplementation of zinc and selenium was found to provide significant benefits to elderly patients by increasing their humoral response after vaccination, and thus the authors indicated that low-dose supplementation could be of considerable importance in view of public health as it can reduce morbidity due to respiratory tract infections. In another study on elderly subjects (> 55 years), zinc deficiency, cell-mediated immune dysfunction, susceptibility to infections, and increased oxidative stress were observed. Compared with a group of younger adults, the older subjects showed a significantly lower plasma zinc concentration, higher ex vivo generation of inflammatory cytokines, particularly interleukin-10, and higher levels of plasma oxidative stress markers and endothelial cell adhesion molecules. After zinc supplementation (45 mg elemental Zn per day orally for 12 months), the plasma zinc level was significantly increased and the incidence of infections and ex vivo generation of tumor necrosis factor-alpha and plasma oxidative stress markers were significantly decreased compared to the placebo group (Prasad et al., 2007). In a randomized, doubleblind, placebo-controlled study of Allsup et al. (2004) a total of 164 residents (aged 60 years and older) living in long-term care homes received a micronutrient supplement providing the reference nutrient intake for all vitamins and trace elements or identical placebo for a period of 8 weeks. Despite a significant increase in serum concentrations of selenium, no beneficial effect on antibody response to influenza vaccine was observed in the supplemented older people. According to El-Kadiki and Sutton (2005), the evidence for routine use of mineral supplements to reduce infections in the elderly people is weak and conflicting. The available evidence does not support the routine use of such supplements in elderly people, and therefore, further trials are needed. It must be noted that selenium supplementation may lead to harmful effects in people with adequate intake. For example, selenium supplementation in subjects who already have adequate intake might increase their risk of type 2 diabetes. Rayman (2012) indicated that the crucial factor that needs to be emphasized with regard to the health effects of selenium is the inextricable U-shaped link with status of this trace element; while additional selenium intake may be beneficial to people with low status, those with adequate and high status can be affected adversely and hence should avoid taking supplements. Stranges et al. (2007) examined the effect of long-term selenium supplementation (200 mg/day) on the incidence of type 2 diabetes in 1202 older persons, and found that supplementation did not prevent type 2 diabetes but increased the risk for the disease. This lack of benefit of selenium supplementation on the incidence of type 2 diabetes was observed in all analyses stratified by age, sex, body mass index, and smoking status. A study showed that zinc supplementation (25 mg zinc sulfate for 3 months) decreased plasma lipid peroxides (Fortes et al., 1997). It also reported that adequate zinc intake or supplementation could play an important role in the prevention and/or modulation of CVDs in the elderly people. However, Hughes and Samman (2006) reported that the relationships between zinc and plasma lipids, hemostasis, and other factors play a role in atherogenesis. The results of the study showed that the oxidation of low-density lipoprotein and the concentrations of low-density lipoprotein cholesterol, total cholesterol, and triglycerides in plasma were unaffected by supplementation with up to 150 mg Zn per day. In contrast, plasma concentrations of high-density lipoprotein cholesterol declined when zinc supplements providing a dose of > 50 mg Zn per day were used. Limited data suggest that sustained hyperzincemia predisposes individuals to thrombogenesis, whereas acute zinc depletion impairs platelet aggregation and prolongs bleeding time. In addition, some studies have shown that zinc supplements decrease the activity of Cu/Zn-superoxide dismutase, which is primarily due to the antagonistic relationship between high zinc intakes and copper absorption. Besides the adverse effect of zinc supplementation on plasma concentrations of high-density lipoprotein cholesterol demonstrated in apparently healthy men, there is insufficient evidence to determine the role of zinc supplementation in influencing other risk factors for CVD.

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Andrieu, S., Guyonnet, S., Coley, N., Cantet, C., Bonnefoy, M., et al., 2017. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): A randomised, placebo-controlled trial. Lancet Neurology 16 (5), 377–389. Bae, J.H., Kim, G., 2018. Systematic review and meta-analysis of omega-3-fatty acids in elderly patients with depression. Nutrition Research 50, 1–9. Bai, Z.G., Bo, A., Wu, S.J., Gai, Q.Y., Chi, I., 2018. Omega-3 polyunsaturated fatty acids and reduction of depressive symptoms in older adults: A systematic review and metaanalysis. Journal of Affective Disorders 241, 242–248. Baleztena, J., Ruiz-Canela, M., Sayon-Orea, C., Pardo, M., Añorbe, T., et al., 2018. Association between cognitive function and supplementation with omega-3 PUFAs and other nutrients in  75 years old patients: A randomized multicenter study. PLoS One 13 (3), e0193568. 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Role of multivitamins and mineral supplements in preventing infections in elderly people: Systematic review and meta-analysis of randomised controlled trials. BMJ 330 (7496), 871. Farina, N., Isaac, M.G., Clark, A.R., Rusted, J., Tabet, N., 2012. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database of Systematic Reviews 11, 6–33. Feart, C., Helmer, C., Merle, B., Herrmann, F.R., Annweiler, C., et al., 2017. Associations of lower vitamin D concentrations with cognitive decline and long-term risk of dementia and Alzheimer’s disease in older adults. Alzheimer’s & Dementia 13 (11), 1207–1216. Ford, A.H., Flicker, L., Alfonso, H., Thomas, J., Clarnette, R., et al., 2010. Vitamins B12, B6, and folic acid for cognition in older men. Neurology 75 (17), 1540–1547. Fortes, C., Agabiti, N., Fano, V., Pacifici, R., Forastiere, F., 1997. Zinc supplementation and plasma lipid peroxides in an elderly population. European Journal of Clinical Nutrition 51 (2), 97. Fortes, C., Forastiere, F., Agabiti, N., Fano, V., Pacifici, R., et al., 1998. The effect of zinc and vitamin A supplementation on immune response in an older population. Journal of the American Geriatrics Society 46 (1), 19–26. Fortmann, S.P., Burda, B.U., Senger, C.A., Lin, J.S., Whitlock, E.P., 2013. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: An updated systematic evidence review for the U.S. Preventive Services Task Force. Annals of Internal Medicine 159 (12), 824–834. Girodon, F., Galan, P., Monget, A.L., Boutron-Ruault, M.C., Brunet-Lecomte, P., et al., 1999. Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: A randomized controlled trial. Archives of Internal Medicine 159 (7), 748–754. Goon, J.A., Nor Azman, N.H.E., Abdul Ghani, S.M., Hamid, Z., Wan Ngah, W.Z., 2017. Comparing palm oil tocotrienol rich fraction with a-tocopherol supplementation on oxidative stress in healthy older adults. Clinical Nutrition ESPEN 21, 1–12. Gupta, N., Sprouse, L., Sadeghi, L., Palomo, L., 2017. Are multivitamin supplements associated with periodontal health? EC Dental Science 12, 179–183. Harris, E., Rowsell, R., Pipingas, A., Macpherson, H., 2016. No effect of multivitamin supplementation on central blood pressure in healthy older people: A randomized controlled trial. Atherosclerosis 246, 236–242. Hin, H., Tomson, J., Newman, C., Kurien, R., Lay, M., et al., 2017. Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care. Osteoporosis International 28 (3), 841–851. Holvik, K., Ahmed, L.A., Forsmo, S., Gjesdal, C.G., Grimnes, G., et al., 2015. No increase in risk of hip fracture at high serum retinol concentrations in community-dwelling older Norwegians: The Norwegian Epidemiologic Osteoporosis Studies. 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Maggio, M., de Vita, F., Lauretani, F., Bandinelli, S., Semba, R.D., et al., 2015. Relationship between carotenoids, retinol, and estradiol levels in older women. Nutrients 7 (8), 6506–6519. Martens, C.R., Denman, B.A., Mazzo, M.R., Armstrong, M.L., Reisdorph, N., et al., 2018. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NADþ in healthy middle-aged and older adults. Nature Communications 9 (1), 1–11. McKinley, M.C., McNulty, H., McPartlin, J., Strain, J.J., Pentieva, K., et al., 2001. Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replate. American Journal of Clinical Nutrition 73 (4), 759–764. McKinley, M.C., McNulty, H., McPartlin, J., Strain, J.J., Scott, J.M., 2002. Effect of riboflavin supplementation on plasma homocysteine in elderly people with low riboflavin status. European Journal of Clinical Nutrition 56 (9), 850. Miles, L.M., Allen, E., Clarke, R., Mills, K., Uauy, R., et al., 2017. Impact of baseline vitamin B12 status on the effect of vitamin B12 supplementation on neurologic function in older people: Secondary analysis of data from the OPEN randomised controlled trial. European Journal of Clinical Nutrition 71 (10), 1166–1172. Miller, J.W., Harvey, D.J., Beckett, L.A., Green, R., Tomaszewski, S., et al., 2015. Vitamin D status and rates of cognitive decline in a multiethnic cohort of older adults. JAMA Neurology 72 (11), 1295–1303. Moyer, V.A., 2013. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine 158 (9), 691–696. Muir, S.M., Montero-Odasso, M., 2011. Effect of Vitamin D supplementation n muscle strength, gait and balance in older adults: A systematic review and meta-analysis. Journal of the American Geriatrics Society 59 (12), 2291–2300. Mursu, J., Robien, K., Harnack, L.J., Park, K., Jacobs, D.R., 2011. Dietary supplements and mortality rate in older women: The Iowa Women’s Health Study. Archives of Internal Medicine 171 (18), 1625–1633. Nor Azman, N.H.E., Goon, J.A., Abdul Ghani, S.M., Hamid, Z., 2018. Comparing palm oil, tocotrienol-rich fraction and a-tocopherol supplementation on the antioxidant levels of older adults. Antioxidants 7 (74), 2–13. Olsson, E., Byberg, L., Karlström, B., Cederholm, T., Melhus, H., et al., 2017. Vitamin D is not associated with incident dementia or cognitive impairment: An 18-y follow-up study in community-living old men. The American Journal of Clinical Nutrition 105 (4), 936–943. Peters, R., Burch, L., Warner, J., Beckett, N., Poulter, R., Bulpitt, C., 2008. Haemoglobin, anaemia, dementia and cognitive decline in the elderly, a systematic review. BMC Geriatrics 8 (1), 18. Pfeifer, M., Begerow, B., Minne, H.W., Suppan, K., Fahrleitner-Pammer, A., et al., 2009. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporosis International 20 (2), 315–322. Pirotta, S., Kidgell, D.J., Daly, R.M., 2015. Effects of vitamin D supplementation on neuroplasticity in older adults: A double-blinded, placebo-controlled randomised trial. Osteoporosis International 26 (1), 131–140. Prasad, A.S., Beck, F.W., Bao, B., Fitzgerald, J.T., et al., 2007. Zinc supplementation decreases incidence of infections in the elderly: Effect of zinc on generation of cytokines and oxidative stress. American Journal of Clinical Nutrition 85 (3), 837–844. Presse, N., Belleville, S., Gaudreau, P., Greenwood, C.E., Kergoat, M.J., et al., 2013. Vitamin K status and cognitive function in healthy older adults. Neurobiology of Aging 34 (12), 2777–2783. Rayman, M.P., 2012. Selenium and human health. Lancet 379 (9822), 1256–1268. Reid, I.R., Bolland, M.J., Grey, A., 2008. 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Shea, M.K., O’Donnell, C.J., Hoffmann, U., Dallal, G.E., Dawson-Hughes, B., et al., 2009. Vitamin K supplementation and progression of coronary artery calcium in older men and women. The American Journal of Clinical Nutrition 89 (6), 1799–1807. Shiga, T., Wajima, Z.I., Inoue, T., Ogawa, R., 2004. Magnesium prophylaxis for arrhythmias after cardiac surgery: A meta-analysis of randomized controlled trials. The American Journal of Medicine 117 (5), 325–333. Simental-Mendía, L.E., Sahebkar, A., Rodríguez-Morán, M., Guerrero-Romero, F., 2016. A systematic review and meta-analysis of randomized controlled trials on the effects of magnesium supplementation on insulin sensitivity and glucose control. Pharmacological Research 111, 272–282. Stankiewicz, J.M., Brass, S.D., 2009. Role of iron in neurotoxicity: A cause for concern in the elderly? Current Opinion in Clinical Nutrition and Metabolic Care 12 (1), 22–29. 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Syncope Ahmet Turan Isik and Ali Ekrem Aydin, Dokuz Eylul University, School of Medicine, Department of Geriatric Medicine, Izmir, Turkey © 2020 Elsevier Inc. All rights reserved.

Introduction Definition Epidemiology Classification and Etiologies of Syncope in Older Adults Reflex Syncope Orthostatic Syncope Cardiac Syncope Syndromes With Syncope-Like Symptoms Clinical Approach Management of Syncope Prognosis References Further Reading

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Introduction Syncope is the transient loss of consciousness (TLOC) and postural tone due to transient global cerebral hypoperfusion, characterized by a rapid onset, short duration, and complete spontaneous recovery (Freeman et al., 2011). Syncope is not a diagnosis; it should be considered as a clinical syndrome that can be classified depending on the underlying cause. Older adults are more prone to syncope development due to the accumulation of age and disease-related disorders that can impair cardiovascular adaptation to hypotensive stresses. It is a common clinical problem in older adults and especially with advancing ages it becomes more difficult to evaluate. Since atypical presentations can be seen frequently in the elderly, it can be difficult to recognize and manage syncope (Goyal and Maurer, 2016). The presentation in the elderly may be usually unexplained falls without a prodromal period before syncope, and the patient may never remember the period. The history is unreliable in these unwitnessed events. Also, early investigation and diagnosis are essential since fractures, and head traumas may be common after syncope-induced falls in the elderly (Kenny and Parry, 2005).

Definition Many clinical causes and mechanisms can lead to TLOC. Epileptic seizures, traumatic brain damage, a transient ischemic attack in the posterior circulation, intoxications, metabolic disorders, and psychogenic causes can be considered as examples. Syncope refers to a clinical picture of temporary loss of consciousness and postural tone resulting from global cerebral hypoperfusion with complete spontaneous recovery without neurological sequelae (Freeman et al., 2011). Presyncope (Near-syncope) is used to describe the symptoms and signs of the prodrome of syncope, but which is not followed by loss of consciousness (Brignole et al., 2018).

Epidemiology Specifying a true prevalence for syncope is difficult because of the features defined above, especially in the elderly. The lifetime prevalence of syncope in the general population is from 20% to 40% for people up to 60 years of age (Cheshire, 2017). It is observed that the frequency increases with age. In the Framingham study there is a significant increase in the incidence of syncope after age 70, from 5.7 events per 1000 person-years in aged 60–69, to 11.1 in aged 70–79 (Soteriades et al., 2002). It is responsible for 3%–5% of emergency department visits, with a hospitalization rate in about 40% of cases (da Silva, 2014).

Classification and Etiologies of Syncope in Older Adults The etiology of syncope may vary between age groups due to increased multimorbidity, polypharmacy, and age-related cardiovascular changes. The reasons leading to TLOC in real syncope can generally be grouped into three main categories:

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- Reflex syncope - Orthostatic syncope - Cardiac syncope Reflex syncope is the cause of approximately 2/3 of the cases. The frequency of orthostatic and cardiac causes increases as individuals getting older (Goyal and Maurer, 2016). In a recent study designed to assess the diagnostic outcomes of a multidisciplinary pathway for elderly syncope patients (117 syncope patients, mean age 80.0  6.5 years) it is concluded that orthostatic hypotension (OH) and postprandial hypotension (PPH) were the most common causes of syncope in older adults, followed by cardiac causes (de Ruiter et al., 2018).

Reflex Syncope Reflex syncope is associated with acute vasodilatation of the arterial and venous beds and relative or absolute bradycardia; this is also termed ‘neurally mediated syncope’. All of the neurally mediated syncopal syndromes involve an inappropriate reflex with afferent, central, and efferent pathways. Reflex syncope includes vasovagal (neurocardiogenic) syncope, carotid sinus hypersensitivity (CSH), and situational syncope (SS) (Kaye and Arthur, 2000; Hogan et al., 2016). Vasovagal syncope (VVS) is the most common cause of syncope alone. Syncope is usually triggered by pain, fear, sadness and long-standing. Before syncope occurs, typical prodromal symptoms of autonomic activation such as sweating, nausea, hot flashes, blurred or faded vision and subsequent loss of consciousness develop. CSH is an exaggerated response to stimulation of the carotid sinus and leads to asystole. It is more common in men and can cause falls and serious injuries. SS is usually referred to as reflex syncope associated with specific conditions. It develops after voiding, defecation, coughing, laughing, swallowing and exercise (Brignole et al., 2018; Hogan et al., 2016).

Orthostatic Syncope OH is a common clinical problem among older adults, which affects nearly 25%–30% of this population. In addition, the prevalence of OH has been reported to be 50% in patients staying in nursing homes (Aydin et al., 2017; Shibao et al., 2013). The upright posture results in the pooling of 300 to 800 mL of blood in the lower extremities and splanchnic circulation (Fig. 1). Decreased venous return to the heart results in a reduction in ventricular filling pressure, cardiac output and blood pressure (BP). In response to this, the sympathetic nervous system and ‘renin-angiotensin-aldosterone system’ are activated as a compensatory effect. However, OH develops if there is insufficient intravascular volume, autonomic nervous system dysfunction, decreased venous return, or inadequacy of increasing cardiac flow. According to the consensus statement on the detection of OH published in 2011, the diagnosis of OH is

Figure 1

Postural hemodynamics in OH.

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made in the event of at least 20 mmHg decrease in systolic blood pressure and/or at least 10 mmHg decrease in diastolic blood pressure within the first 3 minutes after standing or head-up tilt to at least 60 on a tilt table. In patients with supine hypertension, it is stated that it would be a more appropriate diagnostic criterion of 30 mmHg or more decrease in systolic blood pressure (Freeman et al., 2011; Shibao et al., 2013). Syncope due to orthostatic hypotension may occur as a result of primary autonomic disorders, secondary autonomic disorders, drugs and volume reduction, superimposed upon age-related autonomic reflexes, adrenergic responsiveness (Goyal and Maurer, 2016). Among the most of older adults, the decline in blood pressure after meals is usually mild and asymptomatic, however, in hypertensive older adults, older adults with diabetes and different types of autonomic dysfunction, and elderly residents of nursing homes, the decrease in postprandial blood pressure may cause syncope. The pathophysiology of PPH is related with baroreflex disorders, inappropriate sympathetic nervous system stimulation, the hypotensive effect of vasoactive gastrointestinal peptides, and vasodilatation induced by insulin. As a result, a decline in the blood pressure that meets OH diagnostic criteria is observed at 15–90 minutes after the meal. It is stated that postprandial hypotension is a common but frequently overlooked impairment in BP regulation in patients with unexplained syncope (Goyal and Maurer, 2016; Jansen et al., 1995).

Cardiac Syncope The prognosis of syncope due to structural heart disease or arrhythmias is worse than the other causes of syncope. Therefore, it is a crucial syncope subtype. Especially in older adults with heart disease, cardiac causes should be taken into consideration for other reasons. The frequency of arrhythmias increases with age. Bradycardia may be due to degenerative changes in sinus and atrioventricular (AV) nodes, as well as to drugs that reduce cardiac output and cerebral blood flow due to decreased heart rate (Chow et al., 2012). Atrial and ventricular tachycardias may also lead to short filling time in the heart, leading to syncope as a result of the decrease in the stroke volume. In structural cardiovascular diseases, there is insufficient blood flow due to mechanical obstruction, causes syncope. Causes such as pulmonary embolism, acute aortic dissection, pulmonary hypertension are also included in syncope associated with cardiopulmonary and major vessels. If an underlying structural heart disease is detected, it should be treated if possible (Goyal and Maurer, 2016; Brignole et al., 2018).

Syndromes With Syncope-Like Symptoms Hypoglycemia, seizures, transient ischemic attacks, and psychiatric conditions are also conditions that can alter consciousness. These syndromes should be considered along with other causes when a patient presents with syncope (Madden, 2017). It is particular important to distinguish between syncope and epileptic seizures, and there are some clinical features that may be useful in this differentiation (Panayiotopoulos, 2012; Blume, 2003) (Table 1).

Clinical Approach The primary goals of the treatment of patients with syncope are prolonging survival, limiting physical injuries and preventing recurrences. Detecting the cause of syncope plays the leading role in the treatment of choice. The second objective is to identify the mechanism that leads to syncope once the cause has been established. A detailed story taken from the patient and/or incident witnesses can provide important clues as to whether the event that causes temporary loss of consciousness is syncope or not. The initial evaluation includes a detailed history of the characteristics of the syncope episodes, a physical examination including measurement of orthostatic blood pressure changes, and an electrocardiogram (Pirozzi et al., 2013). When the history is detailed, some clinical features can be detected (Brignole et al., 2018): Table 1

Clinical features for differentiation of syncope and epileptic seizures

Features

Syncope

Seizure

Precipitating factors Situation Onset Duration of unconsciousness Jerking of limbs Incontinence Recovery Postictal confusion Tongue biting Pulse

Pain, fear, sadness heat, long-standing Awake, mostly upright Gradual; possibly sudden if cardiogenic Seconds Rare Rare Rapid Uncommon Rare Vasovagal: Slow Vasodepressor: Weak

Sleeplessness, flashing lights Awake or asleep Sudden Minutes Frequent More common Slow Common More common Rapid and strong

Syncope n n

n

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Recurrent syncope, absence of heart disease, syncope after defecation, micturition, laughing, swallowing, long-term standing, after exercise, head-turning or carotid sinus pressure (tight shirt collar, shaving) may indicate reflex syncope. Syncope after standing up, long-term standing or being in crowded and hot places, standing after exercise, vasodepressive drugs that have just been started, neurodegenerative disease or autonomic neuropathy history and postprandial hypotension may indicate orthostatic syncope. Presence of structural heart disease, abnormal ECG, a story of the sudden death in the family, syncope after new onset chest pain, shortness of breath, abdominal pain, or a headache, sudden onset palpitation, syncope during training or in a supine position may indicate cardiac syncope.

The medical history of the patient should be documented for chronic diseases and risk factors for cardiac syncope. The details of medication use, in particular, recent drug changes should be questioned. Initial evaluation can identify a syncope cause in approximately 63% of cases (van Dijk et al., 2008). If the cause remains uncertain, further investigation is indicated. Based on these findings additional evaluations may be made if necessary (Brignole et al., 2018); n n n n n

Urgent ECG monitoring for suspected arrhythmic syncope Echocardiography in the presence of known heart disease or suspicion of cardiovascular syncope Carotid sinus massage in patients over 40 years of age with unexplained syncope and falls, Head-up tilt table test in the presence of syncope or reflex syncope due to orthostatic hypotension Blood tests if indicated according to patient history and physical examination. For example; complete blood count when suspected hemorrhage, oxygen saturation, and arterial blood gas analysis when hypoxia is suspected, troponin when syncope associated with cardiac ischemia is suspected, D-dimer when pulmonary embolism is suspected, etc.

The purpose of the initial evaluation is to differentiate syncope from non-syncopal conditions, to determine the cause of syncope, to decide whether the patient needs to be hospitalized and to stratify the risk of major cardiovascular events or death. The high-risk features that suggest a serious condition are (Brignole et al., 2018); n n n n n n n n n

n n n

New onset chest pain, shortness of breath, abdominal pain, or headache Syncope during exercise or in supine position Syncope after sudden onset palpitation Severe structural or coronary artery disease Unexplained low systolic blood pressure (