HANDBOOK OF THE BIOLOGY OF AGING EIGHTH EDITION THE HANDBOOKS OF AGING Consisting of Three Volumes Critical comprehensive reviews of research knowledge, theories, concepts, and issues Editors-in-Chief Laura L Carstensen and Thomas A Rando Handbook of the Biology of Aging, 8th Edition Edited by Matt Kaeberlein and George M Martin Handbook of the Psychology of Aging, 8th Edition Edited by K Warner Schaie and Sherry L Willis Handbook of Aging and the Social Sciences, 8th Edition Edited by Linda K George and Kenneth F Ferraro HANDBOOK OF THE BIOLOGY OF AGING EIGHTH EDITION Edited by Matt R Kaeberlein and George M Martin Associate Editor Tammi L Kaeberlein AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Seventh edition 2011 Eighth edition 2016 Chapters 10 and 13 are in the public domain, published by Elsevier Inc All other chapters Copyright © 2016, 2011 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: 978-0-12-411596-5 For information on all Academic Press publications visit our website at http://store.elsevier.com Publisher: Nikki Levy Acquisition Editor: Emily Ekle Editorial Project Manager: Barbara Makinster Production Project Manager: Melissa Read Designer: Matthew Limbert Printed and bound in the United States of America Foreword Attention to the science of aging involves a concomitant increase in the number of college and university courses and programs focused on aging and longevity With this expansion of knowledge, the Handbooks play an increasingly important role for students, teachers, and scientists who are regularly called upon to synthesize and update their comprehension of the broader field in which they work The Handbook of Aging series provides knowledge bases for instruction in these continually changing fields, both through reviews of core and newly emerging areas, historical syntheses, methodological and conceptual advances Moreover, the interdisciplinary nature of aging research is exemplified by the overlap in concepts illuminated across the Handbooks, such as the profound interactions between social worlds and biological processes By continually featuring new topics and involving new authors, the series has pushed innovation and fostered new ideas One of the greatest strengths of the chapters in the Handbooks is the synthesis afforded by preeminent authors who are at the forefront of research and thus provide expert perspectives on the issues that currently define and challenge each field We express our deepest thanks to the editors of the individual volumes for their incredible dedication and contributions to the series It is their efforts to which the excellence of the products is largely credited We thank Drs Matt Kaeberlein and George M Martin editors of the Handbook of the Biology of Aging; Drs K Warner Schaie The near-doubling of life expectancy in the twentieth century represents extraordinary opportunities for societies and individuals Just as sure, it presents extraordinary challenges In the years since the last edition of the Handbook of Aging series was published, the United States joined the growing list of “aging societies” alongside developed nations in Western Europe and parts of Asia; that is, the US population has come to include more people over the age of 60 than under 15 years of age This unprecedented reshaping of age in the population will continue on a global scale and will fundamentally alter all aspects of life as we know it Science is responsible for the extension of life expectancy and science is now needed more than ever to ensure that added years are high quality Fortunately, the scientific understanding of aging is growing faster than ever across social and biological sciences Along with the phenomenal advances in the genetic determinants of longevity and susceptibility to age-related diseases has come the awareness of the critical importance of environmental and psychological factors that modulate and even supersede genetic predispositions The Handbooks of Aging series, comprised of three separate volumes, the Handbook of the Biology of Aging, the Handbook of the Psychology of Aging, and the Handbook of Aging and the Social Sciences, is now in its eighth edition and continues to provide foundational knowledge that fosters continued advances in the understanding of aging at the individual and societal levels ix x Foreword and Sherry L Willis, editors of the Handbook of the Psychology of Aging; and Drs Linda K George and Kenneth F Ferraro, editors of the Handbook of Aging and the Social Sciences We would also like to express our appreciation to our publishers at Elsevier, whose profound interest and dedication have facilitated the publication of the Handbooks through their many editions And we continue to extend our deepest gratitude to James Birren for establishing and shepherding the series through the first six editions Thomas A Rando and Laura L Carstensen Stanford Center on Longevity, Stanford University, Stanford, CA, USA Preface under examination in that program: rapamycin As described in Chapter 10, by Nadon and colleagues, the ITP has continued to test interventions over the past years and has identified several that also extend lifespan in mice, often in a sex-specific manner Still, rapamycin and its molecular target, the mTOR pathway, remains as arguably the best current candidate for translational applications to improve healthy longevity in people Several chapters touch on this pathway and its importance in age-related phenotypes, and Chapter  2, by Schreiber et  al., details our current understanding of the mTOR pathway and new strategies to pharmacologically modulate this pathway to delay aging Along with mTOR, two chapters discuss the importance of sirtuins and the hypoxic response in aging, and Sutphin and colleagues provide a comprehensive picture of how these various pathways interact within the context of aging as a complex genetic trait in Chapter 1 One area that has achieved growing recognition within the field over the past several years is the importance of assessing healthspan – or the period of time spent with a relatively high quality of life – in addition to lifespan A key question related to this idea is whether interventions that increase lifespan generally or necessarily also improve healthspan Contributions from Fries (Chapter  19) and Crimmins (Chapter  18) address this question by examining the idea of ‘compression of morbidity’ as it applies to healthy aging and lifestyle interventions such as exercise The past years has seen rapid progress in research on the Biology of Aging Several major themes have emerged in the field since 2010, when the most recent seventh edition of this Handbook was published Here we have attempted to capture several of these important advances and themes while at the same time representing the diversity of research that comprises modern biogerontology Perhaps foremost among trends in the field, as well as biological science in general, is the continued development and application of ‘big data’ approaches New strategies are needed to analyze, interpret, and understand the enormous amounts of information being generated through DNA sequencing, transcriptomic, proteomic, and metabolomic methodologies being applied to aging-related problems Several chapters in this edition delve into these approaches as they relate to aging in model organisms, as well as exceptional longevity in people Two chapters are dedicated specifically to the challenges of big data and some solutions, including innovative new tools, being developed to facilitate systems-level approaches to aging research We are also pleased to include several chapters describing important new discoveries related to longevity pathways and interventions that modulate aging, particularly in mammals At the time of publication of the seventh edition of this Handbook, the National Institute on Aging Interventions Testing Program (ITP) had just published the first report of significant lifespan extension from one of the compounds xi xii Preface We are grateful to our authors and outside reviewers for their contributions to this Handbook As the field of aging research continues to mature, this series provides an invaluable collection of insightful and informative reviews by leaders in their respective areas of research We hope that you will find the reading of these chapters as educational and stimulating as we have Dr Matt R Kaeberlein Dr George M Martin About the Editors Matt R Kaeberlein Dr Kaeberlein is a professor of Pathology and adjunct professor of Genome Sciences at the University of Washington He is the co-Director of the University of Washington Nathan Shock Center of Excellence in the Basic Biology of Aging and Director of the Healthy Aging and Longevity Research Institute His activities related to the biology of aging have included serving on the Executive Committee of the Biological Sciences section of the Gerontological Society of America and the Board of Directors for the American Aging Association He also directed the Biology of Aging Summer Course and the Marine Biological Laboratory in Woods Hole, MA, from 2014 to 2015 He has authored more than 130 publications on the basic biology of aging, and has been recognized with several awards, including a Breakthroughs in Gerontology Award from the Glenn Foundation, an Alzheimer’s Association Young Investigator Award, an Ellison Medical Foundation New Scholar in Aging Award, an Undergraduate Research Mentor of the Year Award, and a Murdock Trust Award In 2011, he was named the Vincent Cristofalo Rising Star in Aging Research by the American Federation for Aging Research and appointed as a fellow of the Gerontological Society of America, and in 2014 he was elected as the incoming President of the American Aging Association He currently serves on the editorial boards for Science, Aging Cell, Cell Cycle, PLoS One, Frontiers in Genetics of Aging, npj Aging and Mechanisms of Disease, F1000 Research, Ageing Research Reviews, BioEssays, and Oncotarget George M Martin Dr Martin is Professor Emeritus of Pathology (Active) at the University of Washington, where he has also served as an adjunct professor of Genome Sciences He was the founding director of that institution’s Medical Scientist Training Program, Alzheimer’s Disease Research Center and NIA T32 training grant on genetic approaches to aging research His activities related to the biology of aging have included the Presidency of the Gerontological Society of America, the Scientific Directorship and Presidency of the American Federation for Aging Research, membership on the National Advisory Council and Board of Scientific Counselors of the National Institute on Aging, member and Chair of the Scientific Advisory Board of the Ellison Medical Foundation and Chairmanship of a Gordon Conference on the Biology of Aging Honors for his research have included the Brookdale, Kleemeier and Paul Glenn Foundation awards of the Gerontological Society of America, the Allied-Signal Corporation Award, the Irving Wright Award of the American Federation for Aging Research, the American Aging Association Research Medal and Distinguished Scientist Award, the Pruzanski Award of the American College of Medical Genetics, and a World Alzheimer Congress Lifetime Achievement Award He has also received an Outstanding Alumnus Award from the University of Washington School of Medicine He was elected to the Institute of Medicine of the National Academy of Sciences and now serves as a senior member xiii xiv About the Editors His research focus has been on genetic aspects of aging in mammals, particularly human subjects That research led to the characterizations of mutations responsible for several segmental progeroid syndromes, notably Werner syndrome, as well as early studies of the genetics of dementias of the Alzheimer type Tammi L Kaeberlein Dr Kaeberlein is a research associate in the Department of Pathology at the University of Washington and the lead web designer, communications director, and advertising coordinator for the Dog Aging Project She completed her Ph.D thesis at Northeastern University where she developed novel methods for cultivation of previously uncultivable microorganisms This technology was the basis for foundation of the Cambridge-based company Novobiotic and has led to the identification of new classes of natural product antibiotic and anticancer molecules Her postdoctoral research at the University of Washington focused on the mechanisms of pathogenicity in the bacterium Yersinia pestis, the causative agent of the Black Plague ... three separate volumes, the Handbook of the Biology of Aging, the Handbook of the Psychology of Aging, and the Handbook of Aging and the Social Sciences, is now in its eighth edition and continues... Rando Handbook of the Biology of Aging, 8th Edition Edited by Matt Kaeberlein and George M Martin Handbook of the Psychology of Aging, 8th Edition Edited by K Warner Schaie and Sherry L Willis Handbook. .. 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