Mild Stress and Healthy Aging Applying Hormesis in Aging Research and Interventions Eric Le Bourg Suresh I.S. Rattan (cid:127) Editors Mild Stress and Healthy Aging Applying Hormesis in Aging Research and Interventions Eric Le Bourg Suresh I.S. Rattan Centre de Recherche sur Department of Molecular Biology la Cognition Animale University of Aarhus UMR CNRS 5169, Gustav Wieds Vej 10-C Université Paul-Sabatier DK-8000 Aarhus 118 route de Narbonne Denmark F-31062 Toulouse cedex 9 France ISBN 978-1-4020-6868-3 e-ISBN 978-1-4020-6869-0 Library of Congress Control Number: 2007939822 © 2008 Springer Science + Business Media B.V. No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written p ermission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper. 9 8 7 6 5 4 3 2 1 springer.com Contents Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Chapter 1 Hormesis and Aging: What’s the Deal? . . . . . . . . . . . . . . . . . 1 Éric Le Bourg and Suresh I.S. Rattan Chapter 2 What Is Hormesis?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Edward J. Calabrese Chapter 3 Irradiation and Hormesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Alexander M. Vaiserman Chapter 4 Hypergravity in Drosophila melanogaster . . . . . . . . . . . . . . . 43 Éric Le Bourg Chapter 5 Temperature-Induced Hormesis in Drosophila . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Jesper G. Sørensen, Pernille Sarup, Torsten N. Kristensen and Volker Loeschcke Chapter 6 Hormetic Modulation of Aging in Human Cells . . . . . . . . . . 81 Suresh I.S. Rattan Chapter 7 Physical Activity: A Strong Stimulant for Hormesis During Aging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Li Li Ji Chapter 8 How Xenohormetic Compounds Confer Health Benefi ts. . . 115 Brian J. Morris Chapter 9 Mild Stress in the Aging Heart: Role of Ischemic Preconditioning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Pasquale Abete and Franco Rengo v vi Contents Chapter 10 Clinical Applications of Low-Dose Whole Body Irradiation Hormesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Akmal Safwat Conclusion. Mild Stress and Healthy Aging: Perspectives for Human Beings. . . . . . . . . . . . . . . . . . . . . . . 171 Pasquale Abete, Edward Calabrese, Li Li Ji, Torsten Kristensen, Éric Le Bourg, Volker Loeschcke, Brian Morris, Franco Rengo, Suresh I.S. Rattan, Akmal Safwat, Pernille Sarup, Jesper Sørensen and Alexander M. Vaiserman Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 Contributors Pasquale Abete Cattedra di Geriatria–Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, University of Naples “Federico II”, Italy Edward J. Calabrese Department of Public Health, Environmental Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA 01003, USA Li Li Ji The Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin-Madison, Madison, WI 53706, USA Torsten Kristensen Genetics and Ecology, Department of Biological Sciences, University of Aarhus, Ny Munkegade, Building 1540, DK-8000 Aarhus C, Denmark; Department of Genetics and Biotechnology, University of Aarhus, P.O. Box 50, DK-8830 Tjele, Denmark Éric Le Bourg Centre de Recherche sur la Cognition Animale, UMR CNRS 5169, Université Paul-Sabatier, 118 route de Narbonne, F-31062 Toulouse cedex 9, France Volker Loeschcke Genetics and Ecology, Department of Biological Sciences, University of Aarhus, Ny Munkegade, Building 1540, DK-8000 Aarhus C, Denmark Brian Morris School of Medical Sciences, Building F13, The University of Sydney, New South Wales 2006, Australia vii viii Contributors Suresh I.S. Rattan Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10-C, DK-8000 Aarhus, Denmark Franco Rengo Cattedra di Geriatria–Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, University of Naples “Federico II”Istituto Scientifico di Telese Terme, Fondazione Salvatore Maugeri, IRCCS, Benevento, Italy Akmal Safwat Oncology Department, Aarhus University Hospital, Denmark, Radiotherapy Department, National Cancer Institute, Cairo University, Egypt Pernille Sarup Genetics and Ecology, Department of Biological Sciences, University of Aarhus, Ny Munkegade, Building 1540, DK-8000 Aarhus C, Denmark Jesper Sorensen Genetics and Ecology, Department of Biological Sciences, University of Aarhus, Ny Munkegade, Building 1540, DK-8000 Aarhus C, Denmark Alexander Vaiserman Laboratory of Mathematical Modelling of Aging Processes, Institute of Gerontology, Vyshgorodskaya St. 67, Kiev 04114, Ukraine Chapter 1 Hormesis and Aging: What’s the Deal? Éric Le Bourg1 and Suresh I.S. Rattan2 Our century allows most people of developed countries, and to higher numbers in developing countries, to reach old age. Thanks to sanitation, vaccination, medical care, and social security systems, we all have a good chance to see our children, grandchildren, and great-grandchildren becoming adults, and they also can see us becoming old, and even very old. In such conditions, the next main battle is to improve living conditions in Africa and other least developed countries to increase mean longevity, and to improve healthspan of elderly people. This is the job of physicians and of people involved in medical research trying to improve drugs against the consequences of aging on the various parts of the body. Biogerontologists obviously can be of help in this endeavor, but they also have to propose new ways of thinking, in order to discover new strategies to improve life at old age. To use an analogy, it could be said that the best way to discover such new strategies is to think to electricity rather than searching to improve the candle. The purpose of this book is to try to know whether hormesis could become a means to confine candelabras into the shops of antique dealers, because one has found a better way to provide light. Hormesis is the phenomenon in which adaptive responses to low doses of other- wise harmful conditions improve the functional ability of cells and organisms. These low doses are called mild stress in the following. Mild stress is now consid- ered by many authors as a gerontological research tool. Data are accumulating showing that a mild stress at a young age can slightly increase longevity and delay aging or protect from a severe stress at old age. However, we have not still reached the time when all scientists accept that studying mild stress can be useful to aging research or even think to mild stress in connection with biogerontology. Therefore, the time is ripe for a book on the matter because it is a time of debates: not too early, not too late. We have a dream: if the functional ability of the organism could be 1 Centre de Recherche sur la Cognition Animale, UMR CNRS 5169, Université Paul-Sabatier, 31062 Toulouse cedex 9, France. Tel: 33 5 61 55 65 67; Fax: 33 5 61 55 61 54; e-mail: [email protected] 2 Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10-C, DK-8000 Aarhus, Denmark. Tel: 45 89425034; Fax: 45 86123178; e-mail: [email protected] E. Le Bourg and S.I.S. Rattan (eds.), Mild Stress and Healthy Aging. 1 © Springer 2008 2 É. Le Bourg and S.I.S. Rattan increased at old age, the need for medical care at this age could be reduced, simply because it would be, at least partly, of no use to people enjoying a better health. Therefore, hormesis offers the theoretical possibility not to fight aging by relying on drugs or medical interventions, but to increase healthspan by relying on a pre- treatment with a mild stress. Hopefully, the next years will probably tell us whether our dream was condemned to remain a dream or not. Hormesis research has a rather long story (chapter by Calabrese) but it has been considered in the frame of research on aging very scarcely up to, say, the turn of the century. In 1977, Sacher published a review dealing with hormesis and aging where he noted that “the paucity of scientific information concerning the adaptive value of external stimulation has fostered the view that ‘stress’ is generally deleterious to health and survival”. This may explain why the second review paper was only pub- lished 23 years later (Minois 2000). Neafsey (1990) also published a review on longevity hormesis, but this article was mainly concerned with the use of longevity to study chemical toxicants, and not with aging. Reading these Sacher’s (1977) and Minois’ (2000) reviews side by side shows the main conceptual change which has been done during this time interval. According to Sacher (1977), hormetic effects are “unlikely to occur in the healthy active individual, and are more likely to be significant in the ill or depressed ani- mal” and “hormesis is in one sense an obstacle in the path of gerontological research, and efforts to understand and annul it would be well justified”. For Minois (2000), mild stresses “have beneficial effects on longevity and stress resistance” and they “will be really useful if they are shown to confer global beneficial effects on aging”. Most of recent studies on hormetic effects do not consider that they can be observed only, or mainly, in “ill or depressed” animals but, rather, in good rear- ing conditions. For instance, flies live longer in individual vials than in groups of 15 flies of the same sex. Nevertheless, increased longevity after hypergravity expo- sure, a mild stress, has been observed in these two living conditions, and not only in flies living in groups. By contrast, hypergravity exposure does no increase the longevity of the short-lived mated flies but it increases that of the long-lived virgin ones (chapter by Le Bourg). Therefore, it seems that if hormetic effects can be observed in ill or depressed animals, they are more likely in healthy ones. It is now more and more accepted that mild stresses can increase longevity, in addition to the well-known effect on stress resistance: for instance, Lamb and McDonald (1973) showed that, up to middle age, irradiated Drosophila melanogaster male flies survived for a longer time in dry air than control flies, even if these last flies lived longer in normal rearing conditions. While effects of mild stress on longevity and resistance to several stresses are now documented (see most of the chapters below), less studies have been done on aging, which shows that the Minois’ (2000) conclusion that mild stresses “will be really useful if they are shown to confer global beneficial effects on aging” is not outdated. We may feel that showing such effects of mild stress on aging, and not only on longevity, could be now a priority on the research agenda, simply because living longer seems of no value if this extra-life is paid by a longer decrepitude. 1 Hormesis and Aging: What’s the Deal? 3 Another priority could be to extend the study of hormetic effects to mammals, because most of studies on animals have been done on invertebrate species, mainly D. melanogaster and Caenorhabditis elegans. In these species, the list of stresses with hormetic effects is impressive (heat, cold, hypergravity, irradiation, hyperbaric oygen: see the chapters below). However, results on rodents are scarce and mainly involve the use of physical activity (chapter by Ji) or of irradiation (chapter by Vaiserman). Studies on cells are not a surrogate for such studies on mammals, because there is a gap between studies at the cellular and organismal levels: increasing the resistance of human fibroblasts to heat by subjecting them to a mild heat shock (chaper by Rattan) does not allow to predict that this mild stress will improve survival of elderly people to summer heatwave. It is thus clear that discovering new stresses with hormetic effects at the organismal level, in mammals, is one of the next challenges of biogeron- tologists. Whether the increased longevity of dietary restricted rodents is due to hormetic effects of dietary restriction is a matter of debate, the joke being that the two editors of this book support opposite opinions. Minois (2000) and Le Bourg (2003) have both emphasized the main difference between the effects on longevity of dietary restriction and of mild stresses: dietary restriction strongly increases both mean and maximal longevity in rodents while mild stresses have much lower effects. By contrast, Masoro (2005), Rattan (2004), or Sinclair (2005) consider that dietary restriction is a mild stress increasing longevity and inducing elevations of blood glucocorticoids or of signaling pathways responding to biological stress and low nutrition. We might wonder on the interest to study hormetic effects on longevity if they are of a low magnitude when compared to the effects of dietary restriction (Bertrand et al. 1999) or of mutations, for instance in C. elegans (Olsen et al. 2003). The main reason is that crossing the distance between a mutation with beneficial effects on aging and the discovery of a means to mimick its effects in mammals can be difficult, if not impossible. Similarly, while dietary restriction increases longevity in rodents, there is a debate on its effect in human beings (Le Bourg and Rattan 2006) and on the way to mimick the beneficial effects of dietary restriction in humans (Ingram et al. 2006)… if they indeed exist. In such conditions, using an environmental manipulation to (slightly) increase longevity and (hopefully) improve the physiological state at old age seems of interest. If the effects of these environmental manipulations observed in laboratory animals could be reproduced in elderly people, it would provide a new way to improve life at old age, and this, rather quickly. Nevertheless, we do not think that biogerontolo- gists have to give up research on the genetics of aging and on dietary restriction, but simply that the study of hormesis could be another means to understand aging and, eventually, improve life at old age (see Le Bourg 2003 for a discussion). This book describes the effects of various mild stresses in animal species. The first chapter, written by Edward Calabrese, describes the concept and history of hormesis, and focuses on its use in research on aging. The second chapter written by Alexander Vaiserman deals with the use of irra- diation in D. melanogaster, C. elegans, rodents and human beings. The chapter on hypergravity (Éric Le Bourg) describes results obtained on D. melanogaster flies. The following chapter (Jesper Sørensen, Pernille Sarup, Torsten Kristensen, and Volker Loeschcke) focuses on the use of extreme temperatures, either hot or cold