ADVANCES IN CELL AGING AND GERONTOLOGY SOME ASPECTS OF THE AGING PROCESS Editors: PAOLA S. TIMIRAS Departnient of Molecular and Cell Biology University of California- Berkeley E. EDWARD BITTAR Department of Physiology University of Wisconsin-Madison VOLUME 1 1996 @) JAI PRESS INC. Greenwich, Connecticut London, England Copyright 0 1996 by JAl PRESS INC. 55 Old Post Road No. 2 Greenwich, Connecticut 06836 JAl PRESS LTD. 38 Tavistock Street Covent Garden London WCZE 7PB Engtand All rights reserved. No part of this publication may be reproduced, stored on a retrieJa1 system, or transmitted in any form, or by any means, electronic, mechanical, photocopying, filming, recording, or otherwise without prior permission in writing from the publisher. ISBN: 1-55938-631-2 Manufactured in the United States of America LIST OF CONTRIBUTORS Grzegorz Bartosz Department of Biophysics University of Lodz Lodz, Poland G.J.C.G.M. Bosman Department of Biochemistry University of Nijmegen Nijmegen, The Netherlands Frank W Brown Wesley Woods Geriatric Teaching and Research Hospital Atlanta, Georgia W. J. De Grip Department of Biochemistry University of Nijmegen Nijmegen, The Netherlands James R. Docherty Department of Physiology Royal College of Surgeons in Ireland Dublin, Ireland Peter J. Hornsby Huffington Center on Aging Baylor College of Medicine Houston, Texas Jana Huschenbett Department of Pharmacology and Toxicology University of Kansas Lawrence, Kansas Mary L. Michaelis Department of Pharmacology and Tox ic o I ogy University of Kansas Lawrence, Kansas vii viii LIST OF CONTRIBUTORS Peter H. Millard Division of Geriatric Medicine St. George’s Hospital London, England Daniel Rudman Department of Medicine VA Medical Center Milwaukee, Wisconsin Kaup R. Shetty Department of Medicine VA Medical Center MiI wau kee, Wisconsin Paola S. Timiras Department of Molecular and Cell Biology University of California Berkeley, Cal ifornl a David Wilkinson Thornhill Research Unit Moorgreen Hospital Southampton, Hampshire, England PRE FACE The many books on the subject of aging published during the last two decades stems both from biomedical advances and socioeconomic concerns. Progress in the biomedical and public health sciences has resulted in better diagnosis and treatment of old age-associated diseases and has led to delay in the onset of these diseases and their prevention by better education concerning proper hygiene, diet, and physical exercise. The resulting great proportion of the elderly in the human populatio-he old (65 years of age and older) and the old-old (75 years and older-nd the expected continuation of this trend into the next century have created serious social and financial problems for the aged themselves and of society in general. Biomedical books on aging are usually of two kinds, according to the major areas of competence, and experimental and clinical research of the authors. There are those books concerned with identifying the molecular and genetic causes, and mechanisms of aging (as in Gerontology) and those concerned with the mainte- nance and improvement of health in the elderly and treatment of their diseases (as in Geriatrics). In the present book, we have attempted to combine both approaches: the first chapters deal with cellular, endocrine, cardiovascular, and neural aging with emphasis on molecular and genetic mechanisms, while the last chapters deal with medical and psychiatric interventions. Indeed, the two approaches are not only ix X PREFACE complementary but they may provide an integrated understanding of the aging process. The elderly are particularly heterogeneous in terms of physiologic competence and pathologic involvement: “successfuI)) aging is clearly distinguishable from “usual” aging. Therefore, progress in molecular biology and genetics can be extremely helpful in indicating appropriater egimens for continuing “wellness” and disease treatment for each aged individual, perhaps more so for the old than for any other age period ofthe life span. Studies such as the current Human Genome Project are expected to identify genes responsible for rare, obscure diseases and, more importantly, to provide guidelines for optimizing the physiologic potential of all individuals, particularly the elderly. Medicine as it is currently practiced may be viewed as a “mass” medicine: everyone receives the same regimen for maintenance of good health and the same treatment for the same diseases. Yet, we know that all diseases do not manifest in the same manner in all individuals, and, in the elderly, symptoms of a given disease often differ markedly from those in the young and adults. Many of these differences depend on the genes with which eacti individual is born; for example, genes which are adversely affected by excessive smoking or nutrition or lack ofphysical exercise and poor hygienic habits. The impact of our advancing knowledge of genetics will make it possible to discover which genes are in which form in a particular individual and use this information to refine and individualize prevention and treatment. In other words, in a not too distant future, we may witness a shift from “mass” to “custom” medicine. The individuals most likely to benefit from customized medicine are the elderly, often aMicted simultaneously with multiple diseases and with the side effects of polypharmacy. By presenting a book in which we have included chapters in both basic and clinical studies, we have taken a modest but innovative step toward strengthening communication between molecular and medical sciences. Finally, we are most indebted to the contributors of this book. We are also indebted to Ms. Lauren Manjoney and staff members of JAI Press for their skill and courtesy. PAOLA S. TIMIRAS E. EDWARD BITTAR Chapter 1 The Cell Aging Process PAOLA S. TIMIRAS Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Some Demographic and Epidemiologic Considerations . . . . . . . . . . . . . . . 2 Usual Versus Successful Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Pathology of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Aging Changes in Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Aging Changes in Cytoplasm .............................. 12 Aging Changes in the Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Enzymatic Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Cell Injury and Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Cloudy Swellinflehydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Fat/GlycogenChanges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Age Pigments or Lipofuscin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Amyloid and Amyloidoses ............................... 17 Cell Death. Necrosis. and Apoptosis .......................... 17 Theories of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Molecular Theories and the Genetic Connection .................... 18 Cellular Theories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 System-Level Theories ................................. 23 Single Versus Multiple, Interdependent Theories of Aging . . . . . . . . . . . . . . .2 3 Summary ......................................... 24 Advances in Cell Aging and Gerontology . Volume 1. pages 1.29 Copyright 8 1996 by JAI Press Inc . . All rights of reproductioni n any form reserved ISBN: 1-55938-631-2 1 2 PAOLA S. TlMlRAS INTRODUCTION Aging has been defined as an overall decline of physiological processes that results in failure to adapt to environmental demands (e.g., adaptation to stress) and culminates in death (Timiras, 1994). At the cellular level, the study of aging is concerned with the basic functions of molecules within the cells and of the cells within the tissues. Implicit in such studies is the objective of discovering universal principles capable of explaining aging and of finding means for delaying or treating the pathology of aging. Cellular and molecular theories of aging hold that intrinsic (genetic) processes occurring in the cell in combination with external (environ- mental) factors are responsible for aging. Elucidation of the genetic and epigenetic factors underlying the causes of aging and death is one of the most challenging aspects of contemporary biology (Papaconstantinou, 1994). The aim of this chapter ,'s to discuss the cellular and molecular bases of aging from an essentially physiological viewpoint with the focus on humans. Homeostasis comprises the complex adjustments that living organisms undertake to maintain functional stability and integrity in response to internal and external demands and perturbations. Cellular aging processes are usually viewed as leading to impaired cellular structure and diminished function and ultimately to cell death. However, cell death occurs at all stages of the life span and indeed, is operative during the early stages of development, where it plays an important role in organogenesis. The basic questions on the origins of aging should be concerned not so much about whether certain failing processes are a part of aging but whether they impair viability to such an extent as to induce death. The distinction between specific/ anecdotal and causativehniversal aging remains elusive because of biological heterogeneity, differences in the rates of aging, and the widespread occurrence of alterations with age. The dramatic increase in the elderly population witnessed in this century makes the challenge of understanding aging more pressing. Thus, this chapter is also intended to serve as an introduction to those seeking infomation about specific aspects of systemic aging and geriatrics. SOME DEMOGRAPHIC AND EPIDEMIOLOGIC CONSIDERATIONS Today, the elderly represent a growing proportion of the population in many nations. One of the most dramatic changes in human populations witnessed in the twentieth century is the marked prolongation of the average life span. It is a major achieve- ment of civilization that life expectancy has increased throughout history, but it is during this century that the greatest progress has been made. Life expectancy has increased from 50 years in 1900 to 75 and longer in 1990 in North America, Japan, and several European countries (Figure 1). Not only are the elderly living longer, but they also represent the fastest growing segment of the population in developed countries (Hoover and Siegel, 1986; U.S. Department of Commerce, 1987). In the Cellular Aging 3 $ I I I I I I I ~ I I ~ ~ I ~ ~ I I ~ ~ 1800 1820 1840 1860 1880 1900 1920 1940 1960 1980 Year Figure 1. Life expectancy at birth in France from 1806 to 1986. Obtained through the courtesy of Professor j. R. Wilmoth, who used in part mortality data from Vallin, J. & MeslC, F. (19 89). Vital statistics and mortality records, well kept in France since the beginning of the nineteenth century, provide the opportunity of constructing a reliable curve over almost 200 years of life expectancy for men and women. This curve demonstrates that (1 ) life expectancy grew moderately during the nineteenth century, with a more rapid growth in the last 20 years of the century; (2) from 1900 on, life expectancy increased rapidly and consistently throughout the twentieth century; (3) starting with the second half of the nineteenth century, life expectancy was always higher in women than in men, a differential persisting up to 1980 and continuing today. Of historical interest are the transitory but significant drops in life expectancy over time, especially of men. The first drop coincides with the Napoleonic Wars, conducted outside of France (18 05-1 81 5), hence not involving the female population. The second coincides with the Franco-Prussian War of 1870. France was invaded by Prussian troops and both men and women suffered, although male casualties always prevailed. The third drop coincides with the First World War (1 91 4-1 91 8). Soldier casualties at the front line were very high, but mortality among women was due primarily to epidemics such as that of influenza. The fourth drop coincides with the Second World War (19 39-1 945), when French losses, involving primarily men and women fighting in the Resistance, were much less severe than in the First World War. 4 PAOLA S. TlMlRAS United States today 13% of the population is 65 years old and older, and it is expected that this proportion will increase to 22% by the year 2030. The elderly population itself is aging: of those 65 years and older, 10% are 85 and older, and this proportion will increase to 16% at the beginning of the next century. This is why there is increased concern in the biomedical community about understanding the aging process and the problems of the aged. This trend, the so-called graying of the population, is not limited to the developed countries but has now become a worldwide phenomenon that includes the developingc ountries as well (Kalache, 1991 ). Historically, lonkevity was not a “problem” but a privilege. Most human deaths were premature: lives were cut short, usually by infectious diseases in infancy, childhood, and early maturity, that is, before old age. The question that demogra- phers are expected to answer is, “How much larger” in both absolute and relative terms, will the population over 65 become in our demographic future? As the overall health status of the elderly improves and technology advances, “deceleration of aging may very well raise to 100 years the life expectancy of humans by the middle of the next century, if not sooner” (Siege1 and Taeuber, 1986). A more conservative, and perhaps more realistic forecast predicts an increase in the life expectancy of 10 years between 1995 and 2065 (Table 1). Whereas 46% now survive to age 80, by 2065,46% will survive to age 90; the gains forecast between now and 2065 in length of the average life span will involve 74% of the individuals aged 65 years and older (Lee and Carter, 1992). Old age or senescence in humans has conventionally been accepted as that period of the life cycle that starts around 65 years of age (often coinciding with retirement Table 1. Forecasts of Remaining Life Expectancy at Progressive Ages and at Selective Time Intervals, United States, 1990-2065 (From Period Life Tables with Sexes Combined) ~ ~ Date Age 1990 1995 2010 2050 2065 0 75.83 76.68 79.04 84.34 86.05 20 56.93 57.63 59.67 64.56 66.20 50 28.83 29.39 31.04 35.27 36.75 65 17.16 17.59 18.89 22.31 23.54 70 13.88 14.27 15.43 18.52 19.63 80 8.36 8.63 9.44 11.62 12.42 90 4.46 4.59 4.99 6.1 0 6.52 100 1.91 1.98 2.16 2.55 2.68 105 .oo .oo .31 .88 1.04 Notes: Adapted from: Lee, R.D. & Carter, L.R. (1 992) to which the reader is referred for evaluation of the time series methods utilized to make long-run forecasts. As explained in the text, in 1995, life expectancy at birth is 76.68 years and it will extend to 86.05 by 2065. Furthermore, the expectancy of becoming a centenarian and older will increase significantly from 1995 to 2065.