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3 Principles of Gerontology CONCEPTUAL CONTEXT OF GERONTOLOGY Gerontology is the scientific study of the processes and prow lems of aging from all aspects- biologic, clinical, psychologic, so- ciologic, legal, economic, and political. Geriatrics is the branch of medicine that deals with the diagnosis, management, and preven- tion of medical problems associated with senility and senescence. Although the terms "agings and "senescence" are sometimes used synonymously, they are often differentiated by biologists. For example, Leopold (1978), a plant biologist, said that aging consists of "the processes associated with the accrual of maturity in time, whereas senescence may be defined as the deteriorative processes which are natural causes of death." The implication is that aging begins at birth. Most gerontologists, however, are concerned primarily with age-related alterations in structure and function that occur after maturation. Maturation is usually defined as the achievement of sexual maturity and the adult stage of morphology and physiology. In addition, most gerontologists would not regard phenomena that were strictly coupled to chronologic time as fundamental, intrinsic aging processes. For example, changes (racemization) in amino acids in the ocular lens reveal how old an animal is, but do not 28

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PRINCIPLES OF GERONTOLOGY 29 differentiate between the rate of aging of a short-lived mammal, such as a mouse, and that of a long-lived mammal, such as a human. No one denies that developmental events before maturation are immensely important in setting the stage for the patterns of postmaturational aging. Thus, it is conceivable that perturbation of a particular aspect of development (e.g., the modification of some stem-cell pools by environmental agents) would have drastic effects on some aging processes decades later. For example, a depletion of the precursors of neurons of the substantia nigra could increase the probability of an early onset of Parkinson's disease. A change in the apparent threshoicts for a great many other pathophysiologic phenomena that accompany aging might have, in part, such an etiology. The aged population, however, is the primary focus of geron- tology, and of this report, because it might be particularly vuinera- ble to many environmental agents as a result of normal age-related alterations in cellular structure and function, a general reduction in the ability to maintain physiologic homeostasis, and alterations acquired as a result of environmental exposures. Environmental agents conceivably act at any stage of the life cycle; precisely how they affect aging processes is not known, because the sum ject has not been adequately studied and because aging processes themselves have not been adequately described. Variations in environmental exposure and genetic constitu- tion make it very difficult to establish general indexes of aging, and a satisfactory analysis ot aging processes win have to au- dress the complexity of relationships of gene expression with the environment. Particularly in humans, genetic heterogeneity and environmental heterogeneity are such that probably no two indi- viduals will ever be found to manifest aging in precisely the same fashioneven identical twins. The genetic concepts of genotype and phenotype require defi- nition. Johannsen (1909) originally defined the genotype, now com- monly referred to as the genome, as the sum of the genetic informa- tion carried in the chromosomes of an organism. We now know of nonchromosomal inheritance (e.g., via m~tochondrial DNA), and the term "genotype" is used to include all possible forms of ge- netic information that define a cell or organism and to refer to the particular form (allele) of a single gene or small group of genes. Until the advent of recombinant-DNA technology, the genotype

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30 AGING IN TODAY'S ENVIRON of an organism was deduced, in large part, from mating experi- ments. One can now directly isolate, clonally amplify, and analyze a particular segment of DNA. Johannsen (1909) defined the phenotype as the sum of the observable properties (structural, biochemical, and physiological) of an organism or cell. One can refer to the senescence phenotype (or the aging phenotype) as the collection of attributes that are generally believed to characterize senescence (or aging). Geron- tologists disagree about the extent to which age-related diseases should be considered integral features of that phenotype. One view is that each age-related degenerative or proliferative disorder has a pathogenesis that does not necessarily include an underlying component of intrinsic aging. Another view is that many common age-related human dis- eases are ultimate expressions of underlying, slowly progressive, and insidious aging processes for exa~nple, various forms of ar- teriosclerosis, including atherosclerosis and medial calcinosis; m~- crovascular disease; gIomerulosclerosis; osteoarthritis; osteoporo- sis; adult-onset diabetes mellitus; chronic obstructive pulmonary disease; presenile dementia; Parkinson's disease; cataracts; mac- ular degeneration; and a variety of atrophies, hyperplasias, and neoplasias. Phenotypic expression is the result of interaction between one's inherited genetic potential and the mosaic of one's environ- mental experience. Because of differences in inheritance and en- vironmental experience, patterns of phenotype, including disease, vary. Life span, however, is a constitutional feature of a species, and, although environmental agents can readily modulate the life expectancy of populations, in most instances the life span is not influenced. Indeed, because life span appears to be under poly- genic control that involves several aging processes, one would not expect a single environmental intervention to have global effects on it. Advances in experimental genetics might permit critical tests of the structural and regulatory roles of allelic variation and muta- tion at specific genetic loci. The mouse Mus muscut?~s domesticus, the worm Caenorhabditis elegans, and the fruit fly Drosophila melanogaster are the most-favored organisms for such research. For instance, the maximal life span of C. elegans is under direct genetic control (Johnson, 1987~. In rodents, considerable progress is being made with dietary restriction as a means of extending

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PRINCIPLES OF GERONTOLOGY 31 life span in experimental cohorts. These two approaches, the ge- netic and nutritional, might help to identify basic characteristics of aging and thus set the stage for a more rational exploration of environmental agents that promote aging. Any number of toxic environmental agents can shorten life. One task of the gerontologist is to determine which might do so by influencing intrinsic aging processes. An agent that hastens the onset or increases the progression of a particular process or processes could be referred to as a "gerontogen.~ Such environ- mental agents would be expected to cause the premature onset or accelerated progress of functional decline and age-related disease, thus impairing the quality of life in the later decades. However, much more research on the fundamental mechanisms of aging will be needed before we can definitively evaluate potential environ- mental agents that influence aging processes. Both longitudinal studies of environmental effects on aging in individual human subjects and large-scale cross-sectional studies of populations will be important in determining how aging and the environment are related. In longitudinal studies, observations are associated with different points in time. In cross-sectional studies, measurements of cause and effect are associated with one point in time. Cross-sectional studies are vulnerable to difficulties in inter- pretation, notably-temporal cohort and selection effects. Figure 3-1 illustrates the differences one might file] between comparable data collected in cross-sectional and longitudinal studies (in this case, data on cognitive function). The evolution of changes with age has intrigued evolutionary biologists for at least 40 years. Aging is ordinarily not adaptively advantageous to the individual or to the species, but it seems likely that the changes are inevitable consequences of the action of selective forces (Chariesworth, 1980~. They may be due to the accumulation of late-acting deleterious genes (Medawar, 1952) or to the action of genes that are beneficial early in life but harmful later (Williams, 1957~. Various theories on the evolution of aging have been put forth, but the redisposable some" theory of Kirk- wood (1985), proposing that Fitness is maximized at a level of repair which is less than would be required for indefinite somatic survival, seems to encompass most alternatives.

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32 60 55 llJ A: 0 50 CO 45 40 AGING IN TODAY'S ENVIRONMENT - //' Longitudinal'~ __~ . Cross-secUonal \ _ - - - - 25 30 35 40 45 50 55 60 65 70 AGE FIGURE 3-1 Estimates of cross-sectional versus longitudinal differences with age in performance on a test of cognitive function (the verbal meaning test) by human subjects of various ages. Reprinted with permission from Schaie and Willis (1986~. THEORI1:S OF AGING Theories of aging can be grouped generally into two broad categories: those that invoke deterministic, or "programed," alter- ations in gene expression or gene structure, and those that invoke a variety of stochastic, or "random," alterations in the structure and function of macromolecules, cells, and organ systems. There are limitations to this distinction, however, because stochastic alterations in individual cells can lead to predictable phenomena in the large population of cells. An example of the blurring of the deterministic and stochastic categorization is the use of terminal differentiation to explain the limited replicative life span of somatic cells (Bell et al., 1978; Martin et al., 1974) that is, populations of cells cease dividing because they have differen- tiated into more specialized ceils. For each individual cell, this differentiation is a random event. However, when viewed at the level of a population of many cells, the process appears determin- istic.

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PRINCIPLES OF GERONTOLOGY 33 Although primarily applied to the cell-culture model of cell aging (Hayflick and Moorhead, 1961), the idea of terminal differ- entiation might be applied to cohorts of stem cells in viva (Martin, 1979~. If the idea is valid, any environmental agent, such as retinoic acids (Strickland and Sawey, 1980), that depletes subsets of cells or alters states of differentiation might prove to be an important modulator of aging. Terminal differentiation would also have a large impact on cells undergoing rapid amplification, such as stem cells during early development. The relative contributions of both classes of mechanisms are likely to be coupled to the reproductive strategy of the organism. Programed aging is characteristic of species with single massive episodes of reproduction (e.g., periodical cicadas). Placental mam- mals have ample opportunity for a variety of stochastic processes to tale place during their long reproductive and postreproductive phases. The associated patterns of structural and functional de- cline can vary substantially both qualitatively and quantitatively and both among and within species. It is beyond the scope of this report to describe and evaluate the many theories of aging that have been developed over the last several decades. (See Warner et al., 1987, for a recent monograph on the subject.) For our purposes, however, it is useful to cite and summarize a few examples, in order to illustrate how a suitable theoretical framework could serve as a rationale for the explo- ration of the impact of particular classes of environmental agents on particular processes of aging, age-related diseases, or special susceptibilities of aged people. Dete~i~iistic Theories Developmental Switches in Gene Expression Senescence does not appear to be programed in the same way as development that is, regulated by a series of linked gene actions, whose primary result is to produce a limited life span. Only under special conditions in organisms that have a single episode of reproduction in their lifetime (semelparous organisms) can senescence be seen to be directly ~programed." Senescence does not seem to be driven by the sequential, systematic turning on and off of new genes; indeed, there is little change in the

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34 AGING IN TODAY'S ENVIRONMENT transcripts that are made throughout the organism's adult life (Rothstein, 1982~. This does not mean that modulation of transcriptional activity or gradual loss of tight control of gene transcription plays no role in senescence, and detailed investigation of environmental agents that alter gene expression in a way that suggests an impact on specific aspects of the aging phenotype might be warranted. No examples are yet known, although such agents as amanitin, which perturbs transcription, and cyclohexamide, which perturbs translation, have potential utility. Neuroendocrine-Cascade Theories Finch and Landfield (1985) reviewer! a group of theories that can be classified as neuroendocrine-cascade theories. An excellent example is the glucocorticoid-cascade hypothesis of aging proposed by Sapolsky et al. (1986b). The basis of the hypothesis is the finding in rats that basal plasma corticosterone concentrations increase with age, and that although the increase in plasma corticosterone in response to stress does not change with age, the return to basal concentrations after the removal of stress is markedly delayed with age. The reason for the age-related changes is a gradual impairment in negative feed- back control of plasma glucocorticoid concentration themselves (Sapolsky et al., 1986a). The loss in sensitivity is related initially to a loss of corticosterone receptors in some hippocampal neu- rons and ultimately to a loss of hippocampal neurons themselves (Sapolsky et al., 1983a). Moreover, it is the cumulative exposure to glucocorticoids that is responsible for the decrease in gluco- corticoid receptors and for the loss of the hippocampal neurons themselves (Sapolsky et al., 1986b). The net result is the emergence of hyperadrenocorticism that has been largely caused by the stresses encountered during the rat's lifetime. Hyperadrenocorticism might be responsible for a host of age-associated problems, such as immunosuppression, muscle atrophy, osteoporosis, and glucose intolerance. Evidence exists that hyperadrenocorticism, at least in part, underlies age-related disease in rodents (Riley, 1981b; Sapolsky and Donnelly, 1985~. Although the theory deserves to be further tested experimen- tally, a major problem is that the changes noted in adrenocortical function in rats with advancing age have not been found in most

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PRINCIPLES OF GERONTOLOGY 35 other species. There is no evidence of such an occurrence in nor- mal human aging, although no systematic investigations have been carried out. Such theories have special implications for toxicolo- g~sts because they raise the possibility that global effects on aging would follow exposure to particular environmental agents (e.g., stress, glucocorticoids and their analogues, agonists and antago- nists of particular receptors, and specific neurotoxins). StoEhastic Theories Intrinsic Mutagenesis Theory Burnet (1974) summarized arguments that cumulative dam- age to the genetic material causes aging in mammals. Accord- ing to this proposition, short-lived mammals are more prone to develop somatic-cell mutations than long-lived mammals. That could occur, for example, if the DNA polymerases of short-lived species were comparatively error-prone or if their various DNA repair mechanisms were comparatively inefficient. Support for the theory comes from observations of a positive correlation between species longevity and the efficiency of the cellular repair of DNA damage induced by ultraviolet light (Francis et al., 1981; Hart and SetIow, 1974~. There is controversy, however, about the extent to which such gene mutations accumulate in the tissues of aging mammals (Horn et al., 1984; Inarn~zu et al., 1986; Manor et al., 1984~. Vari- ous types of chromosomal mutations do accumulate with aging, however (Brooks et al., 1973; Crowley and Curtis, 1963; Cur- tis and Miller, 1971; Martin et al., 1985~. Chromosomal muta- tions could arise from different mechanisms, including chromoso- mal breaks initiated by free radicab (Nichols and Murphy, 1976), rearrangement after gene amplification (Schimke et al., 1986), and insertional mutagenesis mediated by transposons (jumping genes) (Collins and Rubin, 1984; Shapiro, 1983~. Genomic instability could also result from mechanisms not associated with classical forms of somatic-cell mutation. By def- inition, the latter involve alterations in the primary structure of the genetic material (including various rearrangements), as well as changes in the amount of the genetic material. Stochastic changes in gene expression, for example, might be attributable to per- turbations of chromatin configuration or of the patterns of DNA

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36 AGING IN TODAY'S ENVIRONMENT methylation. This theory has obvious implications for categories of environmental agents (physical, chemical, and viral mutagens) that could accelerate the aging processes. Protein-Synthesis Error Catastrophe Orge! (1963, 1970) argued that mistakes in the synthesis of proteins that participate in the machinery of protein synthesis, at either the transcriptional or translational level, have the poten- tial, through a positive-feedback loop, to cause a general expo- nential loss in the fidelity of protein synthesis. That loss could lead to an error catastrophe in which a large proportion of pros teins In aged cells would be abnormal in structure and function. Because the abnormal proteins would be expected to include ~rari- ous DNA-dependent DNA polymerases and DNA repair enzymes, the protein-synthesis error-catastrophe theory ~ among the theo- ries of aging that predict the accumulation of somatic mutations. Moreover, the theory predicts a predorn~nance of point mutations (missense and nonsense mutations) and an accumulation that ex- hibits exponential kinetics near the end of the natural life span. Among the many host genetic loci that might modulate the rates of development of errors in protein synthesis, loci that control the quality and quantity of scavenger proteases would be partic- ularly important, in that an error catastrophe could be averted by preventing the inheritance of the abnormal protein-synthetic machinery in sequential generations. Many experiments have at- tempted to support or refute this mechanism of aging, but none can be considered definitive, especially because few studies have addressed the problem in postreplicative celb in viva (e.g., neu- rons). The bulk of the evidence, however, argues strongly against the general validity of the theory (Filion and Laughrea, 1985; Gallant, 1981; Rothstein, 1982~. From the toxicologist's viewpoint, the theory would provide a rationale for examining the effects of such agents as amino acid analogues, a number of which exist in large concentrations in plants. For example, the concentration of canavanine (an argi- nine analogue) constitutes about 1.5~o of the dry weight of alfalfa sprouts and alfalfa seeds (a widely used natural, or organic, food- stuff) (Bell, 1960) and is toxic to primates (Malinow et al., 1982~. Any chemical agent that affected the fidelity of protein syn- thesis would be worth examining in more detail, for example,

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PRINCIPLES OF GERONTOLOGY 37 antibiotics such as streptomycin that perturb ribosomal function and toxins that could affect protease function. Free Radicals Barman first proposed the free-radical theory of aging in 1954 (reviewed by Harman, 1981~. Free radicals are continuously being generated in living systems through the action of ionizing radiation and a wide variety of nonenzymatic and enzymatic reactions. In mammals, the major source of free radicals is the consumption of oxygen by mitochondria for oxidative metabolism; the superoxide radical is an example of the kind of free radical generated (Nohl and Hegner, 1978~. The damage caused by these radicals includes oxidative alter- ations in long-lived molecules, such as DNA or collagen (Herman, 1981; LaBella, 1965~; oxidative degradation of mucopolysaccha- rides (Matsumura et al., 19663; generation of lipofuscin (Norkin, 1966~; and alterations in biologic membrane characteristics (Heg- ner, 1980~. However, cells have defenses to protect them from damage by free radicals, such as antioxidants (e.g., tocopherols and carotenes) (Klebanoff, 1980) and peroxidases and superoxide dismutases (Eridovich, 1977), as well as repair mechanisms, such as those for DNA (Nichols and Murphy, 1977~. Although the free-radical theory is provocative, hard evidence to support it is lacking. One approach to testing the theory has been to study the effects of dietary antioxidants on the longevity of rodents. In some of the studies, life expectancy was increased, but life span was not (Herman, 1981~. Moreover, many of the studies were flawed in that they did not measure food intake or food intake was reduced (Masoro, 1985~. Another line of evidence used to support the free-radical the- ory is the claim that life-prolonging food restriction lowers the metabolic rate (Herman, 1981~. Recent work has shown, however, that food restriction can increase life span without decreasing the metabolic rate (McCarter et al., 1985~. It is conceivable, how- ever, that dietary restriction could decrease the flux of active oxygen species independently of metabolic rate. In any event, the free-radical theory has important implications for investigating environmental effects on aging, notably, the potential of dietary and chemical agents to alter the flux of active oxygen species.

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38 AGING IN TODAY'S ENVIRONMENT Posttranslational Glycation of Proteins and DNA Cerami (1985) proposed that glucose is a mediator of aging. He suggested that a loss of biologic function due to the nonen- zymatic reaction of glucose with proteins and nucleic acids (the glycation of proteins and nucleic acids), yielding advanced glyco- sylation end products, is a basic mechanism of aging. The glycation of proteins and nucleic acids begins with reac- tion of an amino group with the aldehyde group of glucose to form a Schiff base. Once formed, the unstable Schiff base of glucose can undergo an Amadori rearrangement to form a more stable product, the Amadori product (Mortensen and Christophersen, 19833. The Amadori product can undergo a series of dehydra- tion steps and rearrangement to yield brown, fluorescent pigments (Monnier and Cerami, 1981), called advanced glycosylation end products by Cerami (1985~. The end products cross-link proteins and nucleic acids and thereby cause loss of biologic function (Ce- rami, 1985~. The chemical nature of the advanced glycosylation end products has not been fully elucidated, but one appears to be 2-~2-furoyI)-4~5~-~2-furanyI)-lH-imidazole (Pongor et al., 1984~. The rate of formation of advanced glycosylation end products is increased as the concentration of glucose and time of exposure to glucose increase (Monnier et al., 1984~. Although this theory of aging is intriguing, little hard evidence supports it. Cerami noted that the complications of diabetic pa- tients are often put forth as a paradigm of aging. Clearly, those complications could also be related to other alterations in glucose metabolism or to insulin action, rather than to glycation reactions themselves. Nevertheless, Cerami's glycation theory warrants fur- ther testing. One avenue of approach is the use of such compounds as arn~noguanidine, which prevent the protein cros~linking action of glucose (BrownIee et al., 19863. Another is the judicious use of the food-restriction paradigm (Masoro, 1985~. Thymic Involution as a Pacemaker of Immunosenescence The morphologic and functional involution of the thymus gland is a particularly early and striking precursor of immunologic aging in humans and, indeed, in all mammalian species thus far investigated (mostly rodents). In humans, the loss of cellular mass of the thymus begins at sexual maturity and is complete by the age

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PRINCIPLES OF GERONTOLOGY 39 of around 50, when the thymus retains only ~10%o of its maximal mass. Thus, the striking involution of the thymus gland during the first half of life can be largely related to the altered form and function of the immune system observed during the second half of life. These alterations have been well documented in humans and experimental animals. Particularly notable are alterations in T lymphocytes. Two functions of the thymus gland have been recognized: the production of a family of polypeptide hormones and the matura- tion of T-lymphocyte precursors from the bone marrow. Thymic hormones are important in the differentiation of prethymic and postthymic lymphocytes. In humans, thymic hormone activity in serum is maintained from birth until the age of 20~30 and then declines (WeksIer, 1986~. Thymic hormone can no longer be de- tected in healthy normal humans over 60 years old. It has been suggested that the low activity of serum thy~ruc hormone is due to the presence of inhibitors (Weksler, 1986~. Nature lymphocytes from the bone marrow enter the cortex of the thymus gland. With age, fewer immature lymphocytes enter the thymus, and the gland loses its capacity to facilitate the differentiation of these cells (Weksler, 1986~. Perhaps as a consequence of these events, immature T lymphocytes are found in increased numbers in the blood of elderly humans (Weksler, 1986~. Thus, with age, serum thymic hormone activity declines, and the percentages of immature lymphocytes in the thymus gland and in the peripheral blood increase. Environmental agents with the potential to modulate those events early in life, either centrally (e.g., specific neurotoxins) or peripherally (e.g., exposure of the thymus to ionizing radiation), might be expected to have far-reaching effects on the patterns of immunosenescence in later years. BlOMAR1lERS OF AGE OR AGING A biomarker of aging is a biologic event or measurement of a biologic sample that is considered to be an estimate or pre- diction of one or more of the aging processes. The concept has drawn considerable attention in recent years and is the subject of two extensive publications (Ludwig and Masoro, 1983; Refl. and Schneider, 1982~. Most recently, a 1986 workshop on the subject sponsored by the Task Force on Environmental Cancer and Heart

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40 AGING IN TODAY'S ENVIRONMENT and Lung Disease (Baker and Rogul, 1987) discussed biomarkers of aging. The fascination with the concept of biomarkers of aging stems from their immense potential usefulness (e.g., in the context of this report, to assess the effects of environmental agents on aging pro- cesses) and the superficial evidence that they are easy to develop. As an illustration of the latter idea, consider physiologic systems as potential markers. Most physiologic systems change with age, and the extent and rate of such changes differ among individuals. Why, then, is there controversy about biomarkers of aging? The major reason is that the nature of aging itself is unknown. Even the number of primary aging processes is debatable. A few investigators believe that there is a single primary aging process and that all other aging events are secondary or even further removed from it. Most believe that there are several primary aging processes, none of which has been clearly identified. And a few believe that aging is not the result of primary processes at all, but rather is due to subtle changes in interactions of the components of the homeostatic regulatory processes. With so little knowledge about the nature of aging, there is no central standard by which to judge the validity of any of the many biomarkers of aging that have been proposed. Another aspect of the controversy is related to the different uses contemplated for bioma~kers of aging. The uses can be catego- rized as estimation of an individual's chronologic age, estimation of an individual's biologic or physiologic age, prediction of the occurrence of an age-associated disease, prediction of impending death, and prediction of the life span of a species. Each of these uses should be considered in regard to its relevance to aging. A biomarker used to estimate chronologic age is of value only when age is not known. The major, if not the sole, use of such a biomarker is to estunate the ages of animals in a colony of animals of unknown age. A good biomarker for this purpose seems to be amino-acid racem~zation in structural proteins sequestered from metabolic turnover (Bade and Brown, 1980~. The problems of biomarkers proposed to estimate the biologic or physiologic age of an individual are related to the facts that different systems in the same individual can age independently (e.g., the occurrence of grayness of the hair bears no relationship to age-associated deafness) and an individual's rate of aging might

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PRINCIPLES OF GERONTOLOGY 41 not be constant (Costa and McCrae, 1980). Of course, most inves- tigators interested in determining physiologic age have recognized the pitfalls of assessing it on the basis of a single physiologic sys- tem and have turned to examining several systems simultaneously, using either multiple regression analysis (Furukawa et al., 1975) or profile analysis (Borkan, 1978~. Costa and McCrae (1985) have pointed out that there is no evidence that such analyses provide better information about functional age than does chronologic age itself. Biomarkers used to predict the occurrence of an age-associated disease are commonly considered to be risk factors for the disease in question. Increased arterial blood pressure is a risk factor for stroke (Kennel, 1985), and the blood concentration ratio of total cholesterol or arterial low-density lipoprotein to high-density lipoprotein is a risk factor for coronary disease (Gotto, 1986~. These risk factors are, at least in part, linked to stroke and coronary arterial disease, respectively, by promoting the athero- sclerotic process (McGill, 1977~. However, the relation of athero- sclerosis to aging is not clear. That is, do aging and atherosclerosis merely share the same time frame or are they causally related? The uncertainty is similar in the case of other age-associated diseases. Thus, it is questionable whether predictors of the occurrence of age-associated disease are valid biomarkers of aging. Predictors of impending death have been viewed as biomarkers of aging. For example, impairment of pulmonary function predicts a mortality rate over the next ~20 years that is higher than in those lacking the impairment (Beaty et al., 1982~. But cardiovascular disease and cancer, not pulmonary disease, are the major causes of death. Does that mean that impairment of pulmonary function is a biomarker of aging, or is it merely a predictor of two diseases, cancer and cardiovascular disease? It is not yet possible to answer this question, but changes in mortality in the United States during the last 150 years favor the latter. For instance, life expectancy and the median length of life in the United States have markedly increased since 1840 (U.S. Bureau of the Census, 1984~. Most of the increase in longevity is related to the control of infectious diseases by technology and medicine, not to the aging processes. The change in mortality characteristics is an index of the extent to which protection from environmental hazards has enabled the population to age. It is in accord with this view that, although life expectancy has markedly

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42 AGING IN TODAY'S ENVIRONMENT increased in the United States during the last 150 years, the life span of Americans has not changed. This is strong evidence that changes in mortality characteristics might have little to do with aging processes. Predictors of the life span of a species potentially serve as valid biomarkers of aging. Changes in life span are likely to be due to changes in the rate of aging; it is possible that the life span of a species can be increased only by retarding the aging processes. Few manipulations are known to extend the life span (Sacher, 1977~. Low environmental temperature, food restriction, and genetic manipulations have that effect in poikilotherms, and food restriction has that effect in rodents, which are the only mammals in which lifespan extension by manipulation has been rigorously demonstrated. Food restriction in rodents retards many age-related physio- logic changes and age-associated diseases (Masoro, 1985), and all these are potential biomarkers of aging. The challenge is to deter- mine whether a particular physiologic or disease process influenced by food restriction is indeed a biomarker of aging or is related to food restriction in some other way. Exploring this question will require the use of more than one manipulation that affects the life span of a particular species. That is, if a physiologic or disease process can be retarded similarly by several manipulations that extend the life span of a species, this would strongly indicate that the physiologic or disease process in question is a biomarker of aging. Thus, research aimed at identifying such manipulations should have a high priority if valid biomarkers of aging are to be developed. Such biomarkers are essential to the testing of the effects of environmental agents on the aging processes. ALTERED SUSCEPTIBILITY OF TlIE AGED The elderly are in many ways showing more individual varia- tion in biologic responses than the young. The variation probably has more influence on their intrinsic vulnerability to the effects of toxic substances than physiologic aging and precludes broad generalizations about their susceptibility. Nevertheless, both the increased incidence of disease in the elderly population and the normal physiologic changes that occur with aging in the absence of disease can make this population more vulnerable to environ- mental insults.

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PRINCIPLES OF GERONTOLOGY 43 Although only a few studies of altered response to environmen- tal agents in aging humans have been conducted, they show that older people tend to respond to drugs differently from younger per- sons, both qualitatively and quantitatively, and to have a higher incidence of adverse or idiosyncratic drug reactions (Conrad and Bressler, 1982~. Thus, it is reasonable to assume that the el- derly would tend to respond differently to other environmental factors. For example, "experiments of nature" (Chapter 7) such as the air-pollution incidents in London, the Meuse River Val- ley in Belgium, and Donora, Pennsylvania demonstrated that the most vulnerable people were the elderly, probably because of the normal age-associated decline in cardiopulmonary function, and others with pre-existing disease of the cardiopulmonary system. Moreover, inasmuch as response to pathogens depends on immune response, the susceptibility of older persons to diseases caused by pathogens is increased through age-related reductions in immune function. One of the most important factors affecting the elderly popu- lation is the fact that multiple diseases are the rule, rather than the exception. Superimposed on past injuries, illnesses, and operations can be a variety of chronic disorders, such as cataracts, pernicious anemia, osteoarthritis, osteoporosis, atherosclerosis, and diabetes. Malignancy, stroke, Parkinson's disease, dementia, and fracture of the femur all have increased incidences in the elderly. In ad- dition, chronic illness often leads to other complications in the elderly, including thromboembolism, dehydration, urinary tract infection, pressure sores, hypostatic pneumonia, and immobility contractures. The elderly often manifest an altered response, both physical and psychologic, to disease. In geriatric patients, infection is often associated with mild tachycardia and mental confusion or other nonspecific symptoms. Fever, leukocytosis, lymphadenopathy, and lymphangitis can be minimal or absent. The elderly seem to be less sensitive to pain and more stoical. Angina is often atypical, and painless myocardial infarction Is more common in the elderly than in younger patients. Superimposed on the overt diseases so prevalent in the elderly are important and sometimes subtle physiologic changes that occur with normal aging. For example, age-related changes in the physi- ologic processes that control absorption, distribution, metabolism,

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44 AGING IN TODAY'S ENVIRONMENT and elimination of drugs have been shown to affect drug respon- siveness in the elderly in some cases and might reasonably be expected to influence response to other toxic agents. Physiologic changes that are associated with age often alter one's susceptibility to adverse health effects, and a person's ability to withstand various environmental exposures is often compro- mised as a result. Many of the changes are well documented, and not all are associated only with the elderly. For example, changes in the immune system that affect a person's ability to fend off dis- ease occur throughout the life cycle. Involution of the thymus is probably the most striking anatomic change in the immune system that accompanies aging; it begins at sexual maturity and is com- plete by the age of 45-50. The striking increase in the mortality associated with influenza in the elderly is one consequence of this decline in host defense. Aging is also associated with important changes in the ner- vous system that can allow previously masked neurotoxic disorders to become manifest. It is generally believed that altered neural function occurs only after structural and functional redundancy has been expended. For example, a parkinsonian state appears only after a considerable loss of neurons in the substantia nigra; this might occur both as a consequence of aging processes and after exposure to particular chemical substances (i.e., N-methyI- ~phenyI-1,2,3,~tetrahydropyridine, MPTP). More-specific exam- ples of age-associated diseases and physiologic changes and their association with the environment are discussed in Chapter 6. The several changes in human cutaneous anatomy and func- tion now recognized to occur with age can increase the vuinera- bility of the elderly to both chemical and physical environmen- tal insults. For example, altered barrier function of the stratum corneum (horny layer) of the skin in elderly people can increase percutaneous absorption of drugs and other chemicals (Roskos et al., 1986~. The important role of the epidermis in detoxifying per- cutaneously absorbed chemicals has only recently been recognized (Des et al., 1986) and has not been examined with regard to age. Decreases in dermal vascular area (Gilchrest et al., 1982a; Montagna and Carlisle, 1979) and vasoreactivity (Gilchrest et al., 1982a; Grove et al., 1981) in old skin might slow dermal clearance of topically absorbed substances (Kligman, 1979) and diminish the bocly's thermoregulatory capacity. Those effects would contribute

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PRINCIPLES OF GERONTOLOGY 45 to hypothermia and heat stroke during exposure to extreme tem- peratures (Besdine, 1980~. Age-associated loss of epidermal Langerhans cells (Gilchrest et al., 1982b) is presumed to impair recognition of foreign antigens, possibly including malignantly transformed cells, in the skin. The well-documented loss of melanocytes (pigment celIs) 1~20~o of the residual cell population per decade (Gilchrest, 1979) is pow tulated to decrease the body's protection against injurious ultra- violet radiation. In combination with age-associated reductions in immunocompetence (Schneider and Reed, 1985), this loss might predispose the elderly to photocarcinogenesm. A decrease in the vitamin D precursor in the epidermis and a decrease in photocon- vertibility (MacLaughlin and Holick, 1985), in combination with a dietary lack of dairy products and a lack of regular sun exposure, might easily render the elderly deficient in vitamin D and lead to clinically important osteomalacia (Nordin et al., 1980~. Finally, the well-documented age-"sociated decrease in sen- sory perception, including pain perception (Procacci et al., 1974), unquestionably renders the elclerly more vulnerable to some types of environmental injury.