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Executive Summary This report examines the relationships between aging and ex- posure to environmental agents (including natural and man-made agents, as well as life-style factors). Several relationships must be considered the impact of intermittent or lifelong exposure to environmental agents an the rate of aging, the impact of lifelong exposure on health status when one reaches more advanced age, and the special response of the aged compared with that of the young when exposed to environmental agents. There are clear indications that these impacts exist. Expo- sure to sunlight ages the skin. Animal studies indicate that diet influences longevity. It is known that older people may respond differently to environmental and life-style factors than I younger persons. Ambient air that is well tolerated by an exercising young adult may compromise the health of an 85-year-old with impaired respiratory function. Unfortunately, too little is known to permit definitive con- clusions to be reached about the relationships at this tone. Yet, given the importance of the problem, this committee felt that it is essential to gather in one document the pertinent clata that do exist, to examine them for clues and directions for future research, to seek some theoretical and practical frameworks for addressing the issue, and to suggest a course of research.

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2 AGING IN TODAY'S ENVIRONMENT From the age of 30, many of our physiologic systems begin to decIme, and by old age, our overall homeostatic reserveour ability to respond adequately to environmental stress or toxic insult has also declined. The extent to which the environment influences the patterns of disease and functional impairment in aged populations may not now be known. But the amount of the decline caused by lifetime exposure to harmful environmental agents and the amount caused by basic, underlying aging processes are questions of great theoretical and practical significance, given the demographic patterns that show an increasing percentage of older persons in the population. Although the increased incidence of chronic diseases is often associated with aging, such diseases need not be characteristic of the aging processes. The wide variation in the incidences of chronic diseases in the aged in different countries strongly indicates that much of the prevalence of these diseases might be preventable. Thus, old age can occur in the absence of disease. One appealing and testable hypothesis is that reduction of disease in old age can be approached, in part, through modification of the environment. Research in this field will likely lead to an improved understanding of the relationships that exist among aging processes, the environ- ment, and disease and assist in providing the key to preventing environmentally induced age-associated diseases. The study of the relationships between aging and the environ- ment requires the integration of the two disciplines of gerontology and toxicology. Gerontology is the scientific study of aging, un- der which several theories of aging have been developed. Although none of these has been universally accepted as a satisfactory expla- nation of all the phenomena of aging, taken as a whole the theories begin to account for some of the underlying processes. In general, current theories of aging invoke either alterations in genetic factors or alterations in body function as the underlying causes of age- associated decline. The dilemma created by the lack of a unified theory of aging is that the intrinsic aging processes have not been clearly separated from natural disease or toxic response and thus cannot be defined. A primary objective of the science of toxicology is to determine the potential health effects of exposure to chemical and physical agents, often through the use of animals in experimental studies. More specifically with regard to aging, toxicology can be used to study the effects of environmental agents on the aging processes

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EXECUTIVE SUMMARY 3 and the potential for increased toxicity of such agents in aged persons. AGING AND NUTRITION Until fairly recently, the issue of chern~cal toxicity and the environment focused primarily on contamination of the natural environment with industrial and other pollutants. As a whole, however, it appears that one of the most important chemical ex- posures for humans, both in quantity and in diversity, results from diet. Thus, nutrition is one of the most important aspects of the environment that should be taken into account in studies of chemical toxicity and aging. Diet moclulates many adverse effects normally associated with aging, and some dietary regimens actually promote such effects. For instance, a few studies with rodents on a restricted food intake but with ample intake of essential nutrients and other substances for which there is some evidence of antiaging action showed in- creased longevity. Despite claims that such a regimen will extend human life span, there is no evidence that such diets influence the aging processes of humans or that their long-term use will not, in fact, adversely affect the health of humans. A substantial data base exists on nutritional needs of the aged, as well as on the role of nutrition in cancer and other dis- eases. Strategies for the determination of the mechanism by which nutrition modifies aging and chronic diseases are needed. With regard to nutritional requirements, there is an obvious lack of data on oicler age groups. The commonly used reference in the United States is the Recommended Dietary Allowances (RDAs) published periodically by the Comrn~ttee on Dietary Allowances of the National Research Council's Food and Nutrition Board. The nutrient needs of adults, however, are based mainly on studies of young adults, and many of the allowances for older adults are estimated largely by extrapolation. Although the RDAs consider seven age ranges from birth to 22 years, there are only two age ranges for people over 22- specifically, 23-50 years and 50 and older. It is appropriate to consider that the dietary requirements for people 5(:~60 years old may be different from dietary require- ments for those over 80. In addition, the RDAs make no provision for chronic ailments that can influence nutritional needs, especially for the aged.

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4 :: AGING IN TODAY'S ~YIRO~NT AGING AND SUSCEPTIBILITY TO DISEASE Age appeam to be the most important determinant of inci- dence for most human diseases. Characteristic patterns of risk by age have been described for most dmeases, and many of the patterns have provided the basis for important etiologic theories. For example, the peak in incidence of Hodgkin's disease in the third decade of life suggested an infectious origin for one kind of Hodgkin's disease, and the plateau in incidence of breast cancer around the ages of 45-55 suggested that the cessation of ovarian function had an effect on the development of the disease. Data on the premenopausal and postmenopausal incidence of breast can- cer in different countries suggested that environmental factors play an important role in the etiology of postrnenopaus~ breast can- cer, whereas genetic, endocrinologic, and other endogenous factors strongly influence the risk of premenopausal disease. One of the most important bodily defenses is the immune sys- tem. Environmental influences on the immune system include psy- chologic stress (including bereavement), nutrition, environmental temperature, housing, light, noise, and chern~cals. Some environ- mental influences on immune function affect life span (in rodents) and therefore presumably affect susceptibility to disease or to the effects of the aging processes themselves. The thymus plays a central role in cell-mediated immune responses and the regulation of the immune response. Because thy mic involution occurs by midlife (45-50 years in humans)5 im- mune senescence is characterized by a loss of thymu~dependent functions. Inasmuch as the response to many pathogensinclud- ing viruses and fungi, as well as neoplastic cells and some environ- mental agents -depends on celI-mediated immunity, the suscepti- bility of the aged to diseases induced by these agents ~ increased. The striking increase in the morbidity and mortality associated with influenza in elderly people is a common clinical consequence d. - OI Immune senescence. In addition to the loss of cell-mediated immunity with age' the loss of thymic function leads to the dysregulation of irrnmlne ret actions. The striking increases in the frequency of autoantibodies (antibodies that have an affinity for tissues of the subject in whom the antibodies were formed) and in the production of monoclonal immunoglobulins with age reflect this fact. These autoimmune ret actions might be exacerbated when elderly people take such drugs

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EXECUTIVE SUMMARY 5 as procamamide, a-methyIdopa, or estrogen, which themselves stimulate the production of autoantibodies. When autoantibod- ies react with autoantigens, they form unmune complexes that can contribute to vascular injury and thereby to the increasing severity of atherosclerosis in the elderly. AGING, DISEASE, PHARMAC1:UTICAL USE, AND CHEMICAL RESPONSE Along with the age-associated increase in the incidence of chronic disease comes an increase in the use of pharmaceuticals. In the United States, people 65 and over consume approximately 25~o of the prescription drugs dispensed by pharmacists, although they make up only 12% of the population. Even the elderly who live independently commonly use at least one prescription drug regularly, and patients in hospitals and chronic-care institutions typically receive numerous medications. In addition, the elderly have an apparent propensity to suffer adverse reactions to drugs, and many patients, both old and young, fail to take medications according to their physicians' and pharmacists' instructions. Studies of age differences in pharmacodynarnics (biochemical and physiologic ejects of drugs and their mechanisms of action) must take into account possible age differences in pharmacokinet- ics (absorption, distribution, metabolism, and elimination). For example, studies generally show that the elderly are more sensitive to the depressant effects of neuroactive drugs, such as diazepam, and the analgesic effects of narcotics, such as morphine; in con- trast, the In viva sensitivity of the heart to moprotereno! and its antagonist propranolo] appears to decline with age. The qualitative and quantitative differences in the ways older people tend to respond to drugs result from at least two circum- stances: multiple chronic diseases are the rule, rather than the exception, and diseases are accompanied by important and some- times subtle physiologic changes that occur with normal aging. That is, In addition to the normal age-associated changes in the immune system that affect one's ability to ward off disease, al- terations in pharmacokinetics and pharmacodynam~cs alter the response to drug exposures. Thus, it is reasonable to assume that the elderly would tend to respond differently to environmental factors. The percutaneous absorption of drugs and other chemicals

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6 AGING IN TODAY'S ENVIRONMENT also increases with age, and age-associated changes in the skin render the elderly more vulnerable to some types of environmen- tal exposure. For ex~rnple, the ability to tolerate extremes in temperature ~ reduced in the aged, who have decreased vascular area and vasoreactivity in the skin. This also contributes to the onset of heat stroke or hypothermia in the presence of extreme temperatures. Geriatric patients often exhibit a reduced rate of hepatic metabolism of some drugs. However, large differences in the mag- nitude of this effect have been demonstrated. Moreover, age effects are marked for some drugs and negligible for others. Even in the case of drugs whose hepatic metabolism is markedly impaired with age, interindividual variations caused by other factors outweigh the age effects. Nevertheless, the possibility of greatly reduced hepatic capacity exists in many elderly patients. By slightly re- ducing the dosage of potent drugs with low therapeutic indexes or by watching such patients especially carefully, physicians can en- sure the therapeutic efficacy of prescribed medications and detect undesirable drug-related side effects early. AGING AND ENVIRONMENTAL FACTORS Among the best documented examples of age-associated patho- logic conditions that are related to environmental factors is photo- aging the changes in skin appearance and function that are due to habitual exposure to the sun, rather than to the passage of time alone. Photoaging, also called "premature aging" and "dermato- heliosis," is virtually synonymous in the public mind with "true" chronologic aging and has only recently been differentiated by dermatologists. Clinically, photoaging is characterized by coarse ness, wrinkling, mottling, laxity, reduced elasticity, telangiectasia (dilation of blood vessels), atrophy, fibrotic depigmentation (pseu- doscars), and ultimately malignant neoplasia on the face, neck, hands, and other habitually exposed body areas. Photoaging and chronologic aging in the skin have striking similarities, but the processes can be distinguished with an electron microscope. The ability to distinguish between them offers the hope that the effect of environmental factors other than exposure to the sun might also be differentiated from intrinsic aging. Even in the absence of "controls tissue not environmentally

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E'fECUTIVE SUMAf24RY 7 exposed (a major advantage In skin), it wright be possible to oW tain valid information on normal morphologic and physiologic ag- ing changes. However, it will not be easily accomplished. In m~le-aged or elderly people, even casual comparison of habitu- ally exposed skin with protected areas (e.g., face or hand versus buttock or breast) immediately suggests different aging rates, with lines of demarcation corresponding to clothing styles, rather than to anatomic or physiologic compartments. Nevertheless, the ma- jor role of the environment in skin aging has only recently been accepted, and this implies that overwhelming evidence will be ret quired to convince both scientists and the public of other adverse environmental impacts on the aging processes. The nervous system presents another example of how toxic agents can sometimes mimic the clinical and pathologic features of diseases more common in the aged. For example, the parkin- sonian syndrome is observed in workers chronically exposed to manganese ore or carbon disulfide and in persons intoxicated for relatively short periods with methy~pheny~tetrahydropyridine (MPTP). Some types of motor neuron disorders have been asso- ciated with exposure to lead, polyneuropathy follows exposure to a number of occupational chemicals, and psychoses can be exacer- bated by acute exposure to dusopropyIfluorophosphate. Because the nervous system appears to have a number of com- ponents that are vulnerable both to the aging processes and to toxic chemicals, older people with compromised neural structure and function, as well as reduced capacity for liver metabolism and renal clearance, are probably more susceptible to some neurotoxic substances than are younger adults. In addition, it is generally believed that the clinical expression of disordered neural function resulting from aging or chemical toxins becomes evident only af- ter the considerable structural and functional redundancy of the nervous system has been overcome. MODEL SYSTEMS FOR RESEARCH The development of mode} systems in the field of aging is only beginning. Model systems will assist in the two-step process of testing environmental chemicals for their potential to affect aging processes or age-associated diseases and developing a data base for predicting human responses and assisting in regulatory decision-making.

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8 AGING IN TODAY'S ENVIRONMENT Because we know so little about the fundamental nature of the aging processes, a prudent course in assessing the effects of envi- ronmental chemicals might be to use multiple mode! systems. The animals selected for study should meet several criteria, including short life span, previous use in the study of aging and toxicology, ability to develop under defined environmental conditions, knowI- edge of genetic characteristics and known pathologic changes that occur with age, ready availability, economic feasibility, widespread use in other biologic disciplines, and relevance to aspects of human aging. A research strategy for testing should include in vitro, inver- tebrate, and mammalian models. In vitro models are economical and efficient, permit repeated assays and the sharing of common stock among different laboratories, and can be used to investigate cell-cell interactions, such as metabolic cooperation and transfor- mation; however, they cannot completely eliminate the need for experimentation with intact animals. Invertebrates have short life spans, are relatively easy to use, and are relatively inexpensive; many have been widely used as models for the study of aging and meet the proposed criteria for models. However, aging of cold-blooded organisms might well be different from that of warm- blooded organisms. Mammals, because of their long life spans and other characteristics, generally do not fully meet the proposed criteria. Mice and rats are exceptions, however, and indeed have been widely used in aging research. Epidemiologic observations will also provide a useful resource for assessing the impact of toxic exposures on the risk of disease and death in humans. Short-term and long-term chronic releases of toxic agents into the environment have markedly increased disease and death among those exposed, especially affecting the aged. CONCLUSIONS Evidence supports the concept of intrinsic aging or aging as a natural process, and many theories have provided insight into its basic mechanisms. Many components of the environment, how- ever, cause changes that simulate and are often confused with features of intrinsic aging. For example, habitual sun exposure and cigarette smoking accelerate aging of the skin, exposure to ultraviolet radiation also promotes cataract formation, and expo- sure to naturally occurring or industrial and other toxicants can

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EXECUTIVE SUMMARY 9 contribute to age-related neurologic disease. However, no agent has ever been shown to cause the early appearance of all the aging processes. Modifying the environment of the elderly holds considerable potential for improving their quality of life and their longevity. In addition, it seems reasonable to assume that aging consists of many intrinsic processes characterized by progressive declines in function that can take place in the absence of clinical disease. The extent to which major age-related diseases (e.g., cancer, arteriosclero- sis, diabetes, osteoarthritis, osteoporosis, cataracts, hearing loss, amyotrophic lateral sclerosis, Parkinson's disease, and senile de- mentia of the Alzheimer's type) are coupled to underlying aging processes or environmental influences constitutes an important re- search question, in light of the surge in the size of this segment of the population. In view of the paucity of basic information on aging processes, it is premature to embark on a systematic screening of environ- mental agents with an eye to identifying agents that influence these processes. Such an approach would be ill-advised and detrimental to progress in the field of "gerontotoxicology," the study of inter- . . actions between aging pro-cesse-s' and the effects of'e~'nvir''onmental _ . . ... .. .. . . . . ... . . . . substances with toxic potential. Rather, there is a need to develop . . .~ . . .. . . ... . . . an' better understanding of the basic mechanisms of aging, how they can be affected by the environment, and how aging itself affects toxicity.' Toxicologists should identify a group of archetypal toxic agents (reference compounds) that could be used to mimic age-associated diseases or biologic markers of aging. The likely impact of the de- mographic shift that is now under way and will continue into the twenty-first century will be to alter fundamentally the major so- cial and economic commitments of this country. The development of interventions that enable the elderly to live out their lives in- dependently and productively will mitigate the impact. Support of research into aging and into the effects of the environment on aging processes should therefore be given a high priority.