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9 Recommendations 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 ~nter- actions between aging processes and the effects of environmental substances with toxic potential. Rather, there is a need to develop a better understanding of the basic mechanisms of aging, how they can be affected by the environment, and how aging itself affects toxicity. The following is a list of recommendations related to re- search, education, and resources; the order in which they appear does not imply priority. RESEARCH . The identification and elucidation of the fundamental mechanisms of aging are essential. The effects of environmental agents on aging processes, in the causation of age-related diseases, and in the susceptibility of the aging population cannot be fully understood without such knowledge. In this regard, the search for valid biomarkers of aging to assess the impact of environmental factors on aging processes and the aged should be continued. 165

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166 AGING IN TODAY'S ENVIRONMENT ~ The effects of dietary restriction and nutritional constitu- ents on life span and specific physiologic functions should be stud- ied by both gerontologists and toxicologists, especially because these factors might influence the effects of toxic environmental agents. . Toxicity data on older organisms should be collected as part of the normal toxicity testing of agents. These data should include toxicokinetics and pharmacodynarn~cs. . The responses of aged laboratory an~rnals to specific toxic agents should be studied as useful descriptors of the aged state. . To conserve resources, the testing of aged animals should generally be restricted to the study of specific experimental issues rather than aimed at screening environmental agents. . Although general screening is inadvisable, toxicologists should identify a group of archetypal toxic agents (reference com- pounds) and nontoxic agents (negative controls) that could be used to mimic age-associated diseases or biologic markers of ag- ing. Such agents (e.g., methy~pheny~tetrahydropyridine, MPTP, which selectively kills cells in the substantia nigra and causes a parkinsonian syndrome) provide unusual opportunities for basic research on mechanisms of aging and the environmental impact thereon. Current theories of aging should be used to guide the selection of agents that hasten or retard hypothetical aging pro- cesses. ~ With regard to nervous system disorders, prevention can be regarded as a realistic goal, if the cause of subclinical damage can be identified. Epidemiologic attention should be focused on early environmental exposures that can predispose to neurologic disorders later in life. Causal mechanisms that underlie both envi- ronmental damage and the changes associated with aging should be sought. The roles of genomic instability and chemical free radicals should be studied in view of the current understanding of mecha- nisms of aging and evidence of their involvement in the promotion of age-associated diseases.

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RECOMMENDATIONS 167 ~ Populations on which information about toxic exposure is available should be the subject of epidemiologic studies of ages associated characteristics and diseases. Persons exposed to specific chemical substances in an industrial setting or as a result of an ~experunent ~ nature" should be followed throughout life, so that the ejects of such exposure that have long latent periods can be identified and investigated. Special attention should be given to populations in which age-associated conditions and diseases of presumed environmental origin are present in unusually high incidences (e.g., the high incidence of parkinsonism and Alzheimer- type dementia in Guam and elsewhere). . Genetic susceptibility to the effects of drugs and their bio- transformation, as well as multiple drug therapy and severity of disease, might account for the apparent increase in the incidence of adverse drug reactions with age. Efforts to evaluate the effects of age itself on the disposition (absorption, distribution, metabolism, and eliminations of drugs and other chemicals should continue. . The elderly often take multiple drugs and vitamins and are exposed to other environmental agents, and the potential detri- ments to health need to be evaluated. Information on age and nutritional and disease status of the elderly and on type, dosage, and duration of exposure can usually be established with some accuracy and with only modest cost. . Research is needed on the effects of advanced age on pharmacokinetics, bioaccumulation, and other drug and chemi- cat interactions including the effects of inducers and inhibitors of hepatic drug-metabolizing enzymes- and the influence of dietary factors, smoking, and other environmental factors. ~ Research on variations among the aged in susceptibility to the effects of pharmacologic agents and related environmental chemical should consider the impact of polymorphisms at rely vent genetic loci. The frequencies of such polymorphisms might be different among the elderly surviving members of population cohorts. ~ The short- and long-term effects of drugs and chemical substances should be investigated as functions of age in an attempt

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168 AGING IN TODAY'S ENVIRONA~NT to assess the potential unique susceptibilities of the elderly human population. . Efforts to develop animal model systems of aging (whole animals, organs, tissues, and cells) should be increased. ~ Efforts to establish systematic autopsy studies are encour- aged. They should include both randomized age-representative samples of deaths and samples of deaths of people who were ex- posed to high concentrations of environmental agents Ad were followed prospectively. EDUCATION ~ The general public and health-care providers should be better informed about nutritional needs of the healthy elderly and of those who suffer from age-associated diseases and about lifelong nutritional programs aimed at preventing or delaying the onset of age-associated diseases and related problems. Various modes of education, including the mass media, should be used to warn the lay public and health-care providers against unsubstantiated dietary regunens purported to extend life and prevent disease. It should be understood that there ~ very little evidence that such diets-influence the human aging processes. Moreover, there is no evidence that their long-term use will not adversely affect the health of humans. . The evidence that links specific environmental factors to specific disorders in the elderly should be more widely dissem- inated in simple language, for example, the adverse effects of smoking, of exposure to ultraviolet radiation, and of inappropri- ate nutrition. ~ The scientific community should be encouraged to focus attention, through its professional societies, on gerontotoxicology. This combination of the fields of toxicology and gerontology should be given prominence in seminars, symposia, and other programs at annual meetings and special meetings. Topics that deserve at- tention include: models and methods for studying chronic toxicity

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RECOMMENDATIONS 169 and mechanisms of aging; comparative toxicology in young and old mammals; neurotoxicology and aging; immunotoxicology and aging; genetic toxicology and aging; toxicokinetics, toxicodynam- ics, and aging; and the role of diet, including toxic factors in some foods, in aging. ~ Both government and private initiatives in the training of professionals and the development of acaden~c prograrrm that re- quire skills at the interface of gerontology and toxicology should be encouraged. Suggested goals include: development of training grants for predoctoral and postdoctoral students, summer insti- tutes and sabbaticab for established investigators, and improved nutrition education in medical schools. FUNDING AND RESOURCES ~ The comrn~ttee urges those who carry the heavy respon- sibility of setting priorities for the use of what are always finite resources to consider the potential advantages of advances in the knowledge of aging and the environment. There is substantial potential to improve the quality of life during a period that ev- ery person hopes to face and the possibility of elucidating other processes, such as cancer and heart disease, through the study of aging. The use of animals as models for the study of aging and toxicity has made important contributions to knowledge in these fields. Efforts to develop aged animals generally should be encour- aged, so that adequate numbers are available for gerontotoxicologic research. ~ Additions efforts are needed to develop banked collections of cells, tissues, and fluids for future research. The existence of a system to ensure the collection, storage, and study of relevant tis- sues, cells, and body fluids would support studies of body burdens of environmental agents and the consideration of potential causal associations of these agents with tissue changes over time. ~ The likely impact of the demographic shift that is now un- der way and will continue into the twenty-first century will be to

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170 AGING IN TODAY'S ENVIRONMENT alter fundamentally the major social and economic commitments of this country. The development of interventions that enable the elderly to live out their lives independently 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.