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Basic Biomedical Research

The term aging can refer to changes taking place during any stage of life. Some of these changes are benign, with no evident adverse effects; others are eventually harmful. The dysfunctional changes associated with accelerated mortality rates during the later phase of adult life are collectively called senescence. Senescence is associated both with diseases of specific organs and tissues and with diffuse disorders that defy conventional classification. Within the vast scope of these phenomena of aging, many of the problems of senescence can be explored scientifically. Continued research not only will yield new interventions into specific disorders of senescence but also will lead to the discovery of the nature of many basic biological mechanisms that change during the aging process.

A number of puzzling questions about aging have attracted the interest of biomedical researchers. Why, for example, do humans differ so individually in aging changes of bone, brain, and heart? Here we see how genetic and epigenetic factors produce different responses to environmental influences throughout the lifespan. Because the environment begins to influence the organism long before birth, aging represents an array of processes that develop over the entire lifespan. Thus, environmental influences on genetic and epigenetic characteristics of an individual may give rise to preconditions of disability and disability itself long before senescence is manifested. The potential for reversing or delaying disability depends on the still unknown nature and extent of fundamental changes in gene expres-



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Extending Life, Enhancing Life: A National Research Agenda on Aging 2 Basic Biomedical Research The term aging can refer to changes taking place during any stage of life. Some of these changes are benign, with no evident adverse effects; others are eventually harmful. The dysfunctional changes associated with accelerated mortality rates during the later phase of adult life are collectively called senescence. Senescence is associated both with diseases of specific organs and tissues and with diffuse disorders that defy conventional classification. Within the vast scope of these phenomena of aging, many of the problems of senescence can be explored scientifically. Continued research not only will yield new interventions into specific disorders of senescence but also will lead to the discovery of the nature of many basic biological mechanisms that change during the aging process. A number of puzzling questions about aging have attracted the interest of biomedical researchers. Why, for example, do humans differ so individually in aging changes of bone, brain, and heart? Here we see how genetic and epigenetic factors produce different responses to environmental influences throughout the lifespan. Because the environment begins to influence the organism long before birth, aging represents an array of processes that develop over the entire lifespan. Thus, environmental influences on genetic and epigenetic characteristics of an individual may give rise to preconditions of disability and disability itself long before senescence is manifested. The potential for reversing or delaying disability depends on the still unknown nature and extent of fundamental changes in gene expres-

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Extending Life, Enhancing Life: A National Research Agenda on Aging sion through the aging process. Careful study of environmentalgenetic interactions throughout life is required. Clearly, aging is a unique frontier of the life sciences that requires examination by a wide array of scientific disciplines. Research in aging will clarify the basis of many specific disorders of human aging and, in so doing, will add to the proud advances that have eliminated so many diseases of children and younger adults. Moreover, the ability to understand aging requires a powerful intellectual synthesis of diverse research areas that presently stand apart from each other because of their historical focus on specific organs and diseases. Fundamental information about the basic mechanisms of aging still is woefully inadequate. Critically necessary is aging research in the basic disciplines of biology: genetics, biochemistry, cell biology, neurobiology, developmental biology, and others. The history of science amply demonstrates that major advances often come from serendipitous discoveries. Thus, in any agenda designed to establish priorities and to estimate the resources for aging research, it is of utmost importance that investigator-initiated research be protected. This should provide the core from which many major concepts and discoveries will emerge. Research on basic cellular functions has brought many new insights into the biological mechanisms of aging (Röhme, 1981; Stanulis-Praeger, 1981) and research gives ample reason for optimism. Equally, new, improved, and expanded model systems for the study of aging have been uncovered; these include rodents from food-restricted colonies with enhanced lifespans and delayed, reduced, or absent age-related pathologies (Masoro, 1988); methods for the creation of strains of laboratory mice with a wide array of targeted mutations (selection of substrains with specific genetic characteristics); breeding lines of unusually long-lived insects from genetically heterogeneous stocks (Dice and Goff, 1987); and identification of a single gene mutation that increases lifespan in the nematode Caenorhabditis elegans. Progress has been made in the development of chemically defined media for cultivation of normal diploid somatic cells to facilitate analysis of mechanisms of clonal senescence and cellular repair. Major conceptual and methodological advances in the techniques of molecular biology, especially in molecular genetics, are leading to an increased understanding of gene expression at the molecular level. Genetic maps are reaching high resolutions (markers at about one million nucleotide base pairs), with the potential for mapping and cloning the dominant genes responsible for such various age-

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Extending Life, Enhancing Life: A National Research Agenda on Aging related disorders as familial Alzheimer's disease (St. George-Hyslop et al., 1987). Finally, scientists are increasingly aware of the intellectual challenges posed by biogerontology as a major uncharted frontier of biology. The committee believes that elucidation of the biological mechanisms of aging is an achievable goal. The major recommendations that follow focus attention on a broad array of important areas of investigation that are both feasible and critical to our knowledge of aging and its basic processes. Three main criteria were utilized in the selection of the research priorities in the field of basic biomedical investigation: Feasibility of the research in the context of current advances in the biological sciences: Enough is known to permit immediate expansion of existing efforts in these areas and to plan for and develop the resources needed during the next decade. Expansion of these research areas will have an immediate impact on the understanding of a number of aspects of the aging process. Importance of these research areas insofar as potential findings can be applied to the treatment of major disabilities of later life: In the examples discussed, the committee believes that biomedical research eventually will lead to prevention of these disorders. Potential of the research areas selected to catalyze a cascade of productivity in many other areas of health research, including areas outside of aging that share technology or concepts with gerontology. RESEARCH PRIORITIES The committee proposes a major new initiative to achieve understanding of the basis for the pervasive disturbances in the regulation of proliferative homeostasis that accompany aging in essentially all animals, including humans. These disturbances in proliferative homeostasis, a fundamental process responsible for appropriate replacement of cells that have become lost either because of exposure to toxins or because of endogenous physiological processes, play major roles in cellular regeneration and repair and in the genesis of several of the most important age-related human disorders: cancer, atherosclerosis, osteoarthritis, benign prostatic hyperplasia, and altered immune function (Martin, 1979). This new major national initiative should be comparable in emphasis and scope to the NIA's highest research priority—Alzheimer's disease and the neurobiology of aging.

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Extending Life, Enhancing Life: A National Research Agenda on Aging The second priority research recommendation is that basic research in the neurosciences (including the peripheral and central nervous systems) and the current special research initiatives on Alzheimer 's disease should be continued and expanded. Funding allocations for the foregoing should supplement, not supplant, existing research support and should not detract from other areas of investigation. Fundamental studies on aging and the regulation of gene expression and macromolecular syntheses, postsynthetic modifications of proteins and protein degradation, membrane changes, and other fundamental research approaches are essential to the studies envisioned above and to all facets of biomedical exploration. To achieve the above-noted research goals, major new research resources are required for direct support of research projects, additional training programs, expansion of current centers devoted to studies on aging, and enlargement of the current infrastructure for basic biomedical scientific exploration. These are described later in this chapter. ADDITIONAL RESEARCH OPPORTUNITIES The identification of two major research recommendations in no way is intended to detract from the importance of other areas of biogerontological research. Some promising research directions not included in the major recommendations also are worthy of encouragement and support. A brief discussion of some of these important research directions follows. Although one major emphasis of this report is on proliferating cells, the role of nondividing cell types in the process of aging should be explored further. These studies should focus on postmitotic cells, such as neurons and cardiac and skeletal muscle cells, as well as on conditionally proliferating cells, such as hepatocytes (Martin, 1977), and will provide important information about aging mechanisms that have been neglected. Presently, little or no information is available about repair and regeneration in these cells. For example, does macromolecular turnover change with age? How are cell surface properties altered? Do signal transduction mechanisms change? Another area of emphasis is that of systems physiology. Most gerontologists agree that aging is a multifactorial process, involving many cells, tissues, and organ types. Research must be carried out on the major integrative systems in physiology. The effects of aging on the endocrine/neuroendocrine and immune systems (Finch et al.,

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Extending Life, Enhancing Life: A National Research Agenda on Aging 1985; Miller, 1990) must be understood if we are to understand the organism's aging phenotype. Dietary restriction as a modulator of lifespan in rats and mice represents an important probe for understanding aging changes (Masoro, 1988). Similarly, regulation of reproductive physiology and of the developmental process in general represents a potentially important analogue for the aging process and should be emphasized (Finch et al., 1985). The fact that cells, tissues, and organs do not age at the same rate among species or even among individuals within a species poses a key complicating factor for these studies. Hepatocytes, for example, may be functionally youthful in an individual whose nervous system or cardiac function is seriously impaired as a result of aging or disease. The use of lifespan as an end point for aging has further hampered the interpretation of numerous studies. The field sorely needs measures of senescence based on functional capacity. Thus, descriptive studies of each system, evaluated in relation to overall functional competence and mortality risk, are critical to the development of meaningful biomarkers for aging, and for the identification of dysfunctional aging (senescence). Such biomarkers would increase scientific understanding of the factors that influence the rate of aging along the continuum of biological change and would contribute to the development of interventions that might delay or reverse dysfunctional aging (senescence). The concept of biomarkers applies at many levels, from cellular biology to the more complex interactions that are the object of scientific study in clinical, behavioral and social, and other areas of health care research (Sprott and Baker, 1988). Abundant evidence is available of the accumulation of abnormal proteins during the course of aging and in the development of age-related diseases, such as the neurofibrillary tangles and beta-amyloid of Alzheimer's disease (Stadtman, 1988). Moreover, many tissues acquire inactive enzymes during aging (Dice and Goff, 1987). A major question concerns the pathogenesis of such abnormal proteins. The general question of altered gene expression in aging is of the utmost urgency if we are to understand the biological bases of aging, and the role of environmental influences, such as free radicals, radiation, and various toxicants, raises an additional and pressing set of questions about how the environment may influence aging (Ames et al., 1985). While some research is focusing on various types of molecular damage, studies on the mechanisms of selective changes in gene activity should receive special emphasis. The powerful tools of recombinant DNA genetics are being applied to these questions. For

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Extending Life, Enhancing Life: A National Research Agenda on Aging example, the new technique of polymerase chain reaction can be used to ascertain if new genes are being activated in individual cells of different tissues. It is possible that alteration in the activity of a limited number of genes is a common denominator for many cellular changes in metabolism during aging. In effect, many of the same kinds of questions about selective changes in gene activity during development of the organism arise when considering changes resultant from the aging process. The development and characterization of various model systems must receive more attention. The study of comparative genetics and lifespan is a challenging and potentially productive area of research for learning more about aging. New model systems should be developed based on their usefulness in responding to specific biological questions and on their value for comparative genetics. Models are useful insofar as they can be used to answer specific questions about biologic phenomena or mechanisms. Other areas for productive research include the development of optimal methods for the isolation and cryopreservation of tissue biopsies and purified cell populations; extension of current epidemiological studies on the interaction among environment, genetic factors, and aging; and the application of life-parameter techniques to animals of varying lifespans. RESOURCE RECOMMENDATIONS The following summarizes the major resources that the committee believes will be needed to meet the foregoing goals. A discussion of the funding required to develop these resources appears in the section on funding in the Executive Summary and Recommendations for Funding. Funding of Research Proposals The NIH funds about one in four approved research proposals. The committee believes that many worthy research questions are not being examined because of lack of funding and that many promising lines of research are being abandoned or delayed. Therefore, the most important way in which the agenda on basic biomedical research (and other areas in the study of aging) can be implemented is to increase the rate of funding for approved research projects on aging from its present level of one in four to one in two. Clearly, research proposals not only must be approved but also must be of high quality in order to be supported by the additional funding.

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Extending Life, Enhancing Life: A National Research Agenda on Aging Materials Animal Models More species are needed, including primates and other long-lived animals, that resemble humans more closely than those short-lived rodent models having condensed reproductive schedules. There is also a need for expanded support of programs within the NIA and other institutions to make available to researchers aging cohorts of animals of contrasting maximum lifespan potentials. Cell Line and Tissue Samples Increased effort should be directed toward making available cryopreserved cells and tissues. Improved access to these resources has already had an important effect on the progress of tumor biology. A new initiative is required to develop the technology of cryopreservation, banking, characterization, and distribution of postreplicative cells from donors of varying ages and genotypes. Samples of both of these cell and tissue types should be derived from different human populations according to age, sex, and state of disease (including, but not limited to, Type II diabetes mellitus and Alzheimer's disease). Cell lines should be developed from more species, including long-lived avian species such as the Japanese quail, to evaluate lifespan relationships and propensity for spontaneous transformation. Finally, cell lines should be obtained for study from species having different lifespans and from human donors with certain progeroid syndromes (Martin, 1979). Further Development of Existing Longitudinal Studies Although this chapter focuses on fundamental biological processes of aging, this effort is directed primarily at the problems of human aging. Therefore, the committee stresses the resource importance of epidemiological studies of how humans age. Efforts should be made to increase the accessibility of archival information, especially the data from previous major longitudinal studies. These studies include information about childhood and adolescence that may form the basis for future gerontological research (Verdonik and Sherrod, 1984) and a current NIA crosscultural study of Alzheimer's disease that compares Japanese-Japanese with Japanese-Americans. Also, data on mortality rates and incidence of disease or dysfunctions of different human and animal populations should be made available.

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Extending Life, Enhancing Life: A National Research Agenda on Aging Ten additional Centers of Excellence in Research and Education in Geriatrics and Gerontology (Claude Pepper Centers) should be established to maintain the foregoing resources. Also to be developed is resource support to perform high-technology tasks, such as specialized laboratories for cell biology, that are fundamental to a wide range of aging research. Three such laboratories are recommended to serve as regional infrastructure support for basic biomedical studies on aging. There is evidence that the absence of sufficient laboratory space has been a major impediment to more rapid progress in Alzheimer' s disease research. Congress can address this problem, in part, by appropriating construction funds already authorized by legislation creating Alzheimer's Disease Research Centers. In addition, we need to produce at least 200 more well-trained research scientists per year with commitments to research on aging. To the aggressive pursuit of young researchers by existing training programs should be added new programs designed specifically to recruit scientists with established reputations in other fields. In view of the special nature of gerontological research, the committee strongly recommends that mechanisms for long-term research and research training support (5 to 7 years) become more widely available. New funding for research is required to implement these initiatives. Further sums will be needed for training, infrastructure support, and construction and renovation to house the research resources in the field. In addition, the basic biomedical research program will share in the development of additional multidisciplinary centers for research and education (Claude Pepper Centers) and in the support of infrastructure resources (e.g., computer capability; data banks, including population studies; and library support). With additional support for research grants, infrastructure, and centers, a significant increase should follow both in the number of investigators who turn their attention to the phenomena of aging and in a stepped-up intensity in the nature of the research currently under way. Increased support for research careers in the study of aging should also lead to greater enrollment of young professionals in those training programs now undersubscribed. Both cancer biologists and gerontologists are now well aware of the close interrelationships in the regulation of senescence and neoplasia. The expanded effort proposed in this report can be expected to lead to an increased understanding of the nature of cell regulation and how changes in this process lead to those diseases of aging characterized by aberrant proliferation, such as cancer, atherosclerosis, osteoarthritis, and prostatic hypertrophy. In addition, understanding the genetic

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Extending Life, Enhancing Life: A National Research Agenda on Aging and epigenetic regulation of functional capacity as manifested at the cellular level will provide models to understand senescence and its regulation in a wide variety of cell and tissue types. Insight into these regulatory factors will yield substantial dividends in terms of the prevention of and therapy for the illnesses and disabilities of older individuals. CROSSCUTTING ISSUES Biomedical research has only recently begun to examine the role of gender, race, and ethnic background and the relevance of those issues to altered trajectories of aging. The gender differential in lifespan is one fundamental issue that needs clarification. In developed countries, for example, females enjoy a substantially greater average lifespan. Although a major reason for this difference perhaps can be attributed to lifestyle differences (smoking, alcohol, violence, and fat ingestion), other reasons for the female lifespan advantage are obscure. For other mammalian species it is still not clear whether a consistent gender differential in lifespan really exists. In any case, sociobehavioral factors perhaps are crucial in these effects and in the gender differential in the incidence of many age-related disorders. Another crosscutting issue is that of ethics. What are the ethical considerations in doing basic biomedical research? What about the ethical questions attendant upon genetic engineering? In 1990 human gene transplants became a reality. What are the ethics concerning those gene transplants that might prevent the development of age-related dysfunctions but that might as well have adverse effects on younger individuals? Finally, there is and will continue to be a need for regularly updated interdisciplinary education, which should be developed at several levels of sophistication and targeted for a range of professional specialization in health caregiving and administration. REFERENCES Ames, B. N., R. L. Saul, E. Schwiers, R. Adelman, and R. Cathcart. 1985. Oxidative DNA damages related to cancer and aging: Assay of thymine glycol, thymidine glycol, and hydroxymethyluracil in human and rat urine. Pp. 137-144 in Molecular Biology of Aging: Gene Stability and Gene Expression, R. S. Sohal, L. S. Birnbaum, and R. G. Cutler, eds. New York: Raven Press. Dice, J. F., and S. A. Goff. 1987. Error catastrophe and aging: Future directions of research. Pp. 155-168 in Modern Biological Theories of Aging, H. R. Warner, R. N. Butler, R. L. Sprott, and E. L. Schneider, eds. New York: Raven Press. Finch, C., L. S. Felicio, C. V. Mobbs, and J. F. Nelson. 1985. Ovarian and steroidal

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Extending Life, Enhancing Life: A National Research Agenda on Aging influences on neuroendocrine aging processes in female rodents. Endocrinology Review 5: 467-497. Martin, G. M. 1977. Cellular aging—Postreplicative cells. Review (Part 2). American Journal of Pathology 89: 513-530. Martin, G. M. 1979. Proliferative homeostasis and its age-related aberrations. Mechanisms of Aging and Development 9: 385-391. Masoro, E. J. 1988. Minireview. Food restriction in rodents: An evaluation of its role in the study of aging. Journal of Gerontology: Biological Sciences 43: 1359-1364. Miller, R. 1990. Aging and the Immune Response. Pp. 157-180 in Handbook of the Biology of Aging, E. Schneider and J. W. Rowe, eds. New York: Academic Press. Röhme, D. 1981. Evidence for a relationship between longevity of mammalian species and life spans of normal fibroblasts in vitro and erythrocytes in vivo. Proceedings of the National Academy of Sciences U.S.A. 78: 5009-5013. Sprott, R. L, and G. T. Baker III, eds. 1988. Special Issue: Biomarkers of Aging. Experimental Gerontology, vol. 23. Stadtman, E. R. 1988. Protein modification imaging. Journal of Gerontology 43: B112-B120. Stanulis-Praeger, B. M. 1981. Cellular senescence revisited: A review. Mechanisms of Aging and Development 38: 1-48. St. George-Hyslop, P. H., R. E. Tanzi, R. J. Polinsky, J. L. Haines, L. Nee, P. C. Watkins, R. H. Myers, R. G. Feldman, D. Pollen, D. Drachman, J. Growdon, A. Bruni, J. F. Concin, D. Salmon, P. Frommelt, L. Amaducci, S. Sorbi, S. Piacentine, G. D. Stewart, W. J. Hobbs, P. M. Conneally, and J. F. Gusella. 1987. The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science 235: 885-890. Verdonik, F., and L. R. Sherrod. 1984. An Inventory of Longitudinal Research on Childhood and Adolescence New York: Social Science Research Council.