Researchers have not yet been able to fully explain the reasons for the recent improvements in life expectancy at age 65 and older. Further we do not know if the same rate of decline in mortality rates will continue among America's older persons. Therefore, population projections of the size of the 85 plus population vary widely. As important as it is to accurately project the number of oldest old over the next decades, we desperately need information about the likely health status and functional status of the oldest old. Will increases in life expectation translate into more years of healthy, active life or more years of life in a disabled state? Continued research in this important area should help unlock the mystery of recent improvements in life expectancy among the elderly and should improve the accuracy of population projections for the oldest old.

Mr. Stokes: Has NIA initiated a demographic study of this issue? When will it be conducted? What funds have been requested for this purpose?

Dr. Williams: Last year the Committee encouraged the NIA "to undertake a demographic research program on the oldest old that would focus on those who are relatively robust and capable of regaining function." The NIA allocated funds for the development of a medical demographic study of the oldest old. The planning for such a program has been undertaken and the NIA is now ready to undertake such a study. Indeed, a number of special opportunities to "piggyback" on top of other planned studies will exist in 1992 that would allow such a study to be conducted at a lower than expected cost (saving over $2 million over the life of the study). Information from such a program and study would materially assist in the development of more accurate forecasts, as well as provide key information that would lead to new programs to increase the functional independence of this population. Depending on the scope and the extent of oversampling of minorities, the study will cost between $1-1.5 million per year. However, no funds are currently available to actually initiate the study.

Mr. Stokes: In looking at the "oldest old," it has been reported that many of this group are impoverished. Will the study address the issue of poverty? And, secondly what findings can you share with us in reference to poverty and how it impacts the health of the nation's elderly.

Dr. Williams: The oldest old have by far the highest rate of poverty among the elderly. Their levels of near poverty are also extremely high. These rates are especially high among women living alone, with the highest rates being found among the Black elderly living alone. Very little is known about the dynamics of impoverishment among the very old and oldest old, since there has never been any adequate longitudinal study of this process. Widowhood and out-of-pocket health costs are believed to be important factors in the impoverishment at older ages.

The proposed new demographic study of the oldest old will expressly include a special focus on the dynamics of impoverishment.

Poverty is probably a major risk factor for both mortality and morbidity among the elderly population. Longitudinal data are

needed to disentangle the separate, but interrelated effects of low education and low income, and to determine the extent to which poor health causes poverty, and poverty causes poor health. Most research has been done on the young old, and little adequate data exists on the very old or oldest old. One current short-term longitudinal study by an NIA grantee indicates that both low income and low education have negative impacts on the health of older people. Low education, which is easier to measure and which does not change over time, is well established as a very important risk factor for mortality. Earlier studies showed that the strength of low education as a risk factor declined with age, while newer studies are now looking at low education as a risk factor for dementia among the oldest old.

BIOMEDICAL RESEARCH ISSUES

Mr. Stokes: Control of cell proliferation has been identified as an important link between the biology of aging and cancer. Please explain this linkage and describe any recent research findings.

Dr. Williams: Control of cell proliferation is a critical area of basic research with important implications for unraveling the molecular bases of senescence, cellular aging and cancer. Proliferative genes, also known as proto-oncogenes, and antiproliferative genes, also known as tumor suppressor genes or anti-oncogenes, act in a coordinated manner to regulate normal cell proliferation, a critical component of tissue repair and regeneration. Disruption of the cellular regulatory networks which control cell proliferation appears to be a common mechanism responsible for the loss of proliferative potential noted in senescent cells, and the unregulated proliferation characteristic of cancer cells. Thus, the loss of proliferative control is a critical link between senescence and cancer in humans.

Several regulatory steps in cell proliferation have now been shown to be altered in senescent cells and cancer cells. For example, the expression of the c-fos gene, a proto-oncogene required for normal cell proliferation, is repressed or "turned off" in senescent cells. The activity of the retinoblastoma (RB) protein, a key anti-proliferative protein encoded by the RB tumor suppressor gene, is altered in both cancer cells and in senescent cells. Many cancer cells have acquired inactive RB genes, such that the active form of the antiproliferative RB protein is not synthesized. Loss of active RB protein is but one of several genetic mutations which allow cancer cells to escape normal regulatory control and proliferate in an unregulated fashion. the other end of the spectrum, senescent human cells, which have lost the ability to proliferate, are not able to inactivate the RB protein at the required time, and thus cannot undergo normal cell division.

At

The antiproliferative protein p53, also a product of a tumor suppressor gene, has also been implicated in cancer and cellular senescence. Mutations in the p53 protein which cause the loss of its antiproliferative activity have been demonstrated in many

types of cancer cells.

Simultaneous inactivation of the RB and p53 proteins in human senescent cells allows the resumption of proliferation.

The existence of several additional senescence genes on human chromosomes 1, 4, and 11 has recently been demonstrated. The identification of these genes and the determination of their role in cancer and cell senescence is an active area of research supported by the NIA.

Mr. Stokes: The NIA supports a wide variety of research, including research focused on understanding the fundamental mechanisms which determine longevity and the human aging processes. Please give some examples of this "basic" research and why it is an important part of the NIA research effort.

Dr. Williams: Several basic research initiatives aimed at understanding fundamental cellular, biochemical and molecular changes which underlie human aging processes are supported by the NIA. These include Aging and Cancer, Identification of Longevity Assurance Genes, The Molecular Basis of Aging, Mechanisms of Cell Death, and Intervention Strategies in Basic Aging Processes. Unraveling the molecular mechanisms of biological aging is dependent upon understanding the role of age-dependent changes in gene expression in aging processes. The expression of several cellular proteins, including regulatory proteins which control cell proliferation, regulatory proteins which regulate cellular gene expression, metabolic enzymes and structural proteins, are known to be subject to age-dependent changes. Evaluation of the role of these changes in gene expression in aging processes remains a major challenge to understanding human aging and the development of successful intervention strategies.

Calorically restricted rats and/or mice represent powerful experimental models for highlighting those genes involved in normal biological aging processes, identification of longevity assurance genes, and those genes which may predispose an individual to age-related diseases. In addition, identification of the subsets of genes whose expression is modulated by caloric restriction promises to identify critical biomarkers of aging and potential intervention strategies for retarding the rate of aging and eliminating or postponing the appearance of age-related diseases. In fact, several genes whose expression is modulated by aging and restored by caloric restriction have already been identified. Further characterization of factors which regulate the expression of these genes, and additional genes yet to be identified, and determination of the roles of these genes in aging processes and extension of health span promises to provide important clues about fundamental aging processes and the effectiveness of potential intervention strategies in the very near future. In addition, recent advances in molecular biology, especially the technology which allows introduction of candidate genes or genetic loci into embryonic stem cells and the creation of transgenic mice promises to accelerate advances in understanding fundamental aging processes and determining the cellular functions of potential longevity assurance genes.

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Disturbances in proliferative homeostasis, a fundamental process responsible for the orderly replacement of cells in many tissues, are pivotal in many diseases associated with senescence. Abnormal cell proliferation contributes to the development of cancer, atherosclerosis, osteoarthritis, benign prostatic hyperplasia, and disturbed immune function. Thus, identification of the proliferative and antiproliferative genes involved in the coordinated control of normal cell proliferation and determination of the molecular bases for the loss of proliferative capacity which accompanies cell senescence and the unregulated

proliferation characteristic of cancer cells is a high priority research area at the NIA.

ALZHEIMER'S DISEASE

Mr. Stokes: It is estimated that Alzheimer's disease afflicts some four million Americans and that 40 to 60 percent of nursing home residents suffer from some type of dementia, primarily Alzheimer's. The resultant burden of care, both emotionally and financially, must be staggering. What is the approximate annual cost of caring for Alzheimer's patients?

Dr. Williams: Of the four million Alzheimer's disease victims, it is estimated that approximately 80 percent receive care in their own homes and 20 percent receive care in nursing homes. Of the approximately 1.6 million nursing home residents aged 65 and older, approximately half are demented. If family support systems did not exist, it would cost about $18,000 annually to purchase home care at market value, while the average cost nationally of nursing home care is around $30,000. These costs are included in the $90 billion per year estimate for the costs of Alzheimer's disease to the nation. Obviously, this is a growing problem, and without effective treatment to slow or stop the progression of Alzheimer's disease, the problem and the resultant costs will get worse. For example, by the year 2040, when baby-boomers will be in their 80s, the number of nursing home residents aged 65 years and above may be up to 5.9 million, of whom almost 4 million will be aged 85 and above. In that year it is estimated that there could be up to 10 million Americans with moderate to severe dementia, with their care costing up to $149 billion in 1985 dollars.

Explain

Mr. Stokes: Briefly, what are the emotional costs? how the Institute is addressing the research issues raised by caregiving for Alzheimer's patients and their families?

Dr. Williams: NIA research on care for Alzheimer's patients examines the extent, causes, and consequences of the heavy burden of caregiving on family members. Recent findings from such studies suggest a considerable variance among caregivers in the perception of stress and in ways of coping. For example, female caregivers report more depression than males but, unlike females, male caregivers become more depressed the longer they are in the caregiving role. As the disease progresses, caregivers find it especially difficult when the patient has little understanding of their condition and attempts to undertake activities that have become dangerous (e.g. cooking, taking walks alone). One study found that caregivers who focused all their energies on the

caregiving role were initially better able to cope but became progressively more depressed over time while others had times of depression followed by stability.

The

Intervention programs for family caregivers experiencing stress have included educational programs and support groups. NIA also supports several studies developing devices such as a computerized telephone system for caregivers or a home-based computer network to provide information and reduce their sense of isolation. To date, however, the therapeutic benefits of these stress reduction programs have been modest or confounded by other factors such as economic problems or changes in the status of the patient. Development of better measurement and analytic techniques for ascertaining caregiver stress appears needed.

A new emphasis in caregiving research focuses on the emerging mix of formal and informal care for dementia patients. This includes, for example, studies of respite care, special care units in community day care, and of family members' concerns after institutionalization of the patient. Many of these new approaches will be addressed by the 1991 request for applications for studies of "Special Care Units for AD Patients."

MINORITY ISSUES

Mr. Stokes: What is being done to attract more minority investigators into the field of research?

Dr. Williams: A program of small grants to support dissertation research of underrepresented minorities was announced in FY 1991. This program is an innovation for NIH, in that the Agency had not previously provided such a mechanism for research support. The Dissertation Research Award provides support for the investigator's salary and direct research project expenses in amounts not to exceed $25,000 for periods up to 24 months. The applicants for the dissertation research grant must be enrolled in an accredited doctoral degree program in the biomedical, behavioral or social sciences and conducting or intending to conduct dissertation research on issues related to aging. A special mailing of the announcement of the dissertation research award program was sent to Historically Black Colleges and Universities (HBCUs) as well as members of the Association for Gerontology in Historically Black Colleges and Universities.

In March 1991 the NIA held a planning meeting to examine the potential roles of NIA Merit Awardees (investigators with established research records and who receive long term research support) in training of minority scientists, and to determine whether a larger meeting involving Merit Awardees might be beneficial. It was decided that such a meeting be scheduled for August 1991 and include discussions of mechanisms to attract minority students at the baccalaureate level through the junior faculty level, means of matching Merit Awardees and minority investigators, and means for working across institutional boundaries. Some of the minority investigators whom NIA plans to contact will be located at HBCUs.