NATIONAL INSTITUTE ON AGING

STATEMENT OF DR. T. FRANKLIN WILLIAMS, DIRECTOR

SUMMARY STATEMENT

Senator HARKIN. Next, the National Institute on Aging. Dr. Williams, delighted to have you with us.

We have your request for $248.94 million, a 3.96-percent increase. Again, welcome and please proceed.

HISTORIC TIME FOR AGING RESEARCH

Dr. WILLIAMS. Thank you, Mr. Chairman. This is very much a historic moment in time in the field of aging, not only because major advances in research are coming to fruition but also because we now have three subspecialties in geriatrics in the fields of family medicine, internal medicine and psychiatry. This indicates the widespread recognition of this area of knowledge and its application to care.

ALZHEIMER'S DISEASE

I want to touch on a few highlights in our research areas of special emphasis and priority. Certainly the greatest emphasis of our Institute is on the health crisis produced by Alzheimer's disease in older people. Over 4 million people in this country have this disease, and it is now imperative that we halt this growing epidemic through more research. I have previously said that we must have the goal of halting this disease within this century.

There are many lines of research that are quite promising, including advances in understanding the genetics that underlie some forms of this disease, the possible role of neurotoxic substances and infectious agents, and the possibility that Alzheimer's disease may be a widespread systemic disorder. For example, recent studies supported by our Institute show the amyloid changes characteristic of this disease are found in the cells of skin as well as brain. This may, among other things, lead to a simpler and more definitive diagnostic test which could save as much as $1 billion a year.

One of the most promising areas of research in my judgment is that on nerve growth factor which can influence the survival or regeneration of brain cells following injury. We plan within the next 2 years to begin clinical trials on nerve growth factor in Alzheimer's disease and other degenerative diseases.

PHYSICAL FRAILTY

A second area of importance is that of physical frailty and the role rehabilitative approaches play in restoring and maintain independence in older people, which is the greatest goal of all of us and

all older people. Research emphasis is placed on the role falls, hip fractures, and diseases such as osteoporosis play in frailty and on efforts to restore function as well as prevent these problems. An overall related goal is that of health maintenance in older people and the key role of maintaining physical activity. Many studies now show the great benefits of maintained physical activity in maintaining health and independence of life in later years.

CELLULAR SENESCENCE

A third area of exciting research is that of cellular senescence and the genetic basis for the decline in cell proliferation. This work is done primarily with human skin fibroblasts, cell cultures from the skins of humans, which show that in prolonged cultures or in cells removed from older people, there are genes brought into action which then depress further cell proliferation. There are also now proteins that can be isolated and put into young cell systems to depress cell proliferation. Just in the last few weeks there have been reports of findings which show that one of the major oncogenes, the C Foss gene, is turned off in the cell lines of these late proliferating senescent cell lines. Another very recent report shows that there are genes, one of which has been identified on chromosome 1, which will also turn off an oncogene of this type. This provides a great opportunity to understand the aging process itself, plus the potential that some of these genetic findings have for opposing cancer growth.

PREPARED STATEMENT

Finally, special populations we continue our strong commitment to research on special populations of older people, including those in rural settings and various minorities, as well as worldwide comparative studies on populations and cultures. This year we will fund two centers on rural health and aging, and we plan to initiate a project on health and retirement as suggested by Congress.

Our fiscal year 1991 budget request is $248,938,000. I would be very happy to answer questions.

[The statement follows:]

STATEMENT OF DR. T. FRANKLIN WILLIAMS

The field of aging has increasingly attracted major scientific interest since 1974, when the National Institute on Aging was established. Over the past 15 years, there has been an unprecedented and exponential growth of new and exciting research opportunities. It is important to recognize that we are

very much at a historic moment for the field of aging--a period marked by advances in new frontier research. A reflection of this historic development has been the establishment of three new subspecialties in geriatrics. Fifteen years ago it was difficult to find even a handful of medical schools in the country with a special focus on older adults. Today, the fields of internal medicine, family practice, and psychiatry are each establishing a subspecialty in geriatrics--reflecting a whole new level of scientific curiosity and capacity to conduct research on aging. This is further reflected by the significant growth of high quality research grants approved for funding.

The conquest of Alzheimer's disease (AD) remains the NIA's most important priority. Other continuing priorities include understanding of the basic mechanisms and characteristics of aging; promotion of health, effective functioning, and quality of life--including prevention or reduction of physical frailty; long-term care and caregiving; special populations including the oldest old, older persons in rural settings, and minorities; and training and career development in aging research and geriatrics.

Alzheimer's disease has brought on a health crisis of epidemic proportions. It is one of the most prevalent, devastating, and costly diseases of later life. Recently published data indicate that AD may be more prevalent than previously reported. It is now estimated that 4 million people have AD at an estimated cost of $80 billion a year. It is imperative that we halt this growing epidemic through further research.

While progress is being made in understanding AD, we do not yet know the cause(s). Studies on the genetics of AD have shown that there is a linkage between chromosome 21 and the early onset familial form of AD. Recently, studies have begun to yield results that establish an association between chromosome 19 and late onset AD. Other leads on the possible cause of AD suggest that aging may increase susceptibility of the nervous system to toxins and other environmental perturbations. There is growing evidence that neurotoxins cause specific nerve cells to die, thus contributing to the etiology of AD.

Preliminary evidence has indicated that AD may be caused by an infectious agent. Confirmation of these results through additional research is an urgent need. Such research is critical before we can be sure whether some cases of AD have an infectious origin. A multi-center replicative trial is currently under consideration to test this hypothesis.

An abnormal protein, amyloid beta-protein, which is associated with the hallmark of AD brain pathology, has now been found in non-neuronal tissues such as the skin, subcutaneous tissue, and intestine. These data suggest that AD could possibly be a widespread systemic disorder, and support other findings indicative of a metabolic defect in AD. Research in this area suggests that abnormal processing of the amyloid precursor protein could be a consequence of this disease and produce some of the cellular events associated with AD.

Researchers are now finding ways to slow down or prevent cell loss by stimulating the brain with chemicals used to promote cell growth during development. Since AD involves massive cell death, such work has important implications for developing treatments. More specifically, it has been shown that nerve growth factor (NGF) can be administered to targeted areas of the brain in experimental animals such as mice and will produce nerve growth and improve function. A goal is to determine the potential use of NGF and similar substances to prevent or correct cell loss in Alzheimer's and other degenerative diseases.

In relation to the possibility of treating and minimizing the effects of AD through use of medications, the clinical trial on the efficacy and safety of tetrahydroaminoacridine (THA) is proceeding as planned, with the expectation of

definitive answers within this fiscal year.

There are, moreover, additional AD drugs emerging as candidates for clinical trials.

Understanding the basic mechanisms of aging is an important step in the process of identifying interventions to delay or modify human aging. NIA is introducing a research initiative to determine the mechanisms by which lower consumption of calories dramatically lengthens life span and prevents agerelated diseases, such as cancer, in experimental animals. Learning these mechanisms can reveal how these age-associated changes could be prevented or delayed in humans. Researchers supported by NIA are studying age-related changes in cell proliferation--why certain cells in laboratory chemical cultures have a limited life span. The results of one such study just reported this January uncovered new clues about the molecular basis of cellular senescence. A repressed gene was identified, along with a reduced amount of a protein considered essential for normal cell division. Such results have potentially major ramifications not only for understanding underlying mechanisms of aging but in providing new ideas about cancer intervention as well. Whereas in aging, cell proliferation slows, in cancer it grows out of control; cellular mechanims regulating aging may potentially be influenced to regulate various cancers.

A major goal of the NIA is to help older people maintain an independent life style and to reduce the risk of needing long-term care. Physical frailty significantly diminishes the ability to conduct common activities of daily living, and increases risk of falls and hip fractures. Preventive and rehabilitative strategies, however, show strong promise for reducing frailty and injuries. For example, a large scale study has shown that a comprehensive falls prevention program can significantly reduce the number of falls in older people. Other studies have shown that older persons who fall have weaker leg muscles than others of the same age who don't fall, while related studies show that exercise can dramatically restore leg strength even in very old frail 90year-old nursing home residents. In 1990, NIA and the National Center for Nursing Research will jointly initiate the Frailty Clinical Trials, to test interventions to reduce physical frailty and its consequences in older persons.

Another aspect of the frailty initiative is NIA's osteoporosis program which has a special focus on aging-associated aspects of this disease. Because bone loss is almost universal with increasing age, NIA supports research to identify age-associated processes responsible for osteoporosis, and to develop prevention and treatment strategies based on modifying them. Such strategies offer the promise of fundamental major progress in preventing or curing this disease. NIA especially emphasizes osteoporosis in advanced age, when it is most severe and causes the most severe disability and mortality, especially from hip fractures. Because many aging processes are modifiable by exercise, nutrition, and other factors, NIA is placing increasing emphasis on testing interventions against osteoporosis. Interventions developed through NIA's frailty and osteoporosis initiatives could result in major reductions in future long-term care needs.

Geriatric rehabilitation is an area of increasing NIA emphasis. In May 1989, NIA issued a program announcement encouraging research on biomedical and psychosocial aspects of rehabilitation for older persons. In 1990, the NIA will solicit applications for Special Emphasis Research Career Awards in Rehabilitation and Aging. These awards will provide five years of career development support aimed at increasing the small number of researchers with expertise in both aging and rehabilitation. Rehabilitation looked at within the context of aging will also add significantly to reducing the burdens of long-term care.

NIA intramural researchers and researchers supported in other settings are studying the extent to which exercise regimens can forestall or ease ageassociated physiological decrements, inhibit the development of diseases, and increase longevity. Accumulating evidence suggests that expected ageassociated changes in such physiologic parameters as blood glucose tolerance, skeletal muscle strength, and cardiac measures occur to a lesser extent--if at all--in physically fit older persons. Increased research attention is needed on the problem of cardiovascular disease in older persons. Despite progress in preventing cardiovascular disease in middle age, important questions remain