Director's Statement

DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH

Director's Statement
Conquering Alzheimer's Disease
Understanding the Biology of Aging
Reducing Disease and Disability
Conclusion

Director's Statement

Mr. Chairman and Members of the Committee:

I am pleased to present the President's budget request for the National Institute on Aging (NIA) for FY 2004. The FY 2004 budget includes $994,411,000, an increase of $1,342,000 over the FY 2003 enacted level of $993,069,000 comparable for transfers proposed in the President's Request. The NIH budget request includes performance information required by the Government Performance and Results Act (GPRA) of 1993. Prominent in the performance data is NIH's third annual performance report, which compared our FY 2001 results to the goals in our FY 2001 performance plan.

There are today approximately 35 million Americans ages 65 and over, according to the U.S. Bureau of the Census. Thanks to improvements in health care, nutrition, and the overall standard of living, these men and women are more likely than ever before to be healthy, vigorous, and productive: A recent meta-analysis of demographic studies confirms that disability among America's elders has declined steadily over the past decade. More older Americans are able to participate in "instrumental activities of daily living," such as performing household chores and managing their own medications, while fewer are experiencing limitations in basic physical tasks such as walking or climbing stairs. The prevalence of severe cognitive impairment also appears to be declining, although this finding needs verification.

At the same time, diseases of aging continue to affect many older men and women, seriously compromising the quality of their lives. For example, more than half of all Americans over age 65 show evidence of osteoarthritis in at least one joint [1]. Over half of Americans over age 50 have osteoporosis or low bone mass [2]. Cardiovascular disease, cancer, and diabetes remain common among older Americans. And, according to the Alzheimer's Association, as many as 4 million Americans suffer from Alzheimer's disease (AD), the most common cause of dementia among older persons.

Conquering Alzheimer's Disease

We have made progress in several important areas of AD research. For example: We are improving our ability to diagnose AD early. Scientists are developing and refining powerful imaging techniques that target anatomical, molecular, and functional processes in the brain. These new techniques hold promise of earlier and more accurate diagnosis of AD, as well as improved identification of people who are at risk of developing the disease. For example, researchers have developed a new method of functional magnetic resonance imaging (fMRI) based on oxygen use by the brain during rest. This technique permits visualization of signals from minute subregions of the hippocampus, a brain region important for learning and memory that shows degenerative changes in AD, and the researchers are using it to distinguish between hippocampal changes that are related to normal aging and those that may indicate the presence of neurodegenerative disease. Other researchers are working to improve our ability to image AD's characteristic amyloid plaques and neurofibrillary tangles in vivo, which will allow us to diagnose the disease with greater accuracy and more closely follow its progression. These and other NIA-funded neuroimaging studies support the broader goals of the molecular imaging component of the NIH Roadmap Initiative.

We are developing new, more effective treatments and preventive interventions for AD. Research into the underlying biology of AD is suggesting new ways to treat the disease or even prevent it altogether. For example, human stem cells, with their unique capacity to regenerate and give rise to many tissue types, are of particular interest in AD research because of their potential ability to generate new cells that could renew damaged brain tissue, replace dying neurons, or enhance the ability of the brain to respond to age-related impairments. Recent findings suggest that both human embryonic stem cells (hES), which can give rise to many cell types, and adult stem cells, which develop into a specific cell type, show promise for the eventual treatment of AD and other neurodegenerative conditions. Researchers have recently developed a method for inducing hES cells to differentiate into neurons. These newly-derived cells exhibit the properties of cells ordinarily found in the brain and central nervous system, suggesting that hES cells could provide a source for neural progenitor cells and mature neurons for therapeutic use. Investigators have also found that in the adult hippocampus, neural stem cells can give rise to functional neurons that can integrate effectively into existing neural circuits.

NIA is currently supporting 18 AD clinical trials, seven of which are large-scale prevention trials. These trials are testing agents such as estrogen, anti-inflammatory drugs, and anti-oxidants for their effects on slowing progress of the disease, delaying AD's onset, or preventing the disease altogether. Other intervention trials are assessing the effects of various compounds on the behavioral symptoms (agitation, aggression, and sleep disorders) of people with AD. The design and implementation of all of these clinical trials will be carried out in the context of the NIH Roadmap initiative to enhance clinical research infrastructure and methodology.

We are working to reduce the burden on caregivers of persons with AD. Most Americans with AD are cared for at home by an adult child or in-law, a spouse, another relative, or a friend. For this reason, the AD patient is, in a sense, not only the person with the disease, but the entire family unit. The NIA's REACH Project (Resources for Enhancing Alzheimer's Caregiver Health), a large, multisite intervention study aimed at family caregivers of AD patients, was designed to characterize and test promising interventions for enhancing family caregiving. Nine different social and behavioral interventions were tested, and investigators found that the combined effect of interventions alleviated caregiver burden, and that interventions that enhanced caregiver behavioral skills reduced depression. The second phase of the study, REACH II, combines elements of the diverse interventions tested in REACH into a single multicomponent psychosocial behavioral intervention and is ongoing.

Understanding the Biology of Aging

We are continuing to advance our understanding of the molecular and cellular changes that underlie aging processes, with the goals of identifying the factors that affect the life span of an organism and using this information to develop interventions to extend life and delay the onset of disease and/or disability.

Experiments in a number of animal models are providing valuable insights into mechanisms of longevity. Investigators recently created a transgenic mouse carrying a mutation in the Xpd gene, which codes for an enzyme involved in both repair of DNA damage and transcription of DNA into RNA (an important first step in gene activation). These mice appear normal at birth but age rapidly and live only about half as long as normal mice. This new mouse model will be useful for studying a number of aspects of aging, including the roles of DNA damage and cell death, as well as mechanisms by which the genome maintains itself and how such maintenance contributes to longevity.

Researchers are also using animal models to identify interventions that might be useful in delaying aging. For example, in one recent study, fruit flies fed the chemical 4-phenylbutyrate throughout adulthood lived significantly longer than expected, with no negative effects on physical activity, stress resistance, or fertility. In addition, last year the NIA issued a Request for Applications (RFA) for the Aging Intervention Testing Program, a large-scale initiative to test intervention strategies that may slow the rate of aging in animal models. A number of unproven strategies are already in substantial and growing use by older Americans; positive results using such strategies in animals could lead to clinical trials to establish safety and efficacy in humans. An important secondary goal is to identify interventions that are not safe or are ineffective.

Work in animal models is also leading to the identification of genes involved in regulation of the life span. In the tiny worm C. elegans, researchers used a sophisticated genetic screen to identify about 200 genes that cause an increase in longevity; many of these genes were related to the worm's mitochondria (cellular energy centers), while the exact function of many others remains unknown.

Such findings in model systems, as well as our increasing understanding of genetic disorders such as Hutchinson-Gilford progeria syndrome that exhibit features of premature aging, suggest important roles for genes in human aging. Evidence for a genetic basis of human longevity was strengthened by the recent finding that siblings of centenarians have about half the risk of dying at every age compared with people who do not have a centenarian sibling. In the same study, the investigators found that brothers of centenarians were at least 17 times more likely to reach the age of 100 themselves; sisters were at least 8 times more likely to reach 100 years of age.

Reducing Disease and Disability

Evidence of the beneficial effects of exercise on older people continues to increase. In a study last year, researchers assessed the results of a resistive strength training program on men and women in two age groups, 20–30 and 65–75. They found that the effects of the program did not differ between the two groups: Participants in both age groups increased strength and showed similar increases in muscle mass and in resting metabolic rates, which generally decrease with age.

NIA is working to translate research findings in action through its highly successful campaign to encourage older people to exercise. Since the campaign was launched in 1998, NIA has distributed nearly one half-million copies of its exercise guide and almost 60,000 copies of its companion video to the public. A Spanish-language version of the guide was published in January 2002, and over 50,000 copies were distributed last year.

We are also working to reduce the troubling health disparities that still exist among different racial and ethnic groups. In one study of elderly heart attack patients, researchers found that black patients did not live as long after discharge from the hospital as white patients. Much of this disparity could be explained by the lower rate of use of certain cardiac procedures among black patients, suggesting that expanded use of effective procedures could substantially reduce racial differences in long-term survival.

To address disability and disease in special populations, NIA implemented a major new study of health disparities among different racial, ethnic, and socioeconomic groups. The study, Healthy Aging in Nationally Diverse Longitudinal Samples (HANDLS), focuses primarily on cerebrovascular health, cardiovascular health, age-associated changes in cognition, and strength and physical functioning. Through this study, we hope to address hypotheses about aging and health disparities in minority and poor populations to understand the significance of environmental and genetic risk factors for disease. The pilot phase of HANDLS, in which investigators assessed the logistics and feasibility of this community-based study, was completed at the end of 2001, and the larger population-based phase of this study is scheduled to begin in late fall of 2003.

Other areas of research interest include:

Diabetes. Last year, investigators in the multi-institutional Diabetes Prevention Program (DPP) reported that people who are at high risk for diabetes can sharply reduce their risk through a low-fat diet, and a moderate exercise regimen. This effect was most pronounced among study participants age 60 and over. Treatment with the drug metformin (Glucophage7) also reduced diabetes risk among study participants, but for unknown reasons was less effective among older participants. With other participating NIH Institutes, we are continuing to follow up the DPP participants to determine long-term effectiveness of these interventions.

Menopause. Women approaching menopause may experience a variety of uncomfortable symptoms, but uncertainty remains over the safety of hormonal therapy due to reports of serious health risks related to some combinations of hormones. NIA-supported researchers are working to find effective treatments for the symptoms of menopause that do not increase risk of adverse effects.

Conclusion

It is becoming increasingly obvious that old age need not be associated with illness, frailty, or disability. In fact, we have made tremendous progress against all of the major diseases and conditions of aging. However, much work remains to be done. NIA is committed to supporting high-quality research to address all aspects of aging, from conditions and diseases that primarily affect older people to physical, behavioral, and cellular characteristics of the aging process. As more Americans live longer, NIA will meet the challenges of our rapidly aging society by continuing and intensifying research that improves the health and well-being of older people.

1. See: A Handout on Health: Osteoarthritis, National Institute of Arthritis and Musculoskeletal and Skin Diseases, July 2002.
2. See: America's Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation. National Osteoporosis Foundation, February 2002.