Biomedical Researchers Step Up Efforts To Probe Mysteries of Aging

The National Institute on Aging (NIA) is celebrating its 20th anniversary this year. It was established in 1974 when Congress passed the Research on Aging Act, charging the institute to conduct and support biomedical, social, and behavioral research as well as training and education on the process of aging and the diseases and special needs of older individuals. "Our research is very far-ranging, from basic research into cell regulation and cell death, to aging and cancer, to the social and behavioral aspects of aging," says Miriam Kelty, associate director of NIA and director of the office of extramural affairs. Some current NIA statistics: NIA's appropriated budget for fiscal year 1994 is $420 million, of which $38 million went to fund intramural research. For fiscal year 1995 the total appropriated budget is $434 million, with almost 9 percent of that assigned to the intramural program. The extramural program supports more than 900 research project grants in four main areas--the biology of aging; geriatrics; neuroscience and neuropsychology; and behavioral and social science--totaling nearly $250 million. The majority of intramural researchers work at the Gerontology Research Center in Baltimore, while the rest work on the NIH campus in Bethesda, Md. The intramural program covers 11 areas of research, including cardiovascular science, molecular genetics, and cognitive studies. --K.Y.K. The population of the United States is aging. According to the U.S. Census Bureau, the proportion of Americans aged 65 and older is expected to increase from about 12 percent today to about 20 percent in 2030. By then, the average baby boomer--those born in the years immediately following World War II--will be upwards of 80 years old. And, like its subjects, the field of biomedical science that explores the physical, psychological, and sociological effects of the aging phenomenon is visibly maturing. As the baby boomer generation gets older, increased attention is being focused upon geriatrics (the study of illness in older people) and gerontology (the basic science of aging processes). For scientists in these fields, the demographic sea change has conceptually affirmed the need for a more aggressive approach to aging research and, consequently, has fueled growth in funding for it in recent years (see story on page 1). Immunologist Richard Hodes is addressing the challenges of this broad field of scientific study in two venues: the director's office of the National Institute on Aging (NIA), where he's responsible for administering the efforts of about 6,000 intramural and extramural investigators and a budget of more than $420 million; and at the bench of his NIA lab, working with a team of investigators on the relationship of the immune system to the biology of aging. NIA, which was formed in 1974, is the primary source of financial support for aging research in the U.S. According to Hodes, the institute "evolved to provide a perspective that was different from each of the organ- or disease- specific institutes. It developed into an institute with a very broad mission, which is based on the biomedical, behavioral, and social aspects of the quality of life of older citizens." Hodes explains that the research sponsored by the institute looks at a blend of the molecular and cellular mechanisms that influence aging and longevity; behavioral factors, such as diet and exercise, which play a role in mediating the aging process; and the sociological implications of providing care for an aging U.S. population. NIA researchers agree that the dramatic shift in the makeup of the population toward an older majority is the impetus for the growth in their field. "The demography is really the driving force," says Zaven Khachaturian, associate director of the of aging program in neuroscience and neuropsychology. "It's been happening since the turn of the century. People are living longer, and the older age group--85 and over--is growing at a much faster rate than other age groups." These demographic changes have had a direct impact on NIA funding almost from the time the institute was formed. "When I came here 15 years ago, the whole institute had a $28 million budget. And now our budget for fiscal year T94 is over $400 million," notes Richard Sprott, associate director for the biology of aging extramural program. "That would not have happened without the demographic imperative. "Aging and AIDS have been the largest growth areas in health sciences for the last decade." According to George Martin, science director of the intramural program, a significant avenue of NIA research is identifying risk factors such as diet and exercise habits for certain age-related diseases. Sprott adds that NIA's research mission "is not to produce 100-year-old people, but to improve the quality of the terminal third of the lifespan that we've got." And it seems that goal is starting to be realized. A recent National Research Council report funded by NIA and entitled Demography of Aging (L.G. Martin, S.H. Preston, eds., Washington, D.C., National Academy Press, 1994) states that the prevalence of disability among the older population in the U.S. decreased during the 1980s. One major area that NIA funds--both intramurally and extramurally--is the study of Alzheimer's disease. "Research relevant to Alzheimer's is the single largest investment currently at the institute," Hodes says. Khachaturian heads the largest extramural program at the institute--neuroscience and neuropsychology--which primarily funds basic and applied Alzheimer's disease research. Just over $190 million--half of the total NIA extramural budget-- is devoted to this program, with about 80 percent going to fund Alzheimer's-related work. Khachaturian says that research supported by the neuroscience program, which he set up in 1978, ranges from molecular-level basic research to epidemiological studies involving many human subjects. "The notion is," he explains, "that the study of the aging nervous system should not only be done at the basic science level, but that it should be done at the systems level, starting at very molecular, basic areas like genetics and protein chemistry, moving up to neurons and neural systems, and on to behavior and effects on society. "This approach has proved to be very fruitful, as demonstrated by the success of the Alzheimer's program," Khachaturian adds. "There was very little known about the disease in 1978. But in a short time, we have moved Alzheimer's out of the dark ages to the cutting edge of neuroscience because we integrate basic scientists with the clinicians. "In fact, I went out of my way to recruit people from other disciplines--like protein chemistry, medicinal chemistry, molecular biology, and genetics. If you look at the history of many of the people who are in the field now, five to 10 years ago they weren't studying aging nervous systems or Alzheimer's. They're all converts." According to Hodes, it is with good reason that mounting attention has been paid to Alzheimer's disease: "The genes that appear to be responsible for some of the rare, familial, early-onset forms have been identified, although the mechanisms by which they influence disease remain to be elucidated. And most recently, a lot of excitement has been generated in the last year about the identification of the ApoE gene, which has been identified as an epidemiological risk factor for disease. "This is an important first step. It will ultimately allow an avenue by which we can understand the biology [of Alzheimer's] and, hopefully, eventually the cause of the disease, thus leading to diagnostic and, most importantly, therapeutic intervention." Another extramural program focuses on trying to unravel the nature of longevity and aging from a biological perspective. "The main thrust of almost everything we fund is aimed at trying to understand the basic processes that go on at the cellular and molecular levels that underlie the aging phenomenon," says Sprott, referring to the biology of aging program he heads. The "aging phenomenon" has two parts, explains Sprott: "those things that might be the aging processes themselves as well as those which have an influence on age-related phenomena, such as hip fractures and Alzheimer's." Elucidation of the underlying mechanisms of aging processes has become possible because of recent advances in molecular biological techniques, he says: "In the last eight to 10 years, modern molecular biology grew up and provided us with techniques that began to allow us to get answers." As an example, Sprott cites a recent NIA-funded study concerning the possible relationship between the telomere--a part of the human chromosome--and the lifespan of certain populations of cells. "There's been this recent discovery that every time the cell divides the telomere gets shorter. It's as if you're knocking off a little piece and the telomere length is in fact a counter and it can count how many times a cell line has doubled, and when it runs out the line dies." He says this finding is significant because of the possibility that there is a physical "counting mechanism" that would explain human mortality. Another aspect of research in Sprott's program is understanding the relationship among cell maintenance, aging, and genetics. "Inside the cell the job of certain genes is to maintain a very, very delicate balance between senescence, which must happen, vs. immortality. If the senescence genes become too active, they kill off cells, and if they aren't active enough, [the cells] become immortal, or cancerous, and the whole organism dies anyway," Sprott explains. NIA-funded investigators have found single genes that are responsible for maintaining this control over senescence. They call them longevity-assurance genes, or LAGs, according to Sprott. He also mentions that colleagues at the National Cancer Institute have found tumor-suppressor genes that are very similar in composition to LAGs. "What it looks like is that they may be the same genes arrived at from two different directions," says Sprott. "I think that what this says is that, as we understand the basic processes of aging, we're going to understand the basic processes of a lot of other things." Although much of NIA-funded work is devoted to basic biomedicine, another important facet of the NIA mission is to conduct holistic studies of human aging. One intramural program centered at NIA's Gerontology Research Center in Baltimore--the Baltimore Longitudinal Study--is the longest continually running scientific study on human aging. The study started in 1958 with 58 male subjects and was directed by the former National Heart Institute. It now includes more than 1,100 men and women ranging in age from 20 to 96. Its overall purpose is to follow individuals throughout their lifetimes in order to understand the process of aging in the human mind and body. Hodes describes the study as an "insightful venture that recognizes the importance of evaluating aging by studying individuals as they age over time rather than by comparing a given group of people who are young at a specific time with a group of people who are old at the same time." He says that the study has dramatically altered what researchers consider "normal aging." The study has dispelled stereotypes of what it means to grow old, such as the commonly held scientific notion that the amount of blood pumped per minute, or cardiac output, always decreases with advancing age. Now, according to information from the Baltimore study, gerontologists have revised their description of the aging heart. They have found that disease-free hearts in older individuals have a comparable cardiac output to that of younger people. So far the study has generally concluded that there is no single, simple standard to describe human aging. For more information on research grants offered by NIA, contact Miriam Kelty, associate director of NIA and director of the office of extramural affairs, NIH-NIA, Gateway 218, Bethesda, Md. 20892; (301) 496-9322. Fax: (301) 402-2945. The electronic mail address is: kelty@nihniagw.internet.gov.

Biomedical Researchers Step Up Efforts To Probe Mysteries of Aging

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