- The Washington Times - Monday, June 13, 2005

Determining how genes influence the aging process is a slippery slope, scientists engaged in the quest say.

Even defining the word “aging” raises complications, according to David Schlessinger, chief of the Laboratory of Genetics at the National Institute on Aging, an arm of the government’s National Institutes of Health.

Because genes govern all life processes, there is no question of their role in the aging process. The challenge is in knowing how they behave alone and with each other and under what conditions, as well as how they react with the environment and with a person’s lifestyle. Mutation, or changes in genetic behavior, is a key factor.

“What you mean by aging, and the genetics of aging, varies with different people. It’s an unsettled question at present,” Mr. Schlessinger says. “There are many theories of aging, and they are all persuasive. In all cases, there is an environmental component, but the response has a genetic component.

“At one extreme, [aging] can be defined as the composite of a lot of pathological problems — some people develop kidney troubles [as they age], etc. The other view is that there is an independent process of aging quite apart from pathology. Depending on the type of definition, you have a lot of different factors involved.

“Aging becomes like pornography,” he concludes wittily. “You know it when you see it.”

His group is studying the regulation of menopause. Premature ovarian failure, or early menopause, affects about 1 percent of women and has many causes, he notes. His lab, however, has found one gene in a small group of women — among the “considerable fraction” who have a genetic cause — which can be recognized by women born with a droopy eyelid.

“This particular syndrome involves a gene that is extremely important for the formation of follicles,” he says.

Follicles in this context are small ovarian sacs containing an immature egg.

Aging also can be defined strictly as “increased maturity,” Mr. Schlessinger points out. “Not all gets worse as you get old. In many cases, creativity is stable or increases. That is a positive feature of aging that has not been studied much, although new techniques would make it possible.”

It’s necessary, however, to take into account increased susceptibility to disease, especially diseases normally linked with age, such as Alzheimer’s, osteoporosis, stroke, heart disease and cancer. The incidence of such diseases doubles roughly with every 10 years of life, he says.

“So the question is: What are genetic risk factors for those diseases? That really makes the study of the genetics of aging a study of aging-associated disease. That is a field of its own that has seen enormous progress.”

Scientists interested in what Mr. Schlessinger labels “the independent process of aging” have found that genes determine about 30 percent of a person’s longevity, the ability to live a longer life than is the norm.

About 50,000 Americans are centenarians — people living 100 years or more — according to census figures quoted in a 2004 report titled “Longevity Genes: Hunting for the Secrets of the Centenarians.” The study was published by the International Longevity Center-USA, a nonprofit group affiliated with New York’s Mount Sinai School of Medicine.

Much of the research being done in this area is credited to Dr. Thomas Perls and colleagues involved in the New England Centenarian Study at the Boston University School of Medicine. The people studied, who come from varied backgrounds, showed remarkable ability to have escaped or markedly delayed falling victim to aging-associated diseases. The researchers found that 90 percent of them were “functionally independent” until an average age of 92; 75 percent were the same at an average age of 95.

Lifestyle factors most likely helped, and random risk factors come into play. Few of the centenarians studied had a smoking history or were obese. As recorded on the Boston University Medical Campus Web site, studies showed a woman “who naturally has a child after the age of 40” has a four times greater chance of living to 100 compared to women who do not. This was seen as an indication that their reproductive systems — and the rest of their bodies — aged slowly.

Personal habits also might contribute.

“We are far too early in our understanding, even with the human genome now sequenced,” says Daniel Perry, director of the Alliance for Aging Research, a Washington-based public policy and advocacy organization that promotes funding in the field with an eye on increasing the quality of life for growing numbers of elderly persons.

He estimates that out of 140-some medical schools in the country, just about two dozen have “substantial” academic programs dealing with aging.

“It should be more of a growth area because we already know some specific genes that affect mutations affecting cardiovascular health, metabolism and thickness of arterial walls,” he says.

“Specific genes have been identified for many cancers and conditions such as Alzheimer’s. Mostly we know about genes that show up in families with early onset Alzheimer’s, and that is a very rare number.

The majority of Alzheimer’s is so-called random,” he says. “And we know there are certain genes that are expressed, or turned on, by calorie restrictions, so there does seem to be a link there. As we learn more about nongenetic factors — behavior and social inputs — we will be able to remodel aging to our great benefit.”

He compares progress at the moment to “bushmen piecing together a modern airplane by looking at the parts on the ground.”

“Aging is one of the most complex phenomena that occur to human beings, because it is part biology, behavior, environment, psychology and a complex interaction between all those,” he says.

“The genome project is in its earliest stages. We still don’t know what more than half of the genes do,” agrees Caleb E. Finch, professor of gerontology and neurobiology at the University of Southern California. He has been studying brain aging to learn what factors in older brain cells increase the risk of getting Alzheimer’s. He estimates that it could be “between 50 and 100 years before we understand how genes talk to each other.”

Dr. Robert Butler, a professor of geriatrics at Mount Sinai who is founding director of the National Institute on Aging and now heads the International Longevity Center, says that as a physician, he finds it disturbing to realize that some patients “who do everything wrong live forever and those who do the right things drop dead.” That’s the far outside edge of the curve, the one scientists are trying to close.

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