Aug. 31, 1999 MADISON, WISC. - Scientists at the University of Wisconsin-Madison have, for the first time, profiled specific genetic changes during the aging of experimental animals, a discovery that could aid work to extend life span and preserve health.
The work conducted with mice combines a powerful new genetic technique with dietary restriction, the only known way to delay the aging process. The research will be published Friday, Aug. 27, in the journal Science.
The study is a milestone in aging research, providing scientists with an intimate look at the ebb and flow of genetic activity with age, and the roles individual genes play in the process of growing old.
Moreover, it reveals how a low-calorie diet, the only known method of slowing aging in several animal species, works at the most basic level to extend life span and preserve health. Such knowledge, used in concert with new technologies capable of rapidly surveying the activity of thousands of genes at once, promises to accelerate the development of drugs that mimic the age-retarding effects of a low-calorie diet, according to the Wisconsin scientists.
The Wisconsin team, led by Tomas A. Prolla, a UW-Madison professor of genetics, and Richard Weindruch, a UW-Madison professor of medicine, profiled the action of 6,347 genes. The team charted changes in genetic activity in two groups of mice, one group on a standard diet and another group whose diet had been reduced to 76 percent of the standard diet.
"This study has analyzed more genes with regard to aging than all previous studies combined," Prolla said of the study that surveyed 5 to 10 percent of the mouse genome using a "gene chip" -- a small glass plate containing DNA that, when read with a laser, quickly reveals activity levels for thousands of individual genes.
The Wisconsin group found that, with age, the activity of a very small number of genes -- less than 2 percent of those surveyed -- changed markedly. But those genes govern critical biological tasks such as stress responses, protein repair and energy production, and they changed in big ways.
"At the molecular level, normal aging looks like a state of chronic injury," said Prolla.
However, in a big step forward in understanding how a reduced-calorie diet works to dramatically slow the physical manifestations of aging, many of the same genes that exhibited changes in activity with aging in mice on a standard diet remained almost completely intact in mice on a reduced diet.
"This is a leap in our understanding of how caloric restriction works," said Weindruch, a leading authority in the field of diet and aging. "There hasn't been much consensus on how caloric restriction retards aging."
Over many years, studies of several animal species have consistently shown that reduced diets -- 25 to 30 percent less than a typical diet -- retard aging, extend life span and improve overall health in old age.
The new study, Weindruch said, tends to support the idea that caloric restriction works by slowing metabolism, the chemical processes by which living organisms and cells convert food to energy.
In the process of metabolism, some toxic byproducts are produced, damaging proteins and triggering a stress response that acts to repair damaged molecules and that seems to be governed by a few select genes. But with age, the body's ability to repair damaged proteins declines, possibly as a result of shrinking cellular energy levels.
"Taken as a whole, our results provide evidence that during aging there is an induction of a stress response as a result of damaged proteins and other macromolecules," the Wisconsin scientists write in Science. "This response ensues as the systems required for the turnover of such molecules decline, perhaps as a result of an energetic deficit in the cell."
The Wisconsin group plans to extend its studies to monkeys and humans. UW-Madison, at its Wisconsin Regional Primate Research Center, is the site of a decade-old study of rhesus macaques on a reduced-calorie diet.
The new study, according to Weindruch, is important not only because it provides a genetic map of aging, but because it shows the potential of harnessing gene chip technology to screen for the effects of drugs on the process of growing old.
"It gives us a molecular test to see if an agent can affect the rate of aging," said Weindruch. "There are lots of implications. If we can understand the molecular mechanisms, we could perhaps develop drugs that mimic the effects of caloric restriction."
Prolla and Weindruch have filed for a patent covering the use of gene chip technology in aging research through the Wisconsin Alumni Research Foundation.
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