Source: Washington Post
Date: 24 August 2003

Scientists Find Way to Stimulate Anti-Aging Enzyme

By Rick Weiss
Washington Post Staff Writer

Scientists have found for the first time a way to rev up a potent "anti-aging" enzyme in living cells, an advance they said could speed the development of drugs to extend human life span and prevent a wide range of geriatric diseases.

The novel approach has significantly increased the life spans of yeast and human cells in laboratory dishes and extended the lives of flies and worms -- organisms that, on the level of molecular biology, age very much as humans do. Indeed, said the researchers, the compounds seem to have the same anti-aging effect as a drastic reduction in calories, the only strategy ever proven to extend life in mammals but one that most people find difficult to stick to.

It is too soon to say whether the latest findings will ever make the leap from the lab bench to the geriatrics clinic -- though some may choose not to wait: Of all the compounds the researchers tested, the one that boosted the anti-aging enzyme the most was resveratrol, an ingredient in red wine that's been credited with that beverage's ability to lower the risk of heart disease.

But the findings strengthen an increasingly popular notion among many scientists that the cellular enzymes at the core of the experiments -- called sirtuins -- are universal regulators of aging in virtually all living organisms and represent a prime target for new anti-aging drugs.

"It's looking like these sirtuins serve as guardians of the cell," said Harvard Medical School researcher David Sinclair, who led the new work published in yesterday's online edition of the journal Nature. "These enzymes allow cells to survive damage and delay cell death."

Now the race is on, Sinclair said, to find the most potent sirtuin stimulators -- or create synthetic ones -- and test their ability to extend the lives not only of cells, flies and worms but also of mice, monkeys and humans. Other researchers were more cautious, warning that aging is a complex and poorly understood process that is unlikely to be slowed by any single drug. As promising as the research may appear today, they said, sirtuin would not be the first fountain of youth to prove a mirage.

"Let's face it, aging isn't the same in humans and yeast," said Jef Boeke, a yeast geneticist at the Johns Hopkins University School of Medicine. Besides, he said, sirtuins are potent molecules and in cranking them up "one would have to be very careful about potential side effects." The new study caps a three-year string of discoveries involving sirtuins (pronounced sir-TOO-ins), a class of enzymes that are found in virtually every organism, including bacteria, plants and people. As with all enzymes, their job is to promote essential biochemical reactions inside cells.

At first scientists thought sirtuins spent most of their time pulling key molecules off the proteins that surround DNA -- part of the process by which cells turn their genes on and off.

But recently researchers learned that sirtuins are also involved in processes with much more medical -- and commercial -- potential: They are part of a feedback system that enhances cell survival during times of stress, especially if that stress is a lack of food.

For years researchers have known that life span can be extended by 50 percent or more in many kinds of creatures, including flies, worms and mice, if the animal is fed a diet that is nutritious but contains about 30 percent fewer calories than usual. Recently scientists found that the life-extending benefits of calorie restriction do not occur if the animal has been genetically altered to lack sirtuins, indicating these enzymes are crucial to this process.

Now scientists are coming to understand sirtuins' role in that life-extending response. In people, for example, they seem to halt the normal cellular cycle that ends with old cells committing suicide and instead help rejuvenate them by beefing up their DNA repair processes and stimulating production of protective antioxidants.

"What we think is that if a cell is at a point of deciding whether to live or die, these sirtuins push toward the survival mode and let the cell try a little harder and longer to fix itself," said Sinclair, who has a financial stake in a new effort to develop sirtuin-related products with BIOMOL Research Laboratories of Plymouth Meeting, Pa.

Leonard Guarente, a researcher at the Massachusetts Institute of Technology in Cambridge, is also enthusiastic about the compounds' potential as anti-aging aids.

"We're very keen on the idea that this is it" -- that sirtuins are the central regulator of the aging process -- Guarente said. He is a founder of Elixir Pharmaceuticals of Cambridge, Mass., which, like Sinclair and BIOMOL, hopes to capitalize on chemicals that can boost sirtuin activity.

The goal is to make drugs or nutritional supplements that can fool the body into thinking it's living on a radically calorie-reduced diet, in effect allowing people to eat their cake and live longer too.

The new report from Sinclair's team is the first to show that it is indeed possible to tweak the sirtuin pathway. The group screened a large number of biologically active chemicals -- simple compounds that can be made into drugs with relative ease. They found several that increase sirtuin activity at least two-fold, including resveratrol.

When they added some of these compounds to yeast cells growing in culture dishes, the cells produced 70 percent more daughter cells than normal -- a common measure of yeast youthfulness.

Human cells seemed to benefit too. Those treated with sirtuin boosters enjoyed long lives in laboratory dishes even after being exposed to ionizing radiation, which damages DNA and usually shortens a cell's lifespan.

And in experiments not yet completed, Sinclair said, the compounds have shown evidence of being able to extend the life spans of two full-blown organisms: the soil-dwelling nematode worm known as C. elegans and the common fruit fly. Both are popular stand-ins with scientists trying to understand human biological processes.

Sinclair said his group plans to start feeding sirtuin boosters to mice in the next few months and then move up to testing in monkeys. The immediate goal in people would be to slow the progression of diseases of aging such as Alzheimer's, since a more generic slowing of the aging process could take decades to prove.

But others warned against exaggerated expectations. Richard Weindruch, a gerontologist and expert in caloric restriction at the University of Wisconsin in Madison, said the work was "very interesting and deserves to be carefully explored in mammals." But he questioned the relevance of the yeast experiments -- which, strictly speaking, measured not life span but the number of times a yeast cell could divide and produce daughter cells.

"Clearly, numbers of generations are related to time, but it's not the same in my mind as following a single animal over its lifetime." Indeed, Weindruch noted, "What they are really looking at here is increased proliferative capacity," which he and others noted is something akin to what cancer is.

David Finkelstein, an expert in metabolic regulation at the National Institute on Aging, which funded some of Sinclair's work, said the work was "very nice science" but also warned against leaping to conclusions. "We have results in a lower organism," he said, "and at this point there's a lot of hand waving because of how little we know."

Finkelstein also advised against taking the resveratrol results too literally.

"Would the National Institute on Aging recommend you drink red wine every day? The answer is 'no'," he said. "If you were to add a glass of red wine every day without changing your caloric intake, you're going to gain weight. And we know -- we know -- that if you gain weight that's going to be harmful while this 'benefit' is a benefit that may or may not occur."

"People are always looking for a quick fix," Finkelstein said. "Tell people to eat a healthy diet."
Sirtuins, resveratrol and red wine
Does resveratrol enhance longevity?
Supercentenarians, Longevity and Life-Extension

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