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In lab, seeking secret of youth

Chemical abundant in red wine appears to slow aging in study

For millennia, scientists and charlatans alike have sought the pill or potion that would assure immortality -- or, at least, a more robust twilight.

Now, for the first time, researchers at Harvard Medical School have discovered that a chemical abundant in red wine appears to extend the life span of yeast and fruit flies dramatically by boosting the ability of microscopic cells to fend off the rigors of aging, a finding published yesterday in Nature's online edition.

And while a drug or dietary supplement for humans based on the discovery is years or even decades away, scientists in the field of longevity research predict that the Harvard finding will yield tantalizing clues into the ways we age, a subject that has remained largely mysterious and fraught with frustration.

"I'll be honest with you," said Dr. Bernard Roos, director of the Geriatrics Institute at the University of Miami School of Medicine. "We would be jealous of such a fine finding. These data are very convincing."

Likewise, hard-to-impress researchers at the National Institute on Aging were intrigued when they read that yeast treated with a chemical called resveratrol could live 80 percent longer, the key finding from a group directed by Harvard molecular geneticist David Sinclair.

"In 20 years, if it's right, then it wins the fundamental-breakthrough prize," said David Finkelstein, a top researcher at the federal institute. "But in 20 years, it could be nothing, and we will have forgotten about it. That's how science works."

The roots of Sinclair's discovery trace back to the 1930s, when scientists first recognized that feeding rats a low-calorie diet appeared to prevent the dread diseases of old age: cancer, heart disease, osteoporosis.

As some researchers touted the benefits of such a diet for humans, others began unraveling the biochemical mysteries of aging, hunting for ways to derive the same effects of a drastically reduced diet but without the sacrifice.

So the search began for what scientists call "longevity regulators," genes pivotal to warding off the consequences of aging.

"You can think of these so-called longevity regulators as guardians of the human cell," Sinclair said.

One particularly ferocious guardian is an enzyme known as sirtuin. Sinclair explained that sirtuin works like a traffic cop, directing other enzymes to travel to cells to aid in their repair, survival, and defense.

But, he wondered, what if sirtuin could be armed so that it would provide an even better defense?

To find out, Sinclair called on his partnership with a company called BIOMOL. The Pennsylvania biochemical concern has an extensive library of small molecules. The researchers had a hunch that they could find molecules that would act like matches thrown at sirtuin, causing it to burst into activity.

So the researchers used laboratory machinery to plunk thousands of different molecules into tiny wells filled with the human version of sirtuin. They would know they were on to something if a well suddenly glowed with yellow fluorescent light -- a sign that a molecule was spawning a reaction with sirtuin.

At first, they found two that did the trick. Then they isolated 15 more.

"That in itself was the first eureka moment," Sinclair said.

From that field of 17, they chose the molecules that best reacted with sirtuin, homing in on resveratrol. It heightened sirtuin's activity more than tenfold -- better than any other compound.

That, said Sinclair, marked eureka moment number two.

The third moment of discovery arrived when the researchers introduced varying amounts of resveratrol, or none, into petri dishes of yeast.

"One week into the experiment," Sinclair said, "I started to notice that some of the cells were living a lot longer than they normally would."

It turned out that the hardiest cells were, in fact, those treated with resveratrol. But, in a surprising finding, the lowest concentration of the chemical appeared to afford the most protection, leading Sinclair to conclude that while a little resveratrol might be a very good thing, too much might be harmful.

To begin to understand the implications of resveratrol for people, researchers exposed samples of human cells to gamma radiation and then treated some with the chemical to determine whether it would enhance survival. The treated cells did far better than those left untreated.

The Harvard researchers have expanded their research to fruit flies and worms, work they describe as encouraging. However, "we clearly don't know if this will work in anything more complex than a fly," Sinclair said. "That's my cautionary note."

Another warning: Sirtuin deactivates a gene that suppresses tumors, fueling concerns that heightening the enzyme's activity might predispose humans to cancer. But researchers know that animals placed on low-calorie diets, which have a comparable effect in stimulating sirtuin, have lower -- not higher -- rates of cancer.

Sinclair said his objective is not to achieve immortality, but to extend life spans by up to 10 years and to make those 10 years healthier.

The National Institute on Aging is not recommending that people take steps to increase resveratrol levels, such as drinking more red wine.

"Let me put it this way: I'm not taking it now," Finkelstein said. "But I wouldn't rule out that in 20 years, everybody will be."

As for Sinclair, he concedes: "Every time we've made another discovery, we've celebrated with red wine."

Stephen Smith can be reached at stsmith@globe.com.

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