Chemical may lengthen life

An ingredient in red wine extends lifespan and alleviates disease when fed in huge quantities to obese mice, even though the mice remain fat, researchers reported today in the online edition of the journal Nature.

To reach an equivalent dosage, a human would have to drink about 20 bottles of red wine per day.

The chemical, called resveratrol, has previously been found to have life-prolonging effects on yeast, roundworms, flies and fish.

"The fact that you can see such an effect over millions of years of evolutionary differences … bodes extremely well for the likelihood that this is going to work in other organisms," including humans, said Dr. Stephen L. Helfand of Brown University, who was not involved in the research.

The National Institute on Aging, which funded the study, is planning a trial of resveratrol in rhesus monkeys to determine whether the results in mice can be replicated in primates.

And Sirtris Pharmaceuticals Inc. of Cambridge, Mass. — a company founded by the lead researcher of the study — has begun human trials of a related, more potent compound to treat Type 2 diabetes.

"This appears to have a lot of potential," said Dr. Rafael de Cabo of the National Institute on Aging, a coauthor of the paper.

But experts warned against self-medicating with resveratrol, a food supplement that is widely available on the Internet and in health food stores.

The dosages used in the mouse study were hundreds of times greater than those found in wine and other foods, said Dr. Richard J. Hodes, director of the aging institute, and "we still have much to learn about resveratrol's safety and effectiveness in humans."

The products commercially available are also unregulated, so some do not contain the advertised doses of the drug and others have been shown to be contaminated with undesirable materials.

"For now, we counsel patience," wrote Dr. Matt Kaeberlein and Dr. Peter S. Rabinovitch of the University of Washington in an editorial accompanying the report.

The researchers, led by Harvard University pathologist David A. Sinclair, studied 165 male mice beginning when they were 1 year old, the equivalent of middle-aged humans. A third of them were given a healthy diet, a third were given a diet high in calories and fats, and a third were given the high-fat diet plus resveratrol.

Both groups fed the high-fat diet became fat, but those receiving resveratrol were much healthier, the team reported. The levels of glucose and insulin in their bloodstreams remained normal, while levels in the control group rose dramatically, presaging diabetes and other problems.

The livers of mice receiving the supplement remained at normal size, while those of the control group doubled in size and weight and showed evidence of dysfunction. Heart tissue of the resveratrol animals was also healthier. Animals receiving the supplement also had nearnormal mobility on standard tests of agility that are usually failed by obese animals.

By the time the animals were 114 weeks old, 58% of those receiving only the high-fat diet had died, compared with 42% of those receiving the supplement and those on a normal diet.

"The molecule prevented most, if not all, of the negative side effects of being obese," said Sinclair, who is a director of Sirtris. "As a consequence, they lived just as long as lean mice."

Added Helfand, who is not associated with any company in the field, "This is the first real intervention that seems like it might work."

Resveratrol occurs naturally in low concentrations in grape skin, peanuts and some berries. It is a strong antioxidant, and researchers have widely speculated that it could be partially responsible for the so-called French paradox — the observation that the French have a low rate of heart disease even though they consume a high-fat diet.

More than half a century of research by biologist Leonard P. Guarente of MIT, Sinclair and others have also linked it to a gene called SIRT1 in mice. Resveratrol activates SIRT1, which in turn stimulates a plethora of intracellular pathways that suppress the detrimental effects of obesity.

Removal of the gene or its equivalent from yeast, fish, worms and flies completely blocks the life-extending benefits of resveratrol. Sinclair, who said he takes resveratrol supplements, is now working to show that the same effect occurs in mice.

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thomas.maugh@latimes.com