By Rob Stein
Washington Post Staff Writer
Friday, November 17, 2006
A component of red wine recently shown to help lab mice live longer also protects animals from obesity and diabetes and boosts their physical endurance, researchers reported yesterday.
The new research helps confirm and extend the possible benefits of the substance, resveratrol, and offers new insight into how it works -- apparently by revving up the metabolism to make muscles burn more energy and work more efficiently. Mice fed large doses could run twice as far as they would normally.
In addition, the scientists for the first time produced evidence linking the biological pathway activated by the substance to human physiology, showing that the same genetic switch resveratrol mimics seems to naturally endow some people with faster metabolisms.
"It's very exciting," said Johan Auwerx, a professor of medicine at the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France, who led the research being published online and in the Dec. 15 issue of the journal Cell. "This compound could have many applications -- treating obesity and diabetes, improving human endurance, helping the frail. There's a lot of potential."
Auwerx and other researchers cautioned much more research is needed to study the compound and similar agents, especially to see if the approach is safe for people. Humans would have to take hundreds of resveratrol pills sold in health food stores or drink hundreds of glasses of wine a day to get equivalent levels of the substance tested on the mice, neither of which would be safe. But the new research adds to the growing enthusiasm about the approach, experts said.
"This is the first example of a drug that can apparently affect the whole aging process, not just this disease or that disease but the mechanisms that allow these diseases to occur," said Felipe Sierra of the National Institute on Aging. Others agreed.
"The idea of giving someone anything to improve their longevity until very recently would have been considered snake oil or crockery," said Stephen L. Helfand of Brown University. "But here we are possibly being able to move out of the laboratory from extending the lives of flies, worms and mice to humans a lot sooner than we thought."
Resveratrol is found in red wine, grapes and other foods, including peanuts. Scientists suspect it may help explain why French people have fewer heart attacks despite their high-fat diets, and why eating a very low-calorie diet can extend the life spans of many species.
Researchers recently demonstrated resveratrol did the same thing for mammals in a study involving laboratory mice. High doses of the compound neutralized the ill effects of a high-fat, high-calorie diet, extending the animals' life spans and preventing adverse effects on their livers and hearts.
In the new research, researchers fed mice even higher dosages -- 10 times as high -- along with a high-fat, high-calorie diet. Resveratrol significantly reduced the animals' chances of becoming obese and of developing early signs of diabetes. The mice appeared to experience no adverse side effects.
Additional experiments on the animals' cells indicate the substance works by increasing the activity of an enzyme known as SIRT1, boosting the number and activity of structures inside cells called mitochondria, the researchers said. Mitochondria are like power plants inside cells, burning fat and providing energy. They tend to get revved up by exercise, and deteriorate with age.
Mice fed resveratrol had more muscle tissue resembling that of a trained athlete, sharply increasing their endurance. They could run twice as far before collapsing as mice that did not receive the substance.
"In the elderly, many of the disorders that occur with aging occur because of muscle weakness," Helfand said. "This makes you wonder what would happen if you took an older individual and revved up their mitochondria with resveratrol. You could imagine that it could have a profound positive effect on their health."
Auwerx also wondered whether the substance might be abused by professional athletes. "That could be the illicit use of these compounds -- as performance boosters," he said.
In addition to the mouse experiments, the researchers also produced evidence supporting the theory that SIRT1 plays a key role in longevity in humans in an accompanying analysis of 123 Finnish adults. The subjects born with certain variations of the SIRT1 gene had faster metabolisms, naturally burning energy more efficiently, indicating the same pathway works in humans, too.
"We've all seen people who are thin no matter what they eat or do -- that have good metabolisms versus bad. This may help explain that," said Christoph Westphal, chief executive of Sirtris Pharmaceuticals in Cambridge, Mass., which sponsored and helped conduct the study as part of its efforts to develop drugs based on the approach.
The company is testing a potent version of resveratrol on diabetic humans and hopes to eventually test it and similar compounds as a treatment for a variety of diseases.
"We are targeting a gene that controls the aging process," Westphal said. "Many diseases have a link to the aging process. So these kinds of drugs clearly have the potential to treat several diseases of aging. It's very exciting."
Other researchers said the new work was interesting, but they remained cautious, particularly about making the link to SIRT1.
"I think that's part of the story but that it would be a mistake to think that's all that's going on," said Matt Kaeberlein of the University of Washington. Other biological pathways also probably play important roles in the aging process and diseases of aging, he said.