Journal Reports Drug That Doubles Endurance

By NICHOLAS WADE

Given that some athletes will take almost anything to gain a one percent edge in performance, what might they do for a 100 percent improvement? That temptation is made somewhat more real by a report today in a leading journal about a drug that doubles the physical endurance of mice running on treadmills. And it could only be more tempting, because the drug in question has also been reported to extend the lifespan of mice.

An ordinary lab mouse will run about one kilometer — five-eights of a mile — on a treadmill before collapsing from exhaustion. But mice given resveratrol, a minor component of red wine and other foods, run twice as far.

They also have a reduced heart rate and energy-charged muscles, just as trained athletes do, according to an article published online in Cell by Johan Auwerx and his colleagues at the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France.

“Resveratrol makes you look like a trained athlete without the training,” Dr. Auwerx (pronounced OH-wer-ix”) said in an interview.

He and his colleagues said the same mechanism seems likely to operate in humans, based on their analysis, in a group of Finnish subjects, of the gene that is influenced by the drug.

Their rationale for testing resveratrol was evidence obtained three years ago that it could activate a genetic mechanism known to protect mice against the degenerative diseases of aging and to prolong their lifespan by 30 percent.

Dr. Auwerx, whose interest is in the genetic control of metabolism, decided to see if resveratrol would offset the effects of a high-fat diet, specifically the metabolic disturbances that are the precursors of diabetes and obesity, known as metabolic syndrome.

In his report, he and his colleagues say that very large doses of resveratrol protected mice from gaining weight and from developing metabolic syndrome.

Dr. Auwerx attributes this change in large part to the significantly increased number of mitochondria he detected in the muscle cells of treated mice.

Mitochondria are the organelles within the body’s cells that generate energy. With increased mitochondria, the treated mice were able to burn off more fat and thus avoid weight gain and decreased sensitivity to insulin, Dr. Auwerx said. He found that their muscle fibers had been remodeled by the drug into the type more prevalent in trained human athletes.

Dr. Ronald M. Evans, a leading expert on the hormonal control of metabolism at the Salk Institute, said that the report by Dr. Auwerx’s team had “shown very convincingly that resveratrol improves mitochondrial function” and fends off metabolic disease.

Dr. Evans described the study as “very important, because it is rare that we identify orally active molecules, especially natural molecules, that have such a broad-based, positive effect on a problem as widespread in society as metabolic disease.”

Dr. Ronald Kahn, director of the Joslin Diabetes Center in Boston, said the research would focus attention on the sirtuins, a recently discovered group of enzymes that resveratrol is believed to affect. Noting that he is a scientific advisor to Sirtris, a company developing drugs that activate the sirtuins, Dr. Kahn said, “Certainly, drugs that act on this class of proteins have the potential to have major effects on human disease.”

Dr. Auwerx’s study complements one published earlier this month by Dr. David Sinclair of the Harvard Medical School, who found that much more moderate doses of resveratrol protected mice from the metabolic effects of a high-calorie diet. Though his mice did not lose weight, they lived far longer than undosed mice that were fed the same high-calorie diet.

The two studies were started and performed independently, Dr. Auwerx said, though he obtained supplies of resveratrol from Sirtris, which was co-founded by Dr. Sinclair, and he has become a scientific advisor to the company.

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