The New York Times
November 17, 2006
By NICHOLAS WADE
A drug already shown to reverse the effects of obesity in mice and make them live longer has now been shown to increase their endurance as well.
Experts say the finding may open up a new field of research on similar drugs that may be relevant to the prevention of diabetes and other diseases.
An ordinary laboratory mouse will run one kilometer 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 energy-charged muscles and a reduced heart rate, just as trained athletes do, according to an article published online in Cell by Johan Auwerx and 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 seemed likely to operate in humans, based on 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 initiate a genetic mechanism known to protect mice against the degenerative diseases of aging and prolong their life spans by 30 percent.
Dr. Auwerx, whose interest is in the genetic control of metabolism, decided to see whether resveratrol would offset the effects of a high-fat diet, specifically the disturbances known as metabolic syndrome that are the precursors of diabetes and obesity. In his report, he and his colleagues say very large doses of resveratrol protected mice from weight gain and developing the syndrome.
Dr. Auwerx attributes this in large part to the significantly increased number of mitochondria he detected in the muscle cells of treated mice.
Mitochondria are the organelles in the body’s cells that generate energy. With extra mitochondria, the treated mice were able to burn more fat and thus avoid weight gain and decreased sensitivity to insulin, Dr. Auwerx said. He found their muscle fibers had been remodeled by the drug into the type more prevalent in trained human athletes.
Dr. Ronald M. Evans, an expert on the hormonal control of metabolism at the Salk Institute, said the report by Dr. Auwerx’s team had “shown very convincingly that resveratrol improves mitochondrial function” and fends off metabolic disease. He 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 which is as widespread in society as metabolic disease.”
Dr. Ronald Kahn, director of the Joslin Diabetes Center in Boston, said this research would focus more attention on a recently discovered group of enzymes called sirtuins that resveratrol is believed to affect.
Noting that he is a scientific adviser to Sirtris, a company developing drugs that activate sirtuins, Dr. Kahn said that “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 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 the undosed mice fed the same 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 has become a scientific adviser to it.
A drug that prolongs life, averts degenerative disease and makes one into a champion athlete sounds almost too good to be true, especially if all or even some of its properties should turn out to apply to people.
Dr. Christoph Westphal, Sirtris’s chief executive, replied to this objection with a question, “Is it too good to be true that when you are young you get no disease?”
Dr. Westphal said he believed that the activation of sirtuins was what kept the body healthy in youth, but that these enzymes became less powerful with age. This is the process that is reversed by resveratrol and, he hopes, by the more powerful sirtuin activator drugs that his company has developed, though many years of clinical trials will be needed to prove they work and are safe.
The buzz over sirtuin activators has infected scientists who do research on the aging process, several of whom are already taking resveratrol. Dr. Sinclair has been swallowing resveratrol capsules for three years and has said his parents and half the members of his laboratory do the same. So does Dr. Tomas Prolla at the University of Wisconsin, who said, “The fact that investigators in the field are taking it is a good sign there is something there.”
But many others, including Dr. Leonard Guarente of M.I.T., whose 15-year study of sirtuins has laid the basis for the field, say it is premature to take the drug.
It was after working in his laboratory as a postdoctoral student that Dr. Sinclair found in 2003 that resveratrol was a sirtuin activator. Though resveratrol has long been known to be an ingredient of red wine and other foods, its presence there is minuscule compared with the doses used in experiments.
Dr. Sinclair dosed his mice daily with 22 milligrams of resveratrol per kilogram of weight, and Dr. Auwerx used up to 400 milligrams. No one can drink enough red wine to obtain such doses.
Resveratrol is sold as capsules that contain extracts of red wine and giant knotweed, a plant found in China. The company Longevinex makes capsules containing 40 milligrams of resveratrol that are used by several researchers. Longevinex’s president, Bill Sardi, said demand had increased by a factor of 2,400 since Nov. 1. But even Longevinex’s capsules would have to be taken in almost impossible quantities to attain doses equivalent to those used in the mice.
Whether much lower doses than those used in the experiments would benefit athletic performance is not clear, Dr. Evans of the Salk Institute said. And higher doses may not be as safe as the small amounts found in foods and nutraceuticals, he added.
Scientists’ rule of thumb is to believe nothing until it has been confirmed in at least one other laboratory. The Sinclair and Auwerx experiments, though not the same, both point to powerful beneficial effects of resveratrol. But many of the details remain up in the air, and almost all hopes about resveratrol, especially for people, remain subject to revision.
The science of the field is still in flux, as many central details are unclear. The main theory developed by Dr. Guarente and others is that sirtuins sense the level of energy expenditure in living cells and switch the body’s resources from reproduction to tissue maintenance when food is low.
This is an ancient strategy, Dr. Guarente believes, intended to let an organism live through famines and postpone breeding until good times return. The switch to tissue maintenance involves specific action that would stave off the major degenerative diseases of aging like cancer, diabetes, heart disease and degeneration of brain cells.
One major uncertainty is whether resveratrol in the mice experiments even acts through sirtuins, supporting the theory, or in some other way.
Dr. Auwerx cited new evidence that resveratrol did activate sirtuins, but Dr. Evans said the case was not yet convincing.
Dr. Auwerx theorizes that resveratrol activates sirtuin, which in turn activates a substance known as PGC1-alpha in a manner described last year by Dr. Bruce Spiegelman, an expert on fat metabolism at the Harvard Medical School. Subsequent actions by PGC1-alpha then stimulate cells to produce more mitochondria. In an e-mail message, Dr. Spiegelman described Dr. Auwerx’s paper as “pretty good.”
Increased energy production by mitochondria generates dangerous reactive chemicals that are known to damage cells. So it has long been puzzling that exercise, in which extra energy is expended, is good for health, not bad. The answer, Dr. Auwerx suggested, may have been provided by Dr. Spiegelman, who reported in the journal Cell last month that PGC1-alpha not only increases mitochondria but at the same time also generates extra chemicals that detoxify the energy byproducts.