Substance in Red Wine Could Extend Life, Study Says

By NICHOLAS WADE

Can you have your cake and eat it? Is there a free lunch after all, red wine included? Researchers at the Harvard Medical School and the National Institute of Aging report that a natural substance found in red wine, known as resveratrol, offsets the bad effects of a high-calorie diet in mice and significantly extends their lifespan.

Their report, published electronically today in Nature, implies that very large daily doses of resveratrol could offset the unhealthy, high-calorie diet thought to underlie the rising toll of obesity in the United States and elsewhere, should people respond to the drug as mice do.

Resveratrol is found in the skin of grapes and in red wine and is conjectured to be a partial explanation for the French paradox, the puzzling fact that people in France to enjoy a high-fat diet yet suffer less heart disease than Americans.

The researchers fed one group of mice a diet in which 60 percent of calories came from fat. The diet started when the mice, all males, were 1 year old, which is middle-aged in mouse terms. As expected, the mice soon developed signs of impending diabetes, with grossly enlarged livers, and started to die much sooner than mice fed a standard diet.

Another group of mice was fed the identical high-fat diet but with a large daily dose of resveratrol. The resveratrol did not stop them from putting on weight and growing as tubby as the other fat-eating mice. But it averted the high levels of glucose and insulin in the bloodstream, which are warning signs of diabetes, and it kept the mice's livers at normal size.

Even more strikingly, the substance sharply extended the mice's lifetimes. Those fed resveratrol along with the high-fat diet died many months later than the mice on high fat alone, and at the same rate as mice on a standard healthy diet. They had all the pleasures of gluttony but paid none of the price.

The researchers, led by David Sinclair and Joseph Baur at the Harvard Medical School and by Rafael de Cabo at the National Institute of Aging, also tried to estimate the effect of resveratrol on the mice's physical quality of life. They gauged how well the mice could walk along a rotating rod before falling off, a test of their motor skills. The mice on resveratrol did better as they grew older, ending up with much the same staying power on the rod as mice fed a normal diet.

The researchers hope their findings will have relevance to people too. Their study shows, they conclude, that orally taken drugs "at doses achievable in humans can safely reduce many of the negative consequences of excess caloric intake, with an overall improvement in health and survival."

Several experts said that people wondering if they should take resveratrol should wait until more results were in, particularly safety tests in humans. "It's a pretty exciting area but these are early days," said Dr. Ronald Kahn, president of the Joslin Diabetes Center in Boston. Information about resveratrol's effects on human metabolism should be available a year or so, he said, adding, "Have another glass of pinot noir — that's as far as I'd take it right now."

The mice were fed a hefty dose of resveratrol, 24 milligrams per kilogram of body weight. Red wine has about 1.5 to 3 mg of resveratrol per liter, so a person would need to drink from 10 to 20 bottles of red wine a day to get such a dose. Whatever good the resveratrol might do would be negated by the sheer amount of alcohol.

Dr. Richard Hodes, director of the National Institute of Aging, which helped support the study, also said that people should wait for the results of safety testing. Substances that are safe and beneficial in small doses, like vitamins, sometimes prove to be harmful when taken in high doses, he said.

One person who is not following this prudent advice, however, is Dr. Sinclair, the chief author of the study. He has long been taking resveratrol, though at a dose of only 5 milligrams per kilogram. Mice given that amount in a second feeding trial have shown similar, but less dramatic, results as those on the 24 milligram a day dose, he said.

Dr. Sinclair has had a physician check his metabolism, because many resveratrol preparations contain possibly hazardous impurities, but so far no ill effects have come to light. His wife, his parents, and "half my lab" are also taking resveratrol, he said.

Dr. Sinclair declined to name his source of resveratrol. Many companies sell the substance, along with claims that rivals' preparations are inactive. One such company, Longevinex, sells an extract of red wine and knotweed that contains an unspecified amount of resveratrol. But each capsule is equivalent to "5 to 15 5-ounce glasses of the best red wine," the company's Web page asserts.

Dr. Sinclair is the founder of a company, Sirtris Pharmaceuticals, that has developed several chemicals designed to mimic the role of resveratrol but at much lower doses. Sirtris has begun clinical trials of one of these compounds, an improved version of resveratrol, with the aim of seeing if it helps control glucose levels in people with diabetes. "We believe you cannot reach therapeutic levels in man with ordinary resveratrol," said Dr. Christoph Westphal, the company's chief executive.

Behind the resveratrol test is a considerable degree of scientific theory, some of it well established and some yet to be proved. Dr. Sinclair's initial interest in resveratrol had nothing to do with red wine. It derived from work by Leonard Guarente of the Massachusetts Institute of Technology, who in 1955 found a gene that controlled the longevity of yeast, a single-celled fungus. Dr. Guarente and Dr. Sinclair, who had come from Australia to work as a post-doctoral student in Dr. Guarente's lab, discovered the mechanism by which the gene makes yeast cells live longer. The gene is known as sir-2 in yeast, sir standing for silent information regulator, and its equivalent in mice is called SIRT-1.

Dr. Guarente then found that the gene's protein needs a common metabolite to activate it and he developed the theory that the gene, by sensing the level of metabolic activity, mediates a phenomenon of great interest to researchers in aging, the greater life span caused by caloric restriction.

Researchers have known since 1935 that mice fed a calorically restricted diet — one with all necessary vitamins and nutrients but 40 percent fewer calories — live up to 50 percent longer than mice on ordinary diets.

This low-calorie-provoked increase in longevity occurs in many organisms and seems to be an ancient survival strategy. When food is plentiful, live in the fast lane and breed prolifically. When famine strikes, switch resources to body maintenance and live longer so as to ride out the famine.

Researchers had long supposed that the increase in longevity was a passive phenomenon: during famine or on a low-calorie diet, organisms would have lower metabolism and produce less of the violent chemicals that oxidize tissues. But Dr. Guarente and Dr. Sinclair believed that longer life was attained by an active program that triggered specific protective steps against the diseases common in old age. It was because these diseases were averted in calorie restriction, they believed, that animals lived longer.

Most people find it impossible to keep to a diet with 40 percent fewer calories than usual. So if caloric restriction really does make people as well as mice live longer — which is plausible but not yet proved — it would be desirable to have some drug that activated the SIRT-1 gene's protein, tricking it into thinking that days of famine lay ahead.

In 2003 Dr. Sinclair, by then in his own lab, devised a way to test a large number of chemicals for their ability to mimic caloric restriction in people by activating SIRT-1. The champion was resveratrol, already well known for its possible health benefits.

The experiment reported today tests one aspect of caloric restriction, the reduction in metabolic disease. Calorically restricted mice also suffer less cancer and heart disease, and there is some evidence that neurodegenerative diseases are also held at bay.

Critics point out that resveratrol is a powerful chemical that acts in many different ways in cells. The new experiment, they say, does not prove that resveratrol negated the effects of a high-calorie diet by activating SIRT-1. Indeed, they are not convinced that resveratrol activates SIRT-1 at all. "It hasn't really been clearly shown, the way a biochemist would want to see it, that resveratrol can activate sirtuin," said Matt Kaeberlein, a former student of Dr. Guarente who now does research at the University of Washington in Seattle. Sirtuin is the protein produced by the SIRT-1 gene.

Dr. Sinclair said experiments at Sirtris have essentially wrapped up this point. But they have not yet been published, so under the rules of scientific debate he cannot use them to support his position. In his Nature article he therefore has to concede, "Whether resveratrol acts directly or indirectly through Sir2 in vivo is currently a subject of debate."

Given that caloric restriction forces a tradeoff between fertility and lifespan, resveratrol might be expected to reduce fertility in mice. For reasons not yet clear, Dr. Sinclair said he saw no such effect in his experiment.

If resveratrol does act by prodding the sirtuins into action, then there will be much interest in the new class of sirtuin activators now being tested by Sirtris. Dr. Westphal, the company's chief executive, has no practical interest in the longevity-promoting effects of sirtuins and caloric restriction. For the Food and Drug Administration, if for no one else, aging is not a disease and death is not an end-point. The F.D.A. will only approve drugs that treat diseases in measurable ways, so Dr. Westphal hopes to show his sirtuin activators will improve the indicators of specific diseases, starting with diabetes.

"We think that if we can harness the benefits of caloric restriction, we wouldn't simply have ways of making people live longer, but an entirely new therapeutic strategy to address the diseases of aging," Dr. Guarente said.

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