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Red-Wine Compound Keeps Chubby Mice Alive Longer, Study Finds

Obese mice lived 31 percent longer when their high-calorie diets were supplemented with resveratrol

Jacob Gaffney

Posted: Thursday, November 02, 2006

A compound naturally found in red wine can counteract an unhealthy diet in mice and improve the longevity of overweight rodents, according to research published online in Nature. If humans respond the same way to resveratrol, the polyphenol could eventually be used to fight the growing trend of obesity-related health problems.

Given in high doses, resveratrol increased the lifespan of mice on a high-calorie, high-fat diet by up to 31 percent compared to mice on the same diet minus the polyphenol. According to the study, although the mice given resveratrol were much heavier, they lived about as long as the control group of lean mice fed a standard diet.

"We've shown [resveratrol] activates genetic anti-aging pathways and extends lifespan of mice on a bad diet," said David Sinclair, a molecular biologist who led the study along with his Harvard Medical School colleague Joseph Baur. "We hope to find out next year if it extends the lifespan of lean, healthy mice."

Sinclair has been studying resveratrol's ability to extend the lifespan of simple organisms for a number of years, starting with his 2003 report on yeast, then following up with research on fruit flies and earthworms. (An Italian study released earlier this year found resveratrol lengthened the lifespan of tropical killifish.) He felt it was time to begin work on mammals and selected mice because the effects of a high-calorie diet on their quality of life would be easy to observe.

Resveratrol may extend longevity by preventing life-threatening ailments such as cancer and heart disease, Sinclair believes. The compound is abundant in a variety of plants (and is present in grape skins) as a mechanism that responds to stress. If a bug burrows through the skin of a grape, for example, resveratrol helps patch the hole. Previous research has uncovered a wide range of potential health benefits for resveratrol; among others, it contributes to lower cholesterol levels, alleviates some lung diseases, fights certain types of cancer and reduces the growth of skin melanomas.

Sinclair's team worked with "middle-aged" mice--about 1 year old at the onset of the experiment--separated into three, equal groups of 55 mice. One group served as a control, and the other two groups were fed a high-calorie diet, with 60 percent of the energy coming from fat. One of those groups received a resveratrol supplement, equivalent to 23 milligrams per kilogram of body weight. To put that amount into human terms, Sinclair said, "You would need to drink 100 or more glasses of red wine to reach the same resveratrol levels in the mice."

Over the next 24 months, the high-calorie mice grew fatter. The mice that didn't consume resveratrol eventually became lethargic and reluctant to hop onto the exercise wheel, and sometimes even off the wheel once placed there. The mice fed resveratrol grew chubby at about the same rate, but tended to be more active and exercise more.

For both groups on the high-calorie diet, the mice's body weight peaked at about 53 grams, around seven and a half months into the experiment. The mice on a regular diet tended to remain the same weight for the entire 24 months, between 30 to 35 grams.

At the end of the two-year period, more than 60 percent of the mice fed the high-calorie diet with resveratrol were still alive--a survival rate similar to that of the control group. In contrast, only 40 percent of the other obese mice remained alive. This translated into a 31 percent increase in lifespan, but the study noted, "we cannot confidently predict the ultimate mean lifespan expansion."

Livers of mice fed a standard diet (left), an unhealthy diet without resveratrol (center) and an unhealthy diet with resveratrol.

After the remaining mice were killed and examined, Sinclair found that those on the high-calorie diet had alarmingly enlarged livers and extremely high insulin levels in their blood plasma. However, the mice given resveratrol showed none of those predictors of diabetes, heart disease and liver disease; their blood glucose, insulin and cholesterol levels were close to those of the mice on a normal diet.

To further examine how resveratrol offsets the harmful effects of a high-calorie diet, the researchers performed a wide array of genome analysis on the genetic pathways of the mice. Supporting Sinclair's earlier work, they found that resveratrol works on mice by enhancing the activity of sirtuins. These enzymes regulate everyday organ functions--such as maintaining desirable levels of glucose, insulin and cholesterol-- by manipulating genes. Sirtuins are also responsible for the proper metabolism of fats and for cell survival.

In 2003, when Sinclair studied more than 20,000 molecules to see if they enhanced the activity of sirtuins, one molecule--resveratrol--clearly "emerged as the most potent."

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