It's well-worn joke among dieters that if you drink a diet soda with candy, the calories will cancel each other out. But it's actually possible to pull off that feat with red wine, or at least a component thereof: resveratrol.

The resveratrol in wine probably has no therapeutic benefits - one would have to drink oneself to death several times over before getting the blood levels that would lead to any life-extending effect. But it's a known anti-aging compound in the invertebrate world: It prolongs the lifespans of organisms like yeast, worms and fruit flies. Now, in the Nov. 2, 2006, issue of Nature, researchers showed that the compound can reverse some of the deleterious effects of a high-calorie diet in middle-aged mice - the first time such an effect has been demonstrated in a vertebrate.

Resveratrol activates a family of enzymes known as sirtuins, which are Class III histone deacetylases that cells activate to defend against stress. The sirtuins also are activated by caloric restriction, and it's been known for a long time that calorie restriction is theoretically one of the simplest ways to extend lifespan.

Of course, millions of children who have spent much of this week gathering and eating Halloween candy would probably claim that a short life on a high-calorie diet is better than a long one under constant caloric restriction. But adults like their sweet stuff too, so the search for a way to mimic the benefits of caloric restriction without actually having to eat less has been ongoing.

Several of the authors on the Nature paper - from the National Institute on Aging and Johns Hopkins University, both in Baltimore; the University of Sydney in Australia; Universidad Pablo de Olavide-CSIC in Sevilla, Spain; and the Salk Institute in La Jolla, Calif. - are either co-founders or employees of Sirtris Pharmaceuticals Inc., in Cambridge, Mass. Sirtris is testing the SIRT1 activator SRT501, a proprietary formulation of resveratrol with improved bioavailability, for its ability to fight diabetes; the compound is in Phase Ib trials.

Though the Nature paper focuses on resveratrol's anti-aging effects, Sirtris is not pursuing the compound as an anti-aging drug: Sirtris CEO Christoph Westphal told BioWorld Today that "we're not focused in any way" on fighting the effects of time. The main reason being that aging is not recognized as a disease by the FDA.

"We're focused on FDA-approved endpoints," he said. Sirtris also is not trying to develop SRT501 for the treatment of progerias, diseases characterized by abnormally accelerated aging, because "there's no proof that this mechanism would be therapeutically relevant."

Nevertheless, Westphal noted that Sirtris executives consider sirtuin activation to be a platform technology whose uses will not be restricted to diabetes. "Much like kinases in the 1980s, we are taking the view that sirtuins are a druggable class of enzymes," he said, and as such, manipulating them is a therapeutic approach "that deserves multiple shots on goal in various indications."

The company also is testing SRT501 in the treatment of MELAS syndrome, a rare mitochondrial disorder, and Westphal said that several of the sirtuins might turn out to be useful for treating cancer.

In the Nature paper, the researchers compared three groups of middle-aged mice - "the equivalent of a 40-year-old human," senior author David Sinclair told BioWorld Today. Groups of mice received either a standard lab chow diet, a diet high in fat and calories, or the same high-fat, high-calorie diet supplemented with 0.04 percent resveratrol.

Resveratrol had little effect on weight per se: Resveratrol-supplemented mice were much closer in weight to their peers on a high-calorie diet than those on standard lab chow. But on a variety of health measures - including insulin sensitivity, fat metabolism, and the ultimate one, survival - the opposite was true: Resveratrol-supplemented animals were more similar to mice eating lab chow than those eating a straightforward high-fat diet. Gene expression data also showed that resveratrol activated several anti-aging pathways.

Sinclair, assistant professor of pathology at Harvard Medical School, conceded that there still is controversy as to whether the sirtuins have the same effects in humans as they do in lower organisms, but also noted that "you can argue about the mechanisms, but it's nevertheless the first time a small molecule has been shown to activate an anti-aging pathway in a mammal."

"This has now been shown to work in a diverse group of organisms, ranging from fungi to fish to mice and rats," he said. "And from the point of view of a fungus, we're basically fish walking on land."