Guilt-Free Gluttony No Fantasy for Mice

BOSTON, Nov. 1 -- A study in mice is sure to raise grape expectations among overweight humans.

Researchers here say that padding the diet with resveratrol, a compound in the skin of grapes and in red wine, lets mice eat a high-calorie Big Mac-style diet without suffering many of the associated ill effects -- except to get fat.

Compared with animals on the same diet without the compound, the resveratrol-fed mice gained weight but lived longer, remained healthier, and had livers, blood vessels, and muscle tissue that was similar to those seen in mice fed an ostensibly healthier diet.

So reported David Sinclair, Ph.D., of Harvard Medical School online today in Nature. Dr. Sinclair said the effects in the mice were similar to those seen in other organisms, including yeast, flies, and fish. "If it doesn't work in humans," he said, "we might be the only exceptions on this planet."

Exactly how the compound works remains unclear, but Dr. Sinclair and colleagues suspect it affects the products of a family of genes known as SIR2 or sirtuin, they reported.

The finding is a proof-of-concept that a small, orally available molecule can mimic the life-extending properties of a calorie-restricted diet, which has been shown in many creatures to increase lifespan markedly, Dr. Sinclair said.

In the case of the mice, Dr. Sinclair and colleagues said, the increase in lifespan appears to be about 20%, although because not all of the experimental animals have died, it's too early to give an exact figure.

For the study, the researchers took year-old mice -- equivalent to about 40 in people -- and fed them either a standard healthy diet, a diet in which 60% of calories came from fat, or the high-fat diet with the addition of 22.4 mg/kg of resveratrol per day.

The dose is higher than that found in wine or other foods (a glass of red wine has only 0.3% of the relative resveratrol dose given to the gluttonous mice), but could be achievable in humans as a dietary supplement.

The study found:

• At 114 weeks of age, 58% of the high-fat mice had died, compared with 42% of those on either resveratrol or the standard diet.
• A whole genome analysis showed that the resveratrol mice had gene expression patterns that were similar to those seen in the standard-diet animals. Specifically, in the high-fat mice, 153 genetic pathways were significantly altered compared with the standard-diet animals, and the resveratrol opposed that effect in 144 of them.
• Mice on the high-fat diet had increased levels of insulin, glucose and insulin-like growth factor-1, while those getting resveratrol had levels parallel to those seen in the standard-diet animals.
• The hearts and livers of the high-fat mice had an abundance of fatty lesions, degeneration, and inflammation, but again the resveratrol mice had organs that were not distinguishable from those in the standard-diet animals.

The researchers measured the overall health and agility of the animals with a standard test, the length of time they could remain balanced on a rotating rod. At 15 months -- three months after they started on their diet -- the resveratrol animals had abilities similar to the other high-fat mice, and were significantly less able than the standard-diet animals.

But surprisingly, Dr. Sinclair and colleagues found, they got better as they aged, until a year after their started the diet, they were indistinguishable from the standard-diet mice. The high-fat animals, in the meantime, continued to perform poorly.

"Resveratrol shifts the physiology of mice consuming excess calories towards that of mice on a standard diet, modulates known longevity pathways, and improves health," Dr. Sinclair and colleagues concluded.

The findings suggest that "guilt-free gluttony might not be a fantasy," Matt Kaeberlein, Ph.D., and Peter Rabinovitch, M.D., Ph.D., of the University of Washington in Seattle added in an accompanying article entitled "Grapes versus gluttony."

But they said caution is indicated before people begin supplementing their diets with the compound in order to extend their lifespan. For one thing, they noted, it's still not clear if resveratrol will have the same effect in people, or even in mice fed a standard healthy diet rather than a high-calorie diet.

It's also not known what the long-term effects of the high doses used in the mice would be in humans, although resveratrol is commonly viewed as safe, they add.

They concluded, "For now, we counsel patience. Just sit back and relax with a glass of red wine. But if you must have a Big Mac, fries and apple pie, we may soon know if you should supersize that resveratrol shake."