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Fountain of Youth, with caveats

Resveratrol helps hearts in mice, but doesn’t reproduce all the benefits of low-calorie diets

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11:09am, July 3, 2008
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A substance found in red wine and touted as the chemical equivalent of the fountain of youth probably acts more like a wellspring of health — with warning signs.

Resveratrol, as the chemical is known, does a pretty good job of mimicking some age-defying effects found in studies of animals on calorie-restricted diets. But the substance doesn’t make animals live longer, a new study shows.

At the same time, boosting levels of a key enzyme thought to be responsible for resveratrol action and for the life-extending properties of calorie restriction does protect mice fed high-fat diets from heart problems.

But a third group of researchers warns that more activity of the enzyme, called SirT1, may make brain cells vulnerable to damage.

Some scientists are optimistic that in the near future a pill with resveratrol or something like it could provide the health benefits of a very low-calorie diet. But the new research indicates the drug and the diet regimen don’t necessarily work the same way.

“You have to carefully study the reality, and the reality is, it’s complicated,” says Valter Longo, a molecular geneticist at the University of Southern California’s AndrusGerontologyCenter.

For instance, two new studies show that each organ in the body may react differently to calorie restriction, to chemical mimics such as resveratrol, or to different actions of key proteins involved in controlling aging.

Those proteins, called sirtuins, are a group of enzymes found in organisms from bacteria to humans, which have been shown to regulate aging in yeast, roundworms and fruit flies. The proteins were named for the yeast protein Sir2, the first member of the family discovered.

Increasing levels of the mouse sirtuin, SirT1, prevents mice from developing heart problems and fatty livers even when they are fed high-fat diets, researchers at the University of Cincinnati College of Medicine and the SpanishNationalCancerResearchCenter in Madrid reported June 30 in Proceedings of the National Academy of Sciences. These mice with higher levels of SirT1 eat more but also burn more calories than do mice with normal levels of the enzyme.

But Longo’s group reported in the July Cell Metabolism that SirT1 may affect the brain differently. Neurons grown in the laboratory were sensitive to oxidative damage when they made normal amounts of SirT1, but reducing the amount of the enzyme helped the brain cells better resist stress.

“This is backwards,” says Leonard Guarente, a molecular and cellular biologist at MIT. Sirtuins are generally thought to protect cells against oxidative damage believed to play a part in aging. Guarente was not involved in any of the current studies, but his lab pioneered studying aging in yeast. “It’s intriguing, but it will take a little more time to figure out what it means in the context of other evidence to the contrary,” he says.

Mice can’t dispense with SirT1 entirely, though. Longo’s group found that mice from which the SirT1 gene was removed entirely died young. Calorie restriction did not lengthen their lives as it does for yeast lacking the similar gene, Sir2.

If SirT1 really makes neurons vulnerable, that’s potentially bad news for resveratrol. The chemical is found in small amounts in grapes, red wine and other foods and is thought to be the component in red wine responsible for the “French paradox” —in which people who eat a high-fat diet are protected from heart disease by consuming wine. Resveratrol has been shown to keep obese mice healthy enough to live a normal life-span (for a mouse). It has been thought to work in the same way as calorie restriction — by activating sirtuins. Sirtuins then modify other proteins, which, in turn, regulate genes involved in inflammation, immunity, stress responses and other processes of aging.

Indeed, an international group of researchers led by Rafael de Cabo at the U.S. National Institute on Aging reported in the July Cell Metabolism that mice fed resveratrol had similar patterns of gene activity as mice fed only every other day. The resveratrol-treated mice had better bone health, less cataract formation and improved coordination compared with other mice their age. Resveratrol also lowered the mice’s cholesterol and made their hearts function better compared with aged mice fed a standard diet. The findings echo others showing the health benefits of calorie restriction and of increased levels of SirT1.

Unfortunately, “the health benefits resveratrol gives these mice are not the things they are dying of,” de Cabo says. Mice generally die of cancer, not heart disease the way humans do. The mice don’t live longer when given resveratrol probably because the chemical doesn’t fight cancer the way calorie restriction seems to.

So far, resveratrol has shown no toxic side effects either in animal or human studies, de Cabo says. And while he takes Longo’s findings seriously, he says resveratrol is likely to have other actions besides just increasing SirT1 activity.

In fact, Tomas Prolla of the University of Wisconsin–Madison and colleagues suggest that resveratrol doesn’t work through SirT1 at all. In a paper published June 4 in PLoS ONE, Prolla’s group reports that resveratrol mimics some of the effects of calorie restriction, but works differently in some crucial ways, such as in how it regulates glucose uptake by muscles. That process is important in the development of diabetes and other medical problems. The compound did not prevent or slow down tumors in the mice.

But the group demonstrated that even at very low doses, resveratrol is a powerful protector of the heart.

To achieve extension of the maximum human life-span, though, scientists will have to develop a way to prevent cancer too, because “humans, like mice, under normal conditions do develop tumors as a consequence of aging,” Prolla says.

But he is optimistic. “I have no doubt the aging process will be understood at the molecular level and we can do something about it,” Prolla says.

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