Diabetes Forecast

Resveratrol: A Miracle Molecule?

Research Is Finding That A Substance Called Resveratrol May Lower Blood Glucose—and Even Extend Life

By Erika Gebel, PhD , ,

A glass of fine red wine can elevate a good meal to a fantastic one or help unclench the mind after a difficult day. Yet some scientists believe those salubrious effects of le vin rouge pale next to what one of its ingredients may someday do. Perched upon that wineglass stem, masked in crimson, is a molecule that may hold enormous potential for human health: resveratrol.

The substance that has become synonymous with red wine's health benefits was actually first isolated from the roots of white hellebore, a flowering plant, in 1940. But resveratrol got scant attention until 1992, when researchers found an abundance of it in red wine and postulated that resveratrol might explain what's known as the "French paradox." The paradox is this: France is saturated, so to speak, with foods rich in unhealthy fats—cheeses, cream sauces, foie gras, and the ubiquitous croque-monsieur, a gooey grilled ham-and-cheese sandwich. Yet the French have a surprisingly low rate of heart attack and stroke (although some researchers argue the numbers have been underestimated). And what do the French wash all that fatty deliciousness down with? That's right: red wine. The thinking goes that perhaps it's the resveratrol in the wine that keeps the French healthy in spite of a well-larded diet.

Even if the French paradox is eventually disproven, resveratrol research is showing promise. Some data suggest that resveratrol may keep blood from clotting, much like aspirin. There is also evidence that it relaxes blood vessels, exerts an antioxidant effect, and keeps cholesterol and tri­glycerides from forming the arterial lesions that can cause heart attacks and strokes. What's more, resveratrol has the potential to help more than just the heart, it seems. One of the most exciting areas of research is cancer prevention and treatment. In studies of mice, a topical application of resveratrol reduced skin tumors by 98 percent, and a hefty oral dose increased nerve cancer survival rates by 70 percent.

But what works in mice doesn't necessarily work in people. "In humans, we aren't very far along," says Joseph Baur, PhD, an instructor in the Department of Physiology at the University of Pennsylvania, although resveratrol's effect on people is being actively studied. Many of the animal studies have required extremely high doses of resveratrol to produce any effect, and the molecule eventually becomes toxic. Resveratrol metabolism may be to blame: Some scientists think the molecule breaks down too rapidly in the body to be of any benefit. Researchers are trying to tweak resveratrol so that it lingers in the body and can be used in lower doses in human studies.

People with type 2 diabetes may be among the first to benefit from this research, if the positive results of early clinical trials withstand further scrutiny. The trials tested a slowly metabolized version of resveratrol called SRT501, created by a Boston company named Sirtris that was bought last year by pharmaceutical giant GlaxoSmithKline. Last year, Sirtris announced that SRT501, taken once or twice daily, was safe and lowered blood glucose levels in people with type 2 diabetes. A study is just finishing up of SRT501's effects on people with type 2 who take metformin but whose blood glucose remains uncontrolled. Sirtris is also developing agents that act like resveratrol but are chemically distinct and more potent. The small Sirtris studies so far have been designed to assess the safety of the drugs but did show some benefits. Yet for a drug to win Food and Drug Administration approval, it needs to show both safety and efficacy in longer trials that include a large number of people. It could be years before these Sirtris products can be prescribed—if they ever make it that far.

Calories and Longevity

SRT501 and resveratrol are believed to work by triggering a physiological state like that achieved through calorie restriction. Scientists already know that calorie restriction—eating about 30 percent less than what your body needs to maintain a normal weight, while still getting enough nutrients—allows mammals to slow aging and delay age-related diseases like cancer, heart attack, stroke, diabetes, and dementia. And studies have significantly prolonged the lives of worms, flies, and rats through calorie-restriction diets. Since resveratrol has been found to increase the life spans of several lower organisms, scientists have hypothesized that the molecule may mimic the healthful effects of calorie restriction in humans, but without the hunger. That's an enticing prospect for people unable or unwilling to put themselves on such a harsh diet.

In some of those lower organisms, the data suggest that resveratrol and calorie restriction both work by activating proteins called sirtuins. But it's still unclear whether the connection holds in higher organisms, like humans. Studies of mice are encouraging, though, when it comes to
type 2 diabetes. A 2006 study found that resveratrol improved the health and extended the lives of mice on a high-calorie diet. Baur, the study's lead author, says resveratrol improved insulin sensitivity, which could help ward off diabetes by keeping blood glucose levels under control. Another study found that higher doses of resveratrol could trigger weight loss in mice. For people with type 2 diabetes, shedding pounds can make blood glucose control easier and reduce the risk for complications like cardiovascular disease.

In a follow-up study last year, Baur and colleagues found that unlike calorie restriction, resveratrol did not extend the lives of middle-aged mice on a normal diet. "There is something calorie restriction does that we were missing for sure [with resveratrol]," says Baur. Yet these mice were healthier in old age, as resveratrol reduced osteoporosis, cataracts, and vascular dysfunction while improving motor skills. Plus, the researchers found evidence that resveratrol induced biochemical responses like those triggered by calorie restriction. Baur's current research is looking beyond resveratrol for agents that could mimic all the benefits of calorie restriction.

The amount of resveratrol used on these mice is far more than a person could get from just drinking wine. A human would have to down something like 1,000 bottles of red wine a day to even get in the ballpark. Nonetheless, the levels reached in mice are roughly achievable in humans, says Baur, by taking dietary supplements. However, Baur doesn't recommend supplements because, unlike medications, they are not regulated by the Food and Drug Administration, their efficacy is unproven, and their purity and safety aren't assured.

Stress With Benefits

Calorie restriction is thought to put the body under mild physiological stress, prodding it into survival mode. In this state, the body works overtime to keep itself at optimal health. The body unleashes its natural arsenal of cancer-fighting, heart-helping, and metabolism-boosting agents. While "psychological stress is bad," Baur says, physiological stress has its perks. "The mechanism exists to help you get through a tough time," he adds, like when there isn't enough food around. Scientists know that plants make resveratrol at times of stress. Some theorize that evolution might have favored our human ancestors whose response to consuming plant stress signals, like resveratrol, was to activate their own survival mode, giving them a head start on avoiding famine.

For whatever reason, resveratrol seems to have a big impact on animals. But it has a long way to go to prove itself in humans. In the meantime, as you enjoy that glass of ruby red wine, you can ponder the possibility that it really does contain a key to a longer, healthier life.



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