In the News

As reported by the Los Angeles Times, October 8, 2007.

Resveratrol: It's Good For Mice But What About Us?

The Antioxidant Seems To Work Wonders In The Rodents, But there's Little Research In Humans

By Karen Ravn

This antioxidant can protect against cancer, heart disease and diabetes. It can lower cholesterol, reduce inflammation and ease pain. Best of all, perhaps, it can help users live 30% longer than they would without it.

Resveratrol -- a substance found most notably in red wine -- is sometimes called a "miracle molecule." In labs around the world, scientists are devoting their lives to studying it, and they're writing so many papers about it that mere mortals are hard-pressed to keep up with them all. 

That is, if you're a mouse.

For humans, the picture is not so clear. To date, little research has been done on how resveratrol acts in people.

Some researchers have proposed that it explains the French paradox, the fact that French people traditionally eat a high-fat diet, yet remain at relatively low risk for heart attacks. (After all, these researchers reason, the French don't just eat a lot of rich food -- they also drink a lot of red wine.)

And a widely publicized study last year seemed to suggest that high doses of resveratrol could help overeaters live as long as their more abstemious brethren.

But the limitations of the research haven't slowed the marketing of the chemical. Labels on resveratrol supplements and wine alternatives tout the chemical's potential to improve cardiovascular health. At least one wine maker boasts of resveratrol content on bottles of its Pinot Noir. And promotional materials for resveratrol supplements sometimes refer to the longevity study -- without always mentioning that it was done with mice.

Which may be a problem.

"Mice are good models for a lot of things," says Dr. Randall Holcombe, a professor of medicine at UC Irvine. But at the same time he cautions, "They're bad models for a lot of other things."

Some resveratrol researchers are already true believers in its effects, but Holcombe and others are remaining skeptical about the potential benefits of the plant-based chemical (which is also found in peanuts, plums, raspberries and blueberries among other foods).

"Should we change behavior in humans on the basis of evidence in a rodent model?" asks Dr. Dean Brenner of the University of Michigan. "I say no."

Scant research on people
Most studies of resveratrol have been done in vitro -- outside of any living organism -- or in animals. But two early clinical trials in people give reason for optimism, and uncertainty, about its possible medical benefits.

One, published in June in Cancer Epidemiology, Biomarkers & Prevention, looked at resveratrol's bioavailability, i.e., how much of it is absorbed, unchanged, into the blood.

"That's a very important question," says Brenner, lead author of the study. "You can take grams and grams, and if none of it gets absorbed, it's moot."

The researchers gave single doses of resveratrol in uncoated immediate-release caplets to 10 volunteers at each of four dose levels -- 0.5, 1, 2.5 and 5 grams -- and then analyzed their blood to see how much resveratrol was absorbed.

Even at the highest dose, peak levels were only about half as high as the level determined in earlier studies to have cancer-preventive effects in vitro. But various resveratrol metabolites -- forms the antioxidant changes into when digested -- were present in very high levels. It's possible, Brenner speculates, that these have cancer-preventive effects themselves, perhaps being re-converted to resveratrol after they're absorbed into tissues.

"There are all kinds of questions," he says. "All we know right now is that resveratrol is absorbed, but it's not absorbed very much."

In a second clinical trial described this year by a team of researchers at UC Irvine, nine colon cancer patients took resveratrol for about two weeks between their diagnosis and their surgery. It was given either in pill form (20 milligrams a day) or as freeze-dried grape powder (mixed in water, either two or three times a day, at doses corresponding to either two-thirds or one pound of fresh grapes).

Part of the tissue from the patients' diagnostic biopsies was saved and later compared with tissue removed during surgery. The researchers were looking for changes in cellular metabolism that occur in more than 85% of patients with colon cancer. Earlier lab studies had indicated that resveratrol might inhibit these changes.

Preliminary results from six patients -- presented in a poster at the meeting of the American Assn. for Cancer Research in Los Angeles this April -- showed that the changes were indeed inhibited by about 50%, with more inhibition occurring in healthy tissue than in cancerous tissue.

"This doesn't prove that resveratrol definitely prevents colon cancer," says principal investigator Holcombe. "But it provides a rationale for doing more studies. . . . And it suggests that resveratrol may be more useful in prevention than in treatment."

The pace of human clinical trials does seem to be picking up. Two groups of researchers are studying resveratrol's effects in prostate cancer patients, and several trials are currently in progress with a proprietary form of resveratrol, testing its usefulness in preventing and treating diabetes.

An 'elixir' in rodents
If studies of resveratrol in people are few and far between, studies of resveratrol in mice and rats have been coming in right and left.

Perhaps the most famous is a study published in Nature last year that had some people calling resveratrol the "elixir of youth." Researchers at Harvard Medical School and the National Institute on Aging found that obese mice could eat high-fat, high-calorie diets and still live as long as mice fed a usual mouse diet if their pig-outs also included big doses of resveratrol.

And they lived months longer than fellow over-indulgers whose diets did not include resveratrol. (A month in the life of a mouse is equivalent to about three years in the life of a person.)

The mice who lived large also grew large regardless of whether they took resveratrol or not. But if they did take it, they didn't develop the pre-diabetes symptoms of oversized livers and high blood levels of glucose and insulin.

Researchers on this study -- led by David Sinclair and Joseph Baur at Harvard Medical School and Rafael de Cabo at the National Institute on Aging -- suspect that resveratrol works by activating the SIRT1 gene, which they believe is also switched on when mice are fed extremely low-calorie, or famine-level, diets.

Such extreme diets increase the life spans of mice and other animals, and many hypothesize the same is true in people.

Other scientists aren't convinced that resveratrol activates SIRT1, but believe it could work in other ways.

"It would be important to know whether resveratrol has an effect on mice on a normal diet," says Brian Kennedy, a professor of biochemistry at the University of Washington.

"If not, then it isn't mimicking caloric restriction," adds Matt Kaeberlein, a professor of pathology at the University of Washington.

Seeking benefits
Some researchers are tackling age-related diseases one at a time. "Day by day a new property of resveratrol is being added," says Dr. Dipak Das, a professor of surgery at the University of Connecticut, referring to reports on new uses for resveratrol.

For example, in a study now in press in the journal ARS, Das and others report for the first time that resveratrol lessens the sensitivity of rats to pain.

Other recent resveratrol success stories include these findings: Resveratrol in combination with statins works better than either one alone in improving lipid levels in rats with high cholesterol and in improving their recovery after heart attacks (Journal of Molecular and Cellular Cardiology); resveratrol can greatly reduce the risk that mice will develop the most deadly kind of prostate tumors (August online edition of Carcinogenesis); fairly low doses of resveratrol are enough to increase the sensitivity of mice to insulin, which could lead to new therapies for type 2 diabetes (October issue of Cell Metabolism).

Of course, the scientists who are studying resveratrol to a fare-thee-well aren't simply interested in the welfare of rodents. They hope the benefits they're finding in animals will translate into benefits for humans, too.

But though resveratrol doesn't appear to be toxic to people, some research implies there could be problems if it's taken in excess or by people with particular sensitivities.

Resveratrol has been shown to mimic the action of estrogen in some situations and to block it in others. Similarly, in low concentrations, resveratrol has been shown to stimulate angiogenesis -- growth of new blood vessels -- while at high concentrations it can have the opposite effect. Sometimes angiogenesis is good -- e.g., in recovery from a heart attack. And sometimes it's not -- e.g., when trying to stop the growth of a tumor.

In short, many researchers believe, testing in people has been too limited to truly establish resveratrol's safety. (The supplement can be sold without FDA approval because it's a natural compound, not a drug.)

Mystery of red wine
The theory that resveratrol explains the French paradox was the beginning of the resveratrol craze, and the theory is not unsupported.

"There's evidence resveratrol can affect platelet aggregation and mediate the spasming of blood vessels," says Holcombe of UC Irvine.

But is there enough resveratrol in red wine to have such a major effect? There have always been plenty of naysayers.

And a study in Nature last year claimed the French do owe their healthy hearts to some miracle-working chemicals in red wine -- but they're called procyanidins, not resveratrol.

Of course, some researchers question whether red wine has anything to do with the paradox at all.

It's quite possible that the red-hot field of resveratrol research is based on some unfounded jumping to a conclusion.

If so, that initial mistake may end up reaping huge benefits for people down the road. Or it may just be leading people down the garden path.