Excitement over resveratrol in red grapes and wine has been revived by the results of a study in mice
by Craig Weatherby
Along with other phenolic antioxidants, red grapes and wine abound in antifungal phenols that may be key contributors to the “French paradox”.
The paradox in question is that people in some regions of France eat lots of saturated fats but have little heart disease, perhaps because a small glass of red wine most meals.
What is resveratrol?
Grapes, peanuts, and berries are the leading food sources of resveratrol, which plants produce to help fend off unfriendly microbes and fungi.
Resveratrol is also available as a supplement made from red wine or a Chinese plant called hu zhang (Polygonum cuspidatum, AKA giant knotweed).
Like the beneficial flavonoids in colorful fruits and vegetables, resveratrol (3,5,4´-trihydroxy stilbene) is a polyphenol-class antioxidant compound with apparent anti-cancer properties (see "Grape Compound May Help Curb Cancer.")
Of course, the claim that dietary cholesterol and saturated fat cause cardiovascular disease has lost just about all of its never-justified credibility.
Yet, it’s clear that French folks who enjoy red wine with meals possess better cardiovascular health than their abstinent compatriots, and a reduced risk of diabetes.
Animal and test tube studies suggest that resveratrol blunts the bad effects of high-calorie, American-style diets, exerts anti-inflammatory effects and possesses anti-cancer potential.
Two years ago, a constituent of grapes and red wine called resveratrol made headlines when high doses reduced the rate of diabetes, liver problems, and other weight-related problems in obese mice, while extending their lifespan.
Although the organs of the mice made obese by high-fat diets should have shown signs of gross degradation, they remained normal.
And despite eating a high-calorie diet, obese mice fed high-dose resveratrol were about as healthy, agile and active on exercise equipment as their lean counterparts.
For a recap, see “Red Wine Constituent Gives Mice Radical Metabolic Makeovers” and “Antioxidant from grapes and wine might extend life- and health-spans.”
Devil is in the dose details
The excitement faded fast when people realized that a 130-lb person would need to take 94 resveratrol capsules per day to equal the per-pound dose that produced the best results in mice.
However, in another part of the study, obese mice were given a much lower dose—five mg per kilogram per day—and benefited in ways similar to the higher-dose group, albeit to a lesser extent.
This lower dose level would translate to about 300 mg of resveratrol per day for our hypothetical 130-lb person, or about 20 standard resveratrol capsules per day.
In fact, some resveratrol researchers have been taking this very daily dose (five mg per kilogram), with no apparent ill effects.
And the results from new animal studies suggest that resveratrol can produce substantial benefits at very modest doses that would require many fewer pills—and/or much less wine—to achieve.
They also show that low-doses of resveratrol yield these benefits through different bodily mechanisms than those seen at high doses.
Let’s take a look at these findings, which have sparked renewed hope for resveratrol’s potential as a supplement that might blunt the adverse health effects of excess body fat.
Low-dose resveratrol mimics benefits of low-calorie diets
Diets very low in calories trigger a genetically programmed survival mechanism, that switches the body’s focus to maintaining tissue.
In animal studies, the changes that result from this metabolic shift stimulate activity and extend lifespan, in part by reducing the tendency toward the cluster of risk factors known as “metabolic syndrome”, which are associated with diabetes and heart disease.
So-called “calorie restriction” extends rodents’ lives by up to 30 percent, but people cannot generally sustain such famine-like diets, which have not yet been proven to work in humans. (In an article titled “Calorie restriction: Is this anti-aging diet worth a try?,” the Mayo Clinic provides a good overview of the subject.)
Dr. Leonard Guarente of the Massachusetts Institute of Technology discovered that the famine-response mechanisms are triggered by activating certain members of a class of proteins called sirtuins.
Five years ago, one of his former students—Dr. David Sinclair of the Harvard Medical School—reported his finding that resveratrol activate sirtuins strongly.
Dr. Sinclair and others then tested resveratrol in obese mice, at doses far higher than those obtainable from drinking red wine or taking reasonable numbers of standard, 15 mg resveratrol capsules.
Less than a month later, a French team reported that when they fed high-dose resveratrol to fat, sedentary mice, the red grape compound transformed the rodents into eager treadmill runners and doubled their previous endurance.
And last week, a team at the University of Wisconsin reported that resveratrol may be effective in mice and people in much lower doses than previously thought necessary.
They showed that in mice, very low doses of resveratrol trigger the same pattern of gene activity triggered by life-extending, calorie-restricted diets
The effect of the low doses was not tested by observing the behavior and bodily changes living mice. Instead, the Wisconsin team fed mice one of three diets from middle age (14 months) to old age (30 months):
- Regular (control) mouse diet
- Regular (control) mouse diet plus a low dose of resveratrol (4.9 mg per kg body weight)
- Calorie restricted (CR) diet
They then examined changes in genetic switches called transcription factors in cells throughout the animals’ bodies.
Lead author Jamie Barger put their findings this way: “Our findings that a low dose of resveratrol partially mimics calorie restriction at the gene expression level… suggests that clinical trials with resveratrol should be conducted...”
They found a “striking” overlap between the genetic effects of calorie-restricted diets (CR) and resveratrol in the animals’ heart muscle, skeletal muscle, and brains.
And the mice in both the CR diet group and resveratrol group showed the same genetic changes, which are associated with these benefits:
- Reduced aging in cardiac and skeletal muscle
- Slowing of age-related declines in heart function
- Enhanced glucose uptake in muscles
As they wrote, “Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.”
Some skepticism is in order because we can’t be sure that humans would experience similar kinds and degrees of benefit at any dose of resveratrol.
And it is virtually impossible to subject resveratrol to a controlled clinical test, because very few people would be willing to cut their calorie intake to the bone for a decade or more.
Monkey trial may provide answers relevant to humans
Monkeys’ genetics are much closer to people than those of mice. And the outcome of two calorie-restriction studies in monkeys will provide highly relevant results.
The monkeys involved live for up to 40 years, so the trials will take a long time to show definite results.
One of the two trials—which is being conducted by the same Wisconsin team—is beginning to show clear evidence that the calorie-restricted monkeys outlive their control companions.
The results of the other trial, conducted at the National Institutes of Health, remain unclear.
If the outcomes of both studies show that calorie-restricted diets extend monkeys’ lives and enhance their overall health, this would lend greater credibility to the latest mouse results.
Presumably, researchers could mimic the design of the new mouse study in monkeys, to see if primates undergo similar health-enhancing, life-extending genetic changes in response to relatively low doses of resveratrol.
- Barger JL, Kayo T, Vann JM, Arias EB, Wang J, et al. (2008) A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice. PLoS ONE 3(6): e2264. doi:10.1371/journal.pone.0002264