Resveratrol: Don't Buy the Hype
Stephen Barrett, M.D.
Resveratrol (trans-3,5,4'-trihydroxystilbene), a compound found largely in the skins of red grapes, is a component of Ko-jo-kon, an oriental medicine used to treat diseases of the blood vessels, heart [1,2], and liver [2]. It came to scientific attention during the mid-1990s as a possible explanation for the "French Paradox"—the low incidence of heart disease among the French people, who eat a relatively high-fat diet [3]. Since then, it has been touted by manufacturers and examined by scientific researchers as an antioxidant [4], an anti-cancer agent, and a phytoestrogen [5]. It has also been advertised on the Internet as "The French Paradox in a bottle." One company even markets a red-wine extract antioxidant product called "French Parad'ox."
Sources
While present in other plants, such as eucalyptus, spruce, and lily, and in other foods such as mulberries and peanuts, resveratrol's most abundant natural sources are Vitis vinifera, labrusca, and muscadine grapes, which are used to make wines. It occurs in the vines, roots, seeds, and stalks, but its highest concentration is in the skin [1], which contains 50-100 micrograms (µg) per gram [4]. Resveratrol is a phytoalexin, a class of antibiotic compounds produced as a part of a plant's defense system against disease [1]. For example, in response to an invading fungus, resveratrol is synthesized from p-coumaroyl CoA and malonyl CoA [2]. Since fungal infections are more common in cooler climates, grapes grown in cooler climates have a higher concentration [3].
The resveratrol content of wine is related to the length of time the grape skins are present during the fermentation process. Thus the concentration is significantly higher in red wine than in white wine, because the skins are removed earlier during white-wine production, lessening the amount that is extracted [3]. Grape juice, which is not a fermented beverage, is not a significant source of resveratrol. A fluid ounce of red wine averages 160 µg of resveratrol, compared to peanuts, which average 73 µg per ounce [6]. Since wine is the most notable dietary source, it is the object of much speculation and research.
Resveratrol is also available from supplement pills and liquids, in which it is sometimes combined with vitamins and/or other ingredients. It is also an ingredient in topical skin creams. The supplements are generally labeled as containing from 20 to 500 mg per tablet or capsule. However, the purity of these products is unknown. And, because dietary supplements are loosely regulated, it should not be assumed that the labeled dosage is accurate.
Cardiovascular Effects
Many studies suggest that consuming alcohol (especially red wine) may reduce the incidence of coronary heart disease (CHD). Several studies have demonstrated that resveratrol has antioxidant properties [7-10]. It is claimed that because it contains highly hydrophilic and lipophilic properties, it may provide more effective protection than other well-known antioxidants, such as vitamins C and E [7]. On the other hand, it is less effective than the antioxidants quercetin and epicatechin found in red wine [2]. Reduced platelet aggregation has also been demonstrated in studies on resveratrol, which could contribute to prevention of atherosclerosis [2,9]. To date, however, most of the research on resveratrol's antioxidant and anti-platelet properties has been done using test-tube or tissue-culture preparations.
Cancer-Related Effects
Resveratrol is being studied to see how it affects the initiation, promotion, and progression of cancer. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation and as an anti-mutagen in rat models [4]. Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation [4], inhibited enzymes that promote tumor growth [11,12], and exerted antitumor effects in neuroblastomas [13]. Noting that in animal studies, resveratrol was effective against tumors of the skin, breast, gastrointestinal tract, lung, and prostate gland, a recent review concluded:
During the last decade, resveratrol has been shown to possess a fascinating spectrum of pharmacologic properties. Multiple biochemical and molecular actions seem to contribute to resveratrol effects against precancerous or cancer cells. Resveratrol affects all three discrete stages of carcinogenesis (initiation, promotion, and progression) by modulating signal transduction pathways that control cell division and growth, apoptosis, inflammation, angiogenesis, and metastasis. The anticancer property of resveratrol has been supported by its ability to inhibit proliferation of a wide variety of human tumor cells in vitro. These . . . data have led to numerous preclinical animal studies to evaluate the potential of this drug for cancer chemoprevention and chemotherapy [14].
"Anti-Aging" Effect
Recent studies in laboratory mice have found increased survival and lower incidence of several diseases and conditions associated with aging, but the results are contradictory. Protective effects have been found in mice fed a high-fat or a low-calorie diet, but one study found that mice fed a standard diet beginning at age 12 months did not live longer [15-17]. One of the studies was reported in a New York Times article which described how a researcher was taking resveratrol himself and had founded Sirtris Pharmaceuticals to develop chemicals that mimic the role of resveratrol but at much lower doses [18]. GlaxoSmithKline acquired Sirtris for $720 million in 2007 and hopes to develop "drugs that target the sirtiuns, a recently discovered family of seven enzymes associated with the aging process." [19]
After reviewing the animal studies, the highly respected Medical Letter concluded: "Resveratrol appears to produce some of the same effects as calorie-restricted diets that have reduced the incidence of age-related diseases in animals. Whether it has any benefit in humans remains to be established." [20]
Caution Is Advisable
Although laboratory tests have demonstrated that resveratrol might help prevent cardiovascular disease and cancer, there are several reasons why a population-wide increase would be premature.
The research on resveratrol has focused on its short-term effects and has been dominated by in vitro (laboratory) studies on non-human models.
Not enough is known about the absorption and clearance of resveratrol, the identities of its metabolic products, or its effects on the liver.
Resveratrol's role as a potentiator of breast carcinomas may significantly limit its use.
Its main dietary source is red wine. Not only is its concentration in wine extremely variable, but recommending increased consumption of red wine to boost resveratrol intake could certainly do more harm than good. In spite of any beneficial aspects, red wine and other alcoholic beverages pose health risks that include liver damage and physical addiction. While taking resveratrol pills is certainly safer than heavy wine consumption, supplementing with unproven substances is generally unwise. At this point, occasional use of red wine seems far more prudent.
The Bottom Line
Epidemiologic studies can find associations between the consumption of foods or dietary supplements and various health outcomes. Animal experiments can demonstrate what can happen in the species tested. However, only human clinical trials can determine whether supplementation is useful for humans. Resveratrol has not been tested in clinical trials, and most clinical trials of other antioxidants have failed to demonstrate the benefits suggested by preliminary studies. Some substances—most notably beta-carotene—have even produced adverse effects. My advice is to ignore the hype surrounding resveratrol and eat a balanced diet that contains adequate amounts of fruits and vegetables.
References
Celotti E and others. Resveratrol content of some wines obtained from dried Valpolicella grapes: Recioto and Amarone. Journal of Chromatography A 730(1-2): 47-52, 1996.
Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: A molecule whose time has come? And gone? Clinical Biochemistry 30:91-113, 1997.
Kopp P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the 'French paradox'? European Journal of Endocrinology 138:619-620, 1998.
Jang M and others. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218-220, 1997.
Gehm H and others. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proceedings of the National Academy of Sciences U.S.A. 94:557-562, 1997.
Sanders TH, McMichael RW. Occurrence of resveratrol in edible peanuts. Presentation, American Oil Chemists Society, Las Vegas, Nevada, 1998. Discussed in Peanuts contain significant amount of plant compound that may prevent risk of heart disease and cancer, a news release from The Peanut Institute, Sept 8, 1998.
Chanvitayapongs S, Draczynska-Lusiak B, Sun AY. Amelioration of oxidative stress by antioxidants and resveratrol in PC12 cells. Neuroreport 8:1499-1502, 1997.
Belguendouz L, Fremont L, Gozzelino MT. Interaction of transresveratrol with plasma lipoproteins. Biochemical Pharmacology 55:811-816, 1998.
Rotondo S and others. Effect of trans-resveratrol, a natural polyphenolic compound, on human polymorphonuclear leukocyte function. British Journal of Pharmacology 123:1691-1699, 1998.
Frankel EN, Waterhouse AL, Kinsella JE. Inhibition of human LDL oxidation by resveratrol. Lancet 341:1103-1104, 1993.
Clement MV and others. Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood 92:996-1002, 1998.
Fontecave M and others. Resveratrol, a remarkable inhibitor of ribonucleotide reductase. FEBS Letters 421:277-279, 1998.
Chen Y and others. Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Surgery 136:57-66, 2004.
Bishayee A. Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prevention Research 2:409-418, 2009.
Baur JA and others. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337-342, 2006.
Pearson KJ and others. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metabolism 8:157-168, 2008.
Barger JL and others. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3:e2264, 2008.
Wade N. Substance in red wine extends life of mice. New York Times, Nov 1, 2006.
About us. Sirtris Pharmaceuticals Web site, accessed Sept 20, 2009.
Resveratrol. The Medical Letter on Drugs and Therapeutics, 51:74-75, 2009.
