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Resveratrol: Don't Buy the Hype, 11/12/2014
Resveratrol: Don't Buy the Hype

Resveratrol: Don't Buy the Hype

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 , and liver . 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 . Since then, it has been touted by manufacturers and examined by scientific researchers as an antioxidant , an anti-cancer agent, and a phytoestrogen . 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."

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 , which contains 50-100 micrograms (g) per gram . Resveratrol is a phytoalexin, a class of antibiotic compounds produced as a part of a plant's defense system against disease . For example, in response to an invading fungus, resveratrol is synthesized from p-coumaroyl CoA and malonyl CoA . Since fungal infections are more common in cooler climates, grapes grown in cooler climates have a higher concentration .

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 . Grape juice, which is not a fermented beverage, is not a significant source of resveratrol. Since wine is the most notable dietary source, it has been the object of much speculation and research. But a recent review noted that (a) the presence of resveratrol in the human diet is almost negligible, and a role for resveratrol in explaining the "French paradox," has likely been overestimated, and if resveratrol or similar compounds are proven useful against cardiovascular disease, a supplement (or drug) rather diet is likely to be the source .

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.

Several studies have demonstrated that resveratrol has antioxidant properties . 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 . On the other hand, it is less effective than the antioxidants quercetin and epicatechin found in red wine . Reduced platelet aggregation has also been demonstrated in studies on resveratrol, which could contribute to prevention of atherosclerosis . Prior to 2010, however, most of the research on resveratrol's antioxidant and anti-platelet properties was done using test-tube or tissue-culture preparations. Since that time, some human trials have been conducted, but the evidence is not yet sufficient to draw practical conclusions .

Many studies have found that resveratrol can affect the initiation, promotion, and progression of cancer, which has raised hopes that it has potential for both prevention and treatment . A recent review concluded that it is not a good drug candidate because it lacks potency, high efficacy, and target specificity. But researchers hope that similarly-structured derivatives can be found that will be useful .

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 . In 2009, 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."

One of the mouse 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 . GlaxoSmithKline acquired Sirtris for $720 million in 2008 and hopes to develop drugs that target the sirtuins, a group of enzymes associated with the aging process . However, a spokesperson said recently that the company is focused on compounds other than resveratrol that can activate sirtuins .

In 2012, the University of Connecticut announced that it had concluded that Dipak K. Das, Ph.D., a professor in its Department of Surgery and director of the Cardiovascular Research Center, was guilty of 145 counts of fabrication and falsification of data and that the university had notified eleven journals about this problem . In recent years, Das had gained attention for his reports on allegedly beneficial properties of resveratrol. As of March 2014, journals had retracted 20 of his papers, many of which were repeatedly cited by others . Das died in 2013.

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.

In 2011, a systematic review with 21 co-authors noted that people were consuming resveratrol concluded that, "the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources." Curiously, Das was one of the co-authors.

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. 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. Prior to 2010, resveratrol had not been tested in clinical trials. Since that time there have been some, most of which were small, short-term (a year of less), and designed to evaluate possible therapeutic effects rather than disease-preventive effects. A trial to evaluate preventive effects would need to be large and lengthy and would therefore be extremely expensive .

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Functional Foods, 18/6/1999
Those who desire health benefits of wine without potential risk may wish to consider alcohol-free wine, which has been shown to increase total plasma antioxidant capacity (Serafini et al., 1998). Furthermore, Day et al. (1998) showed that commercial grape juice is effective in inhibiting the oxidation of LDL isolated from human subjects. Red wine is also a significant source of trans-resveratrol, a phytoalexin found in grape skins (Creasy and Coffee, 1988). Resveratrol has also been shown to have estrogenic properties (Gehm et al., 1997) which may explain in part the cardiovascular benefits of wine drinking, and it has been shown to inhibit carcinogenesis in vivo (Jang et al., 1997).

Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc. Natl. Acad. Sci. 94: 14138- 14143.

Jang, M., Cai, J., Udeani, G.., Slowing, K.V., Thomas, C.F., Beecher, C.W.W., Fong, H.H.S., Farnsworth, N.R., Kinghorn, A.D., Mehta, R.G., Moon, R.C., and Pezzuto, J.M. 1997. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275: 218-220.

Phony Advertising: The "Amazing" Story of Recovery™, 8/10/2006
The primary ingredient in Recovery is said to be "Nutracol NM, a proprietary purified pharmacologically active polyphenolic complex (epigallocatechin gallate (EGCG), epigallocatechin (EGC), Proanthocyanidin B2, epicatechin gallate (ECG) and resveratrol) extracted from Vitex vinifera and Camellia sinensis." The "secondary ingredients include glucosamine hydrochloride (1000 mg); methyl sulfonyl methane (1200 mg); magnesium (145 mg); calcium (10 mg); zinc (5 mg); vitamin C (445 mg); water-dispersable vitamin E (145 IU); dimethylglycine (200 mg); anthocyanocide-rich freeze-dried raspberries and blueberries; natural flavor; and splenda (sucralose).

Vitex vinifera is the grape, and Camellia sinensis is the plant commonly used for tea. EGCG is present in tea and has been the subject of many research papers; it has antioxidant activity and may have other effects, such as disrupting the cell cycle in cancer cells and inhibiting enzymes that break down proteins. EGC and ECG are similar compounds in tea. Proanthrocyanidine B2 is found in grape seeds and also is an antioxidant. Resveratrol, found in grapes, is an antioxidant and has estrogen-like effects as well.

A Skeptical Look at St. John's Wort, 20/9/2011

Viosan Health Generation Making Shady Claims, 14/8/2009
Resveratrol . . . may provide anti-cancer benefits . . . and helps fight age-related diseases.

Dietary Supplements, Herbs, and Hormones, 24/8/2005

The Grape Cure, 3/11/2001
The American Cancer Society reviewed the "Grape Cure" in 1965, 1971, 1974, and 2000. and found no evidence of benefit against human cancer or any other disease . Grapes contain a few chemicals (resveratrol and proanthocynadins) that are being studied for possible preventive effects. But there is no reason to believe that Brandt's diet will ever be found useful for any purpose.

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