In November 1991 French scientist Serge Renaud appeared on “60 Minutes.” The topic was the mystery of how French people followed diets high in saturated fat yet had a 40 percent lower incidence of cardiovascular disease than Americans. Renaud attributed the difference to the French custom of drinking red wine each day with meals.
The phenomenon came to be known as the French paradox. While alcohol itself was known to elevate a protective cholesterol carrier in the blood called high-density lipoprotein, something else in red wine clearly added to the effect, since no other alcohol-containing beverage could match the protective effects of red wine.
Within a short time the protective factor in wine was identified as an esoteric plant substance called resveratrol. It turned out that, although red wine was by far the richest source in the human diet, resveratrol is found in 72 plants as well.
Resveratrol was first identified in a plant called the white hellebore back in 1940. In 1963 a plant called Polygonum cuspidatum, or Japanese knotwood, which was commonly used in traditional Chinese and Japanese medicine, was found to be a rich source of resveratrol. Plants produce resveratrol when under stress, since it offers a number of protective effects, making resveratrol a phytoalexin.
Subsequent research showed that red wine also contains other natural substances, such as various polyphenols, that work in conjunction with resveratrol to provide beneficial effects. Resveratrol itself has been the subject of hundreds of studies, many still in progress. The studies have indicated that it affects a number of systems and processes at once,1 offering a plethora of health benefits, including cardiovascular protection, cancer prevention and, most intriguing of all, antiaging effects.
The sheer breadth of research purporting to show the health benefits associated with resveratrol has led to a boom in sales of resveratrol supplements derived from extracts of Japanese knotwood, particularly over the Internet. Without doubt, resveratrol has emerged as the most popular—and pricey—antiaging supplement on the market. Countless human guinea pigs are dosing themselves with amounts of resveratrol equivalent to drinking thousands of bottles of red wine daily. It’s costing them several hundred dollars per month. Yet all—I repeat, all—the research that “proves” the effectiveness of resveratrol involves either isolated-cell or animal studies. The only human studies involve dosage safety and pharmacokinetic issues, meaning how the body metabolizes resveratrol.
In fact, while resveratrol is easily absorbed orally, it rapidly—within 30 minutes after intake—undergoes two processes in which it is conjugated, or complexed, with sulfate and glucuronide by enzymes in the liver, converting it into at least five metabolites. Resveratrol itself lasts for an average of only eight to 14 minutes in the body, but the metabolites stay around for an average of 9.2 hours. The big controversy now among scientists is whether the metabolites offer any actual biological activity while they’re there. One theory is that they can be converted back into the active form of resveratrol, called trans-resveratrol, or TREV, in tissues, but that has not yet occurred in any human study.
The impressive animal and isolated-cell studies indicate that resveratrol surely must be doing something in the body. Internet resveratrol groupies think that taking huge doses will overcome the formidable barriers to its activity in the body. Beneficial effects in animals usually involve large doses, and the idea is to duplicate those effects by using megadoses.
That’s nothing short of biochemical gambling. No one yet knows the long-term safety of humans taking huge doses of resveratrol. Short-term studies have shown that people taking as much as 5,000 milligrams a day experience no side effects. Rats have gotten 300 milligrams per kilogram of bodyweight with no apparent detriment, but that’s hardly proof of human safety. There are some initial indications, as we’ll see, that taking huge doses of resveratrol for an extended time could cause some serious health problems.
Does Resveratrol Prevent Cancer?
Animal and test-tube studies show that resveratrol blocks all stages of cancer, from initiation to progression. It acts as a potent antioxidant and affects various enzymes in the body. Cell studies show that it induces the death of tumors found in leukemia, colon, breast, prostate and esophageal cancers. The initial study that found its cancer-preventive effect was published in 1997; applying a topical version of resveratrol inhibited 98 percent of skin tumors in mice exposed to carcinogens.2
Grapes, from which resveratrol comes, were among 600 plants tested for cancer-prevention properties in the study. The research consensus today is that only large doses of resveratrol are capable of initiating a cell signal that causes cancer cells to kill themselves—a process called apoptosis. Resveratrol inhibits enzymes, such as cyclooxygenase, that are involved in inflammatory processes, a cornerstone of cancer. Resveratrol also inhibits angiogenesis, a process whereby tumors develop new blood vessels. It’s a process essential to the maintenance and spread of cancer cells in the body, and blocking it leads to the rapid death of tumors.
Resveratrol inhibits cancer by activating phase-two detoxifying enzymes in the liver. The phase-one system in the liver can activate carcinogens, such as tobacco smoke, but the phase-two system renders the incipient carcinogen harmless. The same phase-two enzymes in the liver convert active resveratrol into its metabolites.
Resveratrol and Cardiovascular Disease
Resveratrol was identified as the primary protective factor found in red wine when nonalcoholic extracts proved equally effective in preventing cardiovascular disease. Later research demonstrated that the more likely protective factors in red wine were polyphenol compounds called procyanidins. Still, resveratrol may offer cardiovascular protection through several mechanisms. By inhibiting the activity of COX enzymes, resveratrol prevents the platelet aggregation that leads to clotting; the immediate cause of most heart attacks and strokes is a clot formed in narrowed arteries. Something that prevents excessive internal clotting may offer protection against cardiovascular disease. Low-dose aspirin works the same way.
Resveratrol aids in vasodilation, the widening of blood vessels, by inhibiting the COX enzymes that produce the lipid thromboxane, which is synthesized from the fatty acid arachidonic acid. Resveratrol also increases the dilation activity of nitric oxide in blood vessels. Oxidation of low-density-lipoprotein cholesterol, or LDL, is known to cause cardiovascular disease, and resveratrol as an antioxidant prevents that by chelating the trace mineral copper, which when free in the blood is a potent oxidizing agent. That, by the way, is a problem with large doses of resveratrol. It’s so effective in chelating copper that it can cause copper deficiency, which in turn leads to problems with collagen production, as copper acts as a coenzyme in collagen synthesis in the body. A lack of copper can cause nerve transmission problems, as well as tendinitis, a common side effect experienced by those taking large doses of resveratrol.
The good news is that two recent studies show that you don’t need huge amounts of resveratrol to get cardiovascular protection. One study found that drinking a moderate amount—a five-ounce glass daily—of red wine was enough to stimulate nitric oxide production in human platelets.3 The other study found that giving middle-aged mice lower doses of resveratrol—4.9 milligrams per kilogram of bodyweight—increased beneficial gene activity in the heart the way a calorie-restricted diet does.4 Researchers said that high doses were not only not required but could prove detrimental.
One way that resveratrol is thought to work is by activating a protective enzyme called sirtuin-1, a.k.a. SIRT1. Overactivating the enzyme induces heart failure in animals, according to a 2007 study published in Circulation Research.
Other recent studies show that resveratrol helps prevent excessive fat accumulation in the liver that occurs in obese people and those who drink too much. In a study involving rats with nonalcoholic fatty liver, giving them resveratrol decreased inflammation in the liver by inhibiting tissue necrosis factor-A, a potent inflammation inducer, and by upregulating the body’s natural antioxidant activity.5 A study found that resveratrol also blocked liver fat accumulation in mice that were given alcohol. Excess fat in the liver predisposes to the development of cirrhosis and liver cancer. The mechanism in the study involved increased production of SIRT1, which then stimulated the activity of AMPK, a compound that aids in fat breakdown.6
The body chemistry of resveratrol tells only half of its story. In Part 2 we’ll look more deeply into its impact on the body’s aging processes and why it’s relevant to bodybuilders.
References
1 Pirola, L., et al. (2008). Resveratrol: One molecule, many targets.IUNMB Life. 60:323-32.
2 Jang, M., et al. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 275:218-220.
3 Gresele, P., et al. (2008). Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J Nutr. 138:1602-1608.
4 Barger, J.L., et al. (2008). A low dose of dietary resveratrol partially minics caloric restriction and retards aging parameters in mice.PLOS One. 3:e2264.
5 Bujanda, L., et al. (2008). Resveratrol inhibits nonalcoholic fatty liver in rats. BMC Gastroenterol. 8:40.
6 Ajmo, T., et al. (2008). Resveratrol alleviates alcoholic fatty liver in mice. Am J Physiol Gastroint Liver Physiol. 295:4. In press. IM
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