Resveratrol (3,5,4�?trihydroxy-trans-stilbene) (Fig. 1) is a compound found in the skins of red fruits, grapes, seeds, berries (especially, mulberries), peanuts, red wine, various herbs, and propolis (a natural honeybee product). Resveratrol occurs in two forms �?cis and trans resveratrol �?but it is the trans isomer that is biologically active. This article reviews resveratrol’s history, mechanisms, dosage and broad range of clinical uses and anti-aging potential.

The Resveratrol Story
Resveratrol was first identified in the early 1980s as the principal active ingredient in the dried roots of Polygonum cuspidatum. As a traditional Japanese and Chinese medicine, Polygonum extracts have been used to treat a wide range of afflictions, including fungal infections, various skin inflammations, and liver and cardiovascular diseases.1

In the early 1990s, scientists were attempting to unravel the “French paradox”—i.e., the surprisingly low incidence of cardiovascular disease observed in France among people consuming a rich, high-fat diet.2 Researchers proposed that the “paradox�?may be due to the routine consumption by the French of resveratrol-rich red wine.

Studies that subsequently compared alcohol consumption to the risk of death from coronary heart disease (CHD) revealed that those with the lowest risk drank red wine, while those who preferred other alcoholic beverages had the highest risk.3 Scientists also discovered that when healthy subjects were given pure alcohol or red wine for 15 days, pure alcohol increased platelet aggregation (a cause of heart attack and stroke-producing blood clots); however, red wine decreased platelet aggregation while elevating HDL-cholesterol (“good�?cholesterol).

As scientists began to appreciate the cardiovascular benefits conferred by red wine polyphenols—especially, resveratrol—a blockbuster article in the prestigious journal Science electrified the scientific community with the finding that “Resveratrol inhibits cellular events associated with tumor initiation, promotion and progression.�?In other words, resveratrol blocks all three mechanisms of cancer formation!4 But resveratrol’s effects don’t stop there.

Mechanisms and Potential Clinical Uses of Resveratrol

Cardio-Protective Effects

Resveratrol has been shown to protect the cardiovascular system by multiple mechanisms. Among these are:

protecting against ischemia-reperfusion injury (see next paragraph)

promoting vasorelaxation (i.e., protect against vasospasm)

protecting and maintaining the smooth, single cell-thick lining of the arteries (endothelium), which produces substances that influence arterial dilation

inhibiting the oxidation of low-density lipoprotein (LDL)5,6  suppressing platelet aggregation.7

“Ischemia-reperfusion injury�?refers to the extensive damage to tissues when blood flow is restored following a temporary loss of circulation. Such a situation occurs due to spasm of an artery, or temporary blockage of blood flow by a thrombus (blood clot), followed by resumption of blood flow.

The ischemia-reperfusion mechanism is the cause of extensive tissue damage in strokes, transient ischemic attacks (TIAs—mini strokes) and heart attacks. Resveratrol has been demonstrated to protect against ischemia-reperfusion injury not only in the heart,5,8 but also in the ovaries9 and spine.10

In these studies, resveratrol administration resulted in a number of beneficial effects, including:

decreased cardiac arrhythmias

reduced cardiac infarct size

increased NO (nitric oxide) release

decreased plasma levels of lactate dehydrogenase (LDH) and creatine kinase (CK) (indicators of tissue damage)

decreased levels of malondial-dehyde and xanthine oxidase (indicators of oxidative stress)

increased glutathione (a protective antioxidant).

Anti-Cancer
Cancer is one of the leading causes of death in the United States, second only to heart disease. The prognosis for patients with metastatic carcinoma of the lung, colon, breast, or prostate undergoing conventional therapeutic and surgical approaches remains dismal.

An ideal natural anti-cancer substance should have certain properties: little or no toxic effects in normal and healthy cells; high efficacy against multiple sites; capability of oral consumption; known mechanism of action; and low cost.11 Resveratrol appears to meet all these criteria.

 
In Vitro (Cellular) Studies
Following the previously mentioned discovery of resveratrol’s ability to block all three stages of carcinogenesis, a number of cellular (in vitro) and animal (in vivo) studies were conducted to evaluate resveratrol’s anti-cancer effects on a number of tumor types. Resveratrol’s cancer fighting effects include the ability to inhibit cell proliferation and induce necrosis (cell death) and apoptosis (“cell suicide�?of abnormal cells). These anti-cancer effects of resveratrol were confirmed in in vitro studies in virtually every type of human cancer on which it was tested, including:

breast12,13

cervix14

ovary15

esophagus16

prostate17-19

lung20-21

neuroblastoma (NB) (an aggressive childhood cancer of the peripheral nervous system)22

melanoma (a highly virulent form of skin cancer)23,24

leukemia.25

In addition, resveratrol sensitizes cancer cells to enhance the effects of anti-cancer drugs, making them more effective against the target cells while reducing their toxic side effects to healthy cells.26

In Vivo (Animal) Studies
Skin Cancer: In Taiwan, a team of Chinese scientists demonstrated that resveratrol-fed mice treated topically with an agent known to cause skin cancer caused a delay in tumor formation, with fewer tumors per mouse compared to control animals.27

Hepatoma:One of the most virulent forms of cancer is that of the liver. In Asia, hepatoma is among the most common of abdominal tumors, although it is rarely found as a primary tumor in the U.S. Scientists in Japan and China treated rats implanted with hepatoma cells with resveratrol. Resveratrol, by itself, suppressed tumor growth and reduced metastases in two studies.6,28 When used in conjunction with the anti-cancer drug 5-FU, resveratrol enhanced the efficacy of the drug and reduced its toxicity.29

Glioma: In animals implanted subcutaneously with gliomas (a type of brain tumor), resveratrol exerted significant antitumor effects, including slower tumor growth rate, longer animal survival time, and higher animal survival rate. The scientists concluded that resveratrol should be considered a possible treatment strategy for gliomas.30

Endocrine Normalizer
Resveratrol also acts as an estrogen receptor sensitizer (i.e., estrogen receptor agonist).31,32 This means that resveratrol will help maintain normal levels of estrogen, and that what estrogen is available will work more efficiently, with fewer estrogenic side effects.

Thus, resveratrol may have anti-aging effects, in conformance with the neuroendocrine theory of aging. (Please see the many articles on the neuroendocrine theory in previous issues of Vitamin Research News, and on the VRP website, www.vrp.com .)
In addition, scientists at the City of Hope in Duarte, California, recently provided evidence that resveratrol is also a potent aromatase inhibitor.33,34 Aromatase is the enzyme that converts testosterone to estrogen. Men who supplement their regimens with testosterone or testosterone precursors to normalize hormone levels (as well as bodybuilders who use testosterone and anabolic steroids) risk their testosterone also elevating their estrogen levels.

One effective way to prevent testosterone from elevating estrogen levels is to use the highly effective (and very expensive) prescription drug, Arimidex®, in a dose of about 1 mg two times per week. However, resveratrol may offer a far less expensive, natural solution to the problem of estrogen excess in men, as well as for women who require aromatase inhibitors in the treatment of cancer.

Other Potential Mechanisms / Clinical Uses
In addition to its unparalleled potential as a cardioprotectant and anti-cancer agent, resveratrol has a number of other beneficial effects including:

anti-inflammatory35,36

anti-infective against fungi37 and viruses (herpes simplex)38

neuroprotective,39-43 including protection from noise-induced hearing loss.44

Anti-Aging / Life-Extension Potential of Resveratrol
Caloric restriction has been shown repeatedly to be one of the most effective means of slowing the rate of aging and extending lifespan. Severely reducing food intake of laboratory mice can increase their lifespan to the human equivalent of 162 years. Experiments demonstrate similar gains in maximum lifespan in virtually every organism in which caloric restriction has been tested. Nevertheless, despite the potential increase in lifespan that could be gained with caloric restriction, few humans willingly choose to live in a constant state of semi-starvation for even a few days, let alone 162 years.

Although the mechanism for the anti-aging effect of caloric restriction has remained elusive, scientists recently identified a class of regulatory “longevity genes”—that are shared by almost all living organisms—which they believe may be at least partially responsible for the effect of caloric restriction. These genes function to enhance survival during times of stress, such as during drought or famine, and have been designated as sirtuins (derived from the term silent information regulator proteins). Once triggered by environmental cues, the longevity genes “switch on�?and induce defensive changes at the cellular level, such as slowing metabolism and enhancing cellular respiration to help the body adapt.45

The human sirtuin, SIRT-1, for example, has been shown to suppress the p53 enzyme system that helps to inhibit tumor growth and trigger cell death (apoptosis). By suppressing p53 activity, SIRT-1 prevents premature aging and apoptosis that is induced when cellular DNA is damaged or stressed, thus giving cells an opportunity to repair the damage. A second sirtuin found in yeast, SIR2, has also been shown to become activated when placed under stress. SIR2 increases DNA stability and speeds cellular repairs, while increasing total cell lifespan.46

Intrigued by the positive health benefits of caloric restriction, a research team from Harvard University began to search for other methods of modulating sirtuin activity without resorting to starvation. The researchers discovered that several plant metabolites acted as sirtuin-activating compounds (STACs), and that the most potent activator of sirtuins was resveratrol.

To test the ability of resveratrol to activate sirtuins in living creatures, the Harvard researchers selected yeast, a single-celled organism that is closely related to animals, including humans. The research team hypothesized that if resveratrol was effective in triggering sirtuin production, it would closely reflect the protein’s role in lifespan extension, at least for yeast. Their study found that even small doses of resveratrol helped yeast cells live as much as 60 to 80 percent longer, as measured by the number of generations. Yeast treated with resveratrol lived for an average of 38 generations, as compared to only 19 generations for untreated yeast47 (Fig. 2).
 

Additional experiments with human cells found that resveratrol enabled 30 percent of the treated human cells to survive gamma radiation compared to 10 percent of untreated cells. In the paper, the Harvard researchers also report that preliminary experiments with flies and worms are encouraging, and mouse studies are in the works.

One of the major impediments to faster progress in anti-aging research is the time required to prove that a substance has life-prolonging effects. Consequently, one of the major goals of biomedical gerontology is to develop a set of biomarkers that can be used to measure biological age to determine—in a reasonably short period—whether a substance has an age-retarding effect. Recently, two research teams have developed such biomarkers—one by scientists in Austria48 for use in the same yeast strain used by the Harvard research team described above, and another by researchers at the University of Connecticut for use in anti-aging studies with fruit flies.49 Interestingly, both of these research teams used their biomarkers to evaluate the anti-aging effects of resveratrol, and both confirmed that resveratrol was an effective anti-aging substance (at least, in yeast and fruit flies).

Bioavailability/Dosage/Safety
Resveratrol appears to be effective in the prevention and treatment of cancer in cells and experimental animals, and as a life-extending substance in yeast and fruit flies.

These findings raise two important questions: Does resveratrol work in humans; and what dose is required to obtain optimal benefits? Unfortunately, the only human studies available are the epidemiological studies showing cardiovascular benefits from consuming red wine. Scientists recently calculated that benefits could be obtained by as little as 1.25 mg of resveratrol per day (based on wine containing about 5 mg of resveratrol per liter, with an average intake of moderate wine drinkers of about 250 ml per day).50

In a recent review article,51 researchers attempted to determine an equivalent human dosage to reproduce the apparent cancer “chemopreventive�?benefits of resveratrol observed in in vitro and in vivo animal studies. The authors pointed out that most animal studies used what would be considered “massive�?human doses, ranging from 10 to 500 mg/kg per day. That would equate directly to a daily human dose of about 700 to 35,000 mg per day! However animal doses can rarely be directly extrapolated to humans, due to differences in physiology and metabolic rates. Three more recent papers demonstrated “extraordinary in vivo [anti-cancer] potency�?of resveratrol in rats, using much lower doses, ranging from 200 mcg/kg per day to 2 mg/kg per day.52-54 That is a doable range of about 14 to 140 times the amount of resveratrol consumed by our “average�?daily wine drinker (i.e., a calculated human therapeutic dose ranging from about 10 to 100 mg of resveratrol per day).

The next question, pending human clinical studies, is what amount �?if any �?is a toxic dose of resveratrol? In a study designed to specifically evaluate potential toxicity of resveratrol, scientists from the National Cancer Institute conducted a four-week study of trans-resveratrol in rats, administered via gavage feeding (i.e., through a tube, directly into the stomach) at doses of 300, 1,000 and 3,000 mg per day. The 300-mg-per-day dosage resulted in absolutely no side effects whatsoever. The 1,000-mg-per-day dosage resulted in slight weight loss in female rats and slight elevation in white blood count in the male rats.

However, the 3,000 mg per day dosage resulted in significant clinical signs of toxicity, as well as reduced body weight and food consumption. Other abnormalities caused by the 3,000 mg “mega dose�?included55:

elevated BUN (blood urea nitrogen)

elevated creatinine

elevated alkaline phosphatase

elevated alanine aminotransferase

elevated total bilirubin

elevated albumin

reduced hemoglobin

reduced hematocrit

reduced red cell counts

increased white cell counts

increased kidney weight

increased incidence and severity of nephropathy (kidney damage)

It should be noted that no studies of resveratrol have ever used the high dosages seen in this study—and that the specific purpose of this study was to determine whether resveratrol was toxic at any dose. This study confirms that resveratrol is clearly one of the safest anti-cancer substances known.

Conclusion
The more we learn about resveratrol and its wide-ranging benefits in life-threatening diseases, the better it looks in terms of its preventive and therapeutic benefits—and overwhelming record of safety. Although optimum dosages of resveratrol for humans have not been definitively determined, based on our present state of knowledge, reasonable dosages for humans appear to be in the range of 1 to 10 mg per day for preventive and anti-aging purposes, and 10 to 100 mg per day for therapeutic purposes, with the higher doses recommended as an adjunctive part of a comprehensive anti-cancer regimen.

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