Resveratrol is a phytoalexin produced by several plants. It has also been produced by chemical synthesis,^[1] and is sold as a nutritional supplement. A number of beneficial health effects, such as anti-cancer, antiviral, neuroprotective, anti-aging, anti-inflammatory and life-prolonging effects have been reported, although these studies used animal subjects (e.g. rats). Resveratrol is found in the skin of red grapes and as a constituent of red wine but, based on extrapolation from animal trials, apparently not in sufficient amounts to explain the “French paradox” that the incidence of coronary heart disease is relatively low in southern France despite high dietary intake of saturated fats.^[2]

David Sinclair of the Harvard Medical School, and cofounder of Sirtris Pharmaceuticals,^[3] has found that resveratrol increases the activity of a protein called SIRT1. Resveratrol significantly increases the lifespan of yeast and mice. There is hope that it could do the same for humans.^[4]

The four stilbenes cis and trans resveratrol, and cis and trans piceid are similar and related, and sometimes analyzed together as a group.^[5]

[edit] Plants and foods

Resveratrol is produced by several plants, apparently due to its antifungal properties. It is found in widely varying amounts in grapes (primarily the skins), raspberries, mulberries, in plums, peanuts, berries of Vaccinium species, including blueberries, bilberries, and cranberries, some pines, such as Scots pine and eastern white pine, and the roots and stalks of giant knotweed and Japanese knotweed, called hu zhang in China. Resveratrol was first isolated from an extract of the Peruvian legume Cassia quinquangulata in 1974.

The amount of resveratrol in food varies greatly. Ordinary non-muscadine Red wine contains between 0.2 and 5.8 mg/L ^[6], depending on the grape variety, whilst white wine has much less — the reason being that red wine is fermented with the skins, allowing the wine to absorb the resveratrol, whereas white wine is fermented after the skin has been removed. Wines produced from muscadine grapes, however, both red and white, may contain more than 40 mg/L.^[7][5]

Fresh grape skin contains about 50 to 100 micrograms of resveratrol per gram.^[4]

In grapes, resveratrol is found primarily in the skin and seeds. This is particularly true for muscadine grapes, whose skin and seeds have about 100 times the concentration as the pulp.^[8] The amount found in grape skins also varies with the grape cultivar, its geographic origin, and exposure to fungal infection. The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content.^[9]

[edit] Total resveratrol content of wines and grape juice

The trans-resveratrol concentration in 40 Tuscan wines ranged from 0.3 to 2.1 mg/L in the 32 red wines and had a maximum of 0.1 mg/L in the 8 white wines tested. Both the cis- and trans- isomers of resveratrol were detected in all tested samples. Cis-resveratrol levels were comparable to those of the trans-isomer. They ranged from 0.5 mg/L to 1.9 mg/L in red wines and had a maximum of 0.2 mg/L in white wines.^[10]

Reports suggest that some aspect of the wine making process converts piceid to resveratrol in wine, as wine seems to have twice the average resveratrol concentration of the equivalent commercial juices.^[5]

"All of the muscadine table wines sampled had greater trans and cis resveratrol concentrations than any other wines sampled. The muscadine table wines varied between 9.2 and 31.9 mg/L cis resveratrol and between 4.9 and 13.4 mg/L trans resveratrol."^[5]

[edit] Total resveratrol content of selected foods

Ounce for ounce, peanuts have more than half the amount of resveratrol in red wine. The average amount of resveratrol in one ounce of peanuts in the marketplace (about 15 whole) is 79.4 µg/ounce. In comparison, some red wines contains approximately 160 µg/fluid ounce.^[12]

"The concentrations of resveratrol were similar in cranberry and grape juice".^[13]

Blueberries have about twice as much resveratrol as bilberries, but there is great regional variation. These fruits have less than ten percent of the resveratrol of grapes. Cooking or heat processing of these berries will contribute to the degradation of resveratrol, reducing it by up to half. ^[14]

When humans ingest resveratrol orally, most of it seems to be rapidly metabolized and excreted.^[11][15]

[edit] Chemical and physical properties

Resveratrol (3,5,4'-trihydroxystilbene) is a polyphenolic phytoalexin. It is a stilbenoid, a derivate of stilbene, and is produced in plants with the help of the enzyme stilbene synthase.

It exists as two structural isomers: cis- (Z) and trans- (E), with the trans-isomer shown in the top image and the cis form in the rotating image. Trans-resveratrol can undergo isomerisation to the cis- form when heated or exposed to ultraviolet irradiation. ^[16]

[edit] Supplement

Resveratrol is available as a nutritional supplement but not as a therapeutic agent (although it has been registered as an investigational drug in some jurisdictions). Supplements, first sourced from ground dried muscadine and red grape skins and seeds (sometimes from residual byproducts of winemaking),^[17] are now primarily derived from the cheaper, more concentrated Japanese knotweed. Capsules are sold containing from 1 mg to 500 mg of resveratrol. A less common form is plain powder, which might be more convenient for frequent ingestion as suggested by the rapid metabolism in the body.

Although no studies have yet appeared regarding proper dosage of Resveratrol for humans, Sirtris Pharmaceuticals along with David Sinclair, have taken to use a dosage of 2500mg and 5000mg of their resveratrol supplement formulation for their phase 1b human trials, and have recently completed phase 1a trials using the formulation.^[18];

Some supplement makers claim that only the trans- form matters, and that the cis- form is not useful or perhaps even a bad thing. Other makers simply report total resveratrol content -- or in some cases, just the quantity of an "extract" source, which only contains some percentage of resveratrol.

The following is an excerpt from a FDA New Dietary Ingredient Notification:

First, trans-Resveratrol is excluded from the definition of a “dietary supplement” under 21 U.S.C. 321 (ff) (3) (B), because it is an article authorized for investigation as a new drug for which substantial clinical investigations have been instituted and made public in the U. S.

FDA authorized trans-Resveratrol, which is also known as “resveratrol” or 3,5,4’-trihydroxystilbene, to be an Investigational New Drug on January 30, 2001. The Dietary Supplement Health and Education Act (DSHEA) of 1994 defined a “new dietary ingredient” as one that was marketed in the U.S. on or after October 15, 1994. This office does not have any information that indicates that trans-Resveratrol was legally marketed as a dietary ingredient in the U.S. before October 15, 1994.

Resveratrol is often called a nutraceutical, like other bioactive plant compounds studied for potential clinical applications: curcumin, EGCG, silibinin, etc.

In a 2004 issue of Science, Dr. Sinclair of Harvard University said resveratrol is not an easy molecule to protect from oxidation. It has been claimed that it is readily degraded by exposure to light, heat, and oxygen.^[19]

The pharmacokinetics of resveratrol metabolism have not been investigated in humans. Rat studies, however, suggest a half life up to 1.6 hours. In a 2002 issue of J Pharm Exper Therapeutics,^[20] Dr. Marier reported that rats given a single oral dose of 50 mg/kg body weight initially experienced a rapid drop in serum resveratrol levels: the half life, or T1/2, of the drug was found to be 8 minutes, meaning that blood levels had dropped to half of peak by that time. However, detectable levels of the drug remained for 12 hours, probably due to enterohepatic recirculation--that it, a release of stored resveratrol from liver tissue, yielding an overall half life of between 1.3 and 1.6 hours. ^[21] It is expected that chemically modified resveratrol-like molecules (drugs) will have a longer half-life and thus more potency.

As a result of extensive news coverage ^[22], sales of supplements greatly increased in 2006^[23], despite cautions that benefits to humans are unproven.^[24][25] The US government is concerned about the potential dangers of increased, unregulated usage but a "preliminary study of existing [non-human] research found little evidence that resveratrol is toxic, even at very high dosages." ^[26] Media reports have claimed that a number of prominent scientists take resveratrol supplements, including Sinclair and Nobelist Frank Wilczek.^[27]

A study by Professor Roger Corder has identified a particular group of polyphenols, known as oligomeric procyanidins, which they believe offer the greatest degree of protection to human blood-vessel cells. These are found in greatest concentration in European red wines from certain areas, which correlates with longevity in those regions. This new data may impact the supplement market.^[28] Because they are present in red wine in more significant quantities, they are a more reasonable explanation of the French paradox than resveratrol (which would seem to require drinking hundreds of glasses of wine a day to get enough to matter). Procyanidins are also found in similar quantities in purple grape juice, green tea, dark-colored fruits and high-cocoa chocolate.

[edit] Physiological effects

[edit] Activities and mechanisms of action

Resveratrol interferes with all three stages of carcinogenesis - initiation, promotion and progression. Experiments in cell cultures of varied types and isolated subcellular systems in vitro imply many mechanisms in the pharmacological activity of resveratrol. These mechanisms include modulation of the transcription factor NF-kB^[29], inhibition of the cytochrome P450 isoenzyme CYP1A1 ^[30] (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene ^[31]), alterations in androgenic^[32] actions and expression and activity of cyclooxygenase (COX) enzymes.

Resveratrol was reported effective against neuronal cell dysfunction and cell death, and in theory could help against diseases such as Huntington's disease ^[33] and Alzheimer's disease.^[34] Again, this has not yet been tested in humans for any disease.

Research at the Northeastern Ohio Universities College of Medicine and Ohio State University indicates that resveratrol has direct inhibitory action on cardiac fibroblasts and may inhibit the progression of cardiac fibrosis.^[35]

Note that resveratrol bioavailability depends on its conjugate forms: glucuronate and sulfonate, despite that most in-vitro studies use the aglycone form of resveratrol ('aglycone' means without a sugar molecule attached, as in the figure in this article).

[edit] Cancer Prevention

In some lineages of cancer cell culture, resveratrol has been shown to induce apoptosis, which means it kills cells and may kill cancer cells.^{[32][36][37][38][39][40]} Resveratrol has been shown to induce Fas/Fas ligand mediated apoptosis, p53 and cyclins A, B1 and cyclin-dependent kinases cdk 1 and 2. Resveratrol also possesses antioxidant and anti-angiogenic properties. ^{[41] [42]}

Resveratrol is under extensive investigation as a cancer chemopreventive agent.^{[43] [44]} . Indeed, the Chemoprevention Database reports six studies showing that small doses of dietary resveratrol can reduce colon carcinogenesis in rats and mice. One German study has already been shown to that under special conditions, resveratrol induces apoptosis in human fat cells. In addition, it inhibits production of cytokines which are involved in the development of obesity-related disorders^[45].

[edit] Life extension and anti-aging

Experiments from the Harvard laboratory of David Sinclair (Biologist) published in 2003 the journal Nature demonstrated that resveratrol significantly extends the lifespan of the yeast Saccharomyces cerevisiae. ^[46] Dr. Sinclair then founded Sirtris Pharmaceuticals to commercialize resveratrol or related compounds as an anti-aging drug.

Later studies showed that resveratrol prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster.^[47] In 2006, it also extended the maximum lifespan of a short-lived fish, Nothobranchius furzeri, by 59%, and extended its median lifespan by 56%. Also noted were an increase in swimming performance, an increase in cognitive performance (learning tasks), and a lack of neurofibrillary degeneration (found in a control group). The authors observed that "[resveratrol's] supplementation with food extends vertebrate lifespan and delays motor and cognitive age-related decline could be of high relevance for the prevention of aging-related diseases in the human population."^[48] Later in 2006, a report in the journal Nature by Sinclair's laboratory showed that the compound improves health and survival of mice on a high-calorie diet.^[49]

The mechanisms of resveratrol's apparent effects on life extension are not fully understood, but they appear to mimic several of the biochemical effects of calorie restriction. This seems to function by means of lipase inhibition, reducing the absorption of fat through intestinal walls. A new report indicates that resveratrol activates SIRT1 and PGC-1α and improve functioning of the mitochondria.^[50]

Only the "Trans" form of the molecule is capable of activating the mammalian SIRT1 gene in vitro; this is also the form predominantly found in red grape skins and red wine. Red grapes grown in some regions (such as New York state) often have much higher concentrations of resveratrol based on the cooler climate and the resulting increase in fungal attacks that promote resveratrol production. However, the amount in any wine, including Muscadine grape wines, is negligible compared to the amount that in theory is needed for health benefits: 1-10 milligrams per liter of wine versus hundreds to thousands of milligrams/day.

Recent research calls into question this theory connecting resveratrol, SIRT1 and calorie restriction.^[51][52]

Follow up studies by David Sinclair, published in November 2006 by the journal Nature, replicated the life extending benefits of resveratrol in mice, the first such demonstration in a mammal. Preliminary results showed that obese mice provided with resveratrol lived an average of 15% longer than obese mice not provided the supplement.

The amounts used in the mouse study were approximately 22.4 mg/kg body weight per day. Scaling this amount to human body weights would imply an "equivalent human dose" of 1.5 to 2.0 grams/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to the range of 150 to 200 mg/day if the resveratrol plasma levels in humans were not known and we wanted to predict a human dosage using FDA guidelines.^[53]

The truth is that many differences exist between mouse and human metabolism, and the effects of any given oral dose in humans remain unknown. In 2004, there was a study to determine absorption, bioavailability, and metabolism of Resveratrol in humans. It indicated that Resveratrol was quickly metabolized using 25mg doses in humans.^[15] Only trace amounts were found in human plasma, and that most of the oral dose was recovered in urine. Mice, on the other hand were found to have much larger amounts of resveratrol measured in their plasma using equivalent doses of resveratrol per kilogram of weight. It was also stated in the study that the systemic bioavailability of resveratrol is very low in humans compared to that of mice, but that accumulation of resveratrol in the human epithelial cells along the aerodigestive tract along with potentially active resveratrol metabolites may still produce cancer-preventive and other effects. Large dosages could theoretically increase the resveratrol in human plasma.

There is no human evidence yet that quantities found in red wine or in standard supplements are sufficient for any health effect.

[edit] Athletic performance

Johan Auwerx (at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France) and coauthors published an online article in the journal CELL in November 2006. Mice fed resveratrol for 15 weeks had better treadmill endurance than controls. The study supported Sinclair's hypothesis that the effects of resveratrol are indeed due to the activation of SIRT1.

Nicholas Wade's interview-article with Dr. Auwerx^[54] states that the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). The following excerpts are from that article:

“'Resveratrol makes you look like a trained athlete without the training,' Dr. Auwerx said in an interview." ...

"Dr. Auwerx attributes this in large part to the significantly increased number of mitochondria he detected in the muscle cells of treated mice.

"'Mitochondria are the organelles in the body’s cells that generate energy. With extra mitochondria, the treated mice were able to burn more fat and thus avoid weight gain and decreased sensitivity to insulin,' Dr. Auwerx said. He found their muscle fibers had been remodeled by the drug into the type more prevalent in trained human athletes.

"Dr. Ronald M. Evans, an expert on the hormonal control of metabolism at the Salk Institute, said the report by Dr. Auwerx’s team had 'shown very convincingly that resveratrol improves mitochondrial function' and fends off metabolic disease."

"The main theory developed by Dr. Guarente and others is that sirtuins sense the level of energy expenditure in living cells and switch the body’s resources from reproduction to tissue maintenance when food is low."

For an 80 kg (176 lb) person, the 400 mg/kg of body weight amount used in Dr. Auwerx's mouse study would come to 32,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4571 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There is limited human safety data (see above). It is premature to take resveratrol and expect any particular results. Long-term safety has not been evaluated in humans.

In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn energy more efficiently -- indicating that the same pathway shown in the lab mice works in humans too. ^[55]

[edit] Antiviral effects

Resveratrol seems to increase the potency of some antiretroviral drugs against HIV in vitro.^[56]

Infection by herpes simplex virus ordinarily activates the cell protein Nuclear Factor κB (NF-κB). A Northeastern Ohio Universities College of Medicine study undertaken in Vero cells found that resveratrol suppresses the activation of this transcription- and apoptosis-related protein. The study further found that multiple viral protein products were reduced or completely blocked, as well as a reduction in viral DNA production.^[57]

A cell culture study found that resveratrol blocks the influenza virus from transporting viral proteins to the viral assembly site, hence restricting its ability to replicate. The effect was 90% when resveratrol was added six hours after infection and continued for 24 hours thereafter.^[58]

[edit] Metabolism of resveratrol

In humans resveratrol rapidly undergoes phase II conjugation, both glucuronidation and sulphation at multiple sites on the molecule. The effect of conjugation on efficacy is debated.^[59][60]

[edit] Adverse effects and unknowns

While the health benefits of resveratrol seem promising, one study has found that it stimulates the growth of human breast cancer cells, possibly because of resveratrol's chemical structure, which is similar to a phytoestrogen.^{[61] [62]} Citing this evidence, some retailers[4] of resveratrol advise that the compound may interfere with oral contraceptives and that women who are pregnant or intending to become pregnant should not use the product.

Dietician Melissa Q.B. McElderry MS RD comments, "While taking resveratrol pills is certainly safer than heavy consumption of red wine, supplementing with unproven substances is generally unwise. At this point, occasional use of red wine seems far more prudent."^[63]

"Reasons why recommending a population-wide increase would be premature: Little is known about the absorption and clearance of resveratrol, the identities of its metabolic products, or its effects on the liver. The research on resveratrol has focused on its short-term effects and has been mainly done on non-human models."^[9]

[edit] References

• Gescher AJ, Steward WP. Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum., Cancer Epidemiol Biomarkers Prev. 2003;12(10):953-957.
• Sinclair, David A., et al. "Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase." Science 305 (July 16 2004): 309-392.
• Wolf, George. "Calorie Restriction Increases Life Span: A Molecular Mechanism." Nutrition Reviews 64.2 (Feb. 2006): 89-92

[edit] See also

• Japanese knotweed
• Mulberry
• Muscadine
• Red wine

[edit] External links

• PDRHealth Resveratrol
• Health Benefits of Red Wine - VIDEO Videovat, March 25, 2007
• Study Shows Resveratrol Heightens Endurance in Mice - VIDEO Videovat, March 25, 2007
• Resveratrol and The French Paradox - VIDEO Videovat, March 25, 2007
• Increases lifespan of fish by 60% (Current Biology, Feb 2006)
• Can Red Wine Help You Live Forever? (Fortune Magazine/CNN, Jan 2007)
• Phytochemicals as Nutraceuticals: Resveratrol
• Gene Silencing in Aging
• A votre santé: now in pill form? Article in the Journal Nature 444, 11 (2 November 2006)
• Resveratrol improves health and survival of mice on a high-calorie diet in (Nature)
• Harvard Medical School, Resveratrol Increases Lifespan in Mice, Sinclair
• Study: Fat, boozing mice stay healthy CNN, November 1, 2006
• Compound in Red Wine May Fight Alzheimer's WebMD, November 04, 2005
• Red Wine Ingredient May Delay Aging WebMD, February 10, 2006
• Bottoms Up WebMD, February 10, 2006
• Red Wine Ingredient May Fight COPD WebMD, October 27, 2003
• Cancer Claims for Red Wine Supplement Suspect WebMD, April 21, 2004
• Drinking Red Wine May Slow Aging WebMD, August 26, 2003
• Wine: How Much Is Good for You? WebMD, January 26, 2005