Resveratrol (trans-resveratrol) is a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi.

Resveratrol is currently a topic of numerous animal and human studies into its effects. The effects of resveratrol on the lifespan of many model organisms remain controversial, with uncertain effects in fruit flies, nematode worms,^[1] and short-lived fish. In mouse and rat experiments, anti-cancer, anti-inflammatory, blood-sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported. Most of these results have yet to be replicated in humans.

In the only positive human trial, extremely high doses (3–5 g) of resveratrol in a proprietary formulation have been necessary to significantly lower blood sugar.^[2] Despite mainstream press alleging resveratrol’s anti-aging effects ^[3], there exists no scientific evidence for the application of these claims to mammals (see Life-Extension section below).

Resveratrol is found in the skin of red grapes and is a constituent of red wine, but apparently not in sufficient amounts to explain the French Paradox. Resveratrol has also been produced by chemical synthesis^[4] and is sold as a nutritional supplement derived primarily from Japanese knotweed.

Discovery and name

Resveratrol seems to have first been mentioned in a Japanese article in 1939 by M. Takaoka, who isolated it from the poisonous but medicinal Veratrum album, variety grandiflorum. The name presumably comes from the fact that it is a resorcinol derivative coming from a Veratrum species.^[5]

Recent studies

Life extension

The groups of Howitz and Sinclair reported in 2003 in the journal Nature that resveratrol significantly extends the lifespan of the yeast Saccharomyces cerevisiae.^[6] Later studies conducted by Sinclair showed that resveratrol also prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster.^[7] In 2007, a different group of researchers were able to reproduce Sinclair’s results with Caenorhabditis elegans,^[8] but a third group could not achieve consistent increases in lifespan of D. melanogaster or C. elegans.^[1]

In 2006, Italian scientists obtained the first positive result of resveratrol supplementation in a vertebrate. Using a short-lived fish, Nothobranchius furzeri, with a median life span of nine weeks, they found that a maximal dose of resveratrol increased the median lifespan by 56%. Compared with the control fish at nine weeks, that is by the end of control fish’s life, the fish supplemented with resveratrol showed significantly higher general swimming activity and better learning to avoid an unpleasant stimulus. The authors noted a slight increase of mortality in young fish caused by resveratrol and hypothesized that it is its weak toxic action that stimulated the defense mechanisms and resulted in the life span extension.^[9]

Later the same year, Sinclair reported that resveratrol counteracted the detrimental effects of a high-fat diet in mice. The high fat diet was compounded by adding hydrogenated coconut oil to the standard diet; it provided 60% of energy from fat, and the mice on it consumed about 30% more calories than the mice on standard diet. Both the mice fed the standard diet and the high-fat diet plus 22 mg/kg resveratrol had a 30% lower risk of death than the mice on the high-fat diet. Gene expression analysis indicated the addition of resveratrol opposed the alteration of 144 out of 153 gene pathways changed by the high-fat diet. Insulin and glucose levels in mice on the high-fat+resveratrol diet were closer to the mice on standard diet than to the mice on the high-fat diet. However, addition of resveratrol to the high-fat diet did not change the levels of free fatty acids and cholesterol, which were much higher than in the mice on standard diet.^[10] A further study by a group of scientists, which included Sinclair, indicated that resveratrol treatment had a range of beneficial effects in elderly mice but did not increase the longevity of ad libitum–fed mice when started midlife.^[11]

Cancer prevention

In 1997, Jang reported that topical resveratrol applications prevented skin cancer development in mice treated with a carcinogen.^[12] There have since been dozens of studies of the anti-cancer activity of resveratrol in animal models.^[13] No results of human clinical trials for cancer have been reported.^[14] However, clinical trials to investigate the effects on colon cancer and melanoma (skin cancer) are currently recruiting patients.^[15]

In vitro resveratrol interacts with multiple molecular targets (see the mechanisms of action), and damaged cells of breast, skin, gastric, colon, esophageal, prostate, and pancreatic cancer, and leukemia.^[13] However, the study of pharmacokinetics of resveratrol in humans concluded that even high doses of resveratrol might be insufficient to achieve resveratrol concentrations required for the systemic prevention of cancer.^[16] This is consistent with the results from the animal cancer models, which indicate that the in vivo effectiveness of resveratrol is limited by its poor systemic bioavailability.^[14][17][18] The strongest evidence of anti-cancer action of resveratrol exists for tumors it can come into direct contact with, such as skin and gastrointestinal tract tumors. For other cancers, the evidence is uncertain, even if massive doses of resveratrol are used.^[14]

Thus, topical application of resveratrol in mice, both before and after the UVB exposure, inhibited the skin damage and decreased skin cancer incidence. However, oral resveratrol was ineffective in treating mice inoculated with melanoma cells. Resveratrol given orally also had no effect on leukemia and lung cancer;^[14][19] however, injected intraperitoneally, 2.5 or 10 mg/kg of resveratrol slowed the growth of metastatic Lewis lung carcinomas in mice.^[14][20] Resveratrol (1 mg/kg orally) reduced the number and size of the esophageal tumors in rats treated with a carcinogen.^[21] In several studies, small doses (0.02–8 mg/kg) of resveratrol, given prophylactically, reduced or prevented the development of intestinal and colon tumors in rats given different carcinogens.^[14]

Resveratrol treatment appeared to prevent the development of mammary tumors in animal models; however, it had no effect on the growth of existing tumors. Paradoxically, treatment of pre-pubertal mice with high doses of resveratrol enhanced formation of tumors. Injected in high doses into mice, resveratrol slowed the growth of neuroblastomas.^[14]

Other applications

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 fifteen 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 the Sirtuin 1 gene.

Nicholas Wade’s interview-article with Dr. Auwerx^[22] states that the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (176 lb) person, the 400 mg/kg of body weight amount used in 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). 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.^[23]

Neuroprotective effects: In November 2008, researchers at the Weill Medical College of Cornell University reported that dietary supplementation with resveratrol significantly reduced plaque formation in animal brains, a component of Alzheimer and other Neurodegenerative diseases.^[24] In mice, oral resveratrol produced large reductions in brain plaque in the hypothalamus (-90%), striatum (-89%), and medial cortex (-48%) sections of the brain. In humans it is theorized that oral doses of resveratrol may reduce beta amyloid plaque associated with aging changes in the brain. Researchers theorize that one mechanism for plaque eradication is the ability of resveratrol to chelate (bind) copper. The neuroprotective effects have been confirmed in several animal model studies.^{[25][26][27][28][29]}

Anti-inflammatory effects: The anti-inflammatory effects of resveratrol have been demonstrated in several animal model studies. In a rat model of carrageenan-induced paw edema, resveratrol inhibited both acute and chronic phases of the inflammatory process.^[30] Similarly, preincubation with resveratrol decreased arachidonic acid release and COX-2 induction in mouse peritoneal macrophages stimulated with tumor promoter PMA, ROI, or lipopolysaccharides (LPS.^[31] In an experimental rabbit inflammatory arthritis model, resveratrol has showed promise as a potential therapy for arthritis. When administered to rabbits with induced inflammatory arthritis, resveratrol protected cartilage against the progression of inflammatory arthritis.^[32]

Cardioprotective effects: It has long been known that moderate drinking of red wine reduces the risk of heart disease.^[33] This is best known as “the French paradox.”^[34][35][36] Studies suggest that resveratrol in red wine may play an important role in this phenomenon.^[37] It achieves the effects by the following functions: (1) Inhibition of vascular cell adhesion molecule expression;^[38][39] (2) Inhibition of vascular smooth muscle cell proliferation;^[40][41][42] (3) Stimulation of endolethelial nitric oxide synthase (eNOS) Activity;^[43][44][45] (4) Inhibition of platelet aggregation;^[46][47][48] (5) Inhibition of LDL peroxidation;^[49][50] The cardioprotective effects of resveratrol are also theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy.^[51]

Anti-diabetic effects: Studies have shown that resveratrol possesses hypoglycemic and hypolipidemic effects in both streptozotocin (STZ)-induced diabetes rats and STZ-nicotinamide-induced diabetes rats. Resveratrol ameliorates common diabetes symptoms, such as polyphagia, polydipsia, and body weight loss.^[52] Other diabetic animal model studies by different researchers have also demonstrated the anti-diabetic effects of resveratrol.^{[53][54][55][56][57][58][59][60]} In human clinical trials, resveratrol has lowered blood sugar levels in both Phase Ib and Phase IIa, conducted by Sirtris Pharmaceuticals, Inc.^[61][62]

Antiviral effects: Studies show that resveratrol inhibits herpes simplex virus (HSV) types 1 and 2 replication by inhibition of an early step in the virus replication cycle. In vivo studies in mice show that resveratrol inhibits or reduces HSV replication in the vagina and limits extra-vaginal disease. The skin of resveratrol-treated animals showed no apparent dermal toxicity such as erythema, scaling, crusting, lichenification, or excoriation.^[63][64][65] Studies also show that resveratrol inhibit varicella-zoster virus, certain influenza virus, respiratory viruses, and human cytomegalovirus. Furthermore, resveratrol synergistically enhances the anti-HIV-1 activity of several anti-HIV drugs.^{[66][67][68][69][70][71]}

Pharmacokinetics

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One way of administering resveratrol in humans appears to be buccal delivery, that is without swallowing, by direct absorption through the inside of the mouth. When one mg of resveratrol in 50 mL solution was retained in the mouth for one min before swallowing, 37 ng/ml of free resveratrol were measured in plasma two minutes later. This level of unchanged resveratrol in blood can only be achieved with 250 mg of resveratrol taken in a pill form.^[72] However, the effectiveness via buccal delivery is called into question because this represents only a transient advantage in blood levels. All resveratrol that enters the blood circulation will eventually be conjugated (attached) to detox molecules (glucuronate, sulfate) as it passes through the liver. Without liver metabolism, resveratrol has a relatively short half life (14 minutes) versus 9 hours when glucuronidated.

About 70% of the resveratrol dose given orally as a pill is absorbed; nevertheless, oral bioavailability of resveratrol is low because it is rapidly metabolized in intestines and liver into conjugated forms: glucuronate and sulfonate.^[73] Only trace amounts (below 5 ng/mL) of unchanged resveratrol could be detected in the blood after 25 mg oral dose.^[73] Even when a very large dose of resveratrol (2.5 and 5 g) was given as an uncoated pill, the concentration of resveratrol in blood failed to reach the level necessary for the systemic cancer prevention.^[74] A formulation of resveratrol in a gum form is now in production, and this would be expected to achieve much higher blood levels than oral formulations. Resveratrol given in a proprietary formulation SRT-501 (3 or 5 g), developed by Sirtris Pharmaceuticals, reached 5–8 times higher blood levels. These levels did approach the concentration necessary to exert the effects shown in animal models and in vitro experiments.^[2]

In humans^[73][74] and rats,^[75][76][77] less than 5% of the oral dose is being observed as free resveratrol in blood plasma. The most abundant resveratrol metabolites in humans, rats, and mice are trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate.^[78] Walle suggests sulfate conjugates are the primary source of activity,^[73] Wang et al. suggests the glucuronides,^[79] and Boocock et al. also emphasized the need for further study of the effects of the metabolites, including the possibility of deconjugation to free resveratrol inside cells. Goldberd, who studied the pharmacokinetics of resveratrol, catechin and quercetin in humans, concluded “it seems that the potential health benefits of these compounds based upon the in vitro activities of the unconjugated compounds are unrealistic and have been greatly exaggerated. Indeed, the profusion of papers describing such activities can legitimately be described as irrelevant and misleading. Henceforth, investigations of this nature should focus upon the potential health benefits of their glucuronide and sulfate conjugates.”^[80]

The hypothesis that resveratrol from wine could have higher bioavailability than resveratrol from a pill^[13][81] has been refuted by experimental data.^[80][82] For example, after five men took 600 mL of red wine with the resveratrol content of 3.2 mg/L (total dose about 2 mg) before breakfast, unchanged resveratrol was detected in the blood of only two of them, and only in trace amounts (below 2.5 ng/mL). Resveratrol levels appeared to be slightly higher if red wine (600 mL of red wine containing 0.6 mg/mL resveratrol; total dose about 0.5 mg) was taken with meal: trace amounts (1–6 ng/mL) were found in four out of ten subjects.^[82] In another study, the pharmacokinetics of resveratrol (25 mg) did not change whether it was taken with vegetable juice, white wine or white grape juice. The highest level of unchanged resveratrol in the serum (7–9 ng/mL) was achieved after thirty minutes, and it completely disappeared from blood after four hours.^[80] The authors of both studies concluded that the trace amounts of resveratrol reached in the blood are insufficient to explain the French paradox. It appears that the beneficial effects of wine could be explained by the effects of alcohol^[80] or the whole complex of substances wine contains;^[82] for example, the cardiovascular benefits of wine appear to correlate with the content of procyanidins.^[83]

Adverse effects and unknowns

Long term effects of using resveratrol are as of yet unknown.^[84] While the health benefits of resveratrol seem promising, one study has theorized that it may stimulate the growth of human breast cancer cells, possibly because of resveratrol’s chemical structure, which is similar to a phytoestrogen.^[85][86] However, other studies have found that resveratrol intake is inversely associated with breast cancer risk and acts to slow the progression of breast cancer that has been transplanted into mice.^[87][88] Some studies suggest that resveratrol slows the development of blood vessels, which suppresses tumors, but also slows healing.^[89] Citing the evidence that resveratrol is estrogenic, some retailers 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, while others advise that resveratrol should not be taken by children or young adults under eighteen, as no studies have shown how it affects their natural development. A small study found that a single dose of up to 5 g of trans-resveratrol caused no serious adverse effects in healthy volunteers.^[16]

Mechanisms of action

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. Some studies indicates that resveratrol activates Sirtuin 1 (SIRT1)^[90] and PGC-1? and improve functioning of the mitochondria.^[91] Other research calls into question the theory connecting resveratrol, SIRT1, and calorie restriction.^[92][93] In addition resveratrol’s ability to directly activate sirtuin 1 has been called into question.^[94][95][96]

A paper by Robb et al. discusses resveratrol action in cells. It reports a fourteen-fold increase in the action of MnSOD (SOD2).^[97] MnSOD reduces superoxide to hydrogen peroxide (H₂O₂), but H₂O₂ is not increased due to other cellular activity. Superoxide O₂^- is a byproduct of respiration in complex 1 and 3 of the electron transport chain. It is “not highly toxic, [but] can extract an electron from biological membrane and other cell components, causing free radical chain reactions. Therefore it is essential for the cell to keep superoxide anions in check.”^[98] MnSOD reduces superoxide and thereby confers resistance to mitochondrial dysfunction, permeability transition, and apoptotic death in various diseases.^[99] It has been implicated in lifespan extension, inhibits cancer, (e.g. pancreatic cancer^[100][101]) and provides resistance to reperfusion injury and irradiation damage.^{[102][103][104]} These effects have also been observed with resveratrol. Robb et al. propose MnSOD is increased by the pathway RESV ? SIRT1 / NAD+ ? FOXO3a ? MnSOD. Resveratrol has been shown to cause SIRT1 to cause migration of FOXO transcription factors to the nucleus^[105] which stimulates FOXO3a transcriptional activity^[106] and it has been shown to enhance the sirtuin-catalyzed deacetylation (activity) of FOXO3a. MnSOD is known to be a target of FOXO3a, and MnSOD expression is strongly induced in cells overexpressing FOXO3a.^[107]

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-?B,^[108] inhibition of the cytochrome P450 isoenzyme CYP1A1^[109] (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene^[110]), alterations in androgenic^[111] actions and expression and activity of cyclooxygenase (COX) enzymes. In vitro, resveratrol “inhibited the proliferation of human pancreatic cancer cell lines.” In some lineages of cancer cell culture, resveratrol has been shown to induce apoptosis, which means it kills cells and may kill cancer cells.^{[111][112][113][114][115][116]} 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..^{[89][117][118]}

Resveratrol was reported effective against neuronal cell dysfunction and cell death, and in theory could help against diseases such as Huntington’s disease and Alzheimer’s disease.^[119][120] 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.^[121]

Resveratrol also significantly increases natural testosterone production from being both a selective estrogen receptor modulator^[122][123] and an aromatase inhibitor.^[124][125]

In December 2007, work from Irfan Rahman’s laboratory at the University of Rochester demonstrated that resveratrol increased intracellular glutathione levels via Nrf2-dependent upregulation of gamma-glutamylcysteine ligase in lung epithelial cells, which protected them against cigarette smoke extract induced oxidative stress.^[126]

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 geometric isomers: cis- (Z) and trans- (E), with the trans-isomer shown in the top image. The trans- form can undergo isomerisation to the cis- form when exposed to ultraviolet irradiation.^[127] Trans-resveratrol in the powder form was found to be stable under “accelerated stability” conditions of 75% humidity and 40 degrees C in the presence of air.^[128] Resveratrol content also stayed stable in the skins of grapes and pomace taken after fermentation and stored for a long period.^[129]

Plants and foods

Resveratrol was originally isolated by Takaoka from the roots of white hellebore in 1940, and later, in 1963, from the roots of Japanese knotweed. However, it attracted wider attention only in 1992, when its presence in wine was suggested as the explanation for cardioprotective effects of wine.^[13]

In grapes, resveratrol is found primarily in the skin,^[130] and—in muscadine grapes—also in the seeds.^[131] 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.^[130]

The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/L,^[132] depending on the grape variety, while 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.^[130] A number of reports have indicated that muscadine grapes may contain high concentrations of resveratrol and that wines produced from these grapes, both red and white, may contain more than 40 mg/L.^[131][133] However, subsequent studies have found little or no resveratrol in different varieties of muscadine grapes.^[134][135]

The fruit of the mulberry (esp. the skin^[136]) is a source, and sold as a nutritional supplement.

[edit] Content in wines and grape juice

The trans-resveratrol concentration in forty Tuscan wines ranged from 0.3 to 2.1 mg/L in the 32 red wines tested and had a maximum of 0.1 mg/L in the 8 white wines in the test. 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.^[137]

In a review of published resveratrol concentrations, the average resveratrol concentration in red wines is 1.9 ± 1.7 mg trans-resveratrol/l (8.2 ± 7.5 ?M), ranging from non-detectable levels to 14.3 mg/l (62.7 ?M) trans-resveratrol. Levels of cis-resveratrol follow the same trend as trans-resveratrol.^[138]

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.^[131]

In general, wines made from grapes of the Pinot Noir and St. Laurent varieties showed the highest level of trans-resveratrol, though no wine or region can yet be said to produce wines with significantly higher resveratrol concentrations than any other wine or region.^[138]

[edit] Content in selected foods

Ounce for ounce, peanuts have about half the amount of resveratrol as that found 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 contain approximately 160 µg/fluid ounce.^[140] Resveratrol was detected in grape, cranberry, and wine samples. Concentrations ranged from 1.56 to 1042 nmol/g in Concord grape products, and from 8.63 to 24.84 µmol/L in Italian red wine. The concentrations of resveratrol were similar in cranberry and grape juice at 1.07 and 1.56 nmol/g, respectively.^[141]

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. ^[142]

Supplementation

As a result of extensive news coverage,^[143][144] sales of supplements greatly increased in 2006,^[145] despite cautions that benefits to humans are unproven.^{[145][146][147]}.

Supplements vary in purity, and can contain anywhere from 50 percent to 99 percent resveratrol. Many brands consist of an unpurified extract of Japanese knotweed; these contain about 50 percent resveratrol by weight as well as emodin, which, while considered safe in moderate quantities, can have a laxative effect in high amounts.^[148]

Harvard University scientist Professor David Sinclair is often quoted in online ads. Sinclair, who has studied resveratrol extensively, has gone on record in Business Week to say he never uttered many of the statements attributed to him on these sites.