Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi.

The effects of resveratrol are currently a topic of numerous animal and human studies. Its effects on the lifespan of many model organisms remain controversial, with uncertain effects in fruit flies, nematode worms, and short-lived fish. In mouse and rat experiments, anticancer, anti-inflammatory, blood sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported. In humans, however, such effects have not yet been reported to the same degree.

In one positive human trial, extremely high doses (3–5 g) of resveratrol, in a proprietary formulation designed to enhance its bioavailability, significantly lowered blood sugar. This 28-day Phase 1b study was conducted privately in India by pharmaceutical company Sirtris, and was announced at an investors conference in 2008. However, although it has been alluded to in review articles, the study itself has never been published in a peer-reviewed scientific publication. Despite the mainstream press alleging resveratrol's anti-aging effects, there are no accepted data to form a scientific basis for the application of these claims to mammals (see life extension section below). At the present time, research on resveratrol is in its infancy and the long-term effects of supplementation in humans are not known.

Resveratrol is found in the skin of red grapes and in other fruits. However, red wine contains very little of it, in the order of one milligram per glass. Resveratrol has also been produced by chemical synthesis and by biotechnological synthesis (metabolic engineered microorganisms) and is sold as a nutritional supplement derived primarily from Japanese knotweed.

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.[19] Later studies conducted by Sinclair showed that resveratrol also prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster.[20] In 2007, a different group of researchers were able to reproduce Sinclair's results with C. elegans,[21] but a third group could not achieve consistent increases in lifespan of either D. melanogaster or C. elegans.[5]

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 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 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 its weak toxic action stimulated the defense mechanisms and resulted in the life span extension.[22]

Later the same year, Sinclair reported 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 and became obese and diabetic. Mice on the high-fat diet exhibited a high mortality rate compared to mice fed the standard diet; mice fed the high-fat diet plus 22 mg/kg resveratrol had a 30% lower risk of death than the mice on the high-fat diet alone, making their death rates similar to those on the standard diet. The supplement also partially corrected a subset of the abnormal gene expression profile and abnormal insulin and glucose metabolism. However, resveratrol supplements did not change the levels of free fatty acids and cholesterol, which were much higher than in the mice on standard diet.[23]

A further study by a group of scientists, which included Sinclair, indicated 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.[24] Later, the National Institute on Aging's Interventions Testing Program (ITP)[25] also tested three different doses of resveratrol in mice on a normal diet beginning in young adulthood, and again found no effect on lifespan, even at doses roughly eight times higher than those that had normalized the lifespan of the high-fat-fed, obese mice in the earlier study.[26]

2011 study published in Nature suggested that some of the benefits demonstrated in previous studies were overrepresented.[27][28] However this study was immediately challenged,[29] and few experiments were suggested to be of inferior quality.[30]

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.[citation needed]

Nicholas Wade's interview-article with Dr. Auwerx[31] stated the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (175 lb) person, the 400 mg/kg of body weight amount used in Auwerx's mouse study would total 30,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4000 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There are limited human safety data. Long-term safety has not been evaluated in humans.[citation needed]

In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn more energy, indicating the same pathway shown in the lab mice works in humans.[32]

Cancer prevention

In 1997, Jang reported that topical resveratrol applications prevented skin cancer development in mice treated with a carcinogen.[33] There have since been many studies of the anti-cancer activity of resveratrol in animal models.[12]

Resveratrol has been shown to induce apoptosis in platelets,[34][35] and smooth muscle.[36][37][36]

No results of human clinical trials for cancer have been reported.[38]

Clinical trials to investigate the effects on colon cancer and melanoma (skin cancer) are currently recruiting patients.[39] However, the study of pharmacokinetics of resveratrol in humans concluded even high doses of resveratrol might be insufficient to achieve resveratrol concentrations required for the systemic prevention of cancer.[40]

This is consistent with the results from the animal cancer models, which indicate the in vivo effectiveness of resveratrol is limited by its poor systemic bioavailability.[41][42] The strongest evidence of anticancer action of resveratrol exists for tumors it can contact directly, such as skin and gastrointestinal tract tumors. For other cancers, the evidence is uncertain, even if massive doses of resveratrol are used.[38]

Thus, resveratrol (1 mg/kg orally) reduced the number and size of the esophageal tumors in rats treated with a carcinogen;[43] and 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.[38] Similarly, 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;[38][44] however, injected intraperitoneally, 2.5 or 10 mg/kg of resveratrol slowed the growth of metastatic Lewis lung carcinomas in mice.[38][45]

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 prepubertal mice with high doses of resveratrol enhanced formation of tumors. Injected in high doses into mice, resveratrol slowed the growth of neuroblastomas.[38]

All of the aforementioned in vivo studies have been in animal models in which the cancer has been artificially induced by some experimental means. Three other studies have investigated the effect of resveratrol on the risk of cancer in normal mice living out a normal lifespan; all of them have found resveratrol supplementation has no significant effect on the burden of tumors, nor on the rate of cancer death.[24][26][46]

Cardioprotective effects

Moderate drinking of red wine has long been known to reduce the risk of heart disease.[47] This is best known as “the French paradox”.[48][49][50]

Studies suggest resveratrol in red wine may play an important role in this phenomenon.[51] It achieves the effects by the following functions: (1) Inhibition of vascular cell adhesion molecule expression;[52][53] (2) Inhibition of vascular smooth muscle cell proliferation;[54][55][56] (3) Stimulation of endolethelial nitric oxide synthase (eNOS) Activity;[57][58][59] (4) Inhibition of platelet aggregation;[60][61][62][63] (5) Inhibition of LDL per oxidation;[64][65]

The cardioprotective effects of resveratrol are also theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy.[66] However all of the papers on cardio protective effects from Dr. Das's lab have been retracted by the University of Connecticut and he is under investigation for fraud.[67]A 2011 study concludes, “Our data demonstrate that both melatonin and resveratrol, as found in red wine, protect the heart in an experimental model of myocardial infarction via the SAFE pathway.”[68]

Antidiabetic effects

Studies have shown 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.[69] Other diabetic animal model studies by different researchers have also demonstrated the antidiabetic effects of resveratrol.[32][23][70][71][72][73][74]

In human clinical trials, resveratrol has lowered blood sugar levels in both Phase Ib and Phase IIa, conducted by Sirtris Pharmaceuticals, Inc.[75][76]

Other applications

Neuroprotective effects

In November 2008, researchers at the Weill Medical College of Cornell University reported dietary supplementation with resveratrol significantly reduced plaque formation in animal brains, a component of Alzheimer's disease and other neurodegenerative diseases.[77] 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, oral doses of resveratrol thoretically 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.[78][79][80][81][82]

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.[83] 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).[84] In an experimental rabbit inflammatory arthritis model, resveratrol 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.[85]

Antiviral effects

Studies show 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 found resveratrol inhibits or reduces HSV replication in the vagina and limits extravaginal disease. The skin of resveratrol-treated animals showed no apparent dermal toxicity, such as erythema, scaling, crusting, lichenification, or excoriation.[86][87][88] Studies also show resveratrol inhibits varicella-zoster virus, certain influenza viruses, respiratory viruses, and human cytomegalovirus. Furthermore, resveratrol synergistically enhances the anti-HIV-1 activity of several anti-HIV drugs.[89][90][91][92][93][94]

Effect on testosterone levels

A Korean study showed that trans-resveratrol supplementation increased testosterone levels in mice in vivo,[95] which has led to its marketing as a bodybuilding supplement. A Spanish study has also shown the antioxidant to increase sperm production in rats.[96]

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