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Resveratrol is a substance that is produced by several plants and that 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. Resveratrol is found in the skin of red grapes and as a constituent of red wine may explain the “French paradox” that the incidence of coronary heart disease is relatively low in southern France despite high dietary intake of saturated fats.

Plants and foods

Resveratrol is produced by plants as an antifungal chemical. It is found in the skins of certain red grapes, in peanuts, blueberries, 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 substances varies greatly. Red wine contains approximately 5 mg/L, 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.

Chemical and physical properties

Resveratrol 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 image. Trans-resveratrol can undergo isomerisation to the cis- form when heated or exposed to ultraviolet irradiation.

Supplement

Resveratrol is available as a mass-produced nutritional supplement but not as a therapeutic agent, although it is registered as an investigational drug. The supplement, first sourced as ground dried red grape skins, has shifted somewhat to include some types of knotweeds as a raw material.

FDA Quote from 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 referred to as a nutraceutical, along with other bioactive plant compounds that are being studied for potential clinical applications such as curcumin, EGCG and silibinin, among others.

In a 2004 issue of Science Magazine, Dr. Sinclair of Harvard University said that resveratrol is not an easy molecule to protect from oxidation. Most commonly available supplements tested have no ability to stimulate Sirtuin 1 enzymes.

Physiological effects

Activities and mechanisms of action

Resveratrol interferes with all three stages of carcinogenesis - initiation, promotion and progression. Experiments in various cell types and isolated subcellular systems in vitro implicate a multitude of mechanisms in the pharmacological activity of resveratrol. These mechanisms include inhibition of the transcription factor NF-kB, cytochrome P450 isoenzyme CYP1A1, androgenic actions and expression and activity of cyclooxygenase (COX) enzymes. Resveratrol has been shown to induce Fas/Fas ligand mediated apoptosis, p53 and cyclins A, B1 and cyclin-dependent kinases cdk 1 and 2, furthermore it possesses antioxidant and anti-angiogenic properties. Due to these discoveries, resveratrol is currently being investigated extensively as a cancer chemopreventive agent.

Resveratrol has recently been reported to be effective against neuronal cell dysfunction and cell death, and may be of use for diseases such as Huntington's disease and Alzheimer's disease.

Recent research at Ohio State University indicated that resveratrol inhibits the development of cardiac fibrosis.

It is worth mentioning that resveratrol bioavailability is dependent on its conjugate forms: glucuronate and sulfonate, despite almost all in vitro studies use the aglycone form of resveratrol. Furthermore, if resveratrol is taken in with food, most of it is destroyed by the digestive system.

Life extension and anti-aging

Experiments from the laboratory of David Sinclair at Harvard were published in 2003 the journal Nature claiming that resveratrol significantly extends the lifespan of the yeast Saccharomyces cerevisiae.
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24. PMID 12939617 Dr. Sinclair then founded Sirtris pharmaceuticals to commercialize resveratrol as an anti-aging drug.

Later studies showed that resveratrol prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. In 2006, it was shown that it also extends the maximum lifespan of a short-lived fish, Nothobranchius furzeri, by 59% and the median lifespan by 56%. Also noted were an increase in swimming performance, an increase in cognitive performance (learning tasks), and no neurofibrillary degeneration, which was found in a control group. The authors wrote "the observation 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."Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A "Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate." Current Biology 2006 Feb 7;16 (3):296-300 PMID 16461283

The mechanisms of resveratrol's apparent effects toward life extension are not fully understood.

Seventy years ago, McCay CM, et. al., discovered that by reducing the amount of calories fed to rats, there was a substantial increase in the length of the lifespan - it was almost doubled. For the last seventy years, scientists have proposed hypotheses as to why. Some explanations included reduced cellular divisions, lower metabolism rates, and reduced production of free radicals generated by metabolism. Recently Harvard professor David A. Sinclair has conducted research that provides a new explanation for the lifespan extension caused by calorie restriction. It involves the activation of a gene called Sirt1. When Sirt1 gene activity is increased by genetic manipulation, caloric restriction does not increase it any further. Knocking out the Sirt1 gene also eliminates any beneficial effect from caloric restriction. Resveratrol has been demonstrated to increase the activity of the Sirt1 gene the same way caloric restriction does. When resveratrol increased lifespan, caloric restriction failed to increase it any further. This provides evidence that caloric restriction acts by increasing the activity of the gene Sirt1 and that the benefits of caloric restriction might be had with the use of resveratrol.

Only the trans-form is capable of activating the mammalian SIRT1 gene in vitro; it is also the form predominantly found in red grape skin (red wine).

Recent research by Kaeberlein et al. calls into question this theory connecting resveratrol, Sirt1 and calorie restriction.Kaeberlein M et al. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol. 2004 Sep;2(9):E296. PMID 15328540Kaeberlein et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Apr 29; 280(17):17038-45. PMID 15684413.

Antiviral effects

Resveratrol has also been seen to increase the potency of some antiretroviral drugs against HIV in vitro.Heredia A, Davis C, Redfield R. Synergistic inhibition of HIV-1 in activated and resting peripheral blood mononuclear cells, monocyte-derived macrophages, and selected drug-resistant isolates with nucleoside analogues combined with a natural product, resveratrol. J Acquir Immune Defic Syndr. 2000 Nov 1;25(3):246-55. PMID 11115955

Herpes infection ordinarily activates the cell protein Nuclear Factor kappaB (NF-kappaB). 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 protein products of HSV were reduced or completely blocked, as well as a reduction in viral DNA production.Faith SA, Sweet TJ, Bailey E, Booth T, Docherty JJ. Resveratrol suppresses nuclear factor-kappaB in herpes simplex virus infected cells. Antiviral research 2006 Jul 14 PMID 16876885

A cell culture study has found that resveratrol thwarts the ability of the influenza virus from carrying viral proteins to the viral building site, hence restricting the ability to replicate. The effect was 90% when resveratrol was added six hours after infection and continued for 24 hours thereafter.Palamara AT, Nencioini L, Aquilano K, et al. Inhibition of influenza A virus replication by resveratrol. Journal of Infectious Diseases May 2005 15;191(10):1719-29. PMID 15838800

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 http://www.nutraingredients-usa.com/news/news-NG.asp?id=51583 and http://groups.google.com/group/sci.life-extension/msg/8e6e0ad8fe958e3e ).

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.Free full text
*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

External links

*Phytochemicals as Nutraceuticals: Resveratrol
*Gene Silencing in Aging

Category:Chemopreventive agents
Category:Phytochemicals
Category:Phenols
Category:Antioxidants