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, anti-viral, 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. It is found in the skins of certain red grapes, in peanuts, blueberries, some pines (Scots pine, eastern white pine) and the roots and stalks of Japanese knotweed (hu zhang in China) and giant knotweed. 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 UV irradiation.
Resveratrol is available as a mass-produced nutritional supplement but not as a therapeutic agent (though it is now registered as an investigational drug). The supplement, first sourced as ground dried red grape skins, has shifted somewhat to include certain of the knotweeds as a raw material.
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.
It appears that resveratrol, cholikan and activin GSE 2000 are the same chemical substance.
It should be noted that 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 SIRT1 enzymes.
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. () Dr. Sinclair then founded Sirtris pharmaceuticals to commericalize 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." ()
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. (,
Resveratrol has also been seen to increase the potency of some antiretroviral drugs against HIV in vitro. ()
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.()
Metabolism of resveratrol
In humans resveratrol rapidly undergoes phase II conjugation, both glucuronidation and sulphation at multiple sites on the molecule.
Mechanism of human SIRT1 activation by resveratrol
J Biol Chem. 2005 Apr 29;280(17):17187-95. Epub 2005 Mar 4. Borra MT, Smith BC, Denu JM.
- The NAD+-dependent protein deacetylase family, Sir2 (or sirtuins), is important for many cellular processes including gene silencing, regulation of p53, fatty acid metabolism, cell cycle regulation, and life span extension. Resveratrol, a polyphenol found in wines and thought to harbor major health benefits, was reported to be an activator of Sir2 enzymes in vivo and in vitro. In addition, resveratrol was shown to increase life span in three model organisms through a Sir2-dependent pathway. Here, we investigated the molecular basis for Sir2 activation by resveratrol. Among the three enzymes tested (yeast Sir2, human SIRT1, and human SIRT2), only SIRT1 exhibited significant enzyme activation ( approximately 8-fold) using the commercially available Fluor de Lys kit (BioMol). To examine the requirements for resveratrol activation of SIRT1, we synthesized three p53 acetylpeptide substrates either lacking a fluorophore or containing a 7-amino-4-methylcoumarin (p53-AMC) or rhodamine 110 (p53-R110). Although SIRT1 activation was independent of the acetylpeptide sequence, resveratrol activation was completely dependent on the presence of a covalently attached fluorophore. Substrate competition studies indicated that the fluorophore decreased the binding affinity of the peptide, and, in the presence of resveratrol, fluorophore-containing substrates bound more tightly to SIRT1. Using available crystal structures, a model of SIRT1 bound to p53-AMC peptide was constructed. Without resveratrol, the coumarin of p53-AMC peptide is solvent-exposed and makes no significant contacts with SIRT1. We propose that binding of resveratrol to SIRT1 promotes a conformational change that better accommodates the attached coumarin group.