Resveratrol

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi.[5][6] Sources of resveratrol in food include the skin of grapes, blueberries, raspberries, mulberries, and peanuts.[7][8]

Although commonly used as a dietary supplement and studied in laboratory models of human diseases,[9] there is no high-quality evidence that resveratrol improves lifespan or has an effect on any human disease.[10][11][12]

There is no evidence of benefit from resveratrol in those who already have heart disease.[9][13] A 2014 Chinese meta-analysis found a statistically significant 11.90 mmHg reduction in systolic blood pressure from resveratrol doses of 150 mg/day.[14]

As of 2019, there is no evidence of an effect of resveratrol on cancer in humans.[9][15]

There is no conclusive evidence for an effect of resveratrol on human metabolic syndrome.[9][16][17]

There is no evidence for an effect of resveratrol on lifespan in humans, as of 2019.[5][9][18][12]

In a year long preliminary clinical trial in people with Alzheimer's disease, the most frequent adverse effects were diarrhea, weight loss, and nausea.[19] A 2018 review of resveratrol effects on blood pressure found that some people had increased frequency of bowel movements and loose stools, and one person taking a 1000 mg daily dose developed an itchy rash.[20]

Resveratrol has been identified as a pan-assay interference compound, which produces positive results in many different laboratory assays.[21] Its ability for varied interactions may be due to direct effects on cell membranes.[22]

As of 2015, many specific biological targets for resveratrol had been identified, including NQO2 (alone and in interaction with AKT1), GSTP1, estrogen receptor beta, CBR1, and integrin αVβ. It was unclear at that time if any or all of these were responsible for the observed effects in cells and model organisms.[23]

In vitro studies indicate resveratrol activates sirtuin 1,[24] although this may be a downstream effect from its immediate biological target(s).[25][26] It appears to signal through PGC-1α, thereby affecting mitochondria.[27] In cells treated with resveratrol, an increase is observed in the action of MnSOD (SOD2)[28] and in GPER activity.[29] In vitro, resveratrol was shown to act as an agonist of Peroxisome proliferator-activated receptor gamma, a nuclear receptor under pharmacological research as a potential treatment for type 2 diabetes.[30]

One way of administering resveratrol in humans may be buccal delivery by direct absorption through the saliva. However, the viability of a buccal delivery method is unlikely due to the low aqueous solubility of the molecule.[31][32] The bioavailability of resveratrol is about 0.5% due to extensive hepatic glucuronidation and sulfation.[33]

Resveratrol is extensively metabolized in the body,[5] with the liver and lungs as the major sites of its metabolism.[34]

Resveratrol (3,5,4'-trihydroxystilbene) is a stilbenoid, a derivative of stilbene.[5] It exists as two geometric isomers: cis- (Z) and trans- (E), with the trans-isomer shown in the top image. The trans- and cis-resveratrol can be either free or bound to glucose.[35]

The trans- form can undergo isomerization to the cis- form when exposed to ultraviolet irradiation,[36] a process called photoisomerization:[37]

One study showed that ultraviolet irradiation to cis-resveratrol induces further photochemical reaction, producing a fluorescent molecule named "Resveratrone".[38]

Trans-resveratrol in the powder form was found to be stable under "accelerated stability" conditions of 75% humidity and 40 °C in the presence of air.[39] The trans isomer is also stabilized by the presence of transport proteins.[40] Resveratrol content also was stable in the skins of grapes and pomace taken after fermentation and stored for a long period.[41] lH- and 13C-NMR data for the four most common forms of resveratrols are reported in literature.[35]

Resveratrol is produced in plants by the action of the enzyme, resveratrol synthase.[42]

The grapevine fungal pathogen Botrytis cinerea is able to oxidise resveratrol into metabolites showing attenuated antifungal activities. Those include the resveratrol dimers restrytisol A, B, and C, resveratrol trans-dehydrodimer, leachinol F, and pallidol.[43] The soil bacterium Bacillus cereus can be used to transform resveratrol into piceid (resveratrol 3-O-beta-D-glucoside).[44]

Resveratrol is a phytoalexin, a class of compounds produced by many plants when they are infected by pathogens or physically harmed by cutting, crushing, or ultraviolet radiation.[45]

Plants that synthesize resveratrol include knotweeds, pine trees including Scots pine and Eastern white pine, grape vines, peanut plants, cocoa bushes, and Vaccinium shrubs that produce berries, including blueberries, raspberries, mulberries, cranberries, and bilberries.[5][7][45]

The levels of resveratrol found in food varies considerably, even in the same food from season to season and batch to batch.[5]

In a 2007 review of published resveratrol concentrations, the average in red wines is 1.9±1.7 mg trans-resveratrol/L (8.2±7.5 μM), ranging from nondetectable levels to 14.3 mg/l (62.7 μM) trans-resveratrol. Levels of cis-resveratrol follow the same trend as trans-resveratrol.[46]

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 concentrations than any other wine or region.[46] Champagne and vinegar also contain appreciable levels of resveratrol.[8]

Red wine contains between 0.2 and 5.8 mg/l, depending on the grape variety. White wine has much less because red wine is fermented with the skins, allowing the wine to extract the resveratrol, whereas white wine is fermented after the skin has been removed.[5] The composition of wine is different from that of grapes since the extraction of resveratrol from grapes depends on the duration of the skin contact, and the resveratrol 3-glucosides are in part hydrolysed, yielding both trans- and cis-resveratrol.[5]

Ounce for ounce, peanuts have about 25% as much resveratrol as red wine.[5] Peanuts, especially sprouted peanuts, have a content similar to grapes in a range of 2.3 to 4.5 μg/g before sprouting, and after sprouting, in a range of 11.7 to 25.7 μg/g, depending upon peanut cultivar.[45][8]

Mulberries (especially the skin) are a source of as much as 50 micrograms of resveratrol per gram dry weight.[47]

Sales of resveratrol supplements increased in 2006 after studies on non-humans.[48]

Harvard University scientist and professor David Sinclair co-founded Sirtris Pharmaceuticals, the initial product of which was a resveratrol formulation;[49] Sinclair became known for making statements about resveratrol such as: "(It's) as close to a miraculous molecule as you can find.... One hundred years from now, people will maybe be taking these molecules on a daily basis to prevent heart disease, stroke, and cancer."[50] Most of the anti-aging field was more cautious, especially with regard to what else resveratrol might do in the body and its lack of bioavailability.[50][51]

Sinclair and others obtained significant news coverage about resveratrol.[52][53] Sinclair is often quoted and pictured in online ads for resveratrol supplements, many of which implied endorsement of the advertised product even though Sinclair had not endorsed them.[54]

The first mention of resveratrol was in a Japanese article in 1939 by Michio Takaoka, who isolated it from Veratrum album, variety grandiflorum, and later, in 1963, from the roots of Japanese knotweed.[45][55][56][57]

As of 2019, the extensive research on resveratrol in numerous laboratory models of human diseases – conducted over decades – has failed to show any anti-disease effect in randomized controlled trials on humans.[5][9]

A 2011 systematic review of existing resveratrol research found that there was not enough evidence to demonstrate its effect on longevity or human diseases, nor could there be recommendations for intake beyond the amount normally obtained through dietary sources, estimated as being less than 4 mg/day.[10] Much of the research showing positive effects has been done on animals, with insufficient clinical research on humans.[9][10] Resveratrol research in animals and humans remains active.[58][59]

As of 2014, the results of studies on laboratory animals or human clinical trials concerning the effects of resveratrol on cancer are inconsistent,[15] even if massive doses of resveratrol are used.[60]

Resveratrol is under preliminary research for its potential to limit secondary damage after ischemic stroke or acute brain trauma,[61] and its possible effect on cognition.[19]

A 2018 meta-analysis found no effect on systolic or diastolic blood pressure; a sub-analysis revealed a 2 mmHg decrease in systolic pressure only from resveratrol doses of 300 mg per day, and only in diabetic people.[20] A 2015 meta-analysis found no effect on systolic or diastolic blood pressure; a sub-analysis found an 11.90 mmHg reduction in systolic blood pressure from resveratrol doses of 150 mg per day.[14]

One 2015 review found little evidence for use of resveratrol to treat diabetes.[62] A 2015 meta-analysis found little evidence for an effect of resveratrol on diabetes biomarkers.[63]

Despite considerable in vitro and animal research, there is no evidence that resveratrol taken orally or topically has any effect on human skin.[64] Preliminary studies have been conducted on resveratrol to understand its potential as a therapy for melanoma.[65][66]