From Wikipedia, the free encyclopedia
Resveratrol (trans-resveratrol) is a phytoalexin
produced naturally by several plants when under attack by pathogens such as
bacteria or fungi. Resveratrol has also been produced by chemical synthesis and is sold as a nutritional supplement derived
primarily from Japanese knotweed. 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. 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. Experiments have shown that resveratrol treatment
extended the life of fruit flies, nematode worms and short living fish but it did not increase the life span of mice.
 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. Later studies conducted by Sinclair showed that
resveratrol also prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. In 2007, a different group of researchers was able to
reproduce Sinclair's results with C. elegans, but a third group could not achieve consistent
increases in lifespan of D. melanogaster or C. elegans.
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 the latter'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.
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 155 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. 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
 Cancer prevention
In 1997, Jang reported that topical resveratrol applications prevented the skin cancer development in mice treated with
a carcinogen. There have since been dozens of studies of the
anti-cancer activity of resveratrol in animal models. No results of human clinical trials for cancer
have been reported. However, clinical trials to investigate the
effects on colon cancer and melanoma (skin cancer) are currently recruiting
In vitro resveratrol interacts with multiple molecular targets (see the mechanisms of action), and has positive effects
on the cells of breast, skin, gastric, colon, esophageal, prostate, and pancreatic cancer, and leukemia. 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. 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.  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 equivocal, even if massive doses of resveratrol are used.
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; however, injected intraperitoneally, 2.5 or 10 mg/kg of
resveratrol slowed the growth of metastatic Lewis lung carcinomas in mice. Resveratrol (1 mg/kg
orally) reduced the number and size of the esophageal tumors in rats treated with a carcinogen. 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.
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.
 Resveratrol and experimental
Palsamy and Subramanian have recently published articles on the antihyperglycemic potential of resveratrol in
experimental diabetic rats. In their study, the oral administration of resveratrol (5mg/kg b.w) to
streptozotocin-nicotinamide-induced experimental diabetic rats for 30 days significantly normalizes the levels of blood
glucose, plasma insulin, glycosylated hemoglobin, AST, ALP, ALT, and modulates the altered activities of carbohydrate
metabolizing enzymes in the liver and kidney tissus of diabetic rats. The results thus obtained showed the antidiabetic
property of resveratrol in experimental diabetes. Resveratol activates AMPK.
 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
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
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. 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 (remove) copper.
The most efficient 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.
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. Only trace amounts (below 5 ng/mL) of unchanged
resveratrol could be detected in the blood after 25 mg oral dose. 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. However, 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.
In humans and rats, 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. Walle suggests sulfate conjugates are the primary source of
activity, Wang et al. suggests the glucuronides, 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."
The hypothesis that resveratrol from wine could have higher bioavailability than resveratrol from a pill, has been disproved by experimental data. 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. 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. 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 or the whole complex of substances wine
contains; for example, the cardiovascular benefits of
wine appear to correlate with the content of procyanidins.
 Adverse effects and unknowns
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. However, other studies have found that resveratrol actually
fights breast cancer. Some studies suggest that resveratrol slows the development
of blood vessels, which suppresses tumors, but also slows healing. 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.
 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. A new report indicates that resveratrol activates Sirtuin 1 (SIRT1) and PGC-1α and improve functioning of the mitochondria. Other research calls into question the theory connecting
resveratrol, SIRT1, and calorie restriction.
- For the debate about Resveratrol effects on longevity, see Calorie restriction#Sir2.2FSIRT1
A paper by Robb et al. discusses resveratrol action in cells. It reports a fourteen-fold increase in the action
of MnSOD (SOD2). 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."
MnSOD reduces superoxide and thereby confers resistance to mitochondrial dysfunction, permeability transition, and apoptotic death in various diseases. It has been implicated in lifespan extension, inhibits
cancer, (e.g. pancreatic cancer) and provides resistance to reperfusion injury and
irradiation damage. 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 which stimulates FOXO3a transcriptional activity 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
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-kB, inhibition of the cytochrome P450 isoenzyme CYP1A1 (although this may not be relevant to the CYP1A1-mediated
bioactivation of the procarcinogen benzo(a)pyrene), alterations in androgenic 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. 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.
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. 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.
According to Patrick Arnold, it also significantly increases natural testosterone production from being both a selective estrogen
receptor modulator and an aromatase inhibitor.
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.
 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. 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. Resveratrol content also stayed stable in the
skins of grapes and pomace taken after fermentation and stored for a long
 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.
In grapes, resveratrol is found primarily in the skin, and — in muscadine grapes — also in the seeds. 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
The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/L, 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
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. However, subsequent studies have found little or no
resveratrol in different varieties of muscadine grapes.
The fruit of the mulberry (esp. the skin) is a source, and sold
as a nutritional supplement.
 Content in wines and grape
||Total resveratrol (mg/L)
||Total resveratrol in 150 mL wine (mg)
|Red Wines (Global)
||1.98 - 7.13
||0.30 - 1.07
|Red Wines (Spanish)
||1.92 - 12.59
||0.29 - 1.89
|Red grape juice (Spanish)
||1.14 - 8.69
||0.17 - 1.30
|Rose Wines (Spanish)
||0.43 - 3.52
||0.06 - 0.53
||0.40 - 2.0
||0.06 - 0.30
|White Wines (Spanish)
||0.05 - 1.80
||0.01 - 0.27
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.
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 μM), ranging from non-detectable levels to 14.3 mg/l (62.7 μM)
trans-resveratrol. Levels of cis-resveratrol follow the same trend as trans-resveratrol.
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
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.
 Content in selected foods
||Total resveratrol (mg)
||1 c (146 g)
||0.01 - 0.26
||1 c (180 g)
||0.32 - 1.28
||1 c (258 g)
||0.04 - 0.13
||1 c (160 g)
||0.24 - 1.25
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. 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 micromol/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.
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. 
supplements, first sourced from ground dried grape skins and seeds, are now primarily derived from the less expensive,
more concentrated Japanese knotweed, which contains up to
187 mg/kg in the dried root and can be concentrated in an extract up to 50%.
As a result of extensive news coverage, sales of supplements greatly increased in 2006, despite
cautions that benefits to humans are unproven.
 See also
 Other articles
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