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Resveratrol

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The cis-isomer of resveratrol

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[1], and is sold as a nutritional supplement derived primarily from Japanese knotweed. Resveratrol extends the life span of several short-living species of animals; however, this effect have not yet been demonstrated in mammals. In mouse and rat experiments, anti-cancer, anti-inflammatory, blood-sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported. As of July 2008, most of these results are yet to be confirmed in humans. In the only positive human trial, extremely high doses (3–5g) of resveratrol in a special proprietary formulation have been necessary to significantly lower blood sugar[citation needed]. 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" that the incidence of coronary heart disease is relatively low in southern France despite high dietary intake of saturated fats.[2]


Physiological effects

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.[3] Later studies conducted by Sinclair showed that resveratrol also prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster.[4] In 2007 a different group of researchers was able to reproduce the Sinclair's results with C. elegans[5] but a third group could not achieve consistent increases in lifespan of Drosophila or C. elegans.[6]

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.[7] 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 then 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. [8]

Cancer prevention

In 1997 Jang reported that topical resveratrol applications prevented the skin cancer development in mice treated with a carcinogen.[9] There have since been dozens of studies of the anti-cancer activity of resveratrol in animal models[10] but no results of human clinical trials for cancer have been reported.[11] In vitro resveratrol interacts with multiple molecular targets (see Resveratrol#mechanisms of action), and has positive effects on the cells of breast, skin, gastric, colon, esophageal, prostate, and pancreatic cancer, and leukemia.[10] 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.[12] 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.[13][14][11] 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.[11]

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 lung and pancreatic cancers, and leukemia.[11][15] Resveratrol (1 mg/kg orally) reduced the number and size of the esophageal tumors in rats treated with a carcinogen.[16] 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.[11]

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 and metastatic Lewis lung carcinomas.[11]

Athletic performance

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 15 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 SIRT1.

Nicholas Wade's interview-article with Dr. Auwerx[17] 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 Dr. 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). It is premature to take resveratrol and expect any particular results. 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 humans.[18]

Pharmacokinetics

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 1 mg of resveratrol in 50 mL solution was retained in the mouth for 1 min before swallowing, 37 ng/ml of free resveratrol were measured in plasma 2 minutes later. This level of unchanged resveratrol in blood can only be achieved with 250 mg of resveratrol taken in a pill form.[19]

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.[20] Only trace amounts (below 5 ng/mL) of unchanged resveratrol could be detected in the blood after 25 mg oral dose.[20] Even when a very large dose of resveratrol (2.5 and 5 g) was given as uncoated pill, the concentration of resveratrol in blood failed to reach the level necessary for the systemic cancer prevention.[21] However, resveratrol given in a 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.[22]

In humans[20] [21] and rats,[23] [24] [25] 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.[26] Walle suggests sulfate conjugates are the primary source of activity[20], Wang et al suggests the glucuronides,[27] 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 that "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."[28]

The hypothesis that resveratrol from wine could have higher bioavailability than resveratrol from a pill,[10][29] has been disproved by experimental data.[30][28] 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.[30] In another study, the pharmacokinetics of resveratrol (25 mg) did not change whether it was taken with vegetable juice, white vine or white grape juice. The highest level of unchanged resveratrol in the serum (7-9 ng/mL) was achieved after 30 minutes, and it completely disappeared from blood after 4 hours.[28] The authors of both studies concluded that the trace amounts of resveratrol reached in the blood are insufficient to explain the French paradox. They concluded that the beneficial effects of wine could be explained by the effects of alcohol[28] or the whole complex of substances it contains.[30]

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.[31][32] However, other studies have found that resveratrol actually fights breast cancer.[33][34] 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 18, as no studies have shown how it affects their natural development.[35] A small study found that a single dose of up to 5 g of trans-resveratrol caused no serious adverse effects in healthy volunteers.[12]

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 SIRT1 and PGC-1α and improve functioning of the mitochondria.[36] Other research calls into question the theory connecting resveratrol, SIRT1, and calorie restriction.[37][38]

An article in press as of January 2008 discusses resveratrol action in cells. It reports a 14-fold increase in the action of MnSOD.[39] MnSOD reduces superoxide to 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 is it essential for the cell to keep superoxide anions in check."[40] MnSOD reduces superoxide and thereby confers resistance to mitochondrial dysfunction, permeability transition, and apoptotic death in various diseases.[41] It has been implicated in lifespan extension, inhibits cancer (e.g. pancreatic cancer [42][43]), and provides resistance to reperfusion injury and irradiation damage [44] [45] [46]. These effects have also been observed with resveratrol. Ellen 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 [47] which stimulates FOXO3a transcriptional activity [48] 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 overexpressing FOXO3a [49].

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,[50] inhibition of the cytochrome P450 isoenzyme CYP1A1[51] (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene[52]), alterations in androgenic[53] 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.[53][54][55][56][57][58] 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.[59][60]

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.[61][62] 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.[63]

According to Patrick Arnold it also significantly increases natural testosterone production from being both a selective estrogen receptor modulator[64][65] and an aromatase inhibitor.[66][67]

In December, 2007, work from Irfan Rahman's laboratory at the University of Rochester demonstrated that resveratrol increased intracellular glutathionelevels via Nrf2-dependent upregulation of gamma-glutamylcysteine ligase in lung epithelial cells, which protected them against cigarette smoke extract induced oxidative stress. [68]

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.[69] 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.[70] Resveratrol content also stayed stable in the skins of grapes and pomace taken after fermentation and stored for a long period.[71]

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.[10]

In grapes, resveratrol is found primarily in the skin,[72] and -— in muscadine grapes —- also in the seeds.[73] 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 content.[72]

The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/L,[74] 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 removed.[72] 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.[75][73] However, subsequent studies have found no or little resveratrol in different varieties of muscadine grapes.[76][77]

The fruit of the mulberry (esp. the skin[78]) is a source, and sold as a nutritional supplement.

Content in wines and grape juice

Beverage Total resveratrol (mg/L)[72][73] Total resveratrol in a 5 ounce glass (mg)[72][73]
Muscadine Wines 14.1 - 40 2.12 - 6
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
Pinot Noir 0.40 - 2.0 0.06 - 0.30
White Wines (Spanish) 0.05 - 1.80 0.01 - 0.27

The trans-resveratrol concentration in 40 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.[79]

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.[80]

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 juices.[73]

"All of the muscadine table wines sampled had greater trans and cis resveratrol concentrations than any other wines sampled. The muscadine table wines varied between 9.2 and 31.9 mg/L cis-resveratrol and between 4.9 and 13.4 mg/L trans-resveratrol."[73]

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.[80]

Content in selected foods

Food Serving Total resveratrol (mg)[81]
Peanuts (raw) 1 c (146 g) 0.01 - 0.26
Peanuts (boiled) 1 c (180 g) 0.32 - 1.28
Peanut butter 1 c (258 g) 0.04 - 0.13
Red grapes 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.[82] 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.[83]

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. [84]

Supplementation

Resveratrol nutritional supplements, first sourced from ground dried grape skins and seeds (sometimes from residual byproducts of winemaking),[citation needed] are now primarily derived from the cheaper, more concentrated Japanese knotweed which contains up to 187 mg/kg in the dried root.[citation needed]

As a result of extensive news coverage,[85][86] sales of supplements greatly increased in 2006,[87][88] despite cautions that benefits to humans are unproven.[89][88] There is also concern in the scientific community that many of the currently-available resveratrol supplements contain little or none of the active ingredient. [90]


Scientists are also studying three other synthetic compounds based on resveratrol which more effectively activate the same biological mechanism.[91]

The compound called SRT 1720 seems to be 1000 times more effective than resveratrol, although it only increases SIRT1 activation by 6 times. No data has been publicly produced by Sirtris regarding this difference in SIRT1 efficiency for the new compound.[92]

A study by Professor Roger Corder has identified a particular group of polyphenols, known as oligomeric procyanidins, which they believe offer the greatest degree of protection to human blood-vessel cells. These are found in greatest concentration in European red wines from certain areas, which correlates with longevity in those regions, though a causal effect is still unclear. This new data may impact the supplement market.[93] Because they are present in red wine in more significant quantities, they could offer an alternate explanation of the French paradox.

See also

References

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Further reading


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