ZMA (Zinc monomethionine aspartate and Magnesium Aspartate) is a supplement used by bodybuilders and athletes. It was developed by Victor Conte (founder of BALCO Laboratories in Burlingame, California) and is a combination of zinc, magnesium and vitamin B6. The formula is “patent pending” and the name “ZMA” trademarked by SNAC System Inc, also founded by Victor Conte. ZMA is claimed to raise testosterone and IGF-1 levels which may aid in gaining muscle size and strength.

ZMA is a combination of two minerals, zinc and magnesium, and Vitamin B-6 or pyridoxine. All three of these compounds are important in biological processes, and while studies have shown that most Americans get enough zinc and Vitamin B6,[1] more than 50% are deficient in magnesium.[2]

An increase in exercise can lead to the loss of vitamins and minerals making it particularly important for bodybuilding due to the blood sugar level rises and urination increases, increasing the loss of magnesium, zinc, B12, B6, folic acid, and many other nutrients. Although drinking water re-hydrates an athlete, fruit juice, sports drinks or foods high in water such as vegetables are needed to replenish water-soluble nutrients.

The proportion of ingredients generally used in products is 20-30 mg Zinc, 400-500 mg Magnesium and ~10mg B6. According to the label directions, ZMA should be taken before bed on an empty stomach (2 hours after eating your last meal and at least 30 minutes prior to any other supplements). The product should not be taken with calcium (cheese,milk,etc.), the reason being that calcium blocks the absorption of zinc.

Scientific studies
A 1999 study was undertaken on NCAA Football players during an 8 week spring training program. The control group was told to cease taking any nutritional supplements. Those who took the ZMA tablets showed greater increases in muscle strength, free testosterone levels, and IGF-1 levels.[3] This study was funded by SNAC Systems Inc. (the patent holders) and one of the study’s authors (Victor Conte) has equity in this company.

Another study in 2004 conducted jointly by the Exercise & Sport Nutrition Lab of Baylor University, IMAGINutrition, and the Journal of the International Society of Sports Nutrition, found that ZMA has no effect on strength, hormone levels, or anaerobic capacity.[4]

History
The supplement played a large role in the controversial non-fiction book Game of Shadows by Mark Fainaru-Wada and Lance Williams. It is important to note that “of the 57 Western Washington University football players who signed up for the study, 30 quit. By the end, only a dozen players were using ZMA while 15 took the placebo.” (Game Of Shadows 46)[5]

References
“Ohio State University Extension Fact Sheet”. Retrieved on 2006-08-11.
“More than half of Americans don’t get nearly enough magnesium” (PDF). Retrieved on 2006-08-11.
Lukaski HC (2000). “Magnesium, zinc, and chromium nutriture and physical activity”. American Journal of Clinical Nutrition 72 (2): 585s-593s. PMID 10919964, http://www.ajcn.org/cgi/content/full/72/2/585S.
Fainaru-Wada, Mark, and Lance Williams. Game of Shadows. 1st Edition. New York: Penguin Group , 2006

Courtesy of Wikipedia

Omega 3-6-9 is one product that truly covers all aspects of supporting heart and circulation health – it contains flax and canola seed oils for Omega 3, GLA from primrose for Omega 6, and Oleic acid for Omega 9. Omega 3-6-9 is the perfect product for those wanting to add essential oils to their diet.

Consuming adequate amounts of healthy kinds of fat – “essential fatty acids,” like those found in Omega 3-6-9 formula, is vital for your overall health.

Omega-3 Fatty Acids Promote Heart Health

Studies have shown diets rich in omega-3 fatty acids support heart health by promoting proper triglyceride and cholesterol levels.

The Important Role Played by Omega-6 Fatty Acids

The key type of omega-6 fatty acid is called GLA (gamma linolenic acid). GLA is a precursor to hormone-like prostaglandins (PGE-1). Prostaglandins and specifically PGE-1 are powerful health “gladiators” cascading through the body.

PGE-1 promotes healthy blood flow to and from the heart by supporting blood vessels.

Immune function is also under the powerful influence of PGE-1, which controls the release of lymphokines known to activate immune system cells.

Production and secretion of vital hormones in the pituitary, thyroid and adrenal glands, as well as immune boosting and lean tissue building growth hormone, are all stimulated by “multi-talented” PGE-1. PGE-1 also promotes the release and uptake of neurotransmitters, the chemical messengers of the nervous system, which support healthy sleep patterns and mood.

Healthy levels of fatty acids which lead to adequate PGE-1 are important for those wishing to maintain energy levels.

Omega 9 Fatty Acid
Common to olive oil, peanuts and avocado, Omega 9 fatty acid is also known as oleic acid. While not an essential fatty acid (the body can manufacture omega 9), supplementing with Omega 9 provides a good source of monounsaturated fat that promotes a healthy inflammation response.

7-KETO (3-acetyl-7-oxo-dehydroepiandrosterone) is a naturally occurring metabolite (breakdown product) of the hormone dehydroepiandrosterone (DHEA).1 DHEA is the most abundant of the adrenal steroid hormones and serves as a precursor for sex hormones, such as estrogen and testosterone.

7-KETO was developed by researchers who were looking for biologically active metabolites of DHEA that could not be converted to the potentially cancer-causing sex steroids (e.g., estrogen and testosterone).

Tests in animals and test tubes were performed in the areas of immune modulation, memory enhancement, and thermogenesis (the process the body uses to convert stored calories into energy). In all cases, the effects of 7-KETO were stronger than those produced by DHEA.2 3 4 5

The capacity of 7-KETO to promote weight loss in overweight people been investigated in a double-blind study.6 Participants in the study were advised to exercise three times per week for 45 minutes and to eat an 1,800-calorie per day diet. Each person was given either a placebo or 100 mg of 7-KETO twice daily. After eight weeks, those receiving 7-KETO had lost an average of 6.34 pounds, compared with 2.13 pounds in the placebo group (a statistically significant difference). In addition, the percentage of body fat decreased by 1.8% in the 7-KETO group, compared with only 0.57% in the placebo group. The increased weight loss in the 7-KETO group was associated with a significant increase in levels of T3 (a thyroid hormone that plays a major role in determining a person’s metabolic rate), although the levels of T3 did not exceed the normal range.

Where is 7-keto found?
7-KETO is available as a dietary supplement.

7-KETO has been used in connection with the following conditions (refer to the individual health concern for complete information):

Reliable and relatively consistent scientific data showing a substantial health benefit.
Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit.
For an herb, supported by traditional use but minimal or no scientific evidence. For a supplement, little scientific support and/or minimal health benefit.

Who is likely to be deficient of 7-keto?
Since the level of 7-KETO is directly related to the level of DHEA in the body,7 people with lower DHEA levels likely have low 7-KETO levels as well. Low DHEA levels are primarily associated with aging.

How much 7-keto is usually taken?
The manufacturer of 7-KETO recommends 100 mg twice daily for weight loss.

Are there any side effects or interactions with 7-keto?
A safety study in humans has shown that 7-KETO did not raise estrogen or testosterone levels or produce any other negative effects at levels up to 200 mg per day for eight weeks.8 Short-term animal studies also revealed no adverse effects with large amounts of 7-KETO.9 10 11 However, the long-term safety of 7-KETO for humans has not been demonstrated, and, because it is chemically related to steroid hormones, the potential for adverse effects must be considered. In addition, the increase in T3 levels resulting from taking 7-KETO could, in theory, produce adverse effects on the heart or promote bone loss. For these reasons, people wishing to take 7-KETO, particularly those who have a thyroid disorder or are taking thyroid hormone, should consult a physician.

At the time of writing, there were no well-known drug interactions with 7-KETO.

courtesy of evitamins

Pine bark extract that acts as a powerful anti-oxidant to neutralize free radicals that contribute to premature aging.  As all serious athletes soon learn, peak performance requires more than physical training. Leading athletes need the best delivery and use of energy and oxygen. Energy and oxygen provide the forces and power that make it possible for the body to carry out its physical functions. An efficient vascular (blood flow) system makes sure every body cell is supplied with energy-providing glucose and oxygen. The anti-inflammatory and anti-allergic activity of Pycnogenol is based on its powerful antioxidant activity whereby it can neutralise free radicals. This antioxidant mechanism of PycnoGenol is one explanation why small amounts of red wine appear to have a protective effect on the cardiovascular system. It is thought that some of the natural extracts from the grape seeds are captured during production of wine and supply the protective antioxidants.

What is Pycnogenol®?
Pycnogenol® (pic-noj-en-all) is the brand name for a premium herbal supplement ingredient extracted from the bark of the French maritime pine tree. That special pine bark is loaded with a concentrate of active bioflavonoids, which are also found in fresh fruits and vegetables. The extract from the pine bark is a potent blend of active compounds. Extensive research over a period of more than 35 years was dedicated to safety of Pycnogenol® and to substantiate the manifold benefits for human health of this extraordinary extract. Purity and potency of Pycnogenol® are continuously monitored and Horphag Research guarantees its constant high quality.

 
Where does Pycnogenol® come from?

The source of Pycnogenol® is a large forest of millions of acres in southwestern France near the famous Bordeaux region. The forest is a plantation of French maritime pine trees and represents Europe’s largest forest. The pine trees are cultivated over a period of 30-50 years. Neither pesticides nor herbicides are used in the forest.
How does Pycnogenol® work to improve my health?

As one of the most potent natural scavenger of free radicals, Pycnogenol® mops-up all kinds of aggressive radicals, before they cause any damage by oxidative stress. Its super-antioxidant capabilities help boost the immune system and it strengthens blood vessel walls and capillaries. It supports a better circulation by preventing stress-induced constriction of arteries and blood clotting. Additionally the extract contains substances which act against cramps.
Free radicals – why fight them?

In every day life our body generates free radicals, especially in case of stress. These chemically unbalanced radicals cause damage to our cells by oxidizing them, in the same way as metal becomes rusty and destroyed. Hence, free radicals are dangerous and scientists believe that the continuous exposure to free radicals is the major cause of ageing and also of many degenerative diseases. As a super-antioxidant, Pycnogenol® counteracts that danger in two ways: It stimulates our cells to double their antioxidative power and it catches free radicals in the blood stream. That double defense makes Pycnogenol® unique.

How much Pycnogenol® should I take and for how long?

For general use as a supplement, a typical daily dosage would be 1 mg per kilogram of body weight, or follow the directions on the packaging. Pycnogenol® is available in a wide variety of supplement formulas and most contain between 20mg-100mg of Pycnogenol. Find which one works best for you! When starting a new vitamin or dietary supplement, always allow one month for it to fully take effect and adjust to your body.
Please consult your physician if you are taking Pycnogenol® for a specific condition.
Is Pycnogenol® safe?

Pycnogenol® is one of the most researched food supplements and has passed extensive safety tests. Toxicity test results demonstrated that Pycnogenol® is safe, even at high doses for long periods of time. To date, no serious adverse side effects had been observed or reported in clinical trials. Mild side effects as gastro-intestinal discomfort, headache, nausea and dizziness were seldom reported. Because of its astringent taste, which occasionally causes minor stomach discomfort, it is best to take Pycnogenol® with or after meals. Pycnogenol® is certified kosher and has earned Generally Recognized as Safe (GRAS) status for applications in functional foods and beverages in the U.S.
Should I use Pycnogenol® instead of vitamins?

No. Vitamins are as important for your health. Pycnogenol® acts in synergy with vitamins. It helps to recycle vitamins C and E, so they act longer while in your body. To feel your best, take Pycnogenol® in combination with your vitamins.
Are Pycnogenol®’s health benefits supported by science?

Over the past 35 years, extensive research has resulted in more than 56 published clinical studies and 170 scientific publications.
Pycnogenol® boosts one of the most comprehensive science portfolios of any natural ingredient and through extensive research has proven to be a non-toxic, powerful and effective antioxidant with a variety of health benefits.
Should pregnant women and small children take Pycnogenol®?

As a general precaution, pregnant women should not take Pycnogenol® within the first 3 months of pregnancy. Because there is no experience with small children, children under the age of 6 should not take Pycnogenol. That precaution measure is given beside the fact that no adverse effects had been observed in test series.
Where can I find products with Pycnogenol®?

There are many natural products containing Pycnogenol® available today including vitamin and dietary supplements, functional beverages and cosmetic products. Click here to view a listing of companies that produce products with Pycnogenol® in your country. Products can be found worldwide in pharmacies, health food stores, supermarkets and on the Internet at a variety of web sites.

courtesy of pycnogenol.com

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 has been shown at times to extend the life span of yeast and mice.[2] In mouse and rat experiments, anti-cancer, anti-inflammatory, blood-sugar-lowering, chelating 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 special proprietary formulation have been necessary to significantly lower blood sugar.[3] 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.[4]

Contents
1 Physiological effects
1.1 Life extension
1.2 Cancer prevention
1.3 Athletic performance
2 Pharmacokinetics
2.1 Adverse effects and unknowns
3 Mechanisms of action
4 Chemical and physical properties
5 Plants and foods
5.1 Content in wines and grape juice
5.2 Content in selected foods
6 Supplementation
7 Related compounds
8 See also
8.1 Other articles
9 References
10 Further reading
11 External links
 
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.[5] Later studies conducted by Sinclair showed that resveratrol also prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster.[6] In 2007, a different group of researchers was able to reproduce Sinclair’s results with C. elegans,[7] but a third group could not achieve consistent increases in lifespan of D. melanogaster or C. elegans.[8] However, a large scale study of the effects of resveratrol on lifespan in D. melanogaster and C. elegans, by the Gems and Partridge labs (which are not financially connected the Sirtuin companies Sirtuis and Elexir), demonstrated no lifespan extending effects of resveratrol.[8] Furthermore, no lifespan extension was observed in normal mice.[9]

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.[10] 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.[11] In a recent study by the University of Pittsburgh School of Medicine, it was found that resveratrol may offer protection against radiation exposure.[12]
Cancer prevention
In 1997, Jang reported that topical resveratrol applications prevented the skin cancer development in mice treated with a carcinogen.[13] There have since been dozens of studies of the anti-cancer activity of resveratrol in animal models.[14] No results of human clinical trials for cancer have been reported.[15] However, clinical trials to investigate the effects on colon cancer and melanoma (skin cancer) are currently recruiting patients.[16]

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.[14] 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.[17] 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.[18][19][15] 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.[15]

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;[15][20] however, injected intraperitoneally, 2.5 or 10 mg/kg of resveratrol slowed the growth of metastatic Lewis lung carcinomas in mice.[15][21] Resveratrol (1 mg/kg orally) reduced the number and size of the esophageal tumors in rats treated with a carcinogen.[22] 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.[15]

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.[15]
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 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[23] 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 humans.[24]
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 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.[25]

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.[26] Only trace amounts (below 5 ng/mL) of unchanged resveratrol could be detected in the blood after 25 mg oral dose.[26] 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.[27] 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.[3]

In humans[26] [27] and rats,[28] [29] [30] 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.[31] Walle suggests sulfate conjugates are the primary source of activity[26], Wang et al suggests the glucuronides,[32] 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.”[33]

The hypothesis that resveratrol from wine could have higher bioavailability than resveratrol from a pill,[14][34] has been disproved by experimental data.[35][33] 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.[35] 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.[33] 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[33] or the whole complex of substances it contains.[35]
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.[36][37] However, other studies have found that resveratrol actually fights breast cancer.[38][39] Some studies suggest that resveratrol slows the development of blood vessels, which suppresses tumors, but also slows healing.[40] 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.[41] A small study found that a single dose of up to 5 g of trans-resveratrol caused no serious adverse effects in healthy volunteers.[17]
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.[42] Other research calls into question the theory connecting resveratrol, SIRT1, and calorie restriction.[43][44]

An article in press as of January, 2008, discusses resveratrol action in cells. It reports a fourteen-fold increase in the action of MnSOD (SOD2).[45] 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 is it essential for the cell to keep superoxide anions in check.”[46] MnSOD reduces superoxide and thereby confers resistance to mitochondrial dysfunction, permeability transition, and apoptotic death in various diseases.[47] It has been implicated in lifespan extension, inhibits cancer, (e.g. pancreatic cancer [48][49]) and provides resistance to reperfusion injury and irradiation damage [50] [51] [52]. 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 [53] which stimulates FOXO3a transcriptional activity [54] 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 [55].

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,[56] inhibition of the cytochrome P450 isoenzyme CYP1A1[57] (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene[58]), alterations in androgenic[59] 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.[59][60][61][62][63][64] 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.[65][66]

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.[67][68] 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.[69]

According to Patrick Arnold, it also significantly increases natural testosterone production from being both a selective estrogen receptor modulator[70][71] and an aromatase inhibitor.[72][73]

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.[74]
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.[75] 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.[76] Resveratrol content also stayed stable in the skins of grapes and pomace taken after fermentation and stored for a long period.[77]
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.[14]

In grapes, resveratrol is found primarily in the skin,[78] and -— in muscadine grapes —- also in the seeds.[79] 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.[78]

The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/L,[80] 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.[78] 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.[81][79] However, subsequent studies have found little or no resveratrol in different varieties of muscadine grapes.[82][83]

The fruit of the mulberry (esp. the skin[84]) is a source, and sold as a nutritional supplement.
Content in wines and grape juice
Beverage Total resveratrol (mg/L)[78][79] Total resveratrol in a 5 ounce glass (mg)[78][79]
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 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.[85]

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.[86]

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.[79]

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.[86]
Content in selected foods
Food Serving Total resveratrol (mg)[87]
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.[88] 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.[89]

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. [90]
Supplementation
Resveratrol nutritional supplements, first sourced from ground dried grape skins and seeds, 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,[91][92] sales of supplements greatly increased in 2006,[93][94] despite cautions that benefits to humans are unproven.[95][94][96]
Related compounds
Scientists are also studying three other synthetic compounds based on resveratrol which more effectively activate the same biological mechanism.[97]

The compound called SRT1720 seems to be 1000 times more potent than resveratrol, but only increases SIRT1 activation by six times. No data have been produced publicly by Sirtris regarding this difference in SIRT1 efficiency for the new compound.[98]

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. These new data may have an impact on the supplement market.[99] Because they are present in red wine in more significant quantities, they could offer an alternate explanation of the French paradox.

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