# Resveratrol - How Resveratrol Combats the Leading Causes of Death



## Times Roman (Nov 3, 2012)

Well mates, several years ago, I drank the Kool-aide and purchased a kilo of 40% pure Resveratrol powder.  Split it up with some other blokes, but still have a couple year supply on hand. Yes, it was expensive, but after you read this article from LEF, you will understand a little more about this very powerful anti aging compound.  Enjoy!

http://www.lef.org/magazine/mag2012...es-Death_01.htm?source=search&key=resveratrol

In 1997, the first scientific paper on resveratrol was published showing that this polyphenol could prevent cancer in experimental models.1 

Since then, researchers have documented resveratrol’s ability to favorably modulate multiple processes associated with degenerative disease, from atherosclerosis to obesity.

What had been lacking was a systematic, comprehensive overview of the available data to determine the underlying mechanisms by which resveratrol exerts its anti-aging effect.

Until now!

In 2011, the findings of the 2010 Resveratrol Conference2 held in Denmark were published. Its primary objective was to examine the totality of the evidence for resveratrol’s disease-preventing role in aging humans. Nearly 3,700 published studies were analyzed.

In this article, you will discover the 12 mechanisms of action these experts identified by which resveratrol acts to combat the killer diseases of aging and delay the aging process itself. 

You will also learn of the latest data on resveratrol’s multimodal power to protect cells, tissues, and organ systems against five leading causes of death among Americans, including heart disease, cancer, and diabetes.

The participating scientists at the 2010 conference covered a broad range of research on the biological effects of resveratrol. Since 1997, roughly 3,650 studies on resveratrol have been published, all of which were reviewed.

Based on the most encouraging data, they focused specifically on resveratrol’s capacity to favorably modulate factors involved in cancer, heart disease, neurodegeneration, systemic inflammation, obesity, and diabetes.1,2 

Out of this extensive analysis they isolated 12 mechanisms by which resveratrol exerts its anti-aging, disease-preventing effects (See table 1). 

A thorough review of the literature was then undertaken to identify their relevance in onset of various forms of degenerative disease. 

They found confirmatory evidence of resveratrol’s preventive role in five of the leading causes of death in maturing Americans (See table 2).

Heart Disease .

America’s number one killer is heart disease, which includes the conditions atherosclerosis, hypertension, heart attack, and heart failure.2,3 Resveratrol is known to reduce risks for all of these conditions by targeting multiple factors that set the stage for cardiovascular diseases.2 

Recent studies confirm that a central mechanism of resveratrol’s activity is to mimic the biological effects of calorie restriction, which is known to extend life span in virtually all living organisms.4 

Resveratrol helps to combat high blood pressure (hypertension) by a variety of mechanisms. It decreases inflammatory cell infiltration into blood vessel walls and improves those vessels’ ability to respond to changes in blood pressure.5 In addition, resveratrol has recently been shown to reduce the unfavorable remodeling and stiffening of blood vessels and heart muscle that results from sustained hypertension.5 Resveratrol also acts in the brainstem to reverse increases in blood pressure that are triggered by a variety of dietary and hormonal factors.6 

Studies published in 2011 show that resveratrol helps mitigate the cholesterol elevations that result from obesity and a high-fat diet by directly regulating expression of genes that control lipid metabolism.7 Exposure to resveratrol triggers correction of abnormal fatty acid utilization, by inducing mitochondrial enzymes that help break down fat molecules.8 And in pigs with the equivalent of human metabolic syndrome, resveratrol supplementation lowered body mass indices, serum cholesterol, the inflammatory marker C-reactive protein, improved glucose tolerance and endothelial function.9 

In the presence of sustained hypertension and/or elevated cholesterol and other fats, damage occurs to the delicate, reactive cells lining capillaries, known as endothelial cells. Endothelial dysfunction is a major contributor to heart attacks, strokes, and heart failure, and is an important target of cardiovascular disease prevention. New data show that resveratrol reduces the effects of both hypertension on endothelial cells and inhibits signs of endothelial dysfunction.10 

Build-up of calcium in arteries is a major contributor to arterial stiffening and blockage that occurs fairly late in atherosclerosis.11 It also contributes to the inflammatory changes that exacerbate cardiovascular disease.12 Arterial calcification was formerly thought to be caused by passive accumulation of calcium, similar to mineral deposits in pipes. It is now known to be an active process whereby arterial cells “turn into” bone-forming cells as a result of age- and inflammation-induced genetic changes. Certain drugs, such as the now-withdrawn antidiabetic drug Avandia® (rosiglitazone), can hasten this destructive process.13 New data demonstrate that resveratrol slows or reverses the process by which arterial cells become “bone-like,” reducing the amount and extent of calcium build-up in arterial walls.11,13 Resveratrol limits the inflammation-inducing effects of calcium in cells lining blood vessels.12 

In addition to elevated fat and calcium content in vessel walls, aggregation of clot-forming platelets contributes to arterial blockages resulting in heart attacks, strokes, and other cardiovascular events. New data now show that resveratrol inhibits the platelet aggregation that can trigger formation of a deadly blood clot.14

When an artery in the heart becomes blocked, blood flow to the heart is restricted, causing ischemic damage. Restoration of blood flow (reperfusion) makes matters worse, at first, by flooding the damaged tissue with oxygen free radicals. Sophisticated molecular probes have now revealed that resveratrol leaves a unique “footprint” in heart muscle that has been subjected to ischemia/reperfusion injury.15 The result is a considerable reduction in death (apoptosis) of cardiac cells following such an injury, and improved cardiovascular function.16 

Resveratrol’s calorie restriction-mimicking effects directly improve mitochondrial function in energy-intensive heart muscle cells, making them beat more effectively and reducing their vulnerability to oxidative stress.4 Furthermore, we now understand that resveratrol produces cardioprotective effects in heart muscle cells that do undergo the massive oxidant stress of a heart attack or a serious infection.17 
Cancer 

More than half a million Americans die of cancer each year, despite considerable strides in our understanding of the disease.18 The very first scientific study of resveratrol showed a preventive effect on skin cancer,1 and since that time more than 1,100 papers have been published on the subject of cancers in general.2 Today’s experts refer to resveratrol as “a promising natural weapon in the war against cancer.”19 

Breaking news since the 2010 Resveratrol Conference shows that resveratrol fights cancer on multiple levels.20 The following is a summary of the latest on resveratrol and cancer prevention.

Resveratrol can prevent dangerous DNA “adducts,” modified stretches of DNA that, un-repaired, can trigger a cell to become cancerous in the step known as cancer initiation.21 

Once initiated, cancers grow by proliferation of abnormal cells. Resveratrol is a modest anti-proliferative agent, as new data show. Consumption of resveratrol by human colon cancer patients reduced tumor cell proliferation by 5% at a dose of 500 to 1,000 mg daily for 8 days prior to surgery.22 And resveratrol inhibits an important cancer cell signaling pathway called STAT3, further reducing cancerous proliferation, as was recently shown in certain brain cancer cells.23 

The body naturally controls cancer growth through the process of apoptosis, by which cancer cells are triggered to die off. Proper apoptosis requires activation of important “suicide” genes found in all cancer cells. Resveratrol has recently been found to increase expression and activation of one important “suicide” pathway known as p53.24 

Insulin-like growth factor I (IGF-1) is important in growth and healing, but it also promotes cancer propagation once a malignancy has been initiated. A new human study showed that dosing with resveratrol at 2.5 grams/day (which is much higher than currently recommended) caused a significant decrease in circulating levels of IGF-1 and its binding protein, suggesting that suppression of IGF-1 may be involved in one of resveratrol’s anti-cancer mechanisms.25 




Many carcinogens enter the body as “safe” compounds, but become modified by enzyme systems in the liver to trigger cancer. Interestingly, liver enzymes are responsible for detoxifying active carcinogens before they can cause harm. Resveratrol has recently been shown to favorably modulate both classes of enzymes, reducing activation of potential carcinogens while actively detoxifying known carcinogenic molecules.26 

Inflammation is now widely recognized as a cancer-promoting event. New evidence shows how resveratrol reduces production of inflammatory molecules such as leukotrienes by inhibiting the enzymes that produce them.27,28 Inflammation is also important in promoting cancer spread, or metastasis. In a 2011 study, resveratrol remarkably inhibited invasion and spread of melanoma cells by up to 75%.20

A class of tiny strands of material called RNA, known as microRNAs, is known to regulate cancer cell growth and development. In new research, resveratrol shows the ability to modify the microRNA content of cells, up-regulating cancer-suppressing microRNAs, while down-regulating cancer-promoting ones.29-31 

As tumors grow, they stimulate new blood vessel growth to support their ravenous needs for nutrients. Inhibiting this process, known as angiogenesis, has become a major target of cancer prevention and treatment. Resveratrol, in recent studies, has been shown to stimulate new blood vessels in healthy tissue, but to inhibit their growth in malignant melanoma cell cultures as well as in whole tumors.32,33 

All of this means resveratrol is reaching the level of large-scale clinical trials by mainstream physicians. Phase I, “dose-finding” studies have now been completed that validate resveratrol’s safety even at very high levels of up to 5 grams (this does not mean people should take this high dose yet).25,34

Stroke 

Strokes are caused by many of the same vascular changes that trigger heart attacks: atherosclerosis, plaque formation, and ultimately blood vessel occlusion that deprive brain tissue of vital blood flow. In addition, aging and certain conditions like diabetes cause brain blood vessels to lose their ability to dilate and increase blood flow as needed, exacerbating damage caused during a stroke. When blood flow is restored after the acute blood vessel blockage is resolved, oxygen free radicals occur abundantly and cause the final destruction of brain tissue. That process is known as ischemia/reperfusion injury.

Resveratrol protects brain tissue from ischemia/reperfusion injury, according to a host of recently-released studies.35 Researchers at Johns Hopkins showed that resveratrol induces production of the enzyme heme oxygenase, which is protective against oxidative stress.36,37 Furthermore, resveratrol protects vulnerable mitochondria during ischemia/reperfusion injury, allowing them to continue their important job of providing cells with energy.38 

During the acute phase of a stroke, excitatory neurotransmitters such as glutamate are released in large amounts.39 This release then triggers acute and chronic damage to brain cells. Researchers have now shown that resveratrol significantly prevents dangerous glutamate release following a stroke.39 

Finally, new data show that treating diabetic animals with resveratrol restores the responsiveness of their brain arteries to blood flow variations.40 That allows them to re-direct blood flow to vital areas blocked by the stroke.

The combined effect of these mechanisms is to reduce the size of a stroke significantly.41 Remarkably, this protection even occurs when resveratrol is given up to 6 hours after the stroke begins.41 Some experts are now hailing that discovery as evidence that resveratrol may be a potent new drug for use in treatment of acute ischemic stroke.41 Nonetheless, the strongest and most recent evidence suggests that resveratrol used regularly in advance of a stroke provides the best tolerance to an ischemic event if and when one should arise.42,43




Alzheimer’s Disease 

Nearly 75,000 Americans die annually from Alzheimer’s disease, and more than 230,000 others suffer dementia severe enough to require nursing home care.44 Recent studies suggest that resveratrol holds promise in reducing the risk of Alzheimer’s disease and stroke.45 New science reveals in great detail how resveratrol acts through activation of the “longevity gene” SIRT-1, which triggers many favorable events that may help prevent Alzheimer’s and other neurodegenerative diseases.35,46-48

Much of resveratrol’s neuroprotection arises from its ability to interfere in the cascade of events caused by accumulation of abnormal proteins known as amyloid-beta.49 Amyloid-beta triggers oxidative stress and inflammation that directly damages brain cells, especially in memory centers of the brain. That’s why Alzheimer’s patients have such profound and progressive memory loss.

Resveratrol inhibits amyloid-beta toxicity at multiple points in the cascade.49 Resveratrol acts as a powerful antioxidant, scavenging oxygen free radicals and inducing protective enzymes such as heme oxygenase.36,50 Two recent studies demonstrated that the addition of melatonin synergistically enhances resveratrol’s neuroprotective effects.45,51

New data also show that resveratrol can prevent amyloid-beta molecules from clumping together into damaging oligomers, or small collections of individual molecules.48,52 That action significantly prevents amyloid-beta damage. Exciting new studies also show that resveratrol can remodel existing oligomers into non-toxic forms.53 

Studies released in 2010 revealed that, by activating specific intracellular signaling pathways, resveratrol can reduce toxicity caused by the excitatory neurotransmitter glutamate.54 Glutamate toxicity is thought to be a major trigger for Alzheimer’s disease symptoms.

An intriguing study published in late 2010 demonstrated that, by protecting brain mitochondria, the combination of resveratrol and mitochondria-targeted antioxidants could restore normal function in an experimental model of Alzheimer’s.55 That effect in turn produced new outgrowth of the tiny intercellular connections known as neurites, which are damaged or lost in Alzheimer’s and other neurodegenerative diseases.55 

Finally, an important recent study showed that orally administered resveratrol achieves effective concentrations in brain tissue, meaning it crosses the blood-brain barrier that keeps so many other potentially beneficial compounds out. This finding has important implications for future research into resveratrol’s role in protection against neurodegenerative disease.56

Diabetes 

Diabetes is one of the most preventable chronic conditions known. It kills more than 70,000 Americans annually, and its complications impair function in hundreds of thousands more.3 Overweight and obesity, conditions that cause many cases of diabetes, now occur in nearly 70% of Americans, and contribute to untold numbers of additional untimely deaths.57 Resveratrol’s actions have been shown to protect against the development and consequences of this deadly condition.

High blood sugar, both chronically and acutely following a meal, exerts massive oxidative stress on body proteins, ultimately changing their structure and inducing inflammation. It’s these changes that produce diabetic complications. New studies show that resveratrol, by activating the important SIRT-1 system, inhibits cellular oxidative stress and resulting inflammation in diabetes.58,59

Resveratrol improves insulin sensitivity through its effects on SIRT-1.58,60 New, highly detailed data reveal that these benefits arise from resveratrol’s ability to stimulate metabolic sensing pathways in cells that allow them to use insulin and glucose more effectively, helping to reduce blood sugar levels.61 

Glucose-damaged blood vessels lose their ability to regulate blood flow in brain and heart tissue, contributing to heart attack and stroke damage. Chronic resveratrol treatment has recently been found to restore blood vessel responsiveness in diabetic animals.40 

As a result of these basic mechanisms, resveratrol is showing promise in protecting against virtually all forms of diabetic complications. Resveratrol may be beneficial in treating or preventing diabetic foot syndrome, a devastating loss of nerve function and blood flow that results in thousands of amputations annually.62 Resveratrol treatment retarded progression of diabetic kidney disease through modulation of oxidative stress and inflammation in a 2011 animal study.63 Muscle wasting and deranged lipid metabolism are common in diabetes; resveratrol ameliorated both issues in one recent study.64 Abnormal blood vessel leakiness is a major cause of diabetic eye disease, a condition that can now be blocked by resveratrol treatment in an animal model of early diabetes.65

Summary 

A 2010 international conference found that resveratrol operates via twelve key mechanisms to combat five of the ten leading age-related causes of death in the US. 

Studies released since that time further clarify and amplify the power of resveratrol to prevent, and in some cases reverse, the biological changes associated with chronic disease and aging. Compelling evidence is now available for resveratrol’s ability to favorably modulate factors implicated in the onset of heart disease, cancer, stroke, Alzheimer’s disease, and diabetes.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.


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## Times Roman (Nov 3, 2012)

*Resveratrol - From Wikipedia*

http://en.wikipedia.org/wiki/Resveratrol

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi.

The effects of resveratrol are currently a topic of numerous animal and human studies. Its effects on the lifespan of many model organisms remain controversial, with uncertain effects in fruit flies, nematode worms,[5] and short-lived fish. In mouse and rat experiments, anticancer, anti-inflammatory, blood sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported. In humans, however, while reported effects are generally positive, resveratrol may have lesser benefits.[6] In one positive human trial, extremely high doses (3–5 g) of resveratrol, in a proprietary formulation designed to enhance its bioavailability, significantly lowered blood sugar.[7] This 28-day Phase 1b study was conducted privately in India by the pharmaceutical company, Sirtris, and was announced at an investor conference in 2008.[8] Although it has been alluded to in review articles, the study has never been published in a peer-reviewed scientific publication. Despite the mainstream press alleging resveratrol's anti-aging effects,[9] there are no accepted data to form a scientific basis for the application of these claims to mammals (see life extension section below). At the present time, research on resveratrol is in its infancy and the long-term effects of supplementation in humans are not known.[10][11]

Resveratrol is found in the skin of red grapes and in other fruits. Red wine contains very little of it, however, on the order of 0.1-14.3 mg/l.[12] Resveratrol also has been produced by chemical synthesis [13] and by biotechnological synthesis (metabolic engineered microorganisms),[14][15] and it is sold as a nutritional supplement derived primarily from Japanese knotweed

Discovery and name

The first mention of resveratrol was in a Japanese article in 1939 by Michio Takaoka, who isolated it from the poisonous, but medicinal, veratrum album, variety grandiflorum.[16] The name presumably comes from the fact that it is a resorcinol derivative coming from a veratrum species.[17]

[edit] Recent studies

[edit] 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.[18] Later studies conducted by Sinclair showed that resveratrol also prolongs the lifespan of the worm, Caenorhabditis elegans, and the fruit fly, Drosophila melanogaster.[19] In 2007, a different group of researchers were able to reproduce Sinclair's results with C. elegans,[20] but a third group could not achieve consistent increases in lifespan of either D. melanogaster or C. elegans.[5]

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 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 control fish's life, the fish supplemented with resveratrol showed significantly higher 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 its weak toxic action stimulated the defense mechanisms and resulted in the life span extension.[21]

Later the same year, Sinclair reported 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 and became obese and diabetic. Mice on the high-fat diet exhibited a high mortality rate compared to mice fed the standard diet; mice fed the high-fat diet plus 22 mg/kg resveratrol had a 30% lower risk of death than the mice on the high-fat diet alone, making their death rates similar to those on the standard diet. The supplement also partially corrected a subset of the abnormal gene expression profile and abnormal insulin and glucose metabolism. Resveratrol supplements did not change the levels of free fatty acids and cholesterol, however, which were much higher than in the mice on standard diet.[22]

A further study by a group of scientists, which included Sinclair, indicated resveratrol treatment had a range of beneficial effects in elderly mice, but did not increase the longevity of ad libitum–fed (freely-feeding) mice when started midlife.[23] Later, the National Institute on Aging's Interventions Testing Program (ITP) [24] also tested three different doses of resveratrol in mice on a normal diet beginning in young adulthood, and again found no effect on lifespan, even at doses roughly eight times higher than those that had normalized the lifespan of the high-fat-fed, obese mice in the earlier study.[25]

2011 study published in Nature suggested that some of the benefits demonstrated in previous studies were overrepresented,[26][27] however, this study was challenged immediately,[28] and few experiments were suggested to be of inferior quality.[29]

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.[citation needed]

Nicholas Wade's interview-article with Dr. Auwerx[30] stated the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (175 lb) person, the 400 mg/kg of body weight amount used in Auwerx's mouse study would total 30,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4000 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There are limited human safety data. Long-term safety has not been evaluated in humans.[citation needed]

In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn more energy, indicating the same pathway shown in the laboratory mice works in humans.[31]

[edit] Cancer prevention

In 1997, Jang reported that topical resveratrol applications prevented skin cancer development in mice treated with a carcinogen.[32] There have since been many studies of the anti-cancer activity of resveratrol in animal models.[12]

Resveratrol has been shown to induce apoptosis in platelets,[33][34] and smooth muscle.[35][35][36]

No results of human clinical trials for cancer have been reported.[37]

Clinical trials to investigate the effects on colon cancer and melanoma (skin cancer) are currently recruiting patients.[38] The study of pharmacokinetics of resveratrol in humans concluded, however, that even high doses of resveratrol might be insufficient to achieve the resveratrol concentrations required for the systemic prevention of cancer.[39]

This is consistent with the results from the animal cancer models, which indicate the in vivo effectiveness of resveratrol is limited by its poor systemic bioavailability.[40][41] The strongest evidence of anticancer action of resveratrol exists for tumors it can contact directly, such as skin and gastrointestinal tract tumors. For other cancers, the evidence is uncertain, even if massive doses of resveratrol are used.[37]

Thus, resveratrol (1 mg/kg orally) reduced the number and size of the esophageal tumors in rats treated with a carcinogen;[42] and 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.[37] Similarly, 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;[37][43] however, injected intraperitoneally, 2.5 or 10 mg/kg of resveratrol slowed the growth of metastatic Lewis lung carcinomas in mice.[37][44]

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 prepubertal mice with high doses of resveratrol enhanced formation of tumors. Injected in high doses into mice, resveratrol slowed the growth of neuroblastomas.[37]

All of the aforementioned in vivo studies have been in animal models in which the cancer has been artificially induced by some experimental means. Three other studies have investigated the effect of resveratrol on the risk of cancer in normal mice living out a normal lifespan; all of them have found resveratrol supplementation has no significant effect on the burden of tumors, nor on the rate of cancer death.[23][25][45]

[edit] Cardioprotective effects

Moderate drinking of red wine has long been known to reduce the risk of heart disease.[46] This is best known as “the French paradox”.[47][48][49]

Studies suggest resveratrol in red wine may play an important role in this phenomenon.[50] It achieves the effects by the following functions: (1) inhibition of vascular cell adhesion molecule expression;[51][52] (2) inhibition of vascular smooth muscle cell proliferation;[53][54][55] (3) stimulation of endolethelial nitric oxide synthase (eNOS) activity;[56][57][58] (4) inhibition of platelet aggregation;[59][60][61][62] and (5) inhibition of LDL peroxidation.[63][64]

The cardioprotective effects of resveratrol also are theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy.[65] Study into the cardioprotective effects of resveratrol is based on the research of Dipak K. Das, however, who has been found guilty of scientific fraud and many of his publications related to resveratrol have been retracted.[66][67] A 2011 study concludes, “Our data demonstrate that both melatonin and resveratrol, as found in red wine, protect the heart in an experimental model of myocardial infarction via the SAFE pathway.”[68]

[edit] Antidiabetic effects

Studies have shown resveratrol possesses hypoglycemic and hypolipidemic effects in both streptozotocin (STZ)-induced diabetes rats and STZ-nicotinamide-induced diabetes rats. Resveratrol ameliorates common diabetes symptoms, such as polyphagia, polydipsia, and body weight loss.[69] Other diabetic animal model studies by different researchers have also demonstrated the antidiabetic effects of resveratrol.[22][31][70][71][72][73][74]

In human clinical trials, resveratrol has lowered blood sugar levels in both Phase Ib and Phase IIa research, conducted by Sirtris Pharmaceuticals, Inc.[75][76]

[edit] Other applications
 Neuroprotective effects 
In November 2008, researchers at the Weill Medical College of Cornell University reported dietary supplementation with resveratrol significantly reduced plaque formation in animal brains, a critical part of the pathogenesis of Alzheimer's disease and other neurodegenerative diseases.[77] In mice, oral resveratrol produced large reductions in CNS plaque formation in the hypothalamus (−90%), striatum (−89%), and medial cortex (−48%) sections of the brain. In humans, oral doses of resveratrol theoretically 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 (bind) copper. The neuroprotective effects have been confirmed in several animal model studies.[78][79][80][81][82] These effects may be in part caused by its RIMA effects.
 Anti-inflammatory effects 
The anti-inflammatory effects of resveratrol have been demonstrated in several animal model studies. In a rat model of carrageenan-induced paw edema, resveratrol inhibited both acute and chronic phases of the inflammatory process.[83] Similarly, preincubation with resveratrol decreased arachidonic acid release and COX-2 induction in mouse peritoneal macrophages stimulated with tumor promoter PMA, ROI, or lipopolysaccharides (LPS).[84] In an experimental rabbit inflammatory arthritis model, resveratrol showed promise as a potential therapy for arthritis. When administered to rabbits with induced inflammatory arthritis, resveratrol protected cartilage against the progression of inflammatory arthritis.[85]
 Antiviral effects 
Studies show resveratrol inhibits herpes simplex virus (HSV) types 1 and 2 replication by inhibition of an early step in the virus replication cycle. In vivo studies in mice found resveratrol inhibits or reduces HSV replication in the vagina and limits extravaginal disease. The skin of resveratrol-treated animals showed no apparent dermal toxicity, such as erythema, scaling, crusting, lichenification, or excoriation.[86][87][88] Studies also show resveratrol inhibits varicella-zoster virus, certain influenza viruses, respiratory viruses, and human cytomegalovirus. Furthermore, resveratrol synergistically enhances the anti-HIV-1 activity of several anti-HIV drugs.[89][90][91][92][93][94]
 Effect on testosterone levels 
A Korean study showed that trans-resveratrol supplementation increased testosterone levels in mice in vivo,[95] which has led to its marketing as a bodybuilding supplement. A Spanish study has also shown the antioxidant to increase sperm production in rats.[96]
 Selective and Reversible MAO-A inhibiting effects (RIMA) 
Resveratrol has been found to be a potent and highly selective reversible inhibitor of monoamine oxidase type A (RIMA) with an IC50 of 2.0μM and a Ki value of 2.5μM in rat brains. This effect is expected to be related to its potent antioxidant activity. [97]

[edit] Applications that have been demonstrated ineffective
 Antimicrobial effect 
Resveratrol has been shown to be ineffective in inhibiting the growth of the yeast Candida albicans and other Candida species.[98]

[edit] Pharmacokinetics

One way of administering resveratrol in humans may be buccal delivery, that is without swallowing, by direct absorption through tissues on the inside of the mouth. When one milligram of resveratrol in 50 ml 50% alcohol/ water solution was retained in the mouth for one minute 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.[99] However, the viability of a buccal delivery method is called into question due to the low aqueous solubility of the molecule. For a drug to be absorbed via the transmucosal membrane, the drug must be in free-form or dissolved.[100][101] Resveratrol fits the criteria for oral transmucosal dosing, except for this caveat. The low aqueous solubility greatly limits the amount that can be absorbed through the buccal mucosal, and is why the method has not been seriously explored further. All resveratrol that is attempted to be taken buccaly will fail to pass through the mucous membrane of the mouth and be absorbed as an oral dose,[102] however, a need to explore buccal delivery in future pharmaceutical formulations has been expressed.[101][103]

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.[104] Only trace amounts (below 5 ng/ml) of unchanged resveratrol could be detected in the blood after 25 mg oral dose.[104] Even when a very large dose (2.5 and 5 g) was given as an uncoated pill, the concentration of resveratrol in blood failed to reach the level claimed to be necessary for the systemic cancer prevention.[39] A formulation of resveratrol in a chewing gum form is now in production, and this would be expected to achieve much higher blood levels than oral formulations. Resveratrol given in a proprietary formulation SRT-501 (3 or 5 g), developed by Sirtris Pharmaceuticals, reached five to eight times higher blood levels. These levels did approach the concentration necessary to exert the effects shown in animal models and in vitro experiments.[7] On May 5, 2010, however, GlaxoSmithKline (GSK) said it had suspended a small clinical trial of SRT501, a proprietary form of resveratrol, due to safety concerns, and terminated the study on December 2, 2010.[105] Sirtris Pharmaceuticals, which U.K.-based GlaxoSmithKline bought for $720 million in 2008, was developing the drug. GlaxoSmithKline is now focusing its efforts on more potent and selective SIRT1 activators—SRT2104 and SRT2379—both of which are involved in several exploratory clinical trials.[citation needed]

Full formal pharmacokinetics of oral resveratrol 2000 mg twice daily in humans, studying interaction with concurrent ethanol, quercetin, and fat meal has been published.[106] Mean peak serum resveratrol concentration was 1274 ng/ml at steady-state, which was reduced 46% by a fat meal at dosing. There was no effect of concurrent oral quercetin or ethanol. Healthy volunteers had frequently reported minor diarrhea, and laboratory measures identified slight changes in liver function tests and in serum potassium. No adverse effect on renal function was identified, although only eight healthy adults were observed in the two-week study.

In humans and rats less than 5% of the oral dose was observed as free resveratrol in blood plasma.[39][104] [41][107][108] The most abundant resveratrol metabolites in humans, rats, and mice are trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate.[109] Walle suggests sulfate conjugates are the primary source of activity,[104] Wang et al. suggests the glucuronides,[110] 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."[111]

The hypothesis that resveratrol from wine could have higher bioavailability than resveratrol from a pill [12][112] has been refuted by experimental data.[111][113] 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 a meal: trace amounts (1–6 ng/ml) were found in four out of ten subjects.[113] 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 30 minutes, and it completely disappeared from blood after four hours.[111] The authors of both studies concluded the trace amounts of resveratrol reached in the blood are insufficient to explain the French paradox. The beneficial effects of wine apparently could be explained by the effects of alcohol [111] or the whole complex of substances wine contains;[113] for example, the cardiovascular benefits of wine appear to correlate with the content of procyanidins.[114]

[edit] Adverse effects and unknowns

Long-term effects of using resveratrol are currently unknown.[10] One study has theorized it may stimulate the growth of human breast cancer cells, possibly because of resveratrol's chemical structure, which is similar to a phytoestrogen.[11][115] Other studies have found resveratrol intake is inversely associated with breast cancer risk, however, and acts to slow the progression of breast cancer that has been transplanted into mice.[116][117] Some studies suggest resveratrol slows the development of blood vessels, which suppresses tumors, but also slows healing.[118] Citing the evidence that resveratrol is estrogen antagonistic, 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 a single dose of up to 5 g of trans-resveratrol caused no serious adverse effects in healthy volunteers.[39]

[edit] Possible carcinogenicity

Resveratrol in common with other polyphenols, was found to be a strong topoisomerase inhibitor, sharing similarities to chemotherapeutic anticancer drugs, such as etoposide and doxorubicin.[119][120] This may simultaneously contribute to both the potential anticarcinogenic and carcinogenic properties of the substance in given circumstances. Harmful properties of resveratrol may be pronounced in the human fetus, as it has diminished detoxification systems. Therefore, resveratrol as commonly sold combined with other "bioflavonoids", should not be used by pregnant women.[121]

[edit] Mechanisms of action

See Calorie restriction#Sir2.2FSIRT1 and resveratrol for the details of the debate on resveratrol, calorie restriction and life extension.

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. Some studies indicates resveratrol activates Sirtuin 1 (SIRT1)[122] and PGC-1α and improves the functioning of the mitochondria.[31] Other research calls into question the theory connecting resveratrol, SIRT1, and calorie restriction.[123][124] In addition resveratrol's ability to directly activate sirtuin 1 has been called into question.[124][125][126]

A paper by Robb et al. discusses resveratrol action in cells. It reports a fourteen-fold increase in the action of MnSOD (SOD2).[127] 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 complexes 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."[128] MnSOD reduces superoxide and thereby, confers resistance to mitochondrial dysfunction, permeability transition, and apoptotic death in various diseases.[129] It has been implicated in lifespan extension, inhibits cancer, (e.g. pancreatic cancer) [130][131] and provides resistance to reperfusion injury and irradiation damage.[132][133][134] 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,[135] which stimulates FOXO3a transcriptional activity [136] 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.[137]

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-κB,[138] inhibition of the cytochrome P450 isoenzyme CYP1A1[139] (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene),[140] alterations in androgenic [141] 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.[141][142][143][144][145][146] 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.[118][147][148]

Resveratrol was reported to be effective against neuronal cell dysfunction and cell death, and, in theory, could be effective against diseases such as Huntington's disease and Alzheimer's disease.[149][150] 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 indicated resveratrol has direct inhibitory action on cardiac fibroblasts, and may inhibit the progression of cardiac fibrosis.[151]

Resveratrol also significantly increases natural testosterone production from being both a selective estrogen receptor modulator [96][152] and an aromatase inhibitor.[153][154]

In December 2007, work from Irfan Rahman's laboratory at the University of Rochester demonstrated 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.[155]

Another potentially important mechanism common to both resveratrol supplementation and caloric restriction is the modulation of autophagy [156] SIRT1 is a hypothesized target of both resveratrol and caloric restriction, and has been shown to facilitate autophagy through the inhibition of mTOR, which itself negatively regulates autophagy.[157]

In 2012, it was shown that resveratrol is capable of competitively inhibiting various phosphodiesterases, which results in an increase in cytosolic concentration of cAMP, which acts as a second messenger for the activation of the pathway Epac1/CaMKKβ/AMPK/SIRT1/PGC-1α. This rise of cAMP concentration allows an increase in oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis.[158][159]

[edit] Chemical and physical properties

Resveratrol (3,5,4'-trihydroxystilbene) is a stilbenoid, a derivate of stilbene.

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.[160] The trans- form can undergo isomerisation to the cis- form when exposed to ultraviolet irradiation.[161] 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.[162] Resveratrol content also was stable in the skins of grapes and pomace taken after fermentation and stored for a long period.[163] lH- and 13C-NMR data for the four most common forms of resveratrols are reported in literature.[160]

[edit] Metabolism

[edit] Biosynthesis

Resveratrol is produced in plants with the help of the enzyme, resveratrol synthase.[164]

[edit] Biotransformation

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.[165]

The soil bacterium Bacillus cereus can be used to transform resveratrol into piceid (resveratrol 3-O-beta-D-glucoside).[166]

[edit] Occurrences

[edit] In plants

Resveratrol was originally isolated by Takaoka from the roots of hellebore in 1940, and later, in 1963, from the roots of Japanese knotweed. It attracted wider attention only in 1992, however, when its presence in wine was suggested as the explanation for cardioprotective effects of wine.[12]

In grapes, trans-resveratrol is a phytoalexin produced against the growth of fungal pathogens such as Botrytis cinerea.[167] Its presence in Vitis vinifera grapes can also be constitutive, with accumulation in ripe berries of different levels of bound and free resveratrols, according to the genotype.[168] In grapes, resveratrol is found primarily in the skin,[169] and, in muscadine grapes, also in the seeds.[170] 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.[160][169]

[edit] In foods

The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/l,[171] depending on the grape variety, while 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.[169][172] The composition of wine is different from that of grapes since the extraction of resveratrols from grapes depends on the duration of the skin contact, and the resveratrol 3-glucosides are in part hydrolised, yielding both trans- and cis-resveratrol.[160] A number of reports have indicated 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,[170][173] however, subsequent studies have found little or no resveratrol in different varieties of muscadine grapes.[174][175]

One of the most promising sources is peanuts, especially sprouted peanuts where the content rivals that in grapes. Before sprouting, it was in the range of 2.3 to 4.5 μg/g, and after sprouting, in the range of 11.7 to 25.7 μg/g depending upon peanut cultivar.[176]

The fruit of the mulberry (esp. the skin)[177] is a source, and is sold as a nutritional supplement.

Cocoa powder, baking chocolate, and dark chocolate also have low levels of resveratrol in normal consumption quantities (0.35 to 1.85 mg/kg).[178]

Of growing importance is Japanese knotweed, which is being used by some manufacturers for its high level of resveratrol.[179]




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.[180]

In a 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.[181]

Reports suggest 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.[170]

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.[181]




Ounce for ounce, peanuts have about half as much resveratrol as red wine. The average amount in peanuts in the marketplace is 79.4 µg/ounce.

In comparison, some red wines contain approximately 160 µg/fluid ounce.[183] 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 µmol/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.[184]

Blueberries have about twice as much resveratrol as bilberries, but there is great regional variation. These fruits have less than 10% 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.[185]

[edit] Supplementation

As a result of extensive news coverage,[186][187] sales of supplements greatly increased in 2006.[188] This was despite the existence of studies cautioning that benefits to humans are unproven.[188][189][190]

Supplements vary in purity and can contain anywhere from 50 percent to 99 percent resveratrol. Many brands consist of an unpurified extract of Japanese knotweed (Polygonum cuspidatum), an introduced species in many countries. These contain about 50 percent resveratrol by weight, as well as emodin, which, while considered safe in moderate quantities, can have a laxative effect in high amounts.[191] Resveratrol can be produced from its glucoside piceid from Japanese knotweed fermented by Aspergillus oryzae.[15]

Harvard University scientist and professor, David Sinclair, is often quoted in online ads, however, Sinclair, who has studied resveratrol extensively, has gone on record in Bloomberg Businessweek to say he never uttered many of the statements attributed to him on these sites.[192]


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## Christosterone (Nov 4, 2012)

I think it's a good supplement, but the oral bioavailability is questionable, and the dosage..


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## Times Roman (Nov 4, 2012)

I have the powder, and consume around 100mgs per day.


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## BeauBody38 (Jan 11, 2015)

Resveratrol is naturally present in grapes. I take them daily.


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## ripper (Dec 30, 2019)

I've been using this stuff as an inject for 10yrs.  It's one of but a handful of supps I've run consistently during that time, and plan to run indefinitely.  Usually ~150-200mg/wk.


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## Laser50216 (Nov 11, 2020)

this study shows that resveratrol might not be as good for you as once was thought... https://youtu.be/cVXTVb-0KkQ


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## blundig (Jul 2, 2021)

As far as wine for this substance, the Sardinian wine Cannonau has the largest amount, and is a key part of the diet of this region, where it is quite common to see healthy, active 100 year old men. the same wine is called Grenache in Spain.


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