Resveratrol pill health benefit and side effects, review of anti-aging claims, by Ray Sahelian, M.D. Will this supplement help you live longer?

Resveratrol was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries, cacao, and peanuts. What made resveratrol popular was a November 2006 study that reported mice lived longer when given a resveratrol supplement. More about this resveratrol study later.
   If you haven't already heard about resveratrol (pronounced rez-VER-a-trawl), you will shortly. Resveratrol has been in the news a great deal. Research studies continue to find more interesting benefits from this red wine compound, including potential anti-cancer and anti-aging activity. It is not surprising that extensive research from all over the globe indicates that resveratrol has a wide range of beneficial properties, including vision enhancement. If you would like to improve your vision and have better color perception, see Eyesight.

Purchase Resveratrol 10 mg supplement

Resveratrol ( trans-3,5,4'-trihydroxystilbene ) is a protective compound produced by grapes and other plants in response to environmental stresses. Studies have demonstrated that resveratrol has potent antioxidant activity and also has the ability to inhibit platelet aggregation. These actions may help prevent free radical damage throughout the body and provide protective support to the cardiovascular system. Red wine has about 1.5 to 3 milligrams of resveratrol per liter (a liter is almost 34 ounces).

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Supplement facts
Resveratrol 10 mg - extract from Hy Zhang Root Extract (Polygonum cuspidatum)
Suggested Use:  One capsule with breakfast a few times a week.


Where is resveratrol found?
As red wine is a rich source of resveratrol, many sources will reference resveratrol as "red wine polyphenols," "red-wine extract," etc. Unfortunately, there is a great deal of misinformation about resveratrol, so you need to keep the following in mind when reviewing articles and marketing information about related products. As resveratrol is found in the skins of grapes, red wine will provide several times more resveratrol than white wine. Grape skins are not used in the production of white wine. As resveratrol is produced within the grape skin in response to attack by specific molds, grapes and wine produced in moist, northern climates (where these fungi are more prevalent) yield more resveratrol. As it is vulnerable to fairly rapid destruction by light and oxygen, the fact that wine is stored in air-tight, cool conditions away from sun light protects the resveratrol content. Only immediately after a bottle of wine is opened is the maximum resveratrol potency available. Since making wine also involves the potential damage from alcohol and preservatives, many people prefer a dietary supplement source for resveratrol.
   Much of the resveratrol sold in supplement form is from the herb Polygonum cuspidatum which is available in various extract potencies, ranging from 5 percent resveratrol to 50 percent.

Potential benefits of resveratrol
Over the next few years we are likely to discover that resveratrol has potential in the therapy of many conditions. It is a potent chemical and studies show it has anti-inflammatory, antioxidant, anti-infective properties, and it activates the longevity gene in fruit flies and worms. Other supplements that are excellent antioxidants include acai berry pills, carnosine, acetyl l-carnitine, alpha lipoic acid, vitamin C, vitamin E, and mangosteen pills.

Anti-aging and longevity
Thus far, the research has focused in animals, worms and fruit flies, and we have no idea what would happen if humans ingested this supplement for prolonged periods, and how it interacts with other supplements or medications. Most of the resveratrol supplements on the market are an extract, usually 5 to 40 percent, of an herb called Polygonum cuspidatum which has a very high content of the substance. Therefore, when you take a resveratrol pill, you are also ingesting many other substances found within this herb. It is likely these substances are also beneficial, but we don't know for sure. The resveratrol product sold on the Physician Formulas website has 10 mg of this antioxidant derived from 40 mg of Polygonum Cuspidatum root. Hence it is a 25 % extract.
   Even if this substance has anti-aging benefits in humans, we have no idea what the proper amount would be. Is it 5 mg a day, 10 mg, 50 mg, or more? There are a number of unanswered questions. For practical purposes, if you do wish to take this pill, I think a safe approach is to take one capsule of the 10 mg product 2 or 3 times a week. There are countless beneficial antioxidant substances in the form of supplements available to the consumer and I think taking small amounts of different ones is a reasonable approach until we have a clearer idea of the proper dosages.

Blood flow to brain
Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation
American Journal of Clinical Nutrition, June 2010; From the Brain Performance Nutrition Research Centre Northumbria University Newcastle upon Tyne United Kingdom
The many putative beneficial effects of the polyphenol resveratrol include an ability to bolster endogenous antioxidant defenses, modulate nitric oxide synthesis, and promote vasodilation, which thereby improves blood flow. Resveratrol may therefore modulate aspects of brain function in humans. In this randomized, double-blind, placebo-controlled, crossover study, 22 healthy adults received placebo and 2 doses (250 and 500 mg) of trans-resveratrol in counterbalanced order on separate days. After a 45-min resting absorption period, the participants performed a selection of cognitive tasks that activate the frontal cortex for an additional 36 min. Administration resulted in dose-dependent increases in cerebral blood flow during task performance, as indexed by total concentrations of hemoglobin. There was also an increase in deoxyhemoglobin, which suggested enhanced oxygen extraction, that became apparent toward the end of the 45-min absorption phase and was sustained throughout task performance. Cognitive function was not affected. These results showed that single doses of orally administered resveratrol can modulate cerebral blood flow variables.

Resveratrol and cancer
Recent laboratory studies indicate that resveratrol has promising therapeutic activity in various cancers, including breast, prostate, and neuroblastoma. Human studies are lacking at this time.

Resveratrol and Alzheimer's disease
Red wine ingredient resveratrol protects from beta-amyloid neurotoxicity.
Gerontology. 2003 Nov-Dec. Psychiatric Clinic, University of Basel, Basel, Switzerland.
beta-Amyloid peptide (Abeta), a neutrotoxic substance, has been implicated to a great degree in cell death during the course of Alzheimer's disease. Resveratrol, a natural polyphenol mainly found in red wine, has been shown to be cardioprotective and chemoprotective. Since a moderate wine intake correlates with a lower risk for Alzheimer disease, an additional neuroprotective effect has been postulated for resveratrol. The present study aimed at elucidating the possible neuroprotective effects of resveratrol against Abeta-induced neurotoxicity. The neuroprotective capacity against Abeta-related oxidative stress was studied in a cell culture model suitable for studying such potentially neuroprotective substances. Resveratrol maintains cell viability and exerts an anti-oxidative action by enhancing the intracellular free-radical scavenger glutathione. Our findings suggest that red wine may be neuroprotective through the actions of resveratrol.
       
Anti-Aging and longevity
As to its anti-aging potential, resveratrol activates a cell's survival defense enzyme, which prolongs the time cells have to repair their broken DNA. Resveratrol acts on fruit flies and worms in the same way as a method known to extend the life of animals including monkeys -- sharply restricting how much they eat. Resveratrol has been found to help mice live longer. Whether resveratrol supplements influence human aging is not known.

I am very interested in adding resveratrol to my dietary supplements but I came across an article that quotes research that stated that most of the resveratrol taken orally gets converted by the digestive process to other compounds, and thus it's effect on the "longevity" genes is effectively nullified. The article recommended much higher oral dosages to increase the amount of resveratrol that gets absorbed before the digestive juices alter it. So, a formulation of 10 mg seems very paltry in the face of vitamin companies that are hawking 500 and 1000 mg preparations. Will 500 or 1000 mg of trans-resveratrol tablet be more appropriate? Can we find a formulation that lets most of the resveratrol to be absorbed without being affected by the digestive juices?
   Many assumptions are being made here. There is no proof yet in humans that taking a reseveratrol supplement, at any dosage, will increase longevity. Many people, including some scientists, make the mistake of assuming the same benefits in animals will also occur in humans. Keep in mind that when animals are given a substance, they are not taking anything else with it. In contrast, most humans who take a resveratrol pill are also ingesting other supplements, antioxidants, medications, caffeine, alcohol, and additonal substances that may interact with the resveratrol pills and give an outcome that is different than that obtained in rodents. Even if resveratrol supplements have a benefit in humans, the ideal dosage is not clear and anyone who claims they are certain of the right dosage is not being scientifically honest. Furthermore, some antioxidants or beneficial substances may show early benefits the first few weeks or months and then end up causing toxicity or harm. How do we know that some of the metabolites, when ingested in 500 or 1000 mg dosages, are not harmful? Another point to keep in mind is that it is not easy to find 99 percent or 100 % pure resveratrol on the market as it often used in research studies. The resveratrol supplements on the market are 10 to 50% extracts of herbs and some companies mislead the consumer by mentioning the total amount of the herb rather than the amount of resveratrol in it. When taking a resveratrol supplement, people are likely ingesting other substances found within the herb, for instance Polygonum cuspidatum, that is present in the capsule, and we don't know the long term benefits and risks of taking this herb or others from which the resveratrol is extracted. I have personally tried 10 mg resveratrol capsules and started having headaches when I reached 4 capsules. Mice are not likely to report headaches or other minor symptoms.

Resveratrol improves health and survival of mice on a high-calorie diet.
Nature. 2006 Nov 1; Baur JA, Pearson KJ, et al. Department of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
Resveratrol extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways.
   The mice were fed a large dose of resveratrol, 24 milligrams per kilogram of body weight. Red wine has about 1.5 to 3 milligrams of resveratrol per liter, so a 150-lb person would need to drink 1,000 bottles of red wine a day to get such a dose. Dr. Richard Hodes, director of the National Institute on Aging, which helped support the study, said that people should wait for the results of safety testing. Substances that are safe and beneficial in small doses, like vitamins, sometimes prove to be harmful when taken in high doses.
   Sirtris Pharmaceuticals, a therapeutics company co-founded by David Sinclair, M.D., has started a trial of a proprietary formulation of resveratrol in patients with type 2 diabetes.

Resveratrol research studies
Fungicidal effect of resveratrol on human infectious fungi.
Arch Pharm Res. 2005 May.
Resveratrol, a phenolic antioxidant found in grapes, has been known to mediate various biological activities on the human body. In the present study, we tested the antifungal activity of resveratrol against human pathogenic fungi before carrying out further studies to elucidate the antifungal mechanism(s) of resveratrol. Resveratrol displayed potent antifungal activity against human pathogenic fungi at concentration levels of 10-20 microg/mL. Furthermore, time-kill curve exhibited fungicidal effect of resveratrol on Candida albicans, but the compound had no hemolytic activity against human erythrocytes. The destruction of C. albicans cells by resveratrol was confirmed by scanning electron microscopy. These results suggest that resveratrol could be employed as a therapeutic agent to treat fungal infections of humans.

Resveratrol, a chemical found in red grapes, blocks replication of the influenza virus in cell culture and in animals. In cell culture experiments, resveratrol prevented influenza from replicating. Resveratrol treatment had the greatest effect when administered 3 hours after exposure to influenza. Smaller but significant effects were seen when treatment began 6 hours after infection, but at 9 hours after infection resveratrol treatment had no effect. Pre-treatment also did not change susceptibility to infection. Studies in a mouse model of influenza showed that injections of resveratrol after inoculation of influenza increased survival by 40% compared with placebo injections. The amount of virus present in the lung 6 days after infection was 98% lower in the resveratrol -treated mice. Resveratrol  's anti-influenza activity seems to center on its ability to interfere with key "host-cell functions" that are essential for virus replication, the authors explain in The Journal of Infectious Diseases, May 15, 2005.

Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition.
Chem Biol Interact. 2005 Jan 15;151(2):143-9. King RE, Kent KD, Bomser JA. Department of Food Science and Technology, Ohio State University, Columbus, OH
Epidemiological evidence suggests that moderate wine consumption and antioxidant-rich diets may protect against age-related macular degeneration, the leading cause of vision loss among the elderly. Development of age-related macular degenerationnd other retinal diseases, such as proliferative vitreoretinopathy (PVR), is associated with oxidative stress in the retinal pigment epithelium (RPE), a cell layer responsible for maintaining the health of the retina by providing structural and nutritional support. We hypothesize that resveratrol, a red wine polyphenol, may be responsible, in part, for the health benefits of moderate red wine consumption on retinal disease. To test this hypothesis, the antioxidant and antiproliferative effects of resveratrol were examined in a human RPE cell line (designated ARPE-19). These results suggest that resveratrol can reduce oxidative stress and hyperproliferation of the RPE.

Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies.
Anticancer Res. 2004 Sep-Oct;24(5A):2783-840. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D. Anderson  
Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.

Consumption of red wine is associated with a slight but statistically significant reduction in the development of lung cancer, as reported in the journal Thorax. Red wine contains tannins and resveratrol, substances which could explain the drink’s anti-cancer properties. Tannins act as antioxidants, which mop up free radicals — particles harmful to cells. Resveratrol is known to fight cancer tumor growth.

Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice.
Surgery. 2004 Jul;136(1):57-66.
The prognosis of neuroblastoma patients remains unsatisfactory. Therefore, developing an effective treatment strategy is important. Resveratrol, a natural polyphenol, possesses chemopreventive and antitumor effects. We investigated the effects of resveratrol on the proliferation, apoptosis, and cell cycle alteration of neuroblastoma cells and determined its effects on neuroblastoma tumors in mice. Cytotoxic effects, cellular apoptosis, and alterations in the cell cycle were determined in neuro-2a neuroblastoma cells exposed for varying lengths of time to a series of resveratrol concentrations. Expression of associated cell cycle regulatory proteins, cyclin E and p21, was detected by Western blot analysis, and the antitumor effects of resveratrol were investigated by treating subcutaneous neuroblastoma tumors with intraperitoneal injections of 40 mg/kg resveratrol daily for 28 days. Resveratrol exerted cytotoxic effects on neuroblastoma cells. After resveratrol treatment, the apoptosis rate of the neuroblastoma cells significantly increased, a significant accumulation of cells occurred at the S phase of the cell cycle, p21 was downregulated, and cyclin E was upregulated. In addition, resveratrol treatment suppressed the growth rate of subcutaneous neuroblastomas, resulting in 70% long-term survival. Resveratrol caused significant cytotoxicity and increased apoptosis and S-phase accumulation of neuroblastoma cells. S-phase accumulation was related to the down-regulation of p21 and up-regulation of cyclin E. In addition, resveratrol exerted antitumor effects on neuroblastomas in mice. Thus, resveratrol shows promise for the treatment of neuroblastoma.

Anti-inflammatory Effects of Resveratrol in Lung Epithelial Cells: Molecular Mechanisms.
Am J Physiol Lung Cell Mol Physiol. 2004 Jun 4
Resveratrol is a polyphenolic stilbene found in the skins of red fruits including grapes that may be responsible for some of the health benefits ascribed to the consumption of red wine. Resveratrol has previously been shown to have anti-oxidant properties and can act as an estrogen agonist. This study examined the anti-inflammatory effects of resveratrol on human airway epithelial cells. Resveratrol and the related molecule quercetin, but not deoxyrhapontin, inhibited both interleukin (IL)-8 and granulocyte-macrophage colony stimulating factor (GM-CSF) release from A549 cells. Neither the estrogen receptor antagonist, tamoxifen, nor the glucocorticoid antagonist, mifepristone, altered the inhibitory effect of resveratrol. The mechanism of resveratrol action was investigated further using luciferase reporter genes stably transfected into A549 cells. Both resveratrol and quercetin inhibited NF-kappaB-, AP-1- and CREB-dependent transcription to a greater extent than the glucocorticosteroid, dexamethasone. These compounds also had no significant effect on acetylation or deacetylation of core histones. Resveratrol, but not estradiol or N-acetyl cysteine, inhibited cytokine-stimulated inducible nitric oxide synthase expression and nitrite production in human primary airway epithelial cells. Resveratrol also inhibited GM-CSF release, IL-8 release and cyclo-oxygenase-2 expression in these cells. This study demonstrates that resveratrol and quercetin have novel non-steroidal anti-inflammatory activity that may have applications for the treatment of inflammatory diseases.

Identification of a p53-dependent pathway in the induction of apoptosis of human breast cancer cells by the natural product, resveratrol.
Laux MT, Aregullin M, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. J Altern Complement Med. 2004 Apr;10(2):235-9.
Resveratrol, a constituent found in grapes and various other plants, has been shown to have chemo-preventive activity against cancer, and specifically demonstrated to induce apoptosis by p53-dependent pathways in murine cells. DESIGN: A number of human breast cancer cell lines, as well as a control of a wild-type line (astrocytoma N 1321N1), were investigated for induction of apoptosis by resveratrol using both microscopic evaluation and DNA fragmentation assays. Apoptosis induced by resveratrol was found to occur only in breast cancer cells expressing wild-type p53 but not in mutant p53-expressing cells. CONCLUSIONS: We therefore conclude that the natural product, resveratrol, induces apoptosis in breast cancer cells via p53-dependent pathways.

Curcumin and resveratrol induce apoptosis and nuclear translocation and activation of p53 in human neuroblastoma.
Anticancer Res. 2004 Mar-Apr;24(2B):987-98.
Neuroblastoma (NB) is an aggressive childhood cancer of the peripheral nervous system arising from neural crest sympathoadrenal progenitor cells. Despite current rigorous treatment protocols, prognosis for high stage NB patients is poor and so there remains a need for more effective, less cytotoxic treatments. Curcumin and resveratrol possess anti-tumor properties in adult cancer models and negligible toxicity in normal cells, but little is known about the effect of these agents on pediatric cancers. Stage 4 MYCN-amplified NB cell lines, with wild-type or mutant p53, were treated with curcumin and resveratrol and analyzed for effects on proliferation, cell cycle, induction of apoptosis and p53 function. Treatment with resveratrol and curcumin induced a dose- and time-dependent decrease in cell viability, cell cycle arrest and induction of apoptosis. Observations suggest that the cytotoxicity, cell cycle arrest and apoptosis induced by curcumin and resveratrol in NB cells may be mediated via functionally activated p53 and merit further study.

Resveratrol in raw and baked blueberries and bilberries.
J Agric Food Chem. 2003 Sep 24;51(20):5867-70. Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, van Breemen RB. Food and Nutritional Science Division, California State University-Long Beach, CA 90840
Resveratrol in the fruits of bilberry (Vaccinium myrtillus L.), the lowbush "wild" blueberry (Vaccinium angustifolium Aiton), the rabbiteye blueberry (Vaccinium ashei Reade), and the highbush blueberry (Vaccinium corymbosum L.) were measured using a new assay based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS assay provided lower limits of detection than previous methods for resveratrol measurement, 90 fmol of trans-resveratrol injected on-column, and a linear standard curve spanning >3 orders of magnitude. The recoveries of resveratrol from blueberries spiked with 1.8, 3.6, or 36 ng/g were 91, 95, and 88%, respectively. trans-Resveratrol but not cis-resveratrol was detected in both blueberry and bilberry samples. The highest levels of trans-resvertatrol in these specimens were 140 pmol/g in highbush blueberries from Michigan and 71 pmol/g in bilberries from Poland. However, considerable regional variation was observed; highbush blueberries from British Columbia contained no detectable resveratrol. Because blueberries and bilberries are often consumed after cooking, the effect of baking on resveratrol content was investigated. After 18 min of heating at 190 degrees C, between 17 and 46% of the resveratrol had degraded in the various Vaccinium species. Therefore, the resveratrol content of baked or heat-processed blueberries or bilberries should be expected to be lower than in the raw fruit. Although blueberries and bilberries were found to contain it, the level of this chemoprotective compound in these fruits was <10% that reported for grapes. Furthermore, cooking or heat processing of these berries will contribute to the degradation of resveratrol.

Wine and tumors: study of resveratrol.
Drugs Exp Clin Res. 2003;29(5-6):257-61.
In modern industrial societies the attention to public health, especially in relation to food habits, is increasing day by day. Considering this, it's no wonder that wine, the voluptuary drink that best represents human history, is the most interesting compound. The main and best known wine effects on the human body are caused by alcohol, but several other active compounds are present in wine. Above all, resveratrol is able to neutralize free radicals, which can damage DNA and may lead to cancer onset. In this study, we have indagated resveratrol anticancer action, analyzing its effects on both cell cycle and growing of human lymphoma B (DHL-4) cells. MTT colorimetric test, tripan blue dye exclusion assay, and cell cycle analysis showed that resveratrol has a dose-dependent antiproliferative and antiapoptotic action on DHL-4 cells. These results confirm resveratrol's potential therapeutic role on tumors.

Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in cardiomyocytes: protection against oxidative and electrophilic injury.
Eur J Pharmacol. 2004 Apr 5;489(1-2):39-48. Cao Z, Li Y. St. John's University College of Pharmacy and Allied Health Professions, Jamaica, NY
Resveratrol is known to be protective against oxidative cardiovascular disorders. However, the underlying mechanisms remain unclear. This study was undertaken to determine if resveratrol could increase endogenous antioxidants and phase 2 enzymes in cardiomyocytes, and if such increased cellular defenses could provide protection against oxidative and electrophilic cell injury. Incubation of cardiac H9C2 cells with low micromolar resveratrol resulted in a significant induction of a scope of cellular antioxidants and phase 2 enzymes in a concentration- and/or time-dependent fashion. To investigate the protective effects of the resveratrol-induced cellular defenses on oxidative and electrophilic cell injury, H9C2 cells were first incubated with resveratrol, and then exposed to xanthine oxidase (XO)/xanthine, 4-hydroxy-2-nonenal or doxorubicin. We observed that resveratrol pretreatment afforded a marked protection against the above agent-mediated cytotoxicity in H9C2 cells. Moreover, the resveratrol pretreatment led to a great reduction in XO/xanthine-induced intracellular accumulation of ROS. Taken together, this study demonstrates that resveratrol induces antioxidants and phase 2 enzymes in cardiomyocytes, which is accompanied by increased resistance to oxidative and electrophilic cell injury.

Modulation of androgen receptor-dependent transcription by resveratrol and genistein in prostate cancer cells.
Prostate. 2004 May 1;59(2):214-25. Gao S, Liu GZ, Wang Z. The University of Texas M. D. Anderson Cancer Center, Houston, Texas
The androgen receptor (AR) is a ligand-activated transcription factor that mediates the biological responses of androgens in the prostate gland. This study focuses on the chemopreventive agents, resveratrol and genistein, on AR-mediated transcription in prostate cancer cells. We found that resveratrol and genistein activated AR-driven gene expression at low concentrations, whereas they repressed the AR-dependent reporter gene activity at high concentrations. We determined that resveratrol and genistein induced AR-driven gene expression by activating the Raf-MEK-ERK kinase pathway. The ERK1 kinase phosphorylated the AR on multiple sites in vitro, but this phosphorylation event did not contribute to the resveratrol-induced AR transactivation. In vitro and in vivo studies have indicated that resveratrol and genistein are promising chemopreventive agents. Given the clear evidence that AR pathways are involved in the development and progression of prostate cancer, these data showed that the ability to modulate AR function would contribute the observed chemopreventive activity of resveratrol and genistein.

Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats.
Clin Cancer Res. 2004 Mar 15;10(6):2190-202.
We wanted to investigate the antitumor effects and effect on angiogenesis of resveratrol in rat RT-2 gliomas. RT-2 glioma cells were treated with resveratrol, and then cytotoxicity was assayed, apoptosis was measured by flow-activated cell sorter flow cytometry, and expression of vascular endothelial growth factor was measured by reverse transcription-PCR. Tumor size, animal survival time, and survival rate were followed in resveratrol-treated rats with s.c. or intracerebral gliomas. Furthermore, in vitro proliferation was assayed to explore the effect of resveratrol on the proliferation of ECV304 human umbilical vein endothelial cells. Expression of CD31 in resveratrol-treated gliomas was followed immunohistochemically to study the effect of resveratrol on the glioma-induced angiogenesis. Resveratrol was demonstrated to exert cytotoxic effects and induce glioma cell apoptosis in a concentration- and time-dependent manner. Resveratrol (40 mg/kg/day) exerted significant antitumor effects on s.c. tumors, including slower tumor growth rate, longer animal survival time, and higher animal survival rate. In contrast, resveratrol affected intracerebral tumors at only an increased dose (100 mg/kg/day), prolonging animal survival (P < 0.05) without affecting survival rate. The expression of vascular endothelial growth factor in the glioma cells and the proliferation of ECV304 cells were inhibited by resveratrol in a concentration-dependent manner. Immunohistochemical analyses showed that the s.c. gliomas from resveratrol-treated rats had fewer microvessel densities than did control rats. Resveratrol caused significant glioma cell cytotoxicity and apoptosis, exerted antitumor effects on the s.c. and intracerebral gliomas, and inhibited angiogenesis in s.c. gliomas. Thus, resveratrol might be considered a possible treatment strategy for gliomas.

Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C.
Br J Pharmacol. 2004 Mar;141(6):997-1005.
The present study evaluated the neuroprotective effects of resveratrol against amyloid beta (Abeta)-induced toxicity in cultured rat hippocampal cells and examined the role of the protein kinase C (PKC) pathway in this effect. Pre-, co- and post-treatment with resveratrol significantly attenuated Abeta-induced cell death in a concentration-dependent manner. The present results indicate that PKC is involved in the neuroprotective action of resveratrol against Abeta-induced toxicity.

Do resveratrol supplements interact with Zyflamend supplements?
   I have not seen such combination research, but, as a general rule, it is a good idea to try each supplement by itself for a week before combining.

I would like to know if there is any problem taking both Eyesight Rx product, which contains an undisclosed amount of resveratrol, and a resveratrol supplement at the same time.
   Before combining supplements, it is a good idea to try each one separately for a few days. The amount of resveratrol in Eyesight Rx is not high since this product has more than a dozen different nutrients and herbs in small amounts. Some people can tolerate combinations, others may not. Therefore it is a case by case basis.

Love your website absolutely. I have a question regarding resveratrol products. I am a 56 year old man with Hepatitis C. I am taking various vitamins which through research I've read have helped control the virus. I take NAC, Alpha Lipoic Acid 3 x a week. I take Omega 3, reseveratrol pills a few times a week. Just Started a multivitamin and vitamin C (1000mg) every day. My question is regarding the resveratrol. I' ve read where is helps remove fat from the liver, but needs bile to digest it, that's why the Omega 3 30 minutes before I take the resveratrol pills. Am I taking this properly to get the best results from the vitamin, or should I adjust my schedule?
    I don't think you have to worry about the timing. I find it best to take supplements in the morning a few minutes before breakfast.

I just was looking for information on this supplement and your August 2009 newsletter arrived. Thanks for that information. I have found a Chinese company, apparently a wholesaler, selling the basic product made from grape skins. They seem to have a compelling case for the use of the grape skins as opposed to another common plant that I believe is Japanese knotwood. This Chinese company says that people who use that one often suffer from diarrhea, but not with their product made from the red grapes. The company does emphasis that they are FDA approved and their product is as pure as possible and in varying percentages of the active ingredient. I am sorry that my information is so disjointed, but can you comment? Do you have any supplement made with the grapes skin? I think I would like to try this one, if available. Also, in the newsletter you said it could be wise to take a small variety of the anti-oxidants. Could you suggest those others?
    In addition to resveratrol, one has to see what other substances are present in the product promoted by the Chinese company. The FDA does not approve specific products from companies, therefore it is not accurate for a company to claim their product is FDA approved. We have not had any feedback from consumers using Japanese knotwood resveratrol source that claim they have had diarrhea or gastrointestinal symptoms. See the antioxidant page on this website for additional info.

Since you are one of the most knowledgeable people with respect to the benefits and possible side-effects of resveratrol, I would appreciate it if you could help me with the following question: Do the phyto-estrogens in Resveratrol pose a risk for males, if they take such supplements?
    Resveratrol itself is not a phytoestrogen. However, many products that call themselves resveratrol are not 100 percent of this chemical but derived from various herbs that contain other substances. I am not aware that these other substances, for instances found in the herb Polygonum cuspidatum, have phytoestrogenic activity, but they have not been fully studied in terms of how they influence estrogen receptors in the body.

I'm struggling between whether to go on a 100% natural diet with natural sources of resveratrol, or to use a high potency resveratrol supplement. On one hand, nobody can go wrong essentially with a natural diet. On the other hand, if anti-aging studies are true, perhaps high doses of this substance could help tremendously with aging. But would such high levels such as 100mg -- or 100x that found in peanuts and red grapes -- have negative consequences? I Googled "resveratrol thyroid" and found that it is similar to a thyroid peroxidase substrate and therefore causes goitrogenic or thyroid suppressing results. I'm sure it would be hard to get too much of this compound on a normal diet without eating grapes and only grapes all day everyday, but a high potency supplement could bring negative consequences?
    There is a great deal we don't know about the benefits and side effects of resveratrol taken in pill form and there is not easy answer at this time. Some people take this antioxidant a couple of times a week as opposed to daily.