Resveratrol

Resveratrol is an antioxidant found in foods such as grapes, berries, and peanuts, chocolate and red wine. Although it is still unclear whether resveratrol has any benefits in healthy people, some small clinical trials suggest that it may help those with certain health conditions. Taking resveratrol supplements is generally regarded as safe although long-term use has not been studied.

EFFICACY
Possibly
with   Very limited  evidence
SAFETY WHEN
USED AS DIRECTED
Probably
with   Limited  evidence

Resveratrol is a polyphenol compound found in various foods such as red wine, grapes, berries, chocolate and peanuts. In plants, it helps protect against bacterial and fungal infections [1].  It is also available as a concentrated supplement. In laboratory experiments, resveratrol demonstrates strong antioxidant, anti-inflammatory, anti-viral and anti-cancer capabilities.  Whether these benefits will occur in humans is still under investigation.  Several small clinical trials have confirmed anti-inflammatory and antioxidant benefits [27,29,30,33,42] but other trials have not [25,26,34].  The cancer effects are also under active investigation.

Resveratrol’s beneficial effects  may be related to its ability to activate a family of proteins called sirtuins [2]. In rodents, high levels of certain sirtuins have been connected to a lower occurrence of cancer, improved general health, enhanced metabolism, and longer lifespan,  possibly by mimicking the beneficial effects of caloric restriction [3]. Although their role in humans remains controversial, resveratrol and similar sirtuin-activating compounds continue to be examined for their potential benefits in slowing aging, protecting against aging-related diseases and improving metabolic health.

Did You Know? Resveratrol is made by some plants to help protect them against bacterial and fungal infections!

Resveratrol can be found in foods like peanuts, blueberries and even cocoa, but the highest concentration is found in the skin of red grapes used to make red wine. However, these naturally-occurring sources contain relatively little amounts of resveratrol. For example, one 5-ounce glass of red wine contains about 0.2 to 2 mg of resveratrol; therefore, you would have to drink between 200-650 glasses of red wine to get the amount of resveratrol in a 200 mg supplement capsule.

Purified resveratrol supplements typically contain between 50-350 mg, derived from the skin of red grapes, or more commonly, Japanese knotweed. Doses between 20 mg to 5000 mg per day have been used and are reported to be generally safe in short-term (three or fewer months) clinical trials but have not been tested for longer use.

Resveratrol can affect many proteins and systems of the body.  Experiments in animals and some human clinical trials suggest that resveratrol can reduce oxidative stress and chronic inflammation [4], although probably not in all formulations and patient populations. Laboratory research has also shown that resveratrol can induce autophagy, a cellular process that protects against disease progression in conditions such as Alzheimer's disease, Parkinson's disease, and cancer.  Autophagy also facilitates the longevity-promoting effects of caloric restriction [5].  Much of the benefit of resveratrol may occur through activation of Sirtuin 1, a protein that helps regulate gene expression and may affect the rate of aging and lifespan. Experiments in isolated cells also report that resveratrol can protect against toxicity from the beta-amyloid aggregates associated with Alzheimer’s disease, although no human research has tested those results [6].  One clinical trial has also reported that a certain form of resveratrol increases blood flow to the brain, although the impact of increased flow of oxygen-rich blood to long-term brain health in patient populations is not yet clear [7].  Additionally, results from a pilot clinical trial in overweight, but otherwise healthy, older adults suggest that daily resveratrol supplements (200mg/day) taken for 6 months may improve short-term memory and improve the functioning of the hippocampus, the part of the brain most responsible for memory [8].

Possibly, based on very limited evidence. Whether resveratrol can prevent dementia or slow brain aging in humans has not been examined.   Studies in animals and isolated cells suggest that resveratrol may delay age-related cognitive decline and may protects against dementia. For example, old mice on daily resveratrol supplementation performed better on spatial learning [9] and working memory tests [10] than mice fed a control diet with no resveratrol.  In addition, rodent and cell culture studies report that resveratrol can protect against the beta-amyloid pathology that is characteristic of Alzheimer’s disease [6, 11, 12]. As of now, we await results from well-controlled studies in healthy, older people to show if resveratrol may prevent dementia or delay cognitive decline.

Possibly, based on very limited evidence. Human studies have not reported benefits of resveratrol treatment for people with mild cognitive impairment or dementia. Two clinical trials are underway to determine if resveratrol may help slow or prevent cognitive decline in patients with early-stage Alzheimer’s disease (NCT01504854) or mild cognitive impairment (NCT01219244).  However, two other clinical trials have apparently been done in Alzheimer’s patients, yet the results are not posted or published (NCT00678431, NCT00743743).  Given that positive results are usually published immediately while negative results often go unpublished, these unreported trials raise concern about the promise of resveratrol treatment.

While the clinical studies are ongoing, laboratory studies in mice have suggested that resveratrol may improve brain function and health in Alzheimer’s disease [6, 13, 14]. For example, one hallmark of Alzheimer’s is the accumulation of beta-amyloid plaques and tau protein tangles in the brain [6]. In a mouse model of Alzheimer’s disease, daily doses of resveratrol reduced brain levels of beta-amyloid plaques, an effect that some believe is regulated through increased Sirt1 activation [15]. Indeed, patients with Alzheimer’s disease do have less Sirtuin1 protein in the brain, which indirectly correlates with greater levels of beta-amyloid plaques and tau protein tangles [16, 17]. Interestingly, patients with mild cognitive impairment do not have lower amounts of Sirt1 in the brain [16].

Possibly, based on very limited evidence. There is little evidence to suggest that resveratrol may improve metabolism or extend lifespan in healthy mammals, including humans. Experiments in yeast, worms, and fruit flies showed that resveratrol increased the lifespan of these organisms by as much as 50% [18, 19]. However, the effects of resveratrol on metabolism or longevity in mammals are less clear. One study found that resveratrol extended lifespans of genetically-engineered obese mice (which have shorter lifespans)  to an age comparable to normal mice [20]. However, in healthy mice, resveratrol had no effect on lifespan [20-23], with the exception of one study reporting that resveratrol was able to increase aerobic performance, exercise capacity and telomerase activity in rats [22].

In healthy adults, at least two well-controlled clinical trials were unable to find any health benefits of resveratrol supplementation [7, 24, 25].  One study found that resveratrol reduced the beneficial effects of exercise in a group of healthy older men [26]. However, clinical trials in patient populations and healthy smokers have reported benefit [43], suggesting that resveratrol can alleviate some symptoms of chronic inflammation or metabolic and cardiovascular ailments.
In a clinical trial of patients at high risk for developing heart disease, a combination of statin medication and 350 mg/day of resveratrol resulted in greatly reduced serum LDL levels (sometimes called the “bad” cholesterol), even beyond those achieved with statins alone [27].

Other clinical trials of resveratrol suggest it may enhance insulin sensitivity [28] and improve glycemic control [29] in type 2 diabetes patients, as well as lower blood pressure, reduce inflammation, and improve metabolism in obese adults [30, 31].

Various clinical trials report that resveratrol formulations can reduce biological markers of chronic inflammation like C-reactive protein [27, 32, 33], a marker that has been linked to a higher risk of age-related health problems, although some clinical trials in healthy patients have not observed that effect on inflammation [25, 34].

Likely safe, based on limited evidence. Although there have been relatively few clinical trials examining the safety and efficacy of resveratrol supplements, these studies did not report any adverse side effects for doses between 20mg to 2000mg a day. However, most clinical trials followed subjects for a relatively short time period (three or fewer months), and little is known about its long-term effects.  Because resveratrol has been shown to have blood thinning capabilities [35, 36], patients taking anti-platelet or anti-coagulant medications should avoid resveratrol supplements.  One clinical trial reported serious safety concerns of kidney failure with resveratrol plus standard medical treatment of multiple myeloma (cancer) patients [37].

Doses between 20 mg to 2000 mg a day have been used and reported to be generally safe in short-term (three or fewer months) clinical trials. It is always a good idea to consult your primary care provider before starting resveratrol supplementation, particularly if you use blood thinners or anti-coagulant drugs.

A number of clinical trials are exploring the possible efficacy of resveratrol supplements for various disease conditions. One group in Germany is examining whether 6 months of resveratrol supplementation can improve learning and affect brain changes in older, healthy individuals (NCT00996229). Other ongoing studies are trying to determine if resveratrol can modify Alzheimer’s disease brain proteins, as well as cognition and brain structure in patients with Alzheimer’s disease (NCT01504854) and mild cognitive impairment (NCT01219244). In addition to brain function, resveratrol is also being studied for its possible benefits in diabetes and obesity (NCT01158417), cancer (NCT01476592), and cardiovascular disease (NCT01914081). More information about these and other clinical trials can be found at clinicaltrials.gov.  More information about clinical trials in Europe can be found at clinicaltrialsregister.eu.

Meanwhile, scientists are also working on a variety of ways to improve the delivery of resveratrol to the brain [38] or to create stronger or safer drugs based off of resveratrol and/or Sirtuin 1activitation [39-41].

WebMD offers information on resveratrol dosing and safety.
• The FDA gives an overview on dietary supplements, their regulation and safety.
• A TEDMED talk by Dr. David Sinclair, a leading resveratrol and sirtuin researcher.
• A Nature blog post on the promise and controversies surrounding drug development efforts on the Sirtuin 1 target activated by resveratrol, particularly by the former biotech Sirtris purchased by GlaxoSmithKline.

1.  Hain, R., Bieseler, B., Kindl, H., Schroder, G. & Stocker, R. (1990) Expression of a stilbene synthase gene in Nicotiana tabacum results in synthesis of the phytoalexin resveratrol. Plant Mol. Biol. 15: 325-335.

2.  Hubbard, B. P., Gomes, A. P., Dai, H., Li, J., Case, A. W., Considine, T., Riera, T. V., Lee, J. E., SY, E. et al. (2013) Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339: 1216-1219.

3.  Satoh, A., Brace, C. S., Ben-Josef, G., West, T., Wozniak, D. F., Holtzman, D. M., Herzog, E. D. & Imai, S. (2010) SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J. Neurosci. 30: 10220-10232.

4.  Sun, Q., Shi, L., Prescott, J., Chiuve, S. E., Hu, F. B., De Vivo, I., Stampfer, M. J., Franks, P. W., Manson, J. E. & Rexrode, K. M. (2012) Healthy lifestyle and leukocyte telomere length in U.S. women. 2012/06/08: e38374.

5.  Patel, K. R., Andreadi, C., Britton, R. G., Horner-Glister, E., Karmokar, A., Sale, S., Brown, V. A., Brenner, D. E., Singh, R. et al. (2013) Sulfate metabolites provide an intracellular pool for resveratrol generation and induce autophagy with senescence. Sci. Transl. Med. 5: 205ra133.

6.  Karuppagounder, S. S., Pinto, J. T., Xu, H., Chen, H. L., Beal, M. F. & Gibson, G. E. (2009) Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease. Neurochem. Int. 54: 111-118.

7.  Kennedy, D. O., Wightman, E. L., Reay, J. L., Lietz, G., Okello, E. J., Wilde, A. & Haskell, C. F. (2010) Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. 2010/04/02: 1590-1597.

8.  Witte, A.V., Kerti, L., Marquiles, D.S., Floel, A. (2014) Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci. 34(23):7862-70.

9.  Oomen, C. A., Farkas, E., Roman, V., van der Beek, E. M., Luiten, P. G. & Meerlo, P. (2009) Resveratrol preserves cerebrovascular density and cognitive function in aging mice. Front Aging Neurosci. 1: 4.

10.  Abraham, J. & Johnson, R. W. (2009) Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation. Res. 12: 445-453. PM:20041738

11.  Marambaud, P., Zhao, H. & Davies, P. (2005) Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J. Biol. Chem. 280: 37377-37382.

12.  Richard, T., Pawlus, A. D., Iglesias, M. L., Pedrot, E., Waffo-Teguo, P., Merillon, J. M. & Monti, J. P. (2011) Neuroprotective properties of resveratrol and derivatives. Ann. N. Y. Acad. Sci. 1215: 103-108. PM:21261647

13.  Wang, J., Ho, L., Zhao, Z., Seror, I., Humala, N., Dickstein, D. L., Thiyagarajan, M., Percival, S. S., Talcott, S. T. & Pasinetti, G. M. (2006) Moderate consumption of Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer's disease. 2006/11/02: 2313-2320.

14.  Huang, T. C., Lu, K. T., Wo, Y. Y., Wu, Y. J. & Yang, Y. L. (2011) Resveratrol protects rats from Abeta-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation. 2012/01/06: e29102.

15.  Donmez, G., Wang, D., Cohen, D. E. & Guarente, L. (2010) SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell 142: 320-332.

16.  Julien, C., Tremblay, C., Emond, V., Lebbadi, M., Salem, N., Jr., Bennett, D. A. & Calon, F. (2009) Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J. Neuropathol. Exp. Neurol. 68: 48-58

17.  Theendakara, V., Patent, A., Peters Libeu, C. A., Philpot, B., Flores, S., Descamps, O., Poksay, K. S., Zhang, Q., Cailing, G. et al. (2013) Neuroprotective Sirtuin ratio reversed by ApoE4. Proc. Natl. Acad. Sci. U. S. A 110: 18303-18308.

18.  Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A. et al. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. 2003/08/27: 191-196.

19.  Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M. & Sinclair, D. (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430: 686-689.

20.  Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G. et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. 2006/11/07: 337-342.

21.  Miller, R. A., Harrison, D. E., Astle, C. M., Floyd, R. A., Flurkey, K., Hensley, K. L., Javors, M. A., Leeuwenburgh, C., Nelson, J. F. et al. (2007) An Aging Interventions Testing Program: study design and interim report. 2007/06/21: 565-575.

22.  da Luz, P. L., Tanaka, L., Brum, P. C., Dourado, P. M., Favarato, D., Krieger, J. E. & Laurindo, F. R. (2012) Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats. 2012/07/24: 136-142.

23.  Marchal, J., Pifferi, F. & Aujard, F. (2013) Resveratrol in mammals: effects on aging biomarkers, age-related diseases, and life span. 2013/07/17: 67-73.

24.  Soare, A., Weiss, E. P., Holloszy, J. O. & Fontana, L. (2013) Multiple dietary supplements do not affect metabolic and cardiovascular health. 2013/09/17.

25.  Poulsen, M. M., Vestergaard, P. F., Clasen, B. F., Radko, Y., Christensen, L. P., Stodkilde-Jorgensen, H., Moller, N., Jessen, N., Pedersen, S. B. & Jorgensen, J. O. (2013) High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. 2012/11/30: 1186-1195.

26.  Gliemann, L., Schmidt, J. F., Olesen, J., Bienso, R. S., Peronard, S. L., Grandjean, S. U., Mortensen, S. P., Nyberg, M., Bangsbo, J. et al. (2013) Resveratrol Blunts the Positive Effects of Exercise Training on Cardiovascular Health in Aged Men. 2013/07/24.

27.  Tome-Carneiro, J., Gonzalvez, M., Larrosa, M., Yanez-Gascon, M. J., Garcia-Almagro, F. J., Ruiz-Ros, J. A., Garcia-Conesa, M. T., Tomas-Barberan, F. A. & Espin, J. C. (2012) One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am. J. Cardiol. 110: 356-363.

28.  Brasnyo, P., Molnar, G. A., Mohas, M., Marko, L., Laczy, B., Cseh, J., Mikolas, E., Szijarto, I. A., Merei, A. et al. (2011) Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. 2011/03/10: 383-389.

29.  Bhatt, J. K., Thomas, S. & Nanjan, M. J. (2012) Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr. Res. 32: 537-541.

30.  Timmers, S., Konings, E., Bilet, L., Houtkooper, R. H., van de Weijer, T., Goossens, G. H., Hoeks, J., van der Krieken, S., Ryu, D. et al. (2011) Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. 2011/11/08: 612-622.

31.  Wong, R. H., Howe, P. R., Buckley, J. D., Coates, A. M., Kunz, I. & Berry, N. M. (2011) Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. 2010/08/03: 851-856.

32.  Militaru, C., Donoiu, I., Craciun, A., Scorei, I. D., Bulearca, A. M. & Scorei, R. I. (2013) Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Nutrition 29: 178-183.

33.  Ghanim, H., Sia, C. L., Abuaysheh, S., Korzeniewski, K., Patnaik, P., Marumganti, A., Chaudhuri, A. & Dandona, P. (2010) An antiinflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. J. Clin. Endocrinol. Metab 95: E1-E8.

34.  Yoshino, J., Conte, C., Fontana, L., Mittendorfer, B., Imai, S., Schechtman, K. B., Gu, C., Kunz, I., Rossi Fanelli, F. et al. (2012) Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. 2012/10/30: 658-664.

35.  Wu, J. M., Wang, Z. R., Hsieh, T. C., Bruder, J. L., Zou, J. G. & Huang, Y. Z. (2001) Mechanism of cardioprotection by resveratrol, a phenolic antioxidant present in red wine (Review). 2001/06/16: 3-17.

36.  Wang, Z., Huang, Y., Zou, J., Cao, K., Xu, Y. & Wu, J. M. (2002) Effects of red wine and wine polyphenol resveratrol on platelet aggregation in vivo and in vitro. 2001/12/18: 77-79.

37.  Popat R., Plesner T., Davies F., Cook G., Cook M., Elliott P., Jacobson E., Gumbleton T., Oakervee H., Cavenagh J. (2013) A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br J Haematol 160(5): 714-17.

38.  Frozza, R. L., Bernardi, A., Hoppe, J. B., Meneghetti, A. B., Battastini, A. M., Pohlmann, A. R., Guterres, S. S. & Salbego, C. (2013) Lipid-core nanocapsules improve the effects of resveratrol against Abeta-induced neuroinflammation. J. Biomed. Nanotechnol. 9: 2086-2104.

39.  Hubbard, B. P. & Sinclair, D. A. (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol. Sci.

40.  Li, S. Y., Wang, X. B. & Kong, L. Y. (2014) Design, synthesis and biological evaluation of imine resveratrol derivatives as multi-targeted agents against Alzheimer's disease. Eur. J. Med. Chem. 71: 36-45.

41.  Csuk, R., Albert, S., Kluge, R. & Strohl, D. (2013) Resveratrol derived butyrylcholinesterase inhibitors. Arch. Pharm. (Weinheim) 346: 499-503.

42. Tomé-Carneiro J, Larrosa M, Yáñez-Gascón MJ, Dávalos A, Gil-Zamorano J, Gonzálvez M, García-Almagro FJ, Ruiz Ros JA, Tomás-Barberán FA, Espín JC, García-Conesa MT. (2013) One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol Res. 72:69-82.

43. Bo S, Ciccone G, Castiglione A, Gambino R, De Michieli F, Villois P, Durazzo M, Cavallo-Perin P, Cassader M. (2013) Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Curr Med Chem. 20(10):1323-3.

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