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Review of Resveratrol

What is Resveratrol?

Resveratrol (3,4,5-trihydroxy-trans-stilbene), is a naturally occuring plant polyphenol that is found in some foods such as grapes, red wine, billberry and peanuts.Resveratrol has potent antioxidant and anti-inflammatory properties and has been shown to have a number of positive health benefits including: reduced blood pressure, protection against artherosclerosis, reduced insullin levels & sensitivity, may reduce lipid accumulation and abdominal fat levels, may offer protection against a number of different cancers, and have a neuroprotective effect.

Who Should Consider Taking Resveratrol?

Resveratrol may be of benefit to anyone looking for a potent antioxidant to protect against the damaging effects of free-radicals and provide a number of research proven health benefits. 

Summary of Resveratrol's Phyiological Effects:

  • Resveratrol improves a number of measures of cardiovascular health, including: reduced blood pressure, reduced artherosclerosis, reduced platelet aggregation, and may help to protect against heart failure. 
  • Resveratrol has a vasodillatory and enhances nitric oxide production
  • Resveratrol has a chemopreventative effect on a number of different types of cancer by inhibiting the development, growth and proliferation of cancer cells
  • There is evidence that resveratrol may have be beneficial for weight loss/weight management although further research is needed to confirm this in humans
  • Resveratrol may be of benefit for the treatment of diabetes as it has been shown to enhance insulin sensitivity and lower blood glucose levels
  • Early animal studies have shown that resveratrol can extend lifespan, recent human studies have shown that resveratrol has favourable effects on plasma markers that predict increased risk of diabetes and shorter lifespan 
  • Resveratrol has been shown to reduce plasma markers of inflammation
  • Recent research shows that resveratrol may be beneficial for some neurological disorders by decreasing neural cell death and lowering neurotoxicity of mutant proteins. 
  • Resveratrol may also be of benefit for osteoporosis, rheumatoid arthritis, colitis and protection of the liver.

Reseveratrol Research

Reseveratrol has been shown to have a number of positive effects on cardiovascular health, including reduced artherosclerosis, reduced blood pressure and provides protection against cardiovascular disease and heart failure. One potential cardiovascular health benefit of resveratrol is its ability to prevent platelet aggregation (Szewczuk et al 2004; Shen et al., 2007). By protecting against/preventing platelet aggregation resveratrol can help to reduce the risk of heart attack and stroke.

Resveratrol is also known to have a vasodilatory effect (Li et al., 2000) and may offer protection against a number of different causes of hypertension, including, spontaneous hypertension, salt-induced hypertension and obesity induced hypertension (Vang et al., 2011). The vasodillatory effect of resveratrol is in part due to enhanced Nitric Oxide (NO) production. Resveratrol may also help to reduce the rate of artherosclerosis (Verschuren et al., 2011) and appears to help lower systolic blood pressure (Timmers et al., 2011).

Resveratrol and Cancer Prevention
Resveratrol has been shown to have chemopreventive activity and has the potential to inhibit the development, growth and spread of cancer cells. Animal studies have demonstrated that resveratrol has a strong chemopreventative action and may help to protect/prevent a number of different cancers, including: inhibition of skin cancers (Jang et al., 1997; Roy et al., 2009), suppresion of prostate cancers (Harper 2009), chemopreventative effect on breast cancer (Le Corre et al., 2005), inhibition of liver cancer (Bishayee and Dhi, 2009) and colon cancers (Patel et al., 2010).

Resveratrol is believed to exert its chemopreventative activity on a number of levels, including: inhibition of key enzymes, inhibition of available oestrogen and oestrogen receptor activity, regulation of apoptosis (the natural death of cells) of cancer, inhibition of cancer cell proliferation (growth and spreading), and interference with cancer cell survival.

Resveratrol and Weight Management
Resveratrol shows potential for the treatment of both obesity and diabetes (Szkudelska K & Szkudelski T, 2010). Animal studies have demonstrated that high doses of resveratrol were able to suppress seasonal gains in body weight (Dal-Pan et al., 2010). However, the doses used in this study were large - 200mg/kg body mass, equivalent to 14g of resveratrol in a 70kg human. Studies using smaller doses have failed to demonstrate significant reductions in bodymass. Lower dose studies have however demonstrated reductions in abdominal fat, improved insulin sensitivity, and reduced blood glucose levels (Rivera et al., 2009; Vang et al., 2011).

Resveratrol and Lifespan
Resveratrol produces a number of changes that are associated with increased lifespan, including: increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, improved mitochondrial function, maintenance of metabolic homeostasis, protect against insulin resistance, and reduces blood glucose levels. It has been shown to extend the lifespan and have a positive effect on aging in a number of different animal species (Gerhardt et al., 2011; Barger et al., 2008; Lagouge et al., 2006; Baur et al., 2006). A recent study in humans found that the consumption of resveratrol (150mg/day) over 30 days had a number of positive effects that may indicate a reduced risk of both diabetes and shortened lifespan (Timmers et al., 2011).

Resveratrol and Inflammation
Resveratrol has been shown to reduce markers of inflammation in a number of studies (Tili & Michaille 2011; Timmers et al., 2011; Vang et al., 2011; Zhong et al., 2011;). This is important since inflammatory responses are implicated in a number of diseases and conditions including: artherosclerosis, rheumatoid arthritis, heart disease, diabetes, cancer, and neurodegeneratory disorders like Multiple Sclerosis and Alzheimers disease.

Resveratrol and Neurological Disorders
There is strong evidence that inflammation plays a key role in neurodegeneration. Since resveratrol possess anti-inflammatory properties and is known to pass through the blood brain barrier there has been considerable interest in the role that resveratrol could play in reducing/protecting against neuro-degeneration. Resveratrol shows promise in the treatment of a number of neurological disorders - possibly through its anti-oxidant, anti-neuroinflammatory activity including the inhibition of pro-inflammatory enzymes and cytokines, and producing a protective effect against neurotoxicity (Zhong et al., 2012; Kim et al., 2007; Foti et al., 2011). In fact research suggests that it produces neuroprotection against a number of neurological disorders, possibly by repressing expression of neurotoxic proinflammatory mediators and cytokines, and it may protect against the death of neuron’s and Beta amyloid (Aβ) neurotoxicity (Zhong et al., 2012; Kim et al., 2007). Resveratrol shows potential in neurodegenerative diseases such as Multiple Sclerosis (Shindler et al., 2010), Huntington’s disease (Maher et al., 2010), Parkinsons disease (Zhang et al., 2010) and may also help to support the healthy aging of the brain (Oomen et al., 2009).

Other Health Benefits of Resveratrol
Reseveratrol has many other promising health benefits, too many to discuss in this one review. Some of the other areas that Reveratrol may benefit include: Osteoporosis (Rayalan et al., 2011), rheumatoid arthritis (Nakayama et al., 2010), protection against liver disease (Bishayee et al., 2010) and suppression of colitis (Hosfeth et al., 2010).

Is Resveratrol effective?

Resveratrol appears to be effective at improving measures of cardiovascular health, lowering blood glucose and insulin levels, enhancing insulin sensitivity, lowering inflammation levels, and enhancing anti-oxidant status. Resveratrol also has the ability to inhibit a number of different types of cancers, has a neuro-protective effect through its anti-neuroinflammatory activity, and has the potential to enhance weight loss/management. However, further research is needed to investigate the effectiveness of Resveratrol on Cancers, neuro-degeneration, and weight loss in humans. 

How to take Resveratrol?

Most of the studies to date have used wide ranges of resveratrol dosage making it difficult to establish an effective dose in humans. However, it appears that a dose of around 150mg/day is sufficient to have positive effects on blood pressure, blood glucose, insulin, and mitochondria (Timmers et al., 2011). Whereas higher doses (~500mg-1000mg) may be sufficient to have anticarcinogenic effects on colon and rectal cancers (Patel et al., 2010).

Resveratrol's Side Effects

Resveratrol appears to be safe and free of serious side effects when taken over a range of doses (500mg-5,000mg) over a short term period (Brown et al., 2010). However, if you have any pre-existing medical condition, are pregnant, under 18, are taking blood thinning medication, or supplements, or have any concerns please consult appropriate medical advice before taking resveratrol. 

Resveratrol References

Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA. (2008) A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One. 2008 Jun 4;3(6):e2264.

Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA.Resveratrol improves health and survival of mice on a high-calorie diet.Nature. 2006 Nov 16;444(7117):337-42.

Bishayee A, Darvesh AS, Politis T, McGory R. (2010) Resveratrol and liver disease: from bench to bedside and community. Liver Int. 2010 Sep;30(8):1103-14.

Brown V A, Patel K R, Viskaduraki M, Crowell J A, Perloff M, Booth T D, Vasilinin G, Sen A, Schinas A M, Piccirilli G, Brown K, Steward W P, Gescher A J, and Brenner D E.(2010) Repeat Dose Study of the Cancer Chemopreventive Agent Resveratrol in Healthy Volunteers: Safety, Pharmacokinetics and Effect on the Insulin-like Growth Factor Axis. Cancer Res. 2010 November 15; 70(22): 9003–9011.

Dal-Pan A, Blanc S, Aujard F. (2010) Resveratrol suppresses body mass gain in a seasonal non-human primate model of obesity. BMC Physiol. 2010 Jun 22;10:11.

Foti Cuzzola V, Ciurleo R, Giacoppo S, Marino S, Bramanti P. (2011) Role of Resveratrol and its Analogues in the Treatment of Neurodegenerative Diseases: Focus on Recent Discoveries.CNS Neurol Disord Drug Targets. 2011 Nov 1. [Epub ahead of print]

Gerhardt E, Gräber S, Szego EM, Moisoi N, Martins LM, Outeiro TF, Kermer P. (2011) Idebenone and resveratrol extend lifespan and improve motor function of HtrA2 knockout mice. PLoS One. 2011;6(12):e28855. Epub 2011 Dec 19.

Harper CE, Cook LM, Patel BB, Wang J, Eltoum IA, Arabshahi A, Shirai T, Lamartiniere CA. (2009) Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats.Prostate. 2009 Nov 1;69(15):1668-82.

Hofseth LJ, Singh UP, Singh NP, Nagarkatti M, Nagarkatti PS. (2010) Taming the beast within: resveratrol suppresses colitis and prevents colon cancer.Aging (Albany NY). 2010 Apr;2(4):183-4.

Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM. (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.Science. 1997 Jan 10;275(5297):218-20.

Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH. (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.EMBO J. 2007 Jul 11;26(13):3169-79.

Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006 Dec 15;127(6):1109-22. Epub 2006 Nov 16.

Le Corre L, Chalabi N, Delort L, Bignon YJ, Bernard-Gallon DJ. (2005) Resveratrol and breast cancer chemoprevention: molecular mechanisms.Mol Nutr Food Res. 2005 May;49(5):462-71.

Li HF, Chen SA, Wu SN. Evidence for the stimulatory effect of resveratrol on Ca(2+)-activated K+ current in vascular endothelial cells. Cardiovasc Res. 2000;45:1035–45.

Maher P, Dargusch R, Bodai L, Gerard PE, Purcell JM, Marsh JL. (2010) ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. Hum Mol Genet. 2011 Jan 15;20(2):261-70. Epub 2010 Oct 15.

Nakayama H, Yaguchi T, Yoshiya S, Nishizaki T. (2010) Resveratrol induces apoptosis MH7A human rheumatoid arthritis synovial cells in a sirtuin 1-dependent manner. Rheumatol Int. 2010 Aug 10.

Oomen C A,Farkas F, Roman V, van der Beek E M, Luiten P G M and Meerlo1 P (2009) Resveratrol Preserves Cerebrovascular Density and Cognitive Function in Aging Mice. Front Aging Neurosci. 2009; 1: 4

Patel KR, Brown VA, Jones DJ, Britton RG, Hemingway D, Miller AS, West KP, Booth TD, Perloff M, Crowell JA, Brenner DE, Steward WP, Gescher AJ, Brown K. (2010) Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010 Oct 1;70(19):7392-9.

Pirola L, Fröjdö S. (2008) Resveratrol: one molecule, many targets.IUBMB Life. 2008 May;60(5):323-32.

Rayalam S, Della-Fera MA, Baile CA. (2011) Synergism between resveratrol and other phytochemicals: implications for obesity and osteoporosis. Mol Nutr Food Res. 2011 Aug;55(8):1177-85.

Rivera L, Moron R, Zarzuelo A, Galisteo M. Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem Pharmacol. 2009;77:1053–1063.

Roy P, Kalra N, Prasad S, George J, Shukla Y. Chemopreventive Potential of Resveratrol in Mouse Skin Tumors Through Regulation of Mitochondrial and PI3K/AKT Signaling Pathways. Pharm Res. 2009;26:211–217.

Shen MY, Hsiao G, Liu CL, et al. Inhibitory mechanisms of resveratrol in platelet activation: pivotal roles of p38 MAPK and NO/cyclic GMP. Br J Haematol. 2007;139:475–85.

Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A. (2010) Oral resveratrol reduces neuronal damage in a model of multiple sclerosis.J Neuroophthalmol. 2010 Dec;30(4):328-39.

Szewczuk LM, Forti L, Stivala LA, et al. Resveratrol is a peroxidase-mediated inactivator of COX-1 but not COX-2: a mechanistic approach to the design of COX-1 selective agents. J Biol Chem. 2004;279:22727–37

Szkudelska K, Szkudelski T. (2010) Resveratrol, obesity and diabetes.Eur J Pharmacol. 2010 Jun 10;635(1-3):1-8.

Tili E, and Michaille J-J. (2011) Resveratrol, MicroRNAs, Inflammation, and Cancer.J Nucleic Acids. 2011; 2011: 102431.

Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MK, Kunz I, Schrauwen-Hinderling VB, Blaak EE, Auwerx J, Schrauwen P. (2011) Calorie Restriction-like Effects of 30 Days of Resveratrol Supplementation on Energy Metabolism and Metabolic Profile in Obese Humans.Cell Metab. 2011 Nov 2;14(5):612-22.

Vang O,Ahmad N, Baile C A, BaurJ A, Brown K, Csiszar A, Das D K, Delmas D, Gottfried C, Lin H-Y, Ma Q-Y, Mukhopadhyay P, Nalini N, Pezzuto J. M, Richard T, YShukla, Surh Y-J, Szekeres T, Szkudelski T, Walle T, Wu J. M. (2011) What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol. PLoS One. 2011; 6(6): e19881.

Verschuren L, Wielinga PY, van Duyvenvoorde W, Tijani S, Toet K, van Ommen B, Kooistra T, Kleemann R. (2011) A dietary mixture containing fish oil, resveratrol, lycopene, catechins, and vitamins E and C reduces atherosclerosis in transgenic mice.J Nutr. 2011 May;141(5):863-9. 

Zhang F, Shi JS, Zhou H, Wilson B, Hong JS, Gao HM. (2010) Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions. Mol Pharmacol. 2010 Sep;78(3):466-77. Epub 2010 Jun 16.

Zhong LM, Zong Y, Sun L, Guo JZ, Zhang W, He Y, Song R, Wang WM, Xiao CJ, Lu D. (2012) Resveratrol Inhibits Inflammatory Responses via the Mammalian Target of Rapamycin Signaling Pathway in Cultured LPS-Stimulated Microglial Cells. PLoS One. 2012;7(2):e32195. Epub 2012 Feb 21.