In this issue of Pharmacol Res, Chiu-Tsun Tang et al.  elegantly and comprehensively review the accumulated evidence on resveratrol’s biological effects. The conclusions are quite clear-cut: after more than 20 years of well-funded research, resveratrol has no proven human activity. Indeed, there is – to date – only one reasonably-sized human study that suggests anti-inﬂammatory activities in cardiovascular patients . Other than that, the near totality of available evidence comes from cell cultures and animal studies. The former are ﬂawed in that they use non-physiological concentrations (see Table 1 of Chiu-Tsun Tang et al.) and the latter also often use doses that are impractical in humans. In brief, 23 years of research led to inconclusive human results. Why? Well, it’s worth reminding that resveratrol research took off in 1991, after a “60 Minutes” show where Drs. Michel de Lorgeril and Serge Renaud proposed the French paradox hypothesis and its corroboration by resveratrol and red wine phenolics’ consumption. Alas, there is no French paradox, i.e. cardiovascular mortality in France is similar to that of neighboring countries and follows a North-South gradient, as expected. In addition, there is barely any resveratrol in good-quality red wine, because stilbenes are produced in response to fungi infection . Finally, the subsequent rapid progress in metabolomics revealed that wine phenolics (including resveratrol) are very poorly bioavailable , which is the mean reason behind this ﬂop. Therefore, any putative bioactivity might be due to resveratrol’s metabolites rather than to the parent compound. From a mere ﬁnancial viewpoint, it should be noted that millions of dollars have been poured into resveratrol research from both private and public institutions. As an example of the former, the much-heralded (and expensive: US$720 million) acquisition of Sitris Pharmaceutical by the pharma colossus GlaxoSmithKline led to an entrepreneurial cul-de-sac and GSK ﬁnally closed down Sirtris. Of note, the notion that resveratrol activates SIRT1, a member of a family of enzymes that remove acetyl groups from proteins and are thought to be involved in aging and metabolism, is probably the result of experimental artifacts.
The resveratrol ﬁasco is not the only one we witnessed in pharma-nutrition research. Notable examples include antioxidants (especially beta-carotene ) and omega 3 fatty acids . The main lesson we should learn is that what makes biological sense and works in test tubes and animals does not always operate in humans. This discrepancy calls for extreme caution when we propose health claims and underscores the need for appropriate and rigorous experimental paradigms in pharma-nutrition research [7,8]. References
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 Chiu-Tsun Tang P, Ng Y-F, Ho S, Gyda M, Chan S-W. Resveratrol and cardiovascular health – promising therapeutic or hopeless illusion? Pharmacol Res 2014. pii:S1043-6618(14)00138-8 [in this issue].  Tome-Carneiro J, Larrosa M, Yanez-Gascon MJ, Davalos A, Gil-Zamorano J, Gonzalvez M, et al. 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 2013;72:69–82.  Poli A, Marangoni F, Avogaro A, Barba G, Bellentani S, Bucci M, et al. Moderate alcohol use and health: A consensus document. Nutr Metab Cardiovasc Dis 2013;23:487–504.  Rotches-Ribalta M, Andres-Lacueva C, Estruch R, Escribano E, Urpi-Sarda M. Pharmacokinetics of resveratrol metabolic proﬁle in healthy humans after moderate consumption of red wine and grape extract tablets. Pharmacol Res 2012;66:375–82.  Davey Smith G, Ebrahim S. Epidemiology – is it time to call it a day? Int J Epidemiol 2001;30:1–11.  Visioli F. Cover story: what is wrong with omega 3 fatty acids? PharmaNutrition 2014;2:A1.  Visioli F. Can experimental pharmacology be always applied to human nutrition? Int J Food Sci Nutr 2012;63(Suppl. 1):10–3.  Visioli F. Pharma and nutrition: crossing the rubicon. PharmaNutrition 2013;1:9.