Evidence Update: Resveratrol

In the first year of this blog, I wrote about a supplement called resveratrol, calling it “a promising but unproven compound.” Last year, I reported on a scandal in which a major researcher of resveratrol retracted over 100 research articles for fraud. At that time, I concluded the product was “still promising but unproven.” Last July, the most recent review of the evidence concerning resveratrol was published in a special issue of the Annals of the New York Academy of Sciences (Vol. 1290). The overall conclusion of this very thorough review seems to support much the same bottom line: there is lots of laboratory research suggesting resveratrol should have all kinds of health benefits, but the actually clinical research showing real-world benefits in humans is still lacking, and virtually no companion animal clinical research appears to exist.

Here are some of the conclusions of various authors contributing to the special issue.

Despite the substantial preclinical evidence, human clinical data are very scarce, and even though the compound is widely distributed as an over-the-counter human nutritional supplement, its therapeutic rationale has not been well characterized.

…the likelihood of benefiting from resveratrol as a result of ordinary dietary intake appears dubious, since a conventional diet at best provides a few milligrams of resveratrol daily.

At the preclinical level, resveratrol has demonstrated reproducible effects in modifying various aspects of metabolic health. This finding is consistent overall with the suggestion that resveratrol acts as a [calorie restriction] mimetic. In terms of cellular experiments, various aspects of resveratrol action have been investigated. Resveratrol seems to be a strong anti-inflammatory compound in cell culture as well as in animal models.

Another prominent effect of resveratrol is the improvement of glucose homeostasis, which has been demonstrated in diverse animal models. Due to the close association between diabetes and obesity, a range of obesity-related measures have also been explored, but only very few studies have been able to demonstrate an antiobesity potential for resveratrol.

Furthermore, resveratrol has demonstrated chemopreventive potential in relation to diverse cancer types, including mammary and colonic cancer. Resveratrol has been shown to provide neuroprotection, and in cardiovascular health, resveratrol has demonstrated cardioprotective potential, partly due to antihypertensive and lipid-lowering properties.

The three most methodologically robust intervention studies were published in December 2011 by Timmers et al., in October 2012 by Yoshino et al., and our own contribution published in December 2012. In the study by Timmers et al….Significant albeit moderate improvements were recorded in various metabolic markers…

In the work by Yoshino et al., 29 nonobese (BMI < 30 mg/m2) postmenopausal women with normal glucose tolerance were randomized…Resveratrol supplementation failed to affect any physiological parameters or putative molecular targets.

This is consistent with the findings in our own human clinical trial: in an investigator-initiated, randomized, double-blinded, placebo-controlled, parallel-group design, 24 male volunteers were randomly assigned treatment for four weeks…Insulin sensitivity was similar in both groups, and endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol supplementation also had no effect on blood pressure, resting energy expenditure, and oxidation rates of lipid, ectopic, and visceral fat content, or inflammatory and metabolic biomarkers.

In terms of human safety and pharmacokinetic properties, the available data are fairly solid, and both acute exposure to high doses of resveratrol (5 g daily for 28 days)as well as more chronic exposure to lower doses (8 mg daily for one year) have not induced any observable adverse events.

Taken as a whole, this paper—and research on resveratrol in general—serves as an illustrative example of the major challenges associated with translating basic research into human clinical practice. Moreover, there are numerous examples in modern medicine of major discordance between treatment effects obtained in animal and human studies.

In contrast to the first review, written by academic researchers (Aarhus University, Denmark), the authors of this review are employed by “DSM Nutritional Products Ltd., a supplier of resveratrol.”  Not surprisingly, this review of the same evidence is somewhat more positive.

Numerous animal and in vitro studies suggest that resveratrol could improve cardiovascular and metabolic health in humans. In view of this compelling preclinical evidence, several human studies investigating the effects of resveratrol on vascular and metabolic health have been initiated. Collectively, the animal, human epidemiological, and first human intervention studies support a role of resveratrol in vascular and metabolic health.

The study indicates that resveratrol, at doses that can be readily achieved in humans, mimics some aspects of the action of CR and may be a useful micronutrient to help prevent age-related chronic diseases.

Recently, Timmers et al. showed that the metabolic benefits observed in animal obesity models could also be translated into effects in humans…resveratrol significantly reduced systolic blood pressure and improved blood glucose levels as well as insulin…Moreover, a significant decrease in liver fat and inflammatory markers was observed.

However, Yoshino et al. found that 75 mg/day of resveratrol after three months of supplementation did not improve metabolic function in nonobese healthy women with normal glucose tolerance. Moreover Poulsen et al. observed no effect on glucose turnover and insulin sensitivity with a high dose of resveratrol (1 g/day).

Future studies need to further evaluate the effects of different doses of resveratrol and discriminate possible distinct effects in various target populations like the obese, diabetics, children, and the elderly.

…many clinical trials investigating the beneficial effects of resveratrol are ongoing (see: www.clinicaltrial.gov database). As of April 2013, there were 15 studies in the field of metabolic health and four studies in the area of cardiovascular diseases, indicating relatively high interest.

Bottom Line
So the bottom line appears to be similar to my conclusion from four years ago. There is ample reason to think resveratrol might be a beneficial supplement based on in vitro and animal model studies. There is inconsistent evidence as to whether any beneficial effects actually occur in humans taking it as a supplement. And there is no direct evidence that it is beneficial for companion animals. Additional clinical studies are certainly warranted, and hopefully they will coalesce around a finding of real benefits. In the meantime, supplementation is probably not justified for most people or for our pets, however there is no convincing evidence of harm associated with the supplement so any risk from taking it is probably very small.

The pace of careful, thorough scientific investigation is slower than those of us treating patients in the clinical setting might wish, but the long-term benefits of reliable, trustworthy information are worth waiting for.

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2 Responses to Evidence Update: Resveratrol

  1. Otis says:

    I like the analysis. I would say that there are some issues with a few highly cited and poorly reviewed resveratrol papers that have pulled the field off track and into the realm of “homeopathy” (nonsense, but pushing beyond hope for a grant renewal), but I sincerely home it can get back on track and something can be contributed from all the prior research into the molecule.

  2. Catherine says:

    See also the surprising results of a double-blind study conducted at the University of Copenhagen of resveratrol suggested it may actually *block* the cardiovascular benefits of exercise in senior men. The original research article was published July 22, 2013 in The Journal of Physiology and reported in Science Daily at http://www.sciencedaily.com/releases/2013/07/130722071955.htm

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