Dietary Resveratrol Makes Little Difference to Health

A recent report sprinkles cold water on the trendy notion that resveratrol, a compound found in red wine, is a molecular boon to health. Scientists led by Cristina Andres-Lacueva, University of Barcelona, Spain, found that resveratrol metabolites in people’s urine did not correlate with inflammatory markers, cardiovascular disease, or cancer—nor did they predict mortality. Published May 13 in JAMA Internal Medicine, the findings suggest that the amount of resveratrol people consume in a Western diet does not affect health, or indeed death.

The study says nothing, however, about taking the compound in larger amounts as a supplement, and many experts advise against tossing resveratrol out with the dregs just yet. They were not surprised that the levels attainable by diet alone seemed irrelevant. The benefits previously seen in cell culture, animal models, and people come with much higher concentrations that are achievable only with supplements, said Leonard Guarente, Massachusetts Institute of Technology in Cambridge. Other researchers agreed. No one said that this study casts a shadow over current clinical trials of resveratrol as a therapy for diseases such as diabetes, cancer, and Alzheimer’s. 

“The doses they measured were extremely low compared to those that come from supplements,” said Rafael de Cabo, National Institute on Aging, Baltimore. He and others have found that resveratrol supplements improve glucose use and insulin signaling, and that they reduce inflammation in animals (see Jimenez-Gomez et al., 2013). “It just has to come in much higher doses than you would get from the diet only,” said de Cabo. For instance, while Andres-Lacueva and colleagues detected nanomoles of resveratrol metabolites in urine, scientists routinely administer enough resveratrol to generate hundreds of micromoles, he said. 

Resveratrol is a plant polyphenol credited for the French paradox—the observation that people in that country tend to consume a lot of cholesterol and saturated fat, yet enjoy a low rate of coronary disease. Foie gras without heart attacks? Maybe red wine makes it possible? The French certainly don’t consume resveratrol supplements en masse, and while resveratrol supplements have been reported to fight cancer (see Liu et al., 2007), prevent metabolic disorders in mice (see Nov 2008 news story), and inhibit Aβ aggregation (see June 2008 news story), scant epidemiological evidence ties dietary intake to health benefits. 

First author Richard Semba, Johns Hopkins School of Medicine, Baltimore, studied a large population from Italy who participated in the longitudinal Invecchiare in Chianti (InCHIANTI) study in Tuscany, a region where most people drink at least one glass of red wine a day. At baseline in 1998, 783 participants over age 65 gave a 24-hour urine sample. The researchers measured the concentration of resveratrol metabolites and divided the cohort into four equally sized groups based on lowest to highest amounts. They then observed these people every three years until 2009, to look for differences in death rate, cardiovascular risk, cancer, inflammation, and other health-related factors. They also measured metabolite levels in urine every three years.

After nine years of follow-up, baseline levels of resveratrol correlated with none of the health outcomes tested. While 268 people died, the death rate was the same among quartiles. Roughly equal proportions of each group developed cardiovascular disease and cancer. There was no association with circulating inflammatory factors. “Our study shows that resveratrol levels achieved by diet alone do not show any protective effects for human health,” wrote Semba. However, diabetes and coronary artery disease did afflict a slightly greater proportion of people in the lowest quartile. Few people in the highest quartile had cognitive impairment. 

Most experts interviewed for this article praised the study’s design and implementation. All, however, suggested that higher doses in supplements could prove more effective. David Sinclair, Harvard Medical School, Boston, pointed to meta-analyses showing that supplements lower systolic blood pressure and improve glucose control and insulin sensitivity in diabetes (see Liu et al., 2014; Liu et al., 2014). 

The jury is still out on whether supplements work. Nir Barzilai, Albert Einstein College of Medicine, Bronx, New York, said that Semba and colleagues’ results support the hypothesis that there is more to the French paradox than resveratrol. Scott Turner, Georgetown University, Washington, agreed. “Resveratrol is just one of many potentially beneficial compounds in red wine and chocolate,” he said. Looking at only one of them may reveal no association with health, he added.  Barzilai said this study leaves open the possibility that resveratrol in higher quantities could be a potent drug.

Resveratrol also may work better in certain people. Co-author Luigi Ferrucci noted that the Chianti cohort contains almost no obese people, yet some animal research suggests that resveratrol exerts some of its greatest effects in the context of a high-calorie diet (see Baur et al., 2007). In a population with more overweight people, dietary resveratrol might have proven effective, Ferrucci proposed.

What does the study imply about resveratrol as an Alzheimer’s treatment? Turner was intrigued that people in the highest quartile had the lowest incidence of cognitive impairment, though the authors cautioned that the sole test of cognitive impairment used in the study, the mini-mental state examination, was insufficient to draw conclusions. After correcting for age, sex, and other confounding variables, the association was insignificant, said Semba. 

Other studies are better equipped to address the AD question. Turner is conducting a Phase 2 trial of resveratrol to see if it slows disease progression in people with mild to moderate AD. His group has just finished collecting data on 119 people who took 1 gram of resveratrol, equivalent to hundreds of bottles of wine, twice daily for a year. Analysis will begin next week, and results will be presented in November at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting, said Turner.

At least two other clinical studies are in the works for Alzheimer’s disease. Scientists at the Department of Veterans Affairs have completed a Phase 3 trial of a trio of supplements, including resveratrol, to see if they curb AD progression. A Phase 4 trial is testing a range of dietary and behavioral interventions, including resveratrol supplements, to see whether any stall the progression of mild cognitive impairment.—Gwyneth Dickey Zakaib

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References

Therapeutics Citations

  1. Resveratrol

News Citations

  1. SIRT1 Activator Prevents Metabolic Disorders in Mice
  2. Grape-derived Polyphenols Fight Amyloid, Head to Clinic

Conference Citations

  1. Clinical Trials on Alzheimer’s Disease 2014

Paper Citations

  1. Jimenez-Gomez Y, Mattison JA, Pearson KJ, Martin-Montalvo A, Palacios HH, Sossong AM, Ward TM, Younts CM, Lewis K, Allard JS, Longo DL, Belman JP, Malagon MM, Navas P, Sanghvi M, Moaddel R, Tilmont EM, Herbert RL, Morrell CH, Egan JM, Baur JA, Ferrucci L, Bogan JS, Bernier M, de Cabo R. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab. 2013 Oct 1;18(4):533-45. PubMed.
  2. Liu BL, Zhang X, Zhang W, Zhen HN. New enlightenment of French Paradox: resveratrol's potential for cancer chemoprevention and anti-cancer therapy. Cancer Biol Ther. 2007 Dec;6(12):1833-6. Epub 2007 Oct 13 PubMed.
  3. Liu Y, Ma W, Zhang P, He S, Huang D. Effect of resveratrol on blood pressure: A meta-analysis of randomized controlled trials. Clin Nutr. 2014 Mar 31; PubMed.
  4. Liu K, Zhou R, Wang B, Mi MT. Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. Am J Clin Nutr. 2014 Apr 2;99(6):1510-1519. PubMed.
  5. 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. PubMed.

External Citations

  1. Phase 2 trial
  2. Phase 3 trial
  3. Phase 4 trial

Further Reading

Primary Papers

  1. Semba RD, Ferrucci L, Bartali B, Urpí-Sarda M, Zamora-Ros R, Sun K, Cherubini A, Bandinelli S, Andres-Lacueva C. Resveratrol levels and all-cause mortality in older community-dwelling adults. JAMA Intern Med. 2014 Jul 1;174(7):1077-84. PubMed.

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