Does Resveratrol Blunt the Benefits of Exercise?

Recently, a study by Lasse Cliemann and colleagues suggested that high doses of resveratrol (250 mg/day) may blunt the beneficial effects of exercise. The publication garnered a lot of media attention, with different outlets creating their own spin on the topic. For another perspective, we have asked various professionals for their views on the study.

 

There are many debates such as this one that should continue to take place in the nutrient/nutraceutical research. Perhaps it is a cultural bias that has us assuming “more is better.” Perhaps it is a multibillion-dollar supplement industry with a vested interest in perpetuating this bias. We now know that minute quantities of reactive oxygen species (ROS) are essential to life, and that high levels are detrimental. The concept that nutrients also have doses that are beneficial, beyond which they are detrimental, is in keeping with the idea that optimal physiological function is a balance within the cells and the organism as a whole. Practitioners of many ancient medicines around the world understand this concept; the symbolic yin/yang is familiar to most Westerners as well. I look forward to clarification of natural agents and their optimal doses for physiological benefit. I fully expect that we will learn that each has an elusive “sweet spot dosage,” and that biochemical individuality will keep that “sweet spot dosage” elusive for quite some time.

The fact that low levels of ROS play an important role in promoting health represents a fundamental change in biological understanding.

 

Gliemann L, Schmidt JF, Olesen J, et al. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J Physiol. 2013 Aug 19. [Epub ahead of print]. Click here for full text.

 

The recent clinical trial by Gliemann et al has generated intense media coverage. The purpose of this study was to examine if resveratrol (250 mg/d for 8 weeks) enhances the exercise response in 27 healthy, physically inactive older male adults (M age = 65 years). All the participants engaged in vigorous exercise training and were randomly assigned to either a resveratrol or placebo group. Although the participants engaged in physical activity 3 times a week, information regarding the duration is unknown, rendering it difficult to determine the exact exercise prescription.

 

The authors concluded that “exercise training effectively improves several cardiovascular health parameters in aged men, [but] resveratrol supplementation blunts most of these effects.” Does this mean that resveratrol counteracts the benefits of exercise training and may be harmful? Critical analyses of this study’s results do not support such strong conclusions for at least the following four reasons.

 

First, exercise training improved 12 variables and did not influence 18 variables, independent of group. Thus, resveratrol does not either blunt most of the effects of exercise or produce “mainly negative” effects, because most of the comparisons revealed similar effects for the resveratrol and placebo group.

 

Second, the multiple post hoc comparisons per variable inflated the risk for type I error. For example, the researchers reported that LDL cholesterol decreased significantly in the placebo group but not the resveratrol group. A closer examination of the data revealed a decrease of 0.3 ± 0.2 mmol.L^-1 in the placebo group versus 0.2 ± 0.2 mmol. L^-1 in the resveratrol group—a between-group difference of 0.1 mmol.L^-1. This raises the question of inflated statistical significance versus practical significance.

 

Third, the researchers concluded, based on the deltas computed, that the resveratrol group had a 45% lower increase in maximal oxygen uptake than the placebo group. The absolute magnitude of the difference, however, in ΔVO2max was 1.8 mL.kg.^-1min^-1. Furthermore, percentage changes revealed a raw score improvement of 17.2% for placebo group compared to 12.8% for resveratrol group (a difference of 4.4%). Indeed, a difference of 4.4% is less media-grabbing than a difference of 45%.

 

Finally, the step test (a measure of aerobic fitness) findings revealed that the resveratrol group had a significant improvement compared to the placebo group (between-group difference of 3.1 mL.kg.^-1min^-1). This result represented an 86% increase for the resveratrol group compared to placebo group. It is interesting that this significant result is only mentioned in the supplemental section of the paper.

 

My colleagues and I published in 2008 in the American Journal of Clinical Nutrition a paper showing that administration of vitamin C lowers the efficacy of training in rats.¹ We showed that because vitamin C prevents mitochondriogenesis, which may be activated by reactive oxygen species. In this context, the idea that giving more antioxidants is good for performance should not be considered correct. 

 

Furthermore, later on, approximately one year after us, Dr Michael Ristow, now in Zurich, observed that oral supplementation with antioxidants not only affected performance, but also the beneficial effects on health of exercise. Dr Carmen Gomez-Cabrera and I, together with Ristow, wrote a paper in the American Journal of Physiology titled “Antioxidant supplements in exercise: worse than useless?”²

 

Now let me tell you my view on this topic: I think that when one performs exercise, a small amount of radicals occur, and this has a hormetic (like a vaccination) effect. A few radicals enormously activate the antioxidant defenses, and these are good for you. These radicals also activate the mitochondriogenic pathway. Thus, it is not advisable to take antioxidants when you are training because it hampers the beneficial effects of training. When do I recommend antioxidants? Before a competition. In competitions, the effort is likely to be very heavy and sometimes taken to the very limit of the individual athlete. In this case, the free radicals produced in exercise may overwhelm the defenses and then cause damage. Therefore, I would recommend taking relatively light doses of antioxidant vitamins like 1 g of vitamin C and 400 IU of vitamin E only in cases when people are competing, but not when they are training. 

 

On the other hand, work by Bruce Ames in Berkeley has shown that the vast majority of the population is deficient in one micronutrient or another, and we do not know which ones. For instance, you may be deficient in one vitamin and I may be deficient in one mineral. Thus what we recommend is that one takes multivitamin + multimineral supplements. The more variety the better. Because the dose is relatively small, no toxic effects are likely to occur. However, since we are administering many different micronutrients, we are likely to cover the deficiencies in these micronutrients. Our recommendation is therefore for the general population to take a multivitamin + multimineral supplement, but not to take large amounts of one antioxidant vitamin, unless they are competing. 

 

The findings of Gliemann et al (2013) extend those of others such as Ristow et al³ that one good thing (ingestion of resveratrol at appropriate doses) may blunt the positive effects of another (i.e. exercise). While more research needs to be done on this important area, the original and seminal observations of Ristow and colleagues that some of the benefits of exercise are mediated via reactive oxygen and that these benefits can be blocked by the ingestion of high levels of antioxidants was supported. In future studies with resveratrol, it would be important to extend the dosage to values lower than the 250 mg/day. The fact that low levels of ROS play an important role in promoting health represents a fundamental change in biological understanding, whereby in the past it was assumed that even low dose of ROS were universality harmful. Now we know that they are essential. The implications of this new understanding are extremely important, especially in the areas of drug development, environmental regulation and in activities (eg, diet, exercise) associated with lifestyle.