The effects of resveratrol have been controversial, to say the least. Arguments rage about whether (and how) it affects the various sirtuin pathways, what those various sirtuin pathways are and what they do, and what the compound does in animal models at all (whether you care about the mechanism or not). That last topic recently boiled over once more. I've spoken about the compound and these issues many, many times around here, as long-time readers will know - go here and just keep scrolling back if you're interested. GSK halted its development of resveratrol itself (as opposed to follow-up ligands) last year, it appears.
Get ready for more head-scratching. There's a new paper out from researchers in the Netherlands and Switizerland looking at the effects of resveratrol in obese human subjects. They ran a small (11-subject) double-blind crossover trial vs. placebo of 150mg of resveratrol per day, and found. . .well, let me quote the summary, because I can't put it in fewer words myself. If you're not a technical kind of person, that last line (emphasis added) tells the story:
Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.
Well, that is interesting. What this (and some of the earlier data) seems to be telling us is that resveratrol may well be beneficial - but particularly so under conditions of metabolic stress, such as in obesity. As for the mechanism, when they looked at muscle tissue samples, they found over 400 genes with altered expression (some up, some down). These seem to have particularly concentrated in metabolic and inflammation pathways, particularly mitochondrial oxidative phosphorylation. These are quite similar results to those seen in obese rodents.
On the other hand, some things were very different indeed in the two species. Mice actually showed an increase in energy expenditure during reservatrol treatment - these humans showed a decrease. The plasma concentration reached in both experiments were similar, but mice needed a 200-fold higher dose of resveratrol to reach that, which has to be one confounding factor. (Another is the duration of treatment; the mice got the compound for several months, which is longer by the calendar but also a much higher percentage of their entire lives).
Still, the effects in the human subjects were quite impressive. Not all the changes were huge, but they all seem to point in the same direction: mimicking the effects of caloric restriction and exercise. This is exactly the sort of thorough, well-controlled study this field has been needing, and it makes all the questions in it take on that much more urgency. What does resveratrol do in humans, on a molecular level? Are sirtuins involved, and to what extent? Can other compounds do the same thing, or even more? What are the long-term effects of such compounds on human morbidity and mortality? Do these effects only manifest themselves in obese subjects? How much would happen in people who are under less metabolic stress to start with? And so on. . .