Two weeks ago, Harvard researchers reported that high doses of resveratrol, a compound found in red wine, extend the life span of obese mice on a high-fat diet and keep them as healthy as mice on a normal diet (see “A Life-Extending Pill for Fat Mice”). Their study suggested that resveratrol activates the molecular mechanisms thought to control aging–a good sign for pharmaceutical companies hoping to influence these pathways in order to treat the diseases of aging, from diabetes to cancer.
Another study of resveratrol in mice, published today in the journal Cell, brings even better news: it further illuminates the mechanism of the compound by connecting it with energy expenditure and metabolism. The study was conducted by researchers at Sirtris Pharmaceuticals, in Cambridge, MA; at France’s Institut de Génétique et de Biologie Moléculaire et Cellulaire; and at Johns Hopkins University School of Medicine.
The study reveals that mice given a high-fat diet plus resveratrol put on less fat than other mice on the unhealthy diet. The same held for resveratrol-treated mice on a normal diet. They ingested the same number of calories but burned them at a greater rate. The researchers found that basal energy expenditure–how much energy an animal uses while at rest–was much higher in the treated mice.
The researchers also found that these mice had large, densely folded, highly active mitochondria, the subcellular structures that convert nutrients into energy, in the fat tissue that the animals burn to produce most of their body heat. The researchers noted similar effects, as well as significant changes in gene expression, in the treated mice’s muscle. (In humans, muscle is the tissue in which mitochondria are most active.) In a test of the mice’s endurance–how long they could run before exhaustion hit–those on resveratrol had twice the stamina as those that weren’t.
This study also seems to provide evidence that resveratrol influences molecular aging pathways in mice. In yeast, resveratrol increases life span, and this effect is dependent on the gene Sir2, a master regulator of aging in these organisms. There is not yet any strong evidence connecting the mammalian equivalents of Sir2, called sirtuins, to the control of aging. Researchers in this study found that in mouse muscle cells, the effects of resveratrol on mitochondria were dependent on SIRT1, one of the sirtuins.
The researchers went beyond mice to look for variations in energy expenditure in humans with slight variations in the gene Sirt1. They found three variations that significantly modulated energy expenditure.
Insulin resistance in humans has been tied to poor energy expenditure in mitochondria. Sirtris Pharmaceuticals recently began a clinical trial of a highly active version of resveratrol to treat diabetes.
I know rationally that the benefits of resveratrol have not been demonstrated in humans, and that it’s unclear what dose would be needed to affect people. But after learning of these two studies, I must admit that I’m feeling an irrational urge to go to the health store for some resveratrol supplements. I’m not alone. In fact, David Sinclair, the lead researcher on the Harvard paper, recently said on the Charlie Rose Show (at around 10’ 30” after the jump) that he has been “experimenting on” himself. “I’ve been taking resveratrol for three years, ever since we discovered in yeast that it extends their life span,” he told Rose, although he doesn’t advocate that other people do so.
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