Resveratrol Increases Energy In Humans, Mice

Resveratrol increases energy production in humans and increases mouse endurance on treadmills.

CAMBRIDGE, MA and Strasbourg, France  November 16th, 2006  Sirtris Pharmaceuticals and the University Louis Pasteur, Strasbourg announced that in an article published today in Cell, Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Lagouge et al., Cell. 2006; 127: 114, SIRT1 was shown for the first time in a human population to accelerate metabolic rate. In a human population in Finland, SIRT1 was linked to increased energy expenditure as demonstrated by genetic studies of three variants of the SIRT1 gene. The study also showed that treating mice with resveratrol increased mitochondrial biogenesis leading to increased exercise endurance and protection from diet induced obesity. Activation of SIRT1, the best characterized of the recently-discovered family of sirtuin enzymes, was shown to be the mechanism by which these therapeutic benefits occur.

The doses used in mice, 200 mg/kg and 400 mg/kg, is milligrams per day per kilogram of body weight of the mice. Well, scale that to humans and it becomes clear the dose is very high. A 150 lb human is 68 kilograms. That works out to over 27 grams per day.

Mice were dosed with 200 mg/kg or 400 mg/kg of resveratrol daily in either normal chow or high fat chow. The mice on resveratrol lost weight due to decreased fat, and this was attributed to an increase in the number and function of mitochondria. The resveratrol-treated mice also exhibited improved insulin sensitivity and an increased metabolic rate. Notably, mice treated with resveratrol showed a two-times increase in exercise endurance. These effects were shown to be mediated through SIRT1 and PGC-1α.

The scientists who did the work are at prestigious research universities.

The authors of the Cell article include the teams of the principal investigator Johan Auwerx, M.D. Ph.D., Professor at the Medical Faculty in Strasbourg, at IGBMC (Unité mixte de recherche CNRS, Inserm, University Louis Pasteur), France, and of Pere Puigserver, Ph.D. from Johns Hopkins University School of Medicine in Baltimore (now at the Dana-Farber Cancer Institute/Harvard Medical School in Boston), both members of the Scientific Advisory Board of Sirtris Pharmaceuticals, and Sirtris scientists: Peter Elliott, Ph.D. Senior Vice President and Head of Development, Phil Lambert, Ph.D. Senior Director of Pharmacology, and Jill Milne, Ph.D., Senior Director of Biology.

It would be hard to get regulatory approval for a drug that increased life expectancy because it is a claim that is hard to prove in a clinical trial. But Sitris is chasing a more provable claim: That their modified resveratrol molecule, SRT501, will reduce the symptoms of old age and obesity such as high unhealthy blood lipids and insulin resistance in the form of type II diabetes.

This work is significant because it shows that a SIRT1 activator can protect against metabolic disease, highlighting the therapeutic potential of sirtuins. Resveratrol a compound found in the skin of red grapes and hence in red wine, could very well explain the French Paradox, said Johan Auwerx. Sirtris has initiated a human Phase 1b clinical trial in diabetes with SRT501, a proprietary formulation of resveratrol with improved bioavailability. SRT501 is the first small molecule to enter human clinical trials that is designed to activate SIRT1. Sirtris has applied this scientific discovery to the development of SRT501, which activates SIRT1, for the treatment of diseases of aging such as metabolic and mitochondrial disorders. In addition, Sirtris has a robust pipeline of novel small molecule drug candidates that are potent SIRT1 activators and are chemically distinct from resveratrol. This important work highlights the significance of SIRT1 as a therapeutic target for metabolic disease. Based on the continuing scientific evidence, as shown in this most recent Cell article, we are continuing to advance drug candidates to translate the science of sirtuins into new treatments for diseases of aging, such as diabetes, said Peter Elliott, Ph.D. Senior Vice President and Head of Development at Sirtris Pharmaceuticals. These new human data support SIRT1 as a therapeutic target for metabolic disease. Our broad pipeline of sirtuin modulators have potential in a number of diseases of aging, said Christoph Westphal, M.D., Ph.D., Chief Executive Officer of Sirtris Pharmaceuticals.

Now for the qualifiers and caveats.

Back in March 2005 Sirtris co-founder David Sinclair of Harvard said that most commercial resveratrol preparations have no active resveratrol in them - with activity measured by the ability to activate the SIR2 enzymes.

Resveratrol is not an easy molecule to protect from oxidation. Most commercially available supplements I have tested have no ability to stimulate SIR2 enzymes.

Longevinex sells resveratrol to many researchers. But their commercial resveratrol preparation has only 100 mg of resveratrol per capsule and costs more than $1 per capsule. But the recent study by David Sinclair and Rafael de Cabo showing resveratrol protected mice from the harms of obesity used a dose of resveratrol that would be the equivalent of 1600 mg for a 150 lb human. Whereas the study above on mice used the equivalent of 27 grams (27,000 milligrams) of resveratrol for a 150 lb human.

Bulk sources of resveratrol from knotweed can be found on the internet. But which of those sources is selling real active resveratrol? Your guess is as good as mine.

Then there's the question of whether this stuff is safe. We do not know. Okay? Really, we do not know. We need a big study of large numbers of people taking a gram of resveratrol a day with all sorts of checks done on them to look for bad signs. My guess is we are not going to see such a study on resveratrol because the money is in making a patentable commercial variation of resveratrol into a marketable drug. That'll take 6, 7, 8 years more and hundreds of millions of dollars.

In the comments section of my post on the David Sinclair and Rafael de Cabo study on resveratrol you'll see a reader who claims he's taking over 1 gram of resveratrol a day with very beneficial effects. He thinks he has a good trustworthy source for large doses.

Where do resveratrol and the Sirtris drug SRT501 fit into the larger picture of anti-aging treatments and life extension? If they work then they probably work by slowing down aging the same way that calorie restriction does. The interest in the Sir1 and similar sirtuin genes comes from studies on calorie restriction's effects on gene expression in yeast and rodents. But we do not know for sure that calorie restriction will increase human life expectancies.

Now, if resveratrol and SRT501 do extend life that's a good thing because they'll help keep us alive until rejuvenation therapies such as gene therapies and stem cell therapies become available. That companies are trying to develop drugs that mimic the effects of calorie restriction is a good thing. I wish them luck and watch their progress closely.

But we still need the rejuvenation therapies and we need even greater efforts to develop rejuvenation therapies. For more on that read about Strategies for Engineered Negligible Senescence (SENS). We won't need to slow the rate of aging when we can reverse aging. Though slowing the rate of aging will still let us go longer between rejuvenation therapy episodes.