CAMBRIDGE, Mass & STRASBOURG, France -- Sirtris Pharmaceuticals and the University Louis Pasteur, Strasbourg announced that in an article published today in Cell, 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.
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-1a.
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. “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.
Sirtuins are a recently discovered family of enzymes that promote normal cellular function. In particular, sirtuins improve the function of mitochondria which generate energy in cells. When organisms face adversity, sirtuins are activated as part of a natural process that maintains healthy function.
Therefore, sirtuins are attractive drug targets which may be therapeutically beneficial for diseases in which mitochondria are dysfunctional, often observed in diseases of aging. These diseases include metabolic diseases such as Type 2 Diabetes and other mitochondrial disorders. Sirtuin therapeutics offer the potential for a novel class of drugs that can treat significant diseases of aging in a new way.
Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1α acetylation and an increase in PGC-1α activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1−/− MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.
Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α. Cell, Vol 127, 1109-1122, 15 December 2006.
Press release: Sirtis Pharmaceuticals