(a) Kaplan-Meier survival curves of mice fed a standard diet (SD) or a high-fat diet (HFD) supplemented with SRT1720 at either a low (HFD-L) or high (HFD-H) dose. Mean and maximum lifespan in weeks and the hazard ratio for mortality are represented below. In the parentheses the increases in maximum lifespan from birth and then diet onset are given. (b) Body weights of the groups over time, with average caloric intake over the course of the feeding study in the inset. Below are images of representative mice to illustrate phenotypic body mass of the groups at 82 weeks of age. (c) SRT1720 maintained normal liver appearance and reduced the onset of fatty liver as depicted by images of whole livers harvested after 12 weeks on diets and subsequent oil red O staining. Quantification of steatosis was performed by a blinded pathologist on livers from 82 week-old mice (26 weeks on diets; n = 6)
The drug, SRT-1720, protects the mice from the usual diseases of obesity by reducing the amount of fat in the liver and increasing sensitivity to insulin. These and other positive health effects enable the obese mice to live 44 percent longer, on average, than obese mice that did not receive the drug, according to a team of researchers led by Rafael de Cabo, a gerontologist at the National Institute on Aging. Despite the positive new results with SRT-1720, Sirtris is not putting it into clinical trials because the company believes another of its resveratrol mimics, SRT-2104, is more promising. That drug “is more suitable for human consumption,” said Dr. Sinclair, a co-author of Dr. de Cabo’s report.
Sirt1 is an NAD+-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals.
The current study shows that SRT1720, a member of a class of drugs that are in vitro Sirt1-activators, has a number of long-term benefits in mice that include shifting physiological parameters in mice consuming a high-fat diet towards those consuming a standard diet, modulating gene expression pathways associated with longevity, and improving overall health. These effects led to improvements in a variety of measures including survival, motor function, insulin sensitivity, organ pathology, and metabolic activity. With regards to energy metabolism, SRT1720 improved insulin sensitivity, maintained liver and pancreatic function, and prevented several metabolic changes associated with a high-fat diet. At the molecular level, SRT1720 reversed the gene expression profile induced by the high-fat diet with regards to markers of inflammation, apoptosis and oxidative stress. In vivo, SRT1720 promoted the deacetylation of hepatic PGC-1α, a known Sirt1 target that regulates mitochondrial biogenesis, stress resistance and survival35. In vitro, SRT1720-driven increases in cell survival and mitochondrial respiration were also Sirt1-dependent. While both mean and maximum lifespans were significantly extended in the mice, mean lifespan extension through reduction of premature death and increased healthspan was the most overt benefit of SRT1720 treatment. This is in agreement with a recent report where transgenic mice overexpressing Sirt1 displayed increased glucose tolerance and reduced susceptibility to induced tumors but not increased survival when fed a standard diet36. In the case of our mice, which were subjected to metabolic stress by the high fat diet, SRT1720 was able to dramatically shift the lifespan curves towards a more rectangular shape by acting to prevent premature death.
Our results continue to support the beneficial pharmacological effect of SRT1720 in models of metabolic disease despite a recent report by Pacholec and colleagues to the contrary where the authors report 100 mg/kg SRT1720 is not tolerable and increases mortality in mice and that the compound does not elicit beneficial effects in the Lepob/ob mouse model of diabetes. This conclusion is inconsistent with not only our findings but also several additional studies where SRT1720 has been reported to exert positive effects in multiple models of metabolic disease including Lepob/ob mice11, diet-induced obese mice MSG-induced hypothalamic obese mice15 and Zucker fa/fa rats. Pacholec and colleagues did report that fasting insulin levels are reduced by SRT1720 administration, which is in agreement with our findings and with data reported previously in diet-induced obese mice11. The putative toxicity of SRT1720 administered at a 100 mg/kg oral dose to 8 mice over 18 days is inconsistent with a study where the compound exhibited no toxicity at a 5-fold higher dose for 15 weeks nor is it consistent with our long-term feeding study involving over 100 mice consuming an equivalent daily dose. In fact, our mice showed increased survival and improvement in multiple physiological parameters in response to SRT1720 treatment and did not display overt signs of toxicity even after more than 80 weeks of treatment.