SIRT6 Overexpression Extends Mean Lifespan in Male Mice

Some more data to add to the muddy waters of sirtuin research: "Since the discovery that overexpression of yeast Sir2 deacetylase extends lifespan by as much as 30% over a decade ago, much effort has been invested in researching whether this effect is conserved in higher organisms as well. Indeed, in worms and flies, two separate groups found that SIR2 extended lifespan as well, by 50% and 18%, respectively. ... In parallel to the work in worms and flies, researchers were trying to make headway in the role of sirtuins in higher organisms. There are seven mammalian homologs to the yeast Sir2, SIRT1-SIRT7. SIRT1 is the most well-researched and has been shown to regulate metabolism and age-related diseases. However, SIRT1 overexpression did not increase lifespan, although this was said to be due to the relatively weak expression of the transgene. Therefore, a role for sirtuins in regulating lifespan of mammals looked bleak. Despite the controversy surrounding sirtuins and longevity, there has never been any doubt that mammalian sirtuins are important regulators of health and disease. Previous results from our lab have shown SIRT6 to be involved in the calorie restriction response, and demonstrate that SIRT6 overexpression in mice protects against diet-induced obesity and its metabolic consequences. These results, along with data that SIRT6 knockout mice display a premature aging-like phenotype, prompted us to turn towards SIRT6 as a potential regulator of mammalian aging. Over the course of three years, we measured the lifespan of mice overexpressing exogenous SIRT6 (MOSES). This study was performed in two separate lines from distinct founders, to ensure that the random integration of the transgene into the genome did not influence the results. We found that the gene insertion in both lines did not disrupt any neighboring genes, and results were similar in both lines. In this way we overcame the issue of site-specific integration, which was previously shown to be a problem in sirtuin studies. Additionally, we chose to work with a mixed background, to ensure no strain-specific effects. Strikingly, both male MOSES lines had significant mean and median lifespan extension, of 14.5% and 9.9%. Even more interesting, there was no lifespan extension in either female lines examined, attesting to a gender-specific role for SIRT6."