The race to control aging and diseases: Sir2/SirT1 against Ras, TOR and Akt/S6K

Abstract

In Saccharomyces cerevisiae, the glucose/nutrient signalling Ras2 and Tor/Sch9 signal transduction pathways promote growth, reduce stress resistance and block entry into a survival mode that can cause an up to 10-fold lifespan extension. The down-regulation of similar pathways activated by the insulin/IGF (insulin-like growth factor)-1-like growth factors extends the lifespan of nematode worms up to 10-fold and, when combined with calorie restriction, doubles that of mice. This lifespan extension is mediated by the activation of transcription factors that regulate metabolic pathways as well as stress-resistance proteins such as antioxidant enzymes. Another family of enzymes whose activation is widely implicated in the regulation of aging is the Sir2/ SirT1 (sirtuin) deacetylase family. Although their overexpression/activation has modest lifespan extension effects in lower eukaryotes and does not appear to extend the lifespan of mice, their central role in the regulation of glucose and fat metabolism and of many other systems makes sirtuin-activating drugs candidates for the treatment and prevention of several diseases. Here I briefly review and compare the effect of sirtuins and glucose/growth factor signalling pathways in the regulation of stress resistance and aging.