Sestrins in Aging and Metabolism

During the 5th Else Kroner-Fresenius Symposium, new data were presented on the role of sestrins (Sesns) in regulating metabolism and therefore the development of aging-related pathologies. Sesns are a highly conserved gene family among eukaryotes. There are three Sesns (Sesn1, Sesn2 and Sesn3) in mammals but one ortholog in Drosophila. Sesns are regulated by many stress insults including DNA damage, oxidative stress, hypoxia, growth factor deprivation, hyperactive TOR and RAS signaling via p53 and FOXOs, and result in enhanced autophagy, reactive oxygen species reduction, reduced protein synthesis, reduced anabolism, and reduced cell growth. These Sesn-dependent effects are conserved in Drosophila and in mammalian cells. Sesns are inhibitors of TOR signaling. Nutritional abundance leads to TORC1 activation, thus enhancing biosynthesis of protein and lipid through p70S6K and SREBP, and inhibiting autophagy through ULK1. Continuous activation of TOR is associated with various pathologies, including obesity-associated diseases, declined cardiac function, and cancer. (C) 2014 S. Karger AG, Basel