Sirtuins, Aging, and Medicine

Abstract

Sirtuins were originally identified as antiaging proteins in model genetic organisms and have emerged as mediators of the beneficial effects of calorie restriction in mammals. The mammalian Sir2 orthologue, SIRT1, is an NAD-dependent deacetylase that is involved in many central pathways governing physiology and stress management. Genetic or pharmacologic activation of SIRT1 can benefit numerous diseases in murine models. Indeed, two different SIRT1-activating compounds are now in a diverse set of phase 1 or phase 2 human trials (ClinicalTrials.gov numbers, NCT00937326, NCT00964340, NCT01014117, NCT01018017, NCT01018628, NCT01262911, NCT01031108, and NCT01154101). Beyond SIRT1, there are six other mammalian sirtuins (SIRT2, 3, 4, 5, 6, and 7), and all may turn out to have therapeutic potential with the use of activators or inhibitors. Among these sirtuins, SIRT3 is extremely interesting, because it appears to suppress one of the contributing causes of aging itself, reactive oxygen species in mitochondria. Indeed, genetic polymorphisms in the SIRT3 promoter have been associated with extreme longevity in an Italian population,89,90 although these studies will have to be replicated in other groups. In conclusion, sirtuins are a unique class of proteins that link protein acetylation to metabolism and exert profound effects on mammalian physiology and diseases of aging. The development of drugs that target sirtuins to treat these diseases is ongoing.