Sirtuins — novel therapeutic targets to treat age-associated diseases

Key Points Sirtuins (SIRTs) are NAD-dependent deacetylases that have a central role in regulating the cellular proteins and their physiological pathways. Interest in therapeutically targeting this class of enzymes is gaining momentum as more data on their function is becoming available. SIRT1 activators have the potential to mimic many aspects of calorie restriction as the levels of the protein seem to be responsive to such a regimen, and studies in lower organisms show that SIRT1 levels and activity are enhanced under conditions of calorie restriction. Efficacy with potent small-molecule activators of SIRT1 is observed in preclinical models of metabolic, neurodegenerative and inflammatory diseases. The strategy of activation holds promise for drug discovery efforts in multiple therapeutic areas. Evidence of therapeutic value comes from the disease area of type 2 diabetes, in which the field is currently most focused. Currently, clinical trials are being conducted with novel small-molecule SIRT1 activators in a mitochondrial disease, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and in type 2 diabetes. There is a need for new type 2 diabetes treatments that are not associated with weight gain or cardiovascular risk, and SIRT1 activators are emerging as a promising alternative to existing therapeutics.