Sirtuin Activation by Small Molecules

Abstract

In recent decades our understanding of the biological process of ageing has reached a level where delaying aging with genetic interventions and small molecules seems like a scientifically reasonable goal. This is supported by discovery of genes and small molecules that can extend lifespan in model organisms such as yeast, worms, flies and mice (Baur et al. 2006; Harrison et al. 2009; Howitz et al. 2003; Wood et al. 2004). The mammalian sirtuins are a class of NAD⁺-dependent deacylases that promote health and lifespan via pathways that overlap with those modulated by exercise and calorie restriction. In recent years, sirtuin activating compounds (STACs) and NAD+ precursors have been the centre stage of research to constitute therapeutic targets to combat age-related diseases. Studies have emerged that suggest a common allosteric mechanism of SIRT1 activation. Two of the synthetic STACs, SIRT1720 and SIRT2104, have now been reported to extend lifespan in mice fed a standard diet (Mercken et al, 2014; Mitchell et al, 2014) making SIRT1 an attractive target for therapeutic interventions for a variety of age related diseases. This review will address recent progress, controversies and challenges surrounding small molecule activators of sirtuins.