Are sirtuins viable targets for improving healthspan and lifespan?

Abstract

Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known to retard ageing and delay functional decline as well as the onset of disease in most organisms. Studies have implicated the sirtuins (SIRT1-SIRT7) as mediators of key effects of caloric restriction during ageing. Two unrelated molecules that have been shown to increase SIRT1 activity in some settings, resveratrol and SRT1720, are excellent protectors against metabolic stress in mammals, making SIRT1 a potentially appealing target for therapeutic interventions. This Review covers the current status and controversies surrounding the potential of sirtuins as novel pharmacological targets, with a focus on SIRT1.

Figure 1. Pleiotropic effects of SIRT1 on age-related diseases

Sirtuin 1 (SIRT1) is a crucial mediator of the physiological adaptive responses to energy availability. Activation of SIRT1 has beneficial effects in several age-related diseases, particularly those associated with metabolic dysregulation. Here, we illustrate the pleiotropy of SIRT1, including just four of the SIRT1 targets and/or regulatory proteins that have been reported to be associated with each particular disease or condition. BMAL1, brain and muscle ARNT-like 1; E2F1, E2F transcription factor 1; eNOS, endothelial nitric oxide synthase; FOXO, forkhead box protein O; HIF1α, hypoxia-inducible factor 1α; KU70, DNA repair factor KU70; LKB1, liver kinase B1; MYOD, myoblast determination protein; NF-κB, nuclear factor-κB; p53, tumour suppressor p53; PARP1, poly(ADP-ribose) polymerase 1; PER2, period circadian protein homolog 2; PGC1α, PPARγ co-activator 1α; RARβ, retinoic acid receptor-β; RUNX2, runt-related transcription factor 2; SOST, sclerostin; SREBP, sterol regulatory element-binding protein; STAT3, signal transducer and activator of transcription 3; UCP2, uncoupling protein 2.