A conserved mechanism of sirtuin signalling through steroid hormone receptors.

Abstract

SIRT1 and orthologous sirtuins regulate a universal mechanism of ageing and thus determine lifespan across taxa; however, the precise mechanism remains vexingly polemical. They also protect against many metabolic and ageing-related diseases by dynamically integrating several processes including autophagy, proteostasis, calorie restriction, circadian rhythmicity and metabolism. These sirtuins are therefore important drug targets particularly because they also transduce allosteric signals from sirtuin-activating compounds such as resveratrol into increased healthspan in evolutionarily diverse organisms. While many of these functions are apparently regulated by deacetylation, that mechanism may not be all-encompassing. Since gonadal signals have been shown to regulate ageing/lifespan in worms and flies, the present study hypothesized that these sirtuins may act as intermediary factors for steroid hormone signal transduction. Accordingly, SIRT1 and its orthologues, Sir2 and Sir-2.1, are shown to be veritable nuclear receptor coregulators that classically coactivate the oestrogen receptor in the absence of ligand; coactivation was further increased by 17β-oestradiol. Remarkably in response to the worm steroid hormone dafachronic acid, SIRT1 reciprocally coactivates DAF-12, the steroid receptor that regulates nematode lifespan. These results suggest that steroid hormones may co-opt and modulate a phyletically conserved mechanism of sirtuin signalling through steroid receptors. Hence, it is interesting to speculate that certain sirtuin functions including prolongevity and metabolic regulation may be mechanistically linked to this endocrine signalling pathway; this may also have implications for understanding the determinative role of gonadal steroids such as oestradiol in human ageing. At its simplest, this report shows evidence for a hitherto unknown deacetylation-independent mechanism of sirtuin signalling.