Oxidative stress impairs the Nur77-SIRT1 axis resulting in a decline in organism homeostasis during aging

Abstract

Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that protects against premature aging and cellular senescence. Aging that is accompanied by oxidative stress leads to a decrease in SIRT1 level and activity, but the regulatory mechanism that connects these events has remained unclear. Here we report that Nur77, an orphan nuclear receptor that shares similar biological pathways with SIRT1, also decreases with age in multiple organs. Our in vivo and in vitro studies revealed that Nur77 and SIRT1 decrease during aging and oxidative stress-induced cellular senescence. Deletion of Nur77 shortens lifespan and accelerates the aging process in multiple mouse tissues. Overexpression of Nur77 protects SIRT1 protein from proteasome degradation through negative transcriptional regulation of the E3 ligase murine double minute 2 (MDM2). Our results show that Nur77 deficiency remarkably aggravates aging related nephropathy, and elucidate a key role for Nur77 in the stabilization of SIRT1 homeostasis during renal aging. We propose a model wherein reduction of Nur77 upon oxidative stress promotes SIRT1 protein degradation through MDM2, which triggers cellular senescence. This creates additional oxidative stress and provides positive feedback for premature aging by further decreasing Nur77 expression. Our findings reveal the mechanism of oxidative stress-reduced SIRT1 during aging and offer an attractive therapeutic strategy for targeting aging organism homeostasis.