Oxidative stress impairs the Nur77-Sirt1 axis resulting in a decline in organism homeostasis during aging

Sirt1 is an NAD(+)-dependent deacetylase that protects against premature aging and cell senescence. Aging accompanied by oxidative stress leads to a decrease in Sirt1 levels and activity, but the regulatory mechanism that connects these events remains unclear. Here, we reported that Nur77, which shares similar biological pathways with Sirt1, was also decreased with age in multiple organs. Our in vivo and in vitro results revealed that Nur77 and Sirt1 decreased during aging and oxidative stress-induced cell senescence. Deletion of Nr4a1 shortened the lifespan and accelerated the aging process in multiple mouse tissues. Overexpression of Nr4a1 protected the Sirt1 protein from proteasomal degradation through negative transcriptional regulation of the E3 ligase MDM2. Our results showed that Nur77 deficiency markedly aggravated aging-related nephropathy and elucidated a key role for Nur77 in the stabilization of Sirt1 homeostasis during renal aging. We proposed a model wherein a reduction of Nur77 in response to oxidative stress promotes Sirt1 protein degradation through MDM2, which triggers cell senescence. This creates additional oxidative stress and provides positive feedback for premature aging by further decreasing Nur77 expression. Our findings reveal the mechanism by which oxidative stress reduces Sirt1 expression during aging and offers an attractive therapeutic strategy for targeting aging and homeostasis in organisms.