氧化应激损害 Nur77-Sirt1 轴，导致衰老过程中机体稳态下降,Aging Cell

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氧化应激损害 Nur77-Sirt1 轴，导致衰老过程中机体稳态下降
Aging Cell ( IF 8.0 ) Pub Date : 2023-03-07 , DOI: 10.1111/acel.13812
Yang Yu _{1,

2} , Xiaoyu Song _{1,

2} , Xiaoxun Wang _{1,

3} , Lixia Zheng ₁ , Guojing Ma ₄ , Weiwei Liu ₁ , Han Su ₁ , Xiyan Liu ₁ , Tingting Liu ₄ , Liu Cao _{1,

2} , Difei Wang ₄

Affiliation

Sirt1 是一种 NAD ⁺依赖性脱乙酰酶，可防止过早衰老和细胞衰老。伴随氧化应激的衰老会导致 Sirt1 水平和活性下降，但连接这些事件的调节机制仍不清楚。在此，我们报道了与 Sirt1 具有相似生物学途径的 Nur77，其在多个器官中也随着年龄的增长而减少。我们的体内和体外结果表明，Nur77 和 Sirt1 在衰老和氧化应激诱导的细胞衰老过程中减少。Nr4a1的缺失会缩短小鼠多种组织的寿命并加速衰老过程。Nr4a1过度表达通过 E3 连接酶 MDM2 的负转录调节，保护 Sirt1 蛋白免遭蛋白酶体降解。我们的研究结果表明，Nur77 缺陷显着加重衰老相关肾病，并阐明了 Nur77 在肾脏衰老过程中稳定 Sirt1 稳态的关键作用。我们提出了一个模型，其中响应氧化应激而减少 Nur77 会通过 MDM2 促进 Sirt1 蛋白降解，从而引发细胞衰老。这会产生额外的氧化应激，并通过进一步降低 Nur77 表达为过早衰老提供正反馈。我们的研究结果揭示了衰老过程中氧化应激减少 Sirt1 表达的机制，并为针对衰老和生物体内稳态提供了一种有吸引力的治疗策略。

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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.

更新日期：2023-03-07

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