线粒体质量和活性的减退是导致衰老以及衰老相关疾病的一个重要原因。因此，改善线粒体的活性与健康将是延缓机体衰老的有效手段。我们的前期研究发现营养应激能够促使SUMO特异性蛋白酶1（SENP1）发生磷酸化修饰，从而进入线粒体对去乙酰化酶Sirt3去SUMO化修饰，激活Sirt3靶蛋白活性，改善线粒体的活性与健康。进一步，我们构建了Sirt3 SUMO修饰位点突变(Sirt3 K223R)的小鼠来模拟这一生理过程，我们发现Sirt3 K223R小鼠能够显著延缓衰老，改善固有免疫，减少炎症因子的分泌。基于此，本研究重点聚焦于：（1）明确激活SENP1-Sirt3轴能够改善固有免疫抵抗衰老；（2）明确SENP1-Sirt3轴改善机体固有免疫的分子机制；（3）筛选激活SENP1-Sirt3轴延缓衰老的小分子化合物。我们期望通过本项研究阐明SENP1-Sirt3轴调控线粒体延缓衰老的机制和方法。

A decline on mitochondrial health is an important reason of aging and age-related diseases, so the improvement of the mitochondria health and metabolism will be one of the effective ways to extend lifespan. Our previous studies found that nutrition stress could promote the SUMO-specific protease 1 (SENP1) phosphorylation, then phosphorylated SENP1 de-SUMOylated the NAD+-dependent de-acetylase Sirt3 in mitochondrial matrix, and activated the activity of Sirt3 target proteins to improve the mitochondrial health. Based on our studies, we constructed Sirt3 SUMOylation deficiency (Sirt3 K223R) mice to mimic this physiological process. In our further study, Sirt3 K223R mice were found to significantly extend the lifespan, improve innate immunity, and reduce the secretion of inflammatory factors. Therefore, we proposed that activation of SENP1-Sirt3 improved the mitochondrial health to extend lifespan. The project will aim: (1) to definite the roles of SENP1-Sirt3 axis on the age-dependent innate immunity; (2) to clarify the molecular mechanism of SENP1-Sirt3 axis to extend lifespan; (3) to screen the small molecular compounds for SENP1-Sirt3 axis activation, mitochondrial health improvement and lifespan extension. This study is expected to clarify the mechanism and method of SENP1-Sirt3 axis on regulating mitochondrial health to extend lifespan.