低氧联合有氧运动激活Sima/dSir2信号通路介导NDA+/NADH平衡稳态的心脏增龄保护作用

适宜刺激可激活机体应激系统产生延寿效应，NAD+为长寿基因dSir2发挥遗传延寿作用所必需，Sima是低氧触发NAD+合成的核心转录调节因子。前期研究发现，缺氧条件下催化NADH生成NAD+的限速酶Ldhal6b具有心脏增龄保护功能，NAD+合成关键酶Nmnat、CG9940在运动延缓心脏功能增龄衰退中发挥重要作用。我们推测，低氧可弥补有氧运动持续时间的局限，有氧运动可加速低氧副产物乳酸清除，两者结合是激活Sima/NAD+/dSir2通路理想应激源。我们前一个基金项目成功解决了对果蝇实施可控运动干预的难题，本项目拟采用转基因技术构建果蝇能量代谢实时表达体系建立低氧联合运动模型，通过研究Sima、dSir2、dFOXO、SOD2基因突变、功能拯救对中老龄果蝇心脏功能的影响，明确低氧联合运动调控Sima/NAD+/dSir2途径的关键基因和下游事件,为心脏抗衰老的科学探索提供新的遗传学证据。

Appropriate stimulus can activate the stress system to produce life-extending effects. NAD+ is necessary for the longevous function of dSir2. Sima is a core transcriptional regulation factor to trigger NAD+ synthesis by hypoxia. Our previous work suggest that Ldhal6b, the rate-limiting enzyme to catalyze NADH produce NAD+ under the condition of hypoxia, possess protection function of heart with age. In addition, as the key enzyme for NAD+ synthesis, Nmnat and CG9940 play an important role in delaying aging recession of cardiac function. We speculate that intermittent hypoxia can compensate limitation of the short lasting-duration of aerobic exercise, meanwhile, aerobic exercise can accelerate eliminating lactic acid, the byproduct from glycolysis. Hypoxia-exercise is ideal stressor for activation of Sima/NAD+/dSir2 signaling pathway. Supported by The National Natural Science Fund, we successfully solve the difficult problem of implementation of controlled exercise intervention on drosophila. This study intends to construct real-time energy metabolism expression system to establish hypoxia combined aerobic exercise Drosophila model using transgenic technology. Apply reverse genetics research strategy of signaling pathway, this research will study the effect of loss-of-function, gain-of-function and function rescue of Sima, dSir2, dFOXO, SOD2 gene on the function of aging heart, and discover the key genes, targets and downstream events of hypoxia and exercise induced activation of Sima/NAD+/dSir2 pathway. This research will be the first study to explore effects and mechanisms of life extension cardioprotection of hypoxia and exercise based on Drosophila model. This project can provide new genetic evidence for earlier scientific exploration for anti-aging methods related to the heart.