本课题假设，编码线粒体Complex I(CI)的核(nDNA)和线粒体(mtDNA)基因变异对人类寿命延长均有影响。前期研究发现mtDNA编码CI基因变异影响人类寿命，然而nDNA编码的CI基因变异与寿命有关否仍未知。为从整体上检验CI变异延缓衰老的机制，拟应用pool外显子测序，系统发生和生物信息学分析识别长寿个体的CI 变异基因，并结合MitoCarta数据库进行功能预测；通过检测和比较长寿、当地自然衰老和当地中年代谢综合征个体的nDNA和mtDNA编码CI基因的变异，及其血清相应代谢指标水平，获得CI基因变异与长寿关联的生理和生化证据。在离体细胞层面考察CI(ND5)变异功能相关的关键靶点分子对衰老过程的保护作用。从细胞衰老及代谢退行性变的机制实验回到人体水平以阐述其作用机理，明确CI变异机制对延长寿命作用的贡献，及其与机体代谢水平的关系。有望为老年疾病防治提供新的思路和靶点。

The application hypothesis is that varies of mitochondrial Complex I (CI) encoded by nuclear (nDNA) and mitochondria (mtDNA) DNA would affect the human longevity. Our previous study have find-out the mtDNA coding CI gene (ND5) variant associated with human long-life, but nDNA encoding CI gene variants associated with life is still unknown. To test the hypothesis of mechanism of anti-aging for overall CI, we intend to use the pool exons sequencing, phylogenic tree, and bioinformatics analysis to identify the CI gene mutations associted with longevity, combining MitoCarta function prediction database; through testing and comparising CI gene mutations of nDNA and mtDNA among longevity, local natural age-group control and local middle-aged individuals with the metabolic syndrome populations, as well as their corresponding serum metabolism index levels, to access to CI physiological and biochemical evidences of genetic variants associated with longevity, determine CI variation impact on human life extension and its relationship with the body metabolism. From integrated CI level, we will explores these functional changes of CI-ND5 variation related to the key molecule targets in the process of ageing protection. Cellular mechanisms from cell biology experimental levels will give us a resonable explain on the mechanism occuring in human body, in order to describe the story of contribution to long-life elderly caused by CI mutations, the research is expected also to provide age-related diseases prevention and control of new ideas and relevant molecule targets.