个体与组织器官的衰老存在内在联系，但参与个体衰老的基因如何影响组织器官的衰老尚不清楚。我们通过对百岁老人的全基因组关联分析、外显子测序以及血管内皮细胞不同衰老模型的转录组测序已发现171个候选基因与个体及血管内皮细胞衰老相关。本项目拟在通过功能组学研究确定调节个体和血管衰老进程的关键信号通路。研究内容包括：1）在内皮细胞复制型衰老模型中通过siRNA逐一敲低这些候选基因，确定调控内皮细胞衰老的基因（功能基因）；2）确定这些功能基因调控内皮细胞衰老的信号通路；3）在确定的信号通路中，选择关键的结点分子，建立小鼠模型，研究它们影响个体和血管衰老的机制；4）利用建立小鼠模型，探讨干预上述重要信号通路探讨干预个体与血管衰老以及衰老相关血管疾病（如动脉粥样硬化）的可能性。通过本研究，我们可以筛选出调节个体和血管衰老进程的关键信号通路，对通过延缓衰老改善衰老相关的血管病变有重要意义。

Organismal and tissue or organ aging has intrinsic relationship, however, how the genes associated with organismal aging modulate the functions of tissues and organs remains unclear. Previously we have carried out genome-wide association study and exome sequencing on Chinese centenarians and transcriptome sequencing of various endothelial cell senescent models. These had led to the identification of 171 candidate genes that are associated with centenarians and endothelial cell senescence. In this proposed study we aim at understanding the critical signaling pathways contributing to organismal aging and endothelial cell senescence. For this purpose, we 1) identify the genes from 171 candidates that functionally contribute to endothelial cell senescence by siRNA knockdown, 2) define the signaling pathways formed by identified genes from 1), 3) identify the key nodes that contribute to endothelial cell senescence by over-expression and siRNA-mediated knockdown, and 4) generate engineered mouse models using the key genes found from 3) to investigate how the age-related disease such as atherosclerosis can be slowed down by modulating aging-associated genes. Through these studies, we can possibly define the critical signaling pathway that contribute to organismal and vascular aging, which has clinical implications in prevention of vascular diseases.