进化中高度保守的胰岛素类生长因子信号和雷帕霉素靶蛋白通路对衰老有重要的调节功能。对于这些信号通路在代谢器官中的作用有大量研究，然而神经系统作为既能感受环境变化又对机体生理活动起主导作用的组织是如何影响衰老的分子机制尚不明确。mRNA可变剪接作为一种转录后调控，对神经元的发育与功能至关重要。申请人在前期研究中发现，敲除秀丽线虫调控mRNA可变剪接的关键因子UNC-75不仅显著的延长寿命，而且能够改善健康衰老表型，其抗衰老机制与已知的信号通路作用方式不同。本研究拟通过基因组学手段，分析unc-75突变体中在mRNA可变剪接以及转录水平有明显变化的基因调控衰老的分子机制。在此基础上，进一步研究UNC-75调控衰老的神经生物学基础，并阐明神经元如何与代谢、生殖组织相互作用从而影响衰老。本申请的实施将阐明神经系统中mRNA可变剪接调控衰老的分子机制，对于代谢、生殖、衰老及相关疾病的研究有广泛的意义。

Aging can be modulated by genetic and environmental factors. Recent studies in the basic biology of aging indicated that the highly conserved insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) pathway play an important role in aging. Previous studies on these pathways have been focusing on their functions in metabolic tissues. Despite the key regulatory functions of the nervous system in major physiological activities, its roles in the modulation of aging remain unclear especially at the molecular level. It has been well documented that mRNA alternative splicing plays important roles in neuronal development and plasticity. Therefore, we set out to characterize whether and how neuronal mRNA alternative splicing modulates aging in C. elegans. Our preliminary results show that knock-out mutants of UNC-75/CELF, a conserved key regulator of neuronal mRNA alternative splicing, significantly extends life span and improves health span. Genetic analysis demonstrates that the unc-75 KO mutant functions through novel mechanisms to delay aging. We propose to perform functional genomics studies to identify genes that are regulated at the mRNA alternative splicing or transcriptional level by UNC-75, and determine their molecular roles in aging. Furthermore, we will characterize the neuronal regulatory basis of aging mediated by UNC-75, as well as the communications among neuronal, reproductive and metabolic tissues. The completion of this project would provide mechanistic insights on the neuronal modulation of aging, which will be of broad interests to the fields of metabolism, reproduction, aging and age-related diseases.