目前人们对于长寿的生物学机制有了较为深入的认识，但寿命与健康寿命的调控机制不尽相同。和寿命调控研究相比，有关衰老过程中行为和认知退化的调控机制研究还比较少。本项目将利用秀丽隐杆线虫动物模型，在全基因组水平上通过RNAi筛选调控神经系统衰老的基因，并构建这些基因之间的相互作用网络；利用大脑基因表达数据库分析该网络中关键节点基因baz-2人类同源基因BAZ2B和衰老及阿尔兹海默氏症病情之间的关联；构建Baz2b敲除和过表达小鼠，分析该基因是否调控行为退化和认知衰老，并探讨相应机制；构建以BAZ2B为靶点的药物筛选系统，寻找通过干预BAZ2B功能预防大脑衰老的方法。本项目充分利用秀丽隐杆线虫、小鼠和大脑基因表达数据库在衰老研究中的各自优势，又使之互相补充，用多方法，从多层次上研究认知衰老的调控机制，推动衰老研究和神经科学交叉。本项目的顺利实施将提出新的衰老调控途径，为延缓衰老提供新的理论依据。

Over past decades, great progresses have been achieved in understanding the regulation of longevity. However, recent studies have demonstrated that lifespan and healthspan could be separated, suggesting that their regulatory mechanisms are different. Compared with aging research on longevity, there are few studies on functional aging and the regulatory mechanism underlying age-related loss of physiological functions remains largely elusive. In this proposal, we will perform genome-wide RNAi screening for genes that regulate aging of the nervous system, and construct a gene network of screening hits; we will analyze correlations between the expression level of BAZ2B, a human homologue of the key node gene baz-2 in the gene network, and brain aging or the progression of Alzheimer's disease by analyzing published datasets on the gene expression profile in human brains; we will construct Baz2b KO and over-expression mice to study whether this gene regulates age-related behavioral and cognitive decline and its underlying mechanism; We will establish assays for screening drugs against BAZ2B to find compounds that prevent age-related behavioral and cognitive decline. In this proposal, we will take advantage of C. elegans/mouse animal models and published datasets on gene expression in human brains, and use multiple methods to study the mechanism underlying age-related behavioral and cognitive decline. Results of this study will help to promote the interdisciplinary research of aging and neuroscience, to discover novel regulatory mechanism of aging of the nervous system, and to provide useful cues for improving quality of life of the elderly and for preventing onset of age-related diseases.