当前衰老研究主要集中在动物寿命调控方面，已经发现上百个基因可以延长动物寿命。衰老也伴随着动物行为和认知的退化，调控寿命和行为退化的分子机制并不完全相同。然而有关动物行为能力随衰老下降的分子神经机制还不是特别清楚。通过全基因组RNAi筛选方法，初步发现组蛋白甲基化酶SET-6及表观遗传调控相关蛋白FLT-1对五羟色胺和多巴胺功能具有调控作用，RNAi下调或敲除set-6和flt-1基因可提高老年线虫五羟色胺和多巴胺功能，进而延缓一些重要行为的退化。本项目将利用遗传学和行为学方法研究set-6和flt-1基因如何影响老年线虫五羟色胺和多巴胺功能，进而调控动物行为退化过程；结合生物化学、分子生物学和生物信息学方法进一步探讨set-6和flt-1调控老年线虫五羟色胺和多巴胺功能的内在机制。研究结果将有利于深入理解衰老过程中动物行为退化的分子神经机制，为提高老年人口的的健康和生活质量提供新的线索。

Much of the current aging studies in model organisms focus on the regulation of animal lifespan. More than one hundred genes have been identified to regulate the lifespan of many animals from C. elegans to vertebrates. Aging is also associated with behavioral and cognitive decline. The underlying mechanism of age-dependent behavioral deterioration does not fully overlap with that of lifespan regulation, and it remains largely unknown. By a genome-wide RNAi screening, we preliminarily revealed that set-6 and flt-1 genes could regulate serotonin and dopamine function in aging animals. SET-6 encodes a putative histone H3 lysine-9 methyltransferase and FLT-1 contains DNA-binding domains which presumably mediate epigenetic regulation. Both downregulation by RNAi and deletion of set-6 or flt-1 gene elevated neuronal level of serotonin and dopamine in late adulthood stage of the animal, and hence delayed age-related deterioration of some important behaviors. In this project, by combining biochemistry, molecular biology, genetics, behavioral analysis and bioinformational method, we will study the role of set-6 and flt-1 in regulating serotonin/dopamine function and behavioral deterioration in aging C. elegans. Results of this study will help to understand the molecular and neuronal basis of behavioral deterioration during aging, and provide useful cues to improve quality of life of the elderly and to delay onset of age-related diseases.