饮食限制作为一种环境干扰手段能够显著的延长寿命并延缓衰老相关疾病的发生。然而饮食限制抗衰老的分子机理，特别是脂类代谢在这个过程中起了什么作用，是衰老研究领域中的关键但尚未解决的问题。在前期工作中，我们利用秀丽线虫为模式进行了遗传学筛选，并发现敲降高度保守的ACS-20脂酰辅酶A合成酶能够完全的抑制由于饮食限制所造成的寿命延长。进一步的研究发现ACS-20在幼虫的发育过程中作用于上皮组织调控衰老。为了更加深入的探索饮食限制延缓衰老的分子机理，我们拟通过转录组分析，识别在饮食限制条件下转录水平受ACS-20影响的下游基因，并分析这些基因如何影响衰老和代谢。我们还将通过分子遗传学手段，阐述调控ACS-20表达时空特异性的机理。本申请的实施将有助于从分子水平阐明饮食限制如何通过影响代谢从而延缓衰老，对于发育、代谢、衰老及相关疾病的研究有着广泛的意义。

Dietary restriction (DR) is one of the most robust environmental manipulations that not only extends life span but also delay age-related pathologies in various species. Previous studies suggest that the insulin-like growth factor-1 (IGF-1) and mechanistic target of rapamycin (mTOR) pathways are likely to be involved in modulating nutrients-regulated aging, but the molecular mechanisms of DR remain largely unknown, especially from the lipid metabolism aspect. Based on a hypothesis-driven RNAi screen, we have identified ACS-20, a highly conserved acyl CoA synthetase, as an essential mediator of life span extension by DR in C. elegans. Further studies indicated that ACS-20 functions in the epidermis during larval development to modulate aging, which is consistent with its spatiotemporal expression patterns. In order to better understand the molecular mechanisms of DR, we propose to identify genes that are differentially expressed under DR conditions in an ACS-20-dependent manner via transcriptome profiling. Further characterization of the roles of these ACS-20 downstream genes in the nutrients-regulated aging process as well as the molecular regulation of ACS-20 expression will help to gain mechanic insights on DR responses, which will be of broad interests to researchers in the fields of development, metabolism, aging and age-related diseases.