Evolutionarily conserved mechanisms of lifespan regulation

尽管不同物种的最长寿命存在巨大差异，但一些 控制寿命的机制是进化保守的；这一提议的目的是 识别和表征新的延长寿命的机制 进化守恒。这个项目的长期目标是确定基因 调节哺乳动物衰老过程的机制。第一个具体目标 检查在RNAi筛查中发现的四个基因是否延长了寿命。这四个人 除了延长成年寿命外，发育后的基因也不能正常调节 生殖系/胞体细胞类型特异性。这种表型虽然以前没有被描述过，但是 与已知的监管机构共享寿命，并可能有助于提高 寿命长，抗压力能力强。《特殊目的2》利用了一种经典的基因 筛选出影响线虫寿命的三条途径中的新调节因子。 一项初步研究已经确定了22个基因突变，它们调节蠕虫对3个 当功能降低时，不同的途径会增加成年人的寿命。尽管 这些细胞通路的多样性是这些突变体的一个子集，它调节着这三种基因 机制，并可能代表寿命的主要调节因素。映射和 这些地理螺旋突变体的特征将识别线虫的新调控因子 长寿。最后，基因之前在发育后的RNAi中被发现 筛查秀丽线虫的寿命。其中90%以上的基因是 从酵母到人类都保存着。具体目标3将描述这些同源词的特征 在苍蝇和小鼠中，v/hich基因可能揭示了延长寿命的保守机制。 我们将测试哺乳动物直系物拯救Joss功能的能力 蠕虫的表型。在蠕虫中使用GFP记者以及生物信息学和 我们获得的小鼠同源基因的RT-PCR表达分析 这些新颖的寿命调节器发挥作用。使用这些标准，我们将挑选出最好的 保守的长寿调节剂候选人和发育后khoekdown测试 在飞行中，并在小鼠中针对特定的时间/组织破坏。

Despite the vast differences in maximal lifespan across species some of the mechanisms that control lifespan are evolutionary conserved; The aim of this proposal is to identify and characterize novel mechanisms of lifespan extension that display evolutionary conservation. The long-term goal of this project is acertain the genetic mechanisms in place that regulate the aging process in mammals. The first specific aim examines four genes identified in a RNAi screten for increased lifespan. These four genes aside from increasing adult lifespan postdevelopmentally also misregulate the germline/soma cell type specificity. This phenotype although previously undeseribed is shared with known regulators of lifespan and may contribute to both the increased lifespan and enhanced resistance to stress. Specific aim 2 utilizes a classical genetic screen to identify new regulators in three pathways that influence lifespan in C. elegans. A pilot study has identified 22 genetic mutants that regulate the worms response to three distinct pathways which when reduced in function increase mean adult lifespan. Despite the diversity in these cellular pathways a subset of these mutants regulate all three mechanisms, and may represent master regulators of lifespan. Mapping and characterization of these gehelic mutants will identify novel regulators of C. elegans longevity. Finally, 64 genis were previously identified in a post-developmentar RNAi screen for increased lifespan in C. elegans. More than 90% of these genes are conserved from yeast to man. Specific aim 3 will characterize the orthologs of these genes in fly and mouse, v/hich may reveal conserved mechanisms of lifespan extension. We will test the ability of the mammalian orthologs to rescue the joss of function phenotype in the worm. Using GFP reporters in the worm along with bioinformatic and RT-PCR expression analysis of the mouse orthologs we wiN compare the tissues where these novel lifespan regulators function. Using these criteria we will pick our best candidates for conserved longevity regulators and test post-developmental khoekdown in the fly and targeted temporal/tissue specific disruptions in the mouse.