Evolutionarily conserved mechanisms of lifespan regulation

尽管不同物种的最长寿命存在巨大差异， 控制寿命的机制是进化保守的;这项建议的目的是 识别和表征寿命延长的新机制， 进化保守这个项目的长期目标是确定 调节哺乳动物衰老过程的机制。第一个具体目标 研究了在RNAi筛选中鉴定的四个基因，以增加寿命。这四 除了增加成年人的寿命外，发育后的基因也会错误调节 生殖系/索马细胞类型特异性。这种表型虽然以前未被发现， 与已知的寿命调节器共享，并可能有助于增加 寿命和增强的抗压力能力。具体目标2利用经典的遗传 筛选以识别影响C寿命的三种途径中的新调节因子。优雅 一项初步研究已经确定了22种基因突变体，这些突变体调节蠕虫对三种 不同的途径，当功能减少时，平均成年寿命会增加。尽管 这些细胞通路的多样性，这些突变体的子集调节所有三个 机制，并可能代表寿命的主调节器。映射和 对这些gehelic突变体的表征将鉴定新的C. elegans 中心blog最后，先前在发育后RNAi中鉴定了64个基因， 筛选C.优雅超过90%的基因是 具体目标3将表征这些同源物的直系同源物， 果蝇和小鼠的基因，这可能揭示了寿命延长的保守机制。 我们将测试哺乳动物直系同源基因拯救功能之神的能力 蠕虫的表型。在蠕虫中使用GFP报告基因，沿着生物信息学和 小鼠直系同源物的RT-PCR表达分析，我们将比较 这些新的寿命调节剂起作用。根据这些标准， 保存的长寿调节剂和测试后发育的候选人 和小鼠中的靶向时间/组织特异性破坏。

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.