Inositol signaling in C. elegans Senescence and Diapause

项目摘要摘要： 在过去的20年里，胰岛素样/daf-2信号通路已经从全基因组的rNAi中出现。 在线虫中是最有效的寿命调节器；它是哺乳动物中一个重要的衰老轴，如 井。我们对寿命调节过程的全基因组筛查也揭示了第二等级的 长寿调节监控细胞的核心成分，例如核糖体，如果检测到缺陷， 夫妇的免疫和长寿控制的内分泌系统与胰岛素样途径不同。 事实上，排毒途径也与小鼠的寿命调节有关。具有非凡的能力 雷帕霉素延长小鼠的寿命很可能是基于其参与这一过程的能力 监控/长寿控制系统。真核生物生活在微生物丰富的环境中，并不断地 受到微生物攻击的挑战。在过去的资助周期中，我们大大扩展了我们对 线虫--我们相信这最终将被证明适用于所有真核生物--是如何监测其 核心细胞成分，尤其是在这笔赠款中，核糖体，用于攻击并发出此类攻击的信号 先天免疫和解毒反应以及对长寿计划的反应。我们最初被吸引到 这些实验通过我们对长寿的调节工作和我们发现核心的基因失活 细胞过程，如翻译，可能会延长寿命。这笔赠款的主要活动 建议是测试我们分离的许多突变体是否不适当地激活了 戒毒途径或不能激活这些途径会对寿命和措施产生影响 动物的衰老。长寿控制与解毒和免疫的结合提供了令人满意的 解释为什么人类女性比男性长寿：我们假设女性有更高的寿命 解毒穴位，保护发育中的脆弱胎儿。这些相同途径的变异将揭示 人类如何对药物或细菌病原体做出适当和不适当的反应，或激活药物 在没有触发药物的情况下的解毒途径，可能会诱导一种虚假的内分泌状态 下毒了。我们提出的研究微生物菌群如何试图颠覆这些途径的建议也将揭示 微生物组的变化如何可能导致人类寿命的变化。

Project Summary Abstract: During the last 20 years, the insulin-like/daf-2 signaling pathway has emerged from genome-wide RNAi screens as the most potent regulator of lifespan in C. elegans; it is a significant aging axis in mammals as well. Our full genome screens for lifespan regulatory processes have also revealed that the second rank of longevity regulation surveils core components of cells, for example, the ribosome, and if deficits are detected, couples to an endocrine system of immunity and longevity control that is distinct from the insulin-like pathway. In fact, detoxification pathways are coupled to lifespan regulation in mice as well. The remarkable ability of rapamycin to extend the lifespan of mice is likely to be based on its ability to engage this surveillance/longevity control system. Eukaryotes live in microbe-rich environments and are continuously challenged by microbial attacks. In the past grant cycle we have greatly expanded our genetic analysis of how C. elegans, and we believe that eventually this will be shown to apply across all eukaryotes, surveils its core cellular components, most especially in this grant, the ribosome, for attacks and signals such attacks to innate immune and detoxification responses as well as to longevity programs. We were initially drawn to these experiments by our work on regulation of longevity and our finding that gene inactivations of core cellular processes such as translation potently induce increased longevity. The major activity of this grant proposal is to test whether the many mutants we have isolated which either inappropriately activate detoxification pathways or fail to activate such pathways have consequences on the lifespan and measures of aging of the animal. The coupling of longevity control to detoxification and immunity provides a satisfying explanation for why human females live longer than males: we hypothesize that females have a higher set point for detoxification to protect the fragile developing fetus. Variation in these same pathways will reveal how humans respond appropriately and inappropriately to drugs or bacterial pathogens, or activate drug detoxification pathways in the absence of a triggering drug, perhaps inducing a false endocrine state of poisoning. Our proposal to study how the microbial flora attempt to subvert these pathways will also reveal how variation in the microbiome may underlie variation in human longevity.