Mechanisms of Longevity Regulation in Yeast

描述(由申请人提供)：Sch9和RAS/cAMP信号转导通路的突变，促进了对葡萄糖/营养的反应的繁殖，激活了多种抗逆系统，并将未分裂酵母的寿命延长了三倍。Sch9与线虫、果蝇和哺乳动物的丝氨酸/苏氨酸激酶Akt/PKB同源，后者也在葡萄糖/营养条件下被激活，并在调节生殖和长寿的途径中发挥作用。我认为，在从酵母到哺乳动物的各种生物中，通过将生长和繁殖的能量投资转移到多个抗逆系统，类似的信号转导通路的调节可以提高对损伤的抵抗力，并延长寿命。这些机制可能是在进化的早期出现的，以便在饥饿期间最大限度地减少衰老。为了验证这一假说，我建议：1)阐明酵母Ras/cAMP和Sch9途径调节寿命的分子机制，重点关注已知的应激抗性基因和高等真核生物中在IGF-1/Ins信号通路中起作用的基因的酵母同源基因；2)进行无偏见筛选并研究以前筛选出的未鉴定的抗逆突变，以确定介导Ras/cAMP/MSN2/4和Sch9下游长寿调节的新基因；3)进一步表征野生型和长寿突变体中的后二位基因寿命，以了解酵母衰老与高等真核生物中衰老的关系4)确定不同的机制来调节“时序寿命”(不分裂酵母的存活)和“复制寿命”(萌芽潜力)。结合短，高代谢后的寿命和转座子突变提供了一种快速的方法来鉴定逆境抗性和延长寿命的介体。这些突变的识别和特征将有助于识别和理解哺乳动物中可能处于休眠状态的饥饿反应途径，这些途径可能被激活，以保护细胞免受衰老和与年龄相关的疾病的影响，而不影响正常功能。

DESCRIPTION (provided by applicant): Mutations in the Sch9 and Ras/cAMP signal transduction pathways, which promote reproduction in response to glucose/nutrients, activate multiple stress resistance systems and extend the life span of non-dividing yeast by up to three-fold. Sch9 is homologous to the C. elegans, Drosophila, and mammalian serine/threonine kinases Akt/PKB, which are also activated in response to glucose/nutrients and function in pathways that regulate reproduction and longevity. I propose that the modulation of analogous signal transduction pathways can increase resistance to damage and extend longevity in organisms ranging from yeast to mammals by shifting the investment of energy from growth and reproduction to multiple stress resistance systems. These mechanisms may have arisen early during evolution in order to minimize aging during periods of starvation. To test this hypothesis I propose to: 1) elucidate the molecular mechanisms responsible for the regulation of longevity by the yeast Ras/cAMP and Sch9 pathways, focusing on known stress resistance genes and on yeast homologs of genes that function in the IGF-1/insulin signaling pathway in higher eukaryotes, 2) perform unbiased screens and study uncharacterized stress resistant mutants isolated in previous screens to identify novel genes that mediate longevity-regulation downstream of Ras/cAMP/Msn2/4 and Sch9, 3) characterize further the post-diauxic life span in wild type and long-lived mutants to understand the relationship between aging in yeast and in higher eukaryotes, 4) identify the distinct mechanisms that regulate the "chronological life span" (survival of non-dividing yeast) and "replicative life span" (budding potential). The combination of the short, high-metabolism post-diauxic life span with transposon mutagenesis provides a rapid method to identify the mediators of stress resistance and longevity extension. The identification and characterization of these mutations should contribute to the identification and understanding of putative dormant starvation-response pathways in mammals, which may be activated to protect cells against aging and age-related diseases without affecting normal functions.