Mechanisms of Longevity Regulation in Yeast

描述（由申请人提供）：Sch 9和Ras/cAMP信号转导途径中的突变，其促进响应葡萄糖/营养素的繁殖，激活多种应激抗性系统，并将非分裂酵母的寿命延长多达三倍。Sch 9与C.线虫、果蝇和哺乳动物的丝氨酸/苏氨酸激酶Akt/PKB，其也响应于葡萄糖/营养物而被激活，并在调节生殖和寿命的途径中起作用。我建议，类似的信号转导途径的调制可以增加抗损伤和延长寿命的生物体，从酵母到哺乳动物的能源投资从生长和繁殖的多个抗应激系统。这些机制可能在进化的早期就出现了，以便在饥饿期间尽量减少衰老。为了验证这个假设，我建议：1）阐明负责通过酵母Ras/cAMP和Sch 9途径调节寿命的分子机制，重点是已知的应激抗性基因和在高等真核生物中在IGF-1/胰岛素信号传导途径中起作用的基因的酵母同源物，2）进行无偏筛选并研究在先前筛选中分离的未表征的抗胁迫突变体，以鉴定介导寿命的新基因，Ras/cAMP/Msn 2/4和Sch 9下游的调节，3）进一步表征野生型和长寿突变体中的二次发育后寿命以理解酵母和高等真核生物中衰老之间的关系，4）确定调节“时间寿命”的独特机制（非分裂酵母的存活）和“复制寿命”（出芽潜力）。转座子诱变与短、高代谢的二次发育后寿命相结合，提供了一种快速鉴定抗逆和长寿介质的方法。这些突变的鉴定和表征应该有助于鉴定和理解哺乳动物中假定的休眠饥饿反应途径，这些途径可能被激活以保护细胞免受衰老和年龄相关疾病的影响，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.