MECHANISMS OF AGING IN SACCHAROMYCES CEREVISIAE

染色体外rDNA环(ERC)的积累已被证明是酵母老化的原因。为了确定ERC积累是否是酵母老化的唯一原因，并了解更多关于ERC如何导致衰老的信息，我们着手鉴定长寿突变体，并揭示它们延长寿命的机制。在一项初步研究中，我们发现环状AMP/蛋白激酶A途径的几个突变体显示出更长的寿命。CAMP/PKA通路控制着许多细胞过程，这些过程也与衰老有关。CAMP/PKA活性减弱的酵母细胞表现出应激基因表达增强和新陈代谢减慢，这种情况可能类似于热量限制。因此，这一途径可能是影响衰老速度的关键信号途径。在这方面，研究这一途径如何影响寿命，以及它是否涉及ERC积累，将是非常有趣的。这项建议的总体目标是：1)确定cAMP/PKA活性受损的突变体(如cdc35-1突变体)延长寿命的遗传和分子途径；2)通过对长寿突变体的遗传筛选，进一步研究衰老的分子途径。

Extrachromosomal rDNA circle (ERC) accumulation has been shown to be a cause of yeast aging. To determine whether ERC accumulation is the only cause of yeast aging, and to learn more about how ERC lead to aging, we set out to identify long-lived mutants and to reveal the mechanisms by which they extend longevity. In a pilot study, we found that several mutants of the cyclic AMP/protein kinase A pathway exhibited prolonged life spans. The cAMP/PKA pathway controls many cellular processes that have also been implicated in aging. Yeast cells with attenuated cAMP/PKA activity exhibit enhanced stress gene expression and a slowing of metabolism, a condition that may be similar to caloric restriction. Thus, this pathway may serve as the key signaling pathway that affects the rate of aging. In this regard, it will be very interesting to study how this pathway affects life spans and whether it involves ERC accumulation. The overall goals of this proposal are: 1) To determine the genetic and molecular pathways leading to prolonged life spans in mutants with compromised cAMP/PKA activity such as the cdc35-1 mutant, and 2) to further study the molecular pathways of aging by a genetic screen for long-lived mutants.