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积累是否是酵母衰老的唯一原因，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AMP/蛋白激酶A途径的几个突变体表现出延长的寿命。 cAMP/PKA途径控制许多也与衰老有关的细胞过程。 具有减弱的cAMP/PKA活性的酵母细胞表现出增强的应激基因表达和代谢减慢，这种情况可能类似于热量限制。 因此，这条通路可能是影响衰老速度的关键信号通路。 在这方面，研究这种途径如何影响寿命以及是否涉及ERC积累将是非常有趣的。 该提案的总体目标是：1）确定导致cAMP/PKA活性受损的突变体（如cdc 35 -1突变体）寿命延长的遗传和分子途径，以及2）通过遗传筛选长寿突变体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.