Characterization of genes isolated in a novel screen for mutants with altered mitotic lifespan in yeast

几个世纪以来，为什么所有的生物体都会衰老一直是一个最有趣的问题。使用简单的模型系统，如苍蝇，蠕虫和酵母，单个保守基因已经被确定，极大地影响细胞和整个动物的寿命。单细胞和多细胞生物的健康状况是衡量细胞维持寿命的能力。每个细胞经历一系列的分裂，直到达到分化或衰老状态。

INTRODUCTION: Why all living organisms age has been a most intriguing question for centuries. Using simple model systems, such as flies, worms, and yeast, single conserved genes have been identified that greatly impact cellular and whole animal lifespan. The health of single cell and multicellular organisms is a measure of cellular capacity to maintain lifespan. Every cell undergoes a series of divisions until a differentiated or senescent state is reached. RECENT PROGRESS: We have designed and implemented the first genome-wide screen for yeast mutants that experience an altered number of cell divisions prior to senescence. The screen yielded 48 mutants with increased lifespan and 87 with reduced lifespan. Many of the identified mutants define cellular processes that have not been previously linked with regulating lifespan, and implicate genes involved in protein trafficking and iron transport. OBJECTIVES: This proposal will focus on testing our central hypotheses that i) protein trafficking is an integral determinant of cellular lifespan in yeast, and ii) that impaired iron uptake and cellular transport results in premature aging in yeast. METHODS: The lifespan phenotypes of mutants identified in the screen will be confirmed using the replicative lifespan assay (RLS). The initial characterization will involve a genetic analysis of interactions to work out functional pathways. Characterizing genetic interactions and potential epistasis is utilized for placement of factors within hierarchical pathways, an approach that we have extensively relied on in the past. The synchrotron at the Canadian Light Source (CLS) will be employed in studies aimed at determining whether free iron accumulates in the mutants and to characterize the iron species that normally accumulate with age. IMPACT: The genes we have identified in yeast are also found in humans, suggesting that our findings in yeast will allow new avenues of research to be explored in aging studies in higher eukaryotic systems.