Abstract
The study of the chronological life span of Saccharomyces cerevisiae, which measures the survival of populations of non-dividing yeast, has resulted in the identification of homologous genes and pathways that promote aging in organisms ranging from yeast to mammals. Using a competitive genome-wide approach, we performed a screen of a complete set of approximately 4,800 viable deletion mutants to identify genes that either increase or decrease chronological life span. Half of the putative short-/long-lived mutants retested from the primary screen were confirmed, demonstrating the utility of our approach. Deletion of genes involved in vacuolar protein sorting, autophagy, and mitochondrial function shortened life span, confirming that respiration and degradation processes are essential for long-term survival. Among the genes whose deletion significantly extended life span are ACB1, CKA2, and TRM9, implicated in fatty acid transport and biosynthesis, cell signaling, and tRNA methylation, respectively. Deletion of these genes conferred heat-shock resistance, supporting the link between life span extension and cellular protection observed in several model organisms. The high degree of conservation of these novel yeast longevity determinants in other species raises the possibility that their role in senescence might be conserved.
Highlights
Yeast, worms, and flies have been studied extensively to identify the genetic determinants of aging
Because yeast are amenable to genetics and genomics studies, they have been used widely as model system for aging research
We have exploited a powerful genomic tool, the yeast deletion collection, to screen a pool of non-essential deletion mutants (,4,800) to identify novel genes involved in the regulation of yeast chronological life span
Summary
Worms, and flies have been studied extensively to identify the genetic determinants of aging Studies conducted in these model organisms have demonstrated a partially conserved life span regulatory role for the nutrient-sensing/insulin/IGF-I-like pathways, which are found in species ranging from yeast to mice [1,2]. Reducing the activity of Sch or Cyr and that of the nutrient-sensing pathways they participate in (TOR/Sch and Ras/Cyr1/PKA), CLS is extended by up to 3-fold, with a concomitant increase in resistance to cellular stress [8]. Consistent with this observation, inactivation of the G-protein Ras, which promotes Cyr function, extends CLS [11]. Mice lacking adenylate cyclase 5 (AC5) have been reported to be long-lived and fibroblasts derived from these mice have been shown to be resistant to oxidative stress, consistently with previous
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