Genome-Wide Screen in Saccharomyces cerevisiae Identifies Vacuolar Protein Sorting, Autophagy, Biosynthetic, and tRNA Methylation Genes Involved in Life Span Regulation

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.

Author Summary

Model organisms have been instrumental in uncovering genes that function to control life span and to identify the molecular pathways whose role in aging is conserved between the evolutionarily distant unicellular yeast and mice. Because yeast are particularly amenable to genetics and genomics studies, they have been used widely as model system for aging research. Here 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. Our results show that normal life span depends on functional mitochondria and on the cell's ability to degrade cellular components and proteins by autophagy. Our data indicate that a cell signaling protein, CK2, and diverse cellular processes such as fatty acid metabolism, amino acid biosynthesis, and tRNA modification modulate yeast chronological aging. The high level of conservation of the novel life span regulatory genes uncovered in this study suggests that their role in longevity regulation might be conserved in higher eukaryotes.