High-Resolution Profiling of Stationary-Phase Survival Reveals Yeast Longevity Factors and Their Genetic Interactions

Lifespan is influenced by a large number of conserved proteins and gene-regulatory pathways. here,we introduce a strategy for systematically finding such longevity factors in saccharomyces cerevisiae and scoring the genetic interactions (epistasis) among these factors. specifically,we developed an automated competition-based assay for chronological lifespan,defined as stationary-phase survival of yeast populations,and used it to phenotype over 5,600 single- or double-gene knockouts at unprecedented quantitative resolution. we found that 14% of the viable yeast mutant strains were affected in their stationary-phase survival; the extent of true-positive chronological lifespan factors was estimated by accounting for the effects of culture aeration and adaptive regrowth. we show that lifespan extension by dietary restriction depends on the swr1 histone-exchange complex and that a functional link between autophagy and the lipid-homeostasis factor arv1 has an impact on cellular lifespan. importantly,we describe the first genetic interaction network based on aging phenotypes,which successfully recapitulated the core-autophagy machinery and confirmed a role of the human tumor suppressor pten homologue in yeast lifespan and phosphatidylinositol phosphate metabolism. our quantitative analysis of longevity factors and their genetic interactions provides insights into the gene-network interactions of aging cells. © 2014 garay et al.