Genome-Wide Mechanisms of Lifespan Extension by Dietary Restriction in Yeast

Dietary restriction is arguably the most promising non-pharmacological intervention to extend human life and health span. Yet, only few genetic regulators mediating the cellular response to dietary restriction are known, and the question remains which other transcription factors and regulatory pathways are involved. To gain a comprehensive view of how lifespan extension under dietary restriction is elicited, we compared the chronological lifespan of most gene deletions of the budding yeast Saccharomyces cerevisiae between restricted and non-restricted conditions. We identified 472 mutants with enhanced or diminished extension of lifespan relative to the WT. Functional analyses of such DR-genes revealed novel processes underlying lifespan extension specifically by dietary restriction. Importantly, our set of DR-genes allowed us to generate a prioritized catalogue of transcription factors, underscoring the relevance of cell-cycle control as a mechanism of chronological-lifespan extension in yeast. In particular, we show that the transcription factor Ste12 is needed for full lifespan extension and cell-cycle arrest in response to nutrient limitation, linking the pheromone-response pathway with cell survivorship. Our global picture of the genetic players of lifespan extension by dietary restriction highlights intricate regulatory cross-talks in aging cells.