Influence of genotype and nutrition on survival and metabolism of starving yeast

Starvation of yeast cultures limited by auxotrophic requirements results in glucose wasting and failure to achieve prompt cell-cycle arrest when compared with starvation for basic natural nutrients like phosphate or sulfate. We measured the survival of yeast auxotrophs upon starvation for different nutrients and found substantial differences: When deprived of leucine or uracil, viability declined exponentially with a half-life of <2 days, whereas when the same strains were deprived of phosphate or sulfate, the half-life was approximate to 10 days. The survival rates of nongrowing auxotrophs deprived of uracil or leucine depended on the carbon source available during starvation, but were independent of the carbon source during prior growth. We performed an enrichment procedure for mutants that suppress lethality during auxotrophy starvation. We repeatedly found loss-of-function mutations in a number of functionally related genes. Mutations in PPM1, which methylates protein phosphatase 2A, and target of rapamycin (TOR1) were characterized further. Deletion of PPM1 almost completely suppressed the rapid lethality and substantially suppressed glucose wasting during starvation for leucine or uracil. Suppression by a deletion of TOR1 was less complete. We suggest that, similar to the Warburg effect observed in tumor cells, starving yeast auxotrophs wastes glucose as a consequence of the failure of conserved growth control pathways. Furthermore, we suggest that our results on condition-dependent chronological lifespan have important implications for the interpretation and design of studies on chronological aging.