Ammonium-dependent shortening of CLS in yeast cells starved for essential amino acids is determined by the specific amino acid deprived, through different signaling pathways.

Ammonium (NH4(+)) leads to chronological life span (CLS) shortening in Saccharomyces cerevisiae BY4742 cells, particularly evident in cells starved for auxotrophy-complementing amino acids (leucine, lysine, and histidine) simultaneously. Here, we report that the effect of NH4(+) on aging yeast depends on the specific amino acid they are deprived of. Compared with no amino acid starvation, starvation for leucine alone or in combination with histidine resulted in the most pronounced NH4(+)-induced CLS shortening, whereas starvation for lysine, alone or in combination with histidine resulted in the least sensitivity to NH4(+). We also show that NH4(+)-induced CLS shortening is mainly mediated by Tor1p in cells starved for leucine or histidine but by Ras2p in cells starved for lysine, and in nonstarved cells. Sch9p protected cells from the effect of NH4(+) under all conditions tested (starved or nonstarved cells), which was associated with Sch9p-dependent Hog1p phosphorylation. Our data show that NH4(+) toxicity can be modulated through manipulation of the specific essential amino acid supplied to cells and of the conserved Ras2p, Tor1p, and Sch9p regulators, thus providing new clues to the development of environmental interventions for CLS extension and to the identification of new therapeutic targets for diseases associated with hyperammonemia.