Serine- and threonine/valine-dependent activation of PDK and Tor orthologs converge on Sch9 to promote aging.

Author Summary Calorie restriction (CR), but also the restriction of specific components of the diet, has been known for decades to affect longevity. However, the understanding of how each component of the macronutrients affects longevity and stress resistance is poorly understood, in part because of the complexity of many of the model organisms studied. Here we studied how each amino acid and glucose cooperate to activate cell sensitizing pathways and promote aging. We identified specific amino acids in the diet that affect cellular protection and aging, describe how different pathways mediate these pro-aging effects, describe the effect of glucose and specific amino acids on the levels/activity of stress resistance kinases and transcription factors, and identify specific nutrient depletions capable of increasing longevity and stress resistance. Because of the conserved pro-aging role of orthologs of many of the genes in the signaling network described in this paper, these results are likely to serve as a foundation for the elucidation of similar nutrient-dependent pro-aging mechanisms in mammals. Dietary restriction extends longevity in organisms ranging from bacteria to mice and protects primates from a variety of diseases, but the contribution of each dietary component to aging is poorly understood. Here we demonstrate that glucose and specific amino acids promote stress sensitization and aging through the differential activation of the Ras/cAMP/PKA, PKH1/2 and Tor/S6K pathways. Whereas glucose sensitized cells through a Ras-dependent mechanism, threonine and valine promoted cellular sensitization and aging primarily by activating the Tor/S6K pathway and serine promoted sensitization via PDK1 orthologs Pkh1/2. Serine, threonine and valine activated a signaling network in which Sch9 integrates TORC1 and Pkh signaling via phosphorylation of threonines 570 and 737 and promoted intracellular relocalization and transcriptional inhibition of the stress resistance protein kinase Rim15. Because of the conserved pro-aging role of nutrient and growth signaling pathways in higher eukaryotes, these results raise the possibility that similar mechanisms contribute to aging in mammals.