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

PLoS Genet. 2014 Feb 6;10(2):e1004113. doi: 10.1371/journal.pgen.1004113. eCollection 2014 Feb.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases / genetics*
  • 3-Phosphoinositide-Dependent Protein Kinases / metabolism
  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Food
  • Gene Expression Regulation, Fungal
  • Glucose / metabolism
  • Longevity / genetics*
  • Mice
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Serine / metabolism
  • Signal Transduction / genetics*
  • Stress, Physiological / genetics
  • Threonine / metabolism
  • Transcription Factors / genetics
  • Valine / metabolism


  • Saccharomyces cerevisiae Proteins
  • TORC1 protein complex, S cerevisiae
  • Transcription Factors
  • Threonine
  • Serine
  • Protein Kinases
  • Rim15 protein, S cerevisiae
  • SCH9 protein kinase
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PKH1 protein, S cerevisiae
  • Cyclic AMP-Dependent Protein Kinases
  • Valine
  • Glucose