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TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO.

The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR influences life span will identify mechanisms of fundamental importance in aging and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop. Rapamycin triggers a similar protective response in C. elegans and mice, but increases worm life span dependent upon SKN-1 and not DAF-16, apparently by interfering with TORC2 along with TORC1. TORC1, TORC2, and insulin/IGF-1-like signaling regulate SKN-1 activity through different mechanisms. We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity.

Pubmed ID: 22560223


  • Robida-Stubbs S
  • Glover-Cutter K
  • Lamming DW
  • Mizunuma M
  • Narasimhan SD
  • Neumann-Haefelin E
  • Sabatini DM
  • Blackwell TK


Cell metabolism

Publication Data

May 2, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: CA129105
  • Agency: NIA NIH HHS, Id: F32 AG032833
  • Agency: NIGMS NIH HHS, Id: GM62891
  • Agency: NCI NIH HHS, Id: R01 CA129105
  • Agency: NCI NIH HHS, Id: R01 CA129105-04
  • Agency: NCI NIH HHS, Id: R01 CA129105-05
  • Agency: NIGMS NIH HHS, Id: R01 GM062891
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-11
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-12
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-13
  • Agency: NIDDK NIH HHS, Id: T32 DK007260
  • Agency: NIDDK NIH HHS, Id: T32 DK007260-34
  • Agency: NIDDK NIH HHS, Id: T32 DK007260-35

Mesh Terms

  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Insulin-Like Growth Factor I
  • Longevity
  • Male
  • Mice
  • Signal Transduction
  • Sirolimus
  • TOR Serine-Threonine Kinases
  • Trans-Activators
  • Transcription Factors
  • Transcription, Genetic