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

Stacey Robida-Stubbs1, Kira Glover-Cutter, Dudley W Lamming

  • 1Joslin Diabetes Center, Harvard Stem Cell Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.

Cell Metabolism
|May 8, 2012
PubMed

Insights

Inhibiting TORC1 in C. elegans activates protective genes via SKN-1/Nrf and DAF-16/FoxO, increasing stress resistance and longevity. Rapamycin extends worm lifespan by impacting TORC1 and TORC2, mediated by SKN-1.

Area of Science:

  • Molecular Biology
  • Gerontology
  • Genetics

Background:

  • The Target of Rapamycin (TOR) kinase, existing as TORC1 and TORC2 complexes, is crucial for cellular growth.
  • TOR signaling is implicated in aging and various diseases, making its role in lifespan regulation a key research area.

Purpose of the Study:

  • To investigate how TOR kinase signaling influences lifespan and stress resistance in C. elegans.
  • To elucidate the roles of transcription factors SKN-1/Nrf and DAF-16/FoxO in mediating TOR's effects on longevity.

Main Methods:

  • Genetic inhibition of TORC1 in Caenorhabditis elegans.
  • Analysis of gene expression changes, stress resistance, and lifespan.
  • Treatment with rapamycin in C. elegans and mice.

Main Results:

  • Genetic inhibition of TORC1 activates SKN-1/Nrf and DAF-16/FoxO, upregulating protective genes and enhancing stress resistance and longevity.
  • SKN-1 exhibits a feedback loop, increasing TORC1 pathway gene expression.
  • Rapamycin treatment in C. elegans and mice induces protective responses; in worms, lifespan extension is dependent on SKN-1 and involves TORC1 and TORC2 inhibition.

Conclusions:

  • Modulation of SKN-1/Nrf and DAF-16/FoxO transcription factors is critical for the impact of TOR signaling on lifespan in vivo.
  • These transcription factors mediate an antagonistic relationship between growth signals regulated by TOR and longevity.

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