TOR/rapamycin extend lifespan by engaging SKN-1/Nrf and DAF-16/FoxO transcriptional programs.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | C. elegans |
| Journal | Cell metabolism |
| Year | 2012 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.cmet.2012.04.007 · PMID 22560223 · Free full text (PMC3348514) |
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.
| Intervention | Genetic + rapamycin (TORC1 inhibition) |
| Target | TORC1 / SKN-1(Nrf) / DAF-16(FoxO) |
| Model | C. elegans |
| Effect | TORC1 inhibition extends lifespan by activating SKN-1/Nrf and DAF-16/FoxO protective programs |