TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxO
Author(s)Robida-Stubbs, Stacey; Glover-Cutter, Kira; Lamming, Dudley W.; Mizunuma, Masaki; Narasimhan, Sri Devi; Neumann-Haefelin, Elke; Sabatini, David M.; Blackwell, T. Keith; Lamming, Dudley W.; Sabatini, David M.; ... Show more Show less
MetadataShow full item record
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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
Robida-Stubbs, Stacey, Kira Glover-Cutter, Dudley W. Lamming, Masaki Mizunuma, Sri Devi Narasimhan, Elke Neumann-Haefelin, David M. Sabatini, and T. Keith Blackwell. “TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxO.” Cell Metabolism 15, no. 5 (May 2012): 713–724. © 2012 Elsevier Inc.
Final published version