TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxO
Name
Robida-Stubbs-2012-TOR Signaling and Ra.pdf
Size
1.87 MB
Format
Adobe PDF
Checksum (MD5)
2013ae7116c3aeb708fde80e33ec3f27
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
Date Issued
May 2012
Journal
Cell Metabolism
Publisher
Elsevier
Citation
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.
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.cmet.2012.04.007
