title: TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO.
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.
authors.affiliation: Joslin Diabetes Center, Harvard Stem Cell Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Robida-Stubbs
authors.forename: Kira
authors.initials: K
authors.lastname: Glover-Cutter
authors.forename: Dudley W
authors.initials: DW
authors.lastname: Lamming
authors.forename: Masaki
authors.initials: M
authors.lastname: Mizunuma
authors.forename: Sri Devi
authors.initials: SD
authors.lastname: Narasimhan
authors.forename: Elke
authors.initials: E
authors.lastname: Neumann-Haefelin
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.forename: T Keith
authors.initials: TK
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D029742:Caenorhabditis elegans Proteins; C519509:Crtc1 protein, mouse; C504923:Crtc2 protein, mouse; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C073702:skn-1 protein, C elegans; D007334:Insulin-Like Growth Factor I; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus