TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxO

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• 作者：Stacey Robida-Stubbs¹ ; Kira Glover-Cutter¹ ; Dudley  ; W. Lamming² ; ³ ; ⁴ ; Masaki Mizunuma¹ ; ⁵ ; Sri  ; Devi Narasimhan¹ ; Elke Neumann-Haefelin¹ ; ⁶ ; David  ; M. Sabatini² ; ³ ; ⁴ ; T.  ; Keith Blackwell¹ ; ^{keith.blackwell@joslin.harvard.edu}
• 刊名：Cell Metabolism
• 出版年：2012
• 期刊代码：46_15504131
• 类别：med
• 出版时间：2 May, 2012
• 卷：15
• 期：5
• 页码：713-724
• 文件大小：1910 K

摘要

| Figures/TablesFigures/Tables | ReferencesReferences<h3 class="h3">Summaryh3>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.聽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聽a feedback loop. Rapamycin triggers a similar protective response in C.聽elegans and mice, but increases worm life span dependent upon SKN-1 and not DAF-16, apparently by interfering with TORC2 along聽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聽vivo and聽that these transcription factors mediate an opposing relationship between growth signals and longevity.