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

被引：503

作者：

Robida-Stubbs, Stacey ^{[1
,2
]}

Glover-Cutter, Kira ^{[1
,2
]}

Lamming, Dudley W. ^{[3
,4
,5
,6
]}

Mizunuma, Masaki ^{[1
,2
,7
]}

Narasimhan, Sri Devi ^{[1
,2
]}

Neumann-Haefelin, Elke ^{[1
,2
,8
]}

Sabatini, David M. ^{[3
,4
,5
,6
]}

Blackwell, T. Keith ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Joslin Diabet Ctr, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA

[3] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[4] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA

[5] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[6] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[7] Hiroshima Univ, Grad Sch Adv Sci Matter, Dept Mol Biotechnol, Higashihiroshima 7398530, Japan

[8] Univ Hosp Freiburg, Renal Div, D-79106 Freiburg, Germany

来源：

CELL METABOLISM | 2012年 / 15卷 / 05期

关键词：

LIFE-SPAN EXTENSION; RESTRICTION-INDUCED LONGEVITY; CAENORHABDITIS-ELEGANS; INHIBITION; STRESS; GROWTH; AUTOPHAGY; PATHWAY; MTORC2; GENES;

D O I：

10.1016/j.cmet.2012.04.007

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：713 / 724

页数：12

共 55 条

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