RRC ID 46646
著者 Mair W, Morantte I, Rodrigues AP, Manning G, Montminy M, Shaw RJ, Dillin A.
タイトル Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB.
ジャーナル Nature
Abstract Activating AMPK or inactivating calcineurin slows ageing in Caenorhabditis elegans and both have been implicated as therapeutic targets for age-related pathology in mammals. However, the direct targets that mediate their effects on longevity remain unclear. In mammals, CREB-regulated transcriptional coactivators (CRTCs) are a family of cofactors involved in diverse physiological processes including energy homeostasis, cancer and endoplasmic reticulum stress. Here we show that both AMPK and calcineurin modulate longevity exclusively through post-translational modification of CRTC-1, the sole C. elegans CRTC. We demonstrate that CRTC-1 is a direct AMPK target, and interacts with the CREB homologue-1 (CRH-1) transcription factor in vivo. The pro-longevity effects of activating AMPK or deactivating calcineurin decrease CRTC-1 and CRH-1 activity and induce transcriptional responses similar to those of CRH-1 null worms. Downregulation of crtc-1 increases lifespan in a crh-1-dependent manner and directly reducing crh-1 expression increases longevity, substantiating a role for CRTCs and CREB in ageing. Together, these findings indicate a novel role for CRTCs and CREB in determining lifespan downstream of AMPK and calcineurin, and illustrate the molecular mechanisms by which an evolutionarily conserved pathway responds to low energy to increase longevity.
巻・号 470(7334)
ページ 404-8
公開日 2011-2-17
DOI 10.1038/nature09706
PII nature09706
PMID 21331044
PMC PMC3098900
MeSH AMP-Activated Protein Kinases / metabolism* Aging / metabolism Aging / physiology Animals Caenorhabditis elegans / enzymology Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans / physiology* Caenorhabditis elegans Proteins / biosynthesis Caenorhabditis elegans Proteins / chemistry Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Calcineurin / metabolism* Calcineurin Inhibitors Cyclic AMP Response Element-Binding Protein / biosynthesis Cyclic AMP Response Element-Binding Protein / metabolism* Down-Regulation Energy Metabolism Enzyme Activation Gene Knockdown Techniques HEK293 Cells Humans Longevity / genetics Longevity / physiology* Phosphorylation Protein Serine-Threonine Kinases / metabolism Trans-Activators / chemistry Trans-Activators / deficiency Trans-Activators / genetics Trans-Activators / metabolism* Transcription Factors / biosynthesis Transcription Factors / metabolism* Transcription, Genetic
IF 42.779
引用数 213
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
線虫 tm1944