Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB
Language: 
English
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.

Author(s): 
Mair, William
Morantte, Ianessa
Rodrigues, Ana P. C.
Manning, Gerard
Montminy, Marc
Shaw, Reuben J.
Dillin, Andrew
Item Type: 
Journal Article
Publication Title: 
Nature
Journal Abbreviation: 
Nature
Publication Date: 
2/17/2011
Publication Year: 
2011
Pages: 
404-408
Volume: 
470
Issue: 
7334
ISSN: 
1476-4687
DOI: 
10.1038/nature09706
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 21331044 PMCID: PMC3098900

Turabian/Chicago Citation

William Mair, Ianessa Morantte, Ana P. C. Rodrigues, Gerard Manning, Marc Montminy, Reuben J. Shaw and Andrew Dillin. 2/17/2011. "Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB." Nature 470: 7334: 404-408. 10.1038/nature09706.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1038/nature09706 | issn = 1476-4687 | volume = 470 | pages = 404-408 | last = Mair | first = William | coauthors = Morantte, Ianessa, Rodrigues, Ana P. C., Manning, Gerard, Montminy, Marc, Shaw, Reuben J., Dillin, Andrew | title = Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB | journal = Nature | date = 2/17/2011 | pmid = | pmc = }} </ref>