Activating AMPK or inactivating calcineurin slows ageing in Caenorhabditis elegans1,2 and both have been implicated as therapeutic targets for age-related pathology in mammals3,4,5. However, the direct targets that mediate their effects on longevity remain unclear. In mammals, CREB-regulated transcriptional coactivators (CRTCs)6 are a family of cofactors involved in diverse physiological processes including energy homeostasis7,8,9, cancer10 and endoplasmic reticulum stress11. 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.
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Gene Expression Omnibus
Data have been deposited at GEO under accession number GSE25513.
W.M. is funded by the George E. Hewitt Foundation for Medical Research, the American Federation for Aging Research and the Glenn Foundation for Medical Research. R.J.S. is funded by National Institutes of Health (NIH) R01 DK080425 and P01 CA120964. A.P.C.R. and G.M. are funded by NIH R01 HG004164, AG031097 and CA14195. A.D. is supported by NIH R01 DK070696 and AG027463. We thank the Caenorhabditis Genetics Center, the National Bioresource Project for the Nematode and Mark Alkema for providing worm strains. We are grateful to M. Raices and M. D’Angelo for critical analysis of the manuscript, DAPI images and the NUP-160::GFP construct. We also thank members of the A.D. laboratory and M. Hansen for comments on the manuscript and discussion and K. Butler for technical assistance in the early stages of this project.
This table displays differentially expressed genes in each of the three mutants relative to wild-type. Each row correponds to a probeset, so a gene may appear in multiple rows. Also, reported are GO functional categories associated with each gene and CRE and TATA motifs identified upstream of each gene, the notation used follows the key: Hit Score | Palindromic | Hit Position | Hit Location in Genome | Distance to TSS | Conservation in other Caernohabditis.
This table displays survival data and statistics for life span experiments.
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