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Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB

Nature volume 470, pages 404–408 (2011)Cite this article

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Abstract

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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Figure 1: CRTC-1 regulates longevity.
Figure 2: CRTC-1 is a target of AAK-2 and TAX-6.
Figure 3: Calcineurin and AMPK regulate lifespan through phosphorylation of CRTC-1.
Figure 4: CREB activity regulates lifespan.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Data have been deposited at GEO under accession number GSE25513.

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Acknowledgements

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.

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Authors and Affiliations

  1. The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    William Mair, Ianessa Morantte, Ana P. C. Rodrigues, Gerard Manning, Marc Montminy, Reuben J. Shaw & Andrew Dillin

  2. Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    William Mair, Ianessa Morantte, Reuben J. Shaw & Andrew Dillin

  3. The Glenn Foundation for Medical Research, The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    William Mair, Ianessa Morantte, Marc Montminy, Reuben J. Shaw & Andrew Dillin

  4. Razavi Newman Center for Bioinformatics, The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Ana P. C. Rodrigues & Gerard Manning

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Contributions

W.M., I.M., M.M., R.J.S. and A.D. designed the experiments. W.M. and I.M. performed the experiments. A.P.C.R analysed the microarray data and performed the promoter analysis and W.M. analysed and performed statistical analysis on all other data. The manuscript was written by W.M. and edited by I.M., A.P.C.R., G.M., R.J.S. and A.D. All authors discussed the results and commented on the manuscript.

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Correspondence to Reuben J. Shaw or Andrew Dillin.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-15 with legends and Supplementary Tables 3 and 4 (see Separate files for Supplementary Tables 1, 2 and 5). (PDF 14949 kb)

Supplementary Table 1

This table displays normalized expression measurements for all probesets. (PDF 24514 kb)

Supplementary Table 2

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. (XLS 2318 kb)

Supplementary Table 5

This table displays survival data and statistics for life span experiments. (XLS 16 kb)

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Mair, W., Morantte, I., Rodrigues, A. et al. Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470, 404–408 (2011). https://doi.org/10.1038/nature09706

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