Letter | Published:

Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

Nature volume 541, pages 102106 (05 January 2017) | Download Citation

  • A Corrigendum to this article was published on 12 July 2017

Abstract

Ageing is driven by a loss of transcriptional and protein homeostasis1,2,3 and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction associated with age therefore have the potential to reduce overall disease risk in the elderly. Precursor mRNA (pre-mRNA) splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to several age-related chronic illnesses4,5. However, the role of splicing homeostasis in healthy ageing remains unclear. Here we demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also demonstrate that overexpression of SFA-1 is sufficient to extend lifespan. Together, these data demonstrate a role for RNA splicing homeostasis in dietary restriction longevity and suggest that modulation of specific spliceosome components may prolong healthy ageing.

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Acknowledgements

C.H. is supported by the Swiss National Science Foundation (P2ZHP3_151609) and the Fonds National de la Recherche Luxembourg (AFR7883116). W.B.M. is funded by The Lawrence Ellison Medical Foundation (U54CA155626), The Glenn Foundation for Medical Research and the National Institutes of Health (NIH, 1R01AG044346). C.E. is supported by the Ligue Nationale contre le Cancer. G.H.B and T.K.D. were supported through a grant to B.S.A. from The Novo Nordisk Foundation (NNF13OC0007939). We are grateful to H. Kuroyanagi for providing the splicing reporter strain and corresponding plasmids. We thank K. Blackwell for providing the glp-4 mutant strain and RNAi constructs. We also thank the Caenorhabditis Genetics Center for providing worm strains. We also thank the Mair laboratory members for comments and discussion on the project and manuscript.

Author information

Author notes

    • Ianessa Morantte

    Present address: Laboratory of Neurophysiology and Behavior, The Rockefeller University, New York City, New York 10065, USA.

    • Thomas K. Doktor
    •  & Anne Lanjuin

    These authors contributed equally to this work.

Affiliations

  1. Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA

    • Caroline Heintz
    • , Anne Lanjuin
    • , Caroline C. Escoubas
    • , Yue Zhang
    • , Heather J. Weir
    • , Sneha Dutta
    • , Carlos Giovanni Silva-García
    • , Ianessa Morantte
    • , Gerta Hoxhaj
    • , Brendan D. Manning
    •  & William B. Mair
  2. Department of Biochemistry and Molecular Biology, and Villum Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark

    • Thomas K. Doktor
    • , Gitte H. Bruun
    •  & Brage S. Andresen
  3. Institute for Research on Cancer and Aging, Nice (IRCAN), CNRS, UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Faculty of Medicine, 06107 Nice, France

    • Caroline C. Escoubas

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Contributions

C.H. and W.B.M. designed the study, C.H. performed the majority of the experiments and analysed results, A.L. performed experiments and edited the manuscript. T.K.D. analysed all the RNA-seq data. C.C.E., C.G.S.-G. and S.D. performed lifespan repeats and C. elegans sample collections, I.M. helped with cloning and crosses. H.J.W. performed the oxygen consumption experiments. G.H.B. and B.S.A. designed and performed the HeLa cells experiments including the sequencing run. Y.Z., G.H. and B.D.M. designed and performed the MEF and C. elegans immunoblotting experiments. C.H. and W.B.M. wrote the manuscript implementing comments and edits from all authors.

Corresponding author

Correspondence to William B. Mair.

Reviewer Information Nature thanks M. Kaeberlein, N. Tavernarakis and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. 1.

    Supplementary Information

    This file contains Supplementary Data 1 - all primers with sequence information used for PCR and qRT-PC, Supplementary Data 2 - all RNAi clone sequences used in this work and Supplementary Figure 1 - uncropped agarose gels and immunoblots. Please note, Supplementary Figure 1 has incorrect labelling, see the Corrigendum associated with this Letter for the corrected Supplementary Figure 1.

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    Supplementary Tables

    This zipped file contains Supplementary Tables 1-10 and a Supplementary Table guide.

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DOI

https://doi.org/10.1038/nature20789

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