title: Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans.
abstract: Ageing is driven by a loss of transcriptional and protein homeostasis 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 illnesses. 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.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Heintz
authors.affiliation: Department of Biochemistry and Molecular Biology, and Villum Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Thomas Koed
authors.initials: TK
authors.lastname: Doktor
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Lanjuin
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.|Institute for Research on Cancer and Aging, Nice (IRCAN), CNRS, UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Faculty of Medicine, Nice, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Escoubas
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Weir
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Sneha
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Carlos Giovanni
authors.initials: CG
authors.lastname: Silva-García
authors.affiliation: Department of Biochemistry and Molecular Biology, and Villum Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Gitte Hoffmann
authors.initials: GH
authors.lastname: Bruun
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Ianessa
authors.initials: I
authors.lastname: Morantte
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Gerta
authors.initials: G
authors.lastname: Hoxhaj
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
authors.affiliation: Department of Biochemistry and Molecular Biology, and Villum Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Brage S
authors.initials: BS
authors.lastname: Andresen
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Mair
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000375:Aging / Q000235:genetics; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D031204:Caloric Restriction; D016678:Genome / Q000235:genetics; D006706:Homeostasis; D008136:Longevity / Q000235:genetics* / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D029742:Caenorhabditis elegans Proteins; D046912:Multiprotein Complexes; D012322:RNA Precursors; D000072260:RNA Splicing Factors; C491515:sfa-1 protein, C elegans; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C571892:Rsks-1 protein, C elegans; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases