title: Functional loss of two ceramide synthases elicits autophagy-dependent lifespan extension in C. elegans.
abstract: Ceramide and its metabolites constitute a diverse group of lipids, which play important roles as structural entities of biological membranes as well as regulators of cellular growth, differentiation, and development. The C. elegans genome comprises three ceramide synthase genes; hyl-1, hyl-2, and lagr-1. HYL-1 function is required for synthesis of ceramides and sphingolipids containing very long acyl-chains (≥C24), while HYL-2 is required for synthesis of ceramides and sphingolipids containing shorter acyl-chains (≤C22). Here we show that functional loss of HYL-2 decreases lifespan, while loss of HYL-1 or LAGR-1 does not affect lifespan. We show that loss of HYL-1 and LAGR-1 functions extend lifespan in an autophagy-dependent manner, as knock down of the autophagy-associated gene ATG-12 abolishes hyl-1;lagr-1 longevity. The transcription factors PHA-4/FOXA, DAF-16/FOXO, and SKN-1 are also required for the observed lifespan extension, as well as the increased number of autophagosomes in hyl-1;lagr-1 animals. Both autophagic events and the transcription factors PHA-4/FOXA, DAF-16, and SKN-1 have previously been associated with dietary restriction-induced longevity. Accordingly, we find that hyl-1;lagr-1 animals display reduced feeding, increased resistance to heat, and reduced reproduction. Collectively, our data suggest that specific sphingolipids produced by different ceramide synthases have opposing roles in determination of C. elegans lifespan. We propose that loss of HYL-1 and LAGR-1 result in dietary restriction-induced autophagy and consequently prolonged longevity.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Mai-Britt
authors.initials: MB
authors.lastname: Mosbech
authors.forename: Rikke
authors.initials: R
authors.lastname: Kruse
authors.forename: Eva Bang
authors.initials: EB
authors.lastname: Harvald
authors.forename: Anne Sofie Braun
authors.initials: AS
authors.lastname: Olsen
authors.forename: Sandra Fernandez
authors.initials: SF
authors.lastname: Gallego
authors.forename: Hans Kristian
authors.initials: HK
authors.lastname: Hannibal-Bach
authors.forename: Christer S
authors.initials: CS
authors.lastname: Ejsing
authors.forename: Nils J
authors.initials: NJ
authors.lastname: Færgeman
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors; D055785:Gene Knockdown Techniques; D050356:Lipid Metabolism; D008136:Longevity / Q000235:genetics; D010088:Oxidoreductases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C113277:Pha-4 protein, C elegans; D025841:Small Ubiquitin-Related Modifier Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C073702:skn-1 protein, C elegans; D010088:Oxidoreductases; C108138:dihydroceramide desaturase
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