title: Mono-unsaturated fatty acids link H3K4me3 modifiers to C. elegans lifespan.
abstract: Chromatin and metabolic states both influence lifespan, but how they interact in lifespan regulation is largely unknown. The COMPASS chromatin complex, which trimethylates lysine 4 on histone H3 (H3K4me3), regulates lifespan in Caenorhabditis elegans. However, the mechanism by which H3K4me3 modifiers affect longevity, and whether this mechanism involves metabolic changes, remain unclear. Here we show that a deficiency in H3K4me3 methyltransferase, which extends lifespan, promotes fat accumulation in worms with a specific enrichment of mono-unsaturated fatty acids (MUFAs). This fat metabolism switch in H3K4me3 methyltransferase-deficient worms is mediated at least in part by the downregulation of germline targets, including S6 kinase, and by the activation of an intestinal transcriptional network that upregulates delta-9 fatty acid desaturases. Notably, the accumulation of MUFAs is necessary for the lifespan extension of H3K4me3 methyltransferase-deficient worms, and dietary MUFAs are sufficient to extend lifespan. Given the conservation of lipid metabolism, dietary or endogenous MUFAs could extend lifespan and healthspan in other species, including mammals.
authors.affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.|Genetics Graduate Program, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schroeder
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Silva-García
authors.affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Katja
authors.initials: K
authors.lastname: Hebestreit
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Mair
authors.affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.|Glenn Laboratories for the Biology of Aging, Stanford University, Stanford, California 94305, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Brunet
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D004041:Dietary Fats / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D005854:Germ Cells / Q000201:enzymology / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000201:enzymology; D050356:Lipid Metabolism / Q000187:drug effects; D008136:Longevity / Q000187:drug effects* / Q000502:physiology*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000172:deficiency / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase; D015854:Up-Regulation
chemical_list: D004041:Dietary Fats; D005231:Fatty Acids, Unsaturated; D006657:Histones; D044943:Fatty Acid Desaturases; D013230:Stearoyl-CoA Desaturase; C029627:delta-9 fatty acid desaturase; D011495:Histone-Lysine N-Methyltransferase; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D008239:Lysine