Journal Article

Mono-unsaturated fatty acids link H3K4me3 modifiers to C. elegans lifespan

Silva-García, Carlos G., Mair, William B., Brunet, Anne, Han, Shuo, Hebestreit, Katja, Schroeder, Elizabeth A.

2017

Overview

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. A deficiency in H3K4me3 methyltransferase causes accumulation of mono-unsaturated fatty acids, which is important for lifespan extension in C. elegans and could be relevant in mammals. Longevity fuelled by fat The lifespan of a worm is extended by H3K4me3 methyltransferase deficiency, but how and why remains unclear. Here it is shown that the loss of H3K4me3 in the germline affects fat metabolism in the worm intestine, resulting in the accumulation of mono-unsaturated fatty acids (MUFAs), but not poly-unsaturated fatty acids (PUFAs). The fat switch appears to be mediated in part by the downregulation of specific targets in the germline, including S6K, and the activation of a transcriptional network in the intestine leading to the upregulation of conserved delta-9 fatty acid desaturases. MUFA accumulation is necessary for the increased longevity caused by H3K4me3-methyltransferase deficiency, and the authors found that dietary MUFAs, but not PUFAs, were sufficient to extend worm lifespan. Whether dietary or endogenous MUFAs could extend lifespan and healthspan in other species remains to be seen.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/39 / 38/91 / 631/208/176 / 631/443/319/2723 / 631/443/7 / 64/11 / 82/58 / 96/63 / Aging - drug effects / Aging - metabolism / Animals / Caenorhabditis elegans / Caenorhabditis elegans - drug effects / Caenorhabditis elegans - enzymology / Caenorhabditis elegans - genetics / Caenorhabditis elegans - physiology / Chromatin / Dietary Fats - administration & dosage / Dietary Fats - metabolism / Dietary Fats - pharmacology / Down-Regulation / Enzymes / Fatty Acid Desaturases - genetics / Fatty Acid Desaturases - metabolism / Fatty acids / Fatty Acids, Unsaturated - administration & dosage / Fatty Acids, Unsaturated - metabolism / Fatty Acids, Unsaturated - pharmacology / Gene expression / Gene Expression Regulation, Enzymologic / Germ Cells - enzymology / Germ Cells - metabolism / Histone-Lysine N-Methyltransferase - deficiency / Histone-Lysine N-Methyltransferase - metabolism / Histones - chemistry / Histones - metabolism / Humanities and Social Sciences / Influence / Intestinal Mucosa - metabolism / Intestines - enzymology / Life span / Life span (Biology) / Lipid metabolism / Lipid Metabolism - drug effects / Lipid research / Lipids / Longevity - drug effects / Longevity - physiology / Lysine - metabolism / Metabolism / Metabolites / Methylation / Monounsaturated fatty acids / multidisciplinary / Physiological aspects / Ribosomal Protein S6 Kinases, 70-kDa - deficiency / Ribosomal Protein S6 Kinases, 70-kDa - metabolism / Science / Stains & staining / Stearoyl-CoA Desaturase / Studies / Up-Regulation