Linking Lipid Metabolism to Chromatin Regulation in Aging

Abstract

The lifespan of an organism is strongly influenced by environmental factors (including diet) and by internal factors (notably reproductive status). Lipid metabolism is critical for adaptation to external conditions or reproduction. Interestingly, specific lipid profiles are associated with longevity, and increased uptake of certain lipids extends longevity in Caenorhabditis elegans and ameliorates disease phenotypes in humans. How lipids impact longevity, and how lipid metabolism is regulated during aging, is just beginning to be unraveled. This review describes recent advances in the regulation and role of lipids in longevity, focusing on the interaction between lipid metabolism and chromatin states in aging and age-related diseases.

Figure 1.. Lipid synthesis and degradation pathways

Fatty acids, including MUFAs and PUFAs, are synthesized and subsequently incorporated into triglycerides and phospholipids. Triglycerides are synthesized and stored in lipid droplets. Triglycerides can be degraded by two different mechanisms. Lysosomes can fuse with lipid droplets, and lysosomal lipases (LIPL1–5/LIPF) in turn can hydrolyze triglycerides during lipophagy, thereby releasing free fatty acids. Alternatively, lipases located directly at the lipid droplet interface such as the adipose tissue lipases (ATGL-1/ATGL1) hydrolyze triglycerides. Free fatty acids are degraded in mitochondria for energy generation. Peroxisomes degrade very long or branched fatty acids, which can be subsequently shuffled to mitochondria for further degradation. Membrane lipid synthesis pathways that are mentioned within the review are shown. SFAs: Saturated fatty acids, MUFAs: Monounsaturated fatty acids, PUFAs: Polyunsaturated fatty acids, PC: Phosphatidylcholine, PE: Phosphatidylethanolamine, PI: Phosphatidylinositol, PS: Phosphatidylserine, S1P: Sphingosine-1 -phosphate.

Figure 2.. Lipid metabolism is targeted by several longevity pathways

Longevity pathways that target lipid metabolism in C. elegans and mouse. Activated transcription factors/activators are circled. Upper panel: Longevity pathways other than germline depletion. Dietary restriction in mouse leads to global DNA methylation changes that inhibit SREBP1. DNA hypermethylation is found on the bodies of genes that are important for fatty acid elongation. Dietary-restricted mice show a decrease in triglyceride level and a shift towards shorter chain fatty acids. In C. elegans, dietary restriction by eat-2 mutation results in activation of the nuclear hormone receptors NHR-49/PPAR and NHR-62/HNF4. eat-2 mutants show decreased triglyceride content. Depletion of insulin signaling via daf-2/InR mutation activates DAF-16/FOXO and the co-activator MDT-15/MED15. This leads to an increase in triglycerides and a higher MUFA to PUFA ratio. Activation of autophagy by mTOR depletion activates multiple transcription factors (HLH-30/TFEB, SKN-1/NRF, DAF-16/FOXO, and PHA- 4/FOXA). Depletion of the COMPASS H3K4me3 modifiers ash-2/set-2 in the germline activates the transcription factors/activators SBP-1/SREBP and MDT- 15/MED15 in the worm soma. H3K4me3 modifier deficient worms have increased triglycerides and a higher MUFA content. Lower panel: Longevity signaling upon germline depletion induced by glp-1 mutation in C. elegans. Multiple transcription factors and regulators are activated in germline-deficient animals (NHR-49/PPAR, MDT-15/MED15, NHR-80/HNF4, DAF-12/LXRα, DAF-16/FOXO, TCER-1/TCERG1, SKN-1/NRF, HLH-30/TFEB, and PHA-4/FOXA,). Germline-deficient animals show higher triglyceride content, an increase in unsaturated fatty acids, and an increase in the MUFA derivative oleoylethanolamide (OEA). MUFAs: Monounsaturated fatty acids, PUFAs: Polyunsaturated fatty acids, NHR: Nuclear hormone receptor.

Figure 3.. Free fatty acid supplementation extends C. elegans lifespan and promotes mammalian youthfulness

Mechanisms of longevity induced by fatty acid supplementation in wild type C. elegans. Upper panel: PUFA-induced longevity. Supplementation of the ω−6 PUFAs arachidonic acid (AA) and dihomo-Y-linolenic acid (DGLA) promotes longevity in C. elegans by inducing autophagy. DGLA and ALA also induce autophagy in mammalian cell culture. Supplementation of the ω−3 PUFA α-linolenic acid (ALA) extends lifespan through induction of NHR-49/PPARα. The oxidized counterparts of ALA activate the SKN-1/NRF transcription factor. In mice, ALA improves insulin sensitivity. Lower panel: MUFA-induced longevity. Supplementation of the MUFAs oleic acid, palmitoleic acid, or cis-vaccenic acid is sufficient to extend lifespan through unknown mechanism in wild type C. elegans. In mammals, MUFAs prevent inflammation induced by saturated fatty acids. The oleic acid derivative oleoylethanolamide (OEA) extends lifespan by activating transcription factors in C. elegans. MUFAs: Monounsaturated fatty acids, PUFAs: Polyunsaturated fatty acids.

Figure 4.. Lipid metabolism interacts with multiple chromatin modifications

A. Dietary lipids are directly incorporated into histone acyl/acetyl marks. Modified lysines (grey) are shown with the corresponding acetyl mark (pink) and acyl mark (yellow). Short-chain fatty acids (octanoate) can provide up to 90% of the acetyl groups on histones in cell culture under glucose starvation. Dietary short-chain fatty acids (crotonate) provide histone acyl marks in human cell lines [112]. Microbiota- derived short-chain fatty acids (butyrate) promote crotonylation at H3K18, H2BK5, and 19 additional lysines on H2A, H2B, H3, H4, and H1.2 in organoids of murine intestinal epithelial cells [118]. B. The shared metabolite SAM connects lipid metabolism to epigenetic modifications. Modified lysines (grey) are shown with the corresponding methylation-mark (blue). Phospholipid metabolism, histone and DNA methylation share the common metabolite precursor SAM. Histones methylation, notably H3K4me3, H3K36me3 and H3K79me3, increases when phospholipid methylation is absent. It remains to be investigated if phospholipid metabolism also interacts with DNA methylation. SAM: S-adenosyl methionine.