Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction

Abstract

Chronic caloric restriction (CR) without malnutrition is known to affect different cellular processes such as stem cell function, cell senescence, inflammation, and metabolism. Despite the differences in the implementation of CR, the reduction of calories produces a widespread beneficial effect in noncommunicable chronic diseases, which can be explained by improvements in immuno-metabolic adaptation. Cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA. In this review, we define these modifications and systematically summarize the current evidence related to CR and the epigenome. We then explain the significance of genome-wide epigenetic modifications in the context of disease development. Although substantial evidence exists for the widespread effect of CR on longevity, there is no consensus regarding the epigenetic regulations of the underlying cellular mechanisms that lead to improved health. We provide compelling evidence that CR produces long-lasting epigenetic effects that mediate expression of genes related to immuno-metabolic processes. Epigenetic reprogramming of the underlying chronic low-grade inflammation by CR can lead to immuno-metabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.

Keywords: DNA methylation; dietary restriction; energy intake; histone acetylation; microRNA; sirtuin.

FIGURE 1

Age-related changes in DNA methylation drift and the effect of CR. (A) DNA methylation is a dynamic process that is regulated during development and throughout life. Early-life DNA methylation patterns are established through genetic and epigenetic imprinting of DMRs. Both early (yellow solid line) and late onset of CR (blue solid line) are able to extend lifespan with differences in health span compared with control without CR (black solid line). Both early (yellow dotted line) and late onsets (blue dotted line) are able to ameliorate age-related methylation drifts. (B) DNA methylation dysregulation with age. (C) Weight loss strategies such as CR and RYGB are able to produce distinct patterns of either hyper- or hypomethylation of many genes (listed in the text boxes) in many metabolic tissues (see color code by tissue), compared with their obese counterparts. AACS2, acetoacetyl-CoA synthetase; ACACA, acetyl-CoA carboxylase α; ACLY, ATP citrate lyase; ACOX1, acyl-CoA oxidase 1; ANP, natriuretic peptide A; ATP10A, ATPase phospholipid transporting 10A; CD, cluster determinant; CETP, cholesteryl ester transfer protein; c-MYC, MYC proto-oncogene; CR, caloric restriction; CXCL3, C-X-C motif chemokine ligand 3; DAT, dopamine transporter; DMR, differentially methylated region; DNMT, DNA methyltransferase; DNMT3b, DNMT 3 β; DRD2, dopamine receptor D2; ELOVL6, fatty acid elongase 6; ESR, estrogen receptor; FADS1, fatty acid desaturase 1; FOXP2, forkhead box P2; GPAM, glycerol-3-phosphate acyltransferase, mitochondrial; HDAC4, histone deacetylase 4; IFN-γ, interferon-γ; Me, methyl (CH3); ME1, malic enzyme 1; MYH2, myosin heavy chain 2; NTS, neurotensin; OXTR, oxytocin receptor; PBMC, peripheral blood mononuclear cell; PDHA1, pyruvate dehydrogenase E1 α 1 subunit; PDK4, pyruvate dehydrogenase kinase 4; PGC-1α, peroxisome proliferator–activated receptor γ coactivator 1 α; PKLR, pyruvate kinase L/R; PLCH2, phospholipase C η 2; PRDM8, PR/SET domain 8; RYGB, Roux-en-Y gastric bypass; SAM, S-adenosyl methionine; SNCA, synuclein α; SORBS3, sorbin and SH3 domain containing 3; TET, Ten Eleven Translocation protein; TNFRSF9, TNF receptor superfamily member 9; WT1, Wilms tumor 1.

FIGURE 2

Epigenetic and genetic regulation of sirtuins by caloric restriction. (A) High energy levels after a feeding period contribute directly to the elevated concentrations of NAM and NADH originated from catabolic pathways. Diverse cells and cellular processes deplete the concentration of NADH, and together with the biosynthetic transformation by NAMPT and NMNAT, high intracellular concentrations of NAD⁺ are produced. (B) Intracellular NAD⁺ is sensed by NAD⁺-dependent enzymes, such as sirtuins that add or remove posttranslational protein modifications from nuclear (blue), cytosolic, nucleolar (grey), and mitochondrial (red) proteins. Seven sirtuins, or SIRTs, have been defined in mammals, and participate in deacetylation, mono ADP-ribosylation, and defatty-acylation [demyristoylation, desuccinylation, demalonylation, deglutarylation, demethylglutarylation, and de-3-hydroxy-3-methylglutaryl(HMG)-ation] of nuclear transcription factors, nucleosomal histones, and various nuclear, nucleolar, and mitochondrial proteins. AACS2, acetoacetyl-CoA synthetase; ACOX1, acyl-CoA oxidase 1; AMPK, AMP-activated protein kinase; BubR1, BUB1 mitotic checkpoint serine/threonine kinase B; CAF1/DDB1/CUL4B, ubiquitin complex CAF1/DDB1/CUL4B; CPS1, carbamoyl-phosphate synthase 1; CPT1a, carnitine palmitoyltransferase 1A; CtIP, C-terminal-binding protein interacting protein; FOXO-3, forkhead box O3; GSK3β, glycogen synthase kinase 3 β; HADHA, hydroxyacyl-CoA dehydrogenase subunit α; HDAC6, histone deacetylase 6; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; H1bK16Ac, histone 1b lysine 16 acetylation; H3K9Ac, histone 3 lysine 9 acetylation; H3K9me3, histone 3 lysine 9 trimethylation; H3K18ac, histone 3 lysine 18 acetylation; H3K56Ac, histone H3 lysine 56 acetylation; H3K79me2, histone 3 lysine 79 dimethylation; H4H16Ac, histone 4 histidine 16 acetylation; H4K16Ac, histone 4 lysine 16 acetylation; H4K20me, histone 4 lysine 20 monomethylation; IDH2, isocitrate dehydrogenase 2, mitochondrial; JNK, JUN N-terminal kinase; KIF5C, kinesin family member 5C; LCADK42Ac, acyl-CoA dehydrogenase long chain lysine 42 acetylation; NAM, nicotinamide; NAMPT, nicotinamide phosphoribosyltransferase; NF-kB, nuclear factor κB; NMNAT, nicotinamide mononucleotide adenylyltransferase 1; NPM1, nucleophosmin 1; OTC, ornithine carbamoyltransferase; PDH, pyruvate dehydrogenase; PDK4, pyruvate dehydrogenase kinase 4; PGC-1α, peroxisome proliferator–activated receptor γ coactivator 1 α; PKM2, pyruvate kinase M1/2; PPARα, peroxisome proliferator–activated receptor α; p53, tumor protein P53; SIRT, sirtuin; SIRT3-K57Ac, sirtuin 3 lysine 57 acetylation; SNF2H, sucrose nonfermenting protein 2 homolog; SOD2K53ac, superoxide dismutase lysine 53 acetylation; SOD2K89ac, superoxide dismutase lysine 89 acetylation; SUV39H1, suppressor of variegation 3-9 homolog 1; TCA cycle, tricarboxylic acid cycle; TF, transcription factor; TNF, tumor necrosis factor; WRN, Werner Syndrome RecQ-like helicase; H3K27ac, histone H3 lysine 27 acetylation; Ac, acetylation; Me, metylation; PPi, pyrophosphate.

FIGURE 3

CR conservation of miR changes across species and tissues. CR and starvation are able to upregulate or downregulate miR signatures in (A) Caenorhabditis elegans, (B) Drosophila melanogaster, (C) rodents (Rattus norvegicus and Mus musculus), and (D) Rhesus macaques (Macaca mulatta) and humans (Homo sapiens). miR signatures associated with CR are involved in antiaging pathways such as immuno-metabolic regulation in different peripheral and central tissues. CR, caloric restriction; miR, the mature for of the miRNA; mir, the pre-miRNA and the pri-miRNA; *, asterisk following the name indicate the mature species found at low levels from the opposite arm of a hairpin.