From inflammaging to healthy aging by dietary lifestyle choices: is epigenetics the key to personalized nutrition?

Abstract

The progressively older population in developed countries is reflected in an increase in the number of people suffering from age-related chronic inflammatory diseases such as metabolic syndrome, diabetes, heart and lung diseases, cancer, osteoporosis, arthritis, and dementia. The heterogeneity in biological aging, chronological age, and aging-associated disorders in humans have been ascribed to different genetic and environmental factors (i.e., diet, pollution, stress) that are closely linked to socioeconomic factors. The common denominator of these factors is the inflammatory response. Chronic low-grade systemic inflammation during physiological aging and immunosenescence are intertwined in the pathogenesis of premature aging also defined as 'inflammaging.' The latter has been associated with frailty, morbidity, and mortality in elderly subjects. However, it is unknown to what extent inflammaging or longevity is controlled by epigenetic events in early life. Today, human diet is believed to have a major influence on both the development and prevention of age-related diseases. Most plant-derived dietary phytochemicals and macro- and micronutrients modulate oxidative stress and inflammatory signaling and regulate metabolic pathways and bioenergetics that can be translated into stable epigenetic patterns of gene expression. Therefore, diet interventions designed for healthy aging have become a hot topic in nutritional epigenomic research. Increasing evidence has revealed that complex interactions between food components and histone modifications, DNA methylation, non-coding RNA expression, and chromatin remodeling factors influence the inflammaging phenotype and as such may protect or predispose an individual to many age-related diseases. Remarkably, humans present a broad range of responses to similar dietary challenges due to both genetic and epigenetic modulations of the expression of target proteins and key genes involved in the metabolism and distribution of the dietary constituents. Here, we will summarize the epigenetic actions of dietary components, including phytochemicals, and macro- and micronutrients as well as metabolites, that can attenuate inflammaging. We will discuss the challenges facing personalized nutrition to translate highly variable interindividual epigenetic diet responses to potential individual health benefits/risks related to aging disease.

Keywords: Aging; Epigenetics; Inflammation; Metabolism; Oxidative stress; Personalized nutrition; Phytochemicals.

Figure 1

Metabolic pathways generate essential metabolites for chromatin- and DNA-modifying enzymes. NAD, acetyl-coenzyme A (Acetyl-coA), and S-adenosylmethionine (SAM) are elemental for epigenetic control of transcription including methylation of DNA and posttranslational modifications of histones and non-histone chromatin factors (not shown). NAD contributes to transcriptional control mainly via the activity of the protein deacetylase sirtuin, which uses NAD as one of the substrates. Sirtuins are also important for maintaining the activity of the acetyl-coA acetyltransferases. Acetyl-coA is synthesized by acetyl-coA-synthetase (ACS) and ATP-citrate lyase that use acetate and citrate as the precursors, respectively. Citrate is an intermediate/product of the TCA cycle. SAM is the methyl donor for DNA, RNA, histones, and non-histone protein methylation. S-adenosylhomocysteine (SAH) generated in each round of methylation reaction is a potent inhibitor of methyltransferases and has to be cleared by SAH hydrolase (SAHH). NAD is an essential coenzyme for SAHH. Synthesis of methionine from homocystein is achieved through extracting the methyl group from betaine, derived from choline, or 5-methyl-THF, a derivative of folic acid. Metabolism of phospholipids and folic acid may thus indirectly contribute to epigenetic regulation. Likewise, the abundance of NAD and citrate is linked to the cellular energy flux, e.g., the TCA cycle. Changes in the expression of certain genes may therefore be influenced significantly. Abbreviations used: Acetyl-coA, acetyl-coenzyme A; ACS, acetyl-coA-synthetase; AC-ACS acetylated-ACS; Ado, adenosine; HAT, histone acetyltransferase; Hcy homocysteine; MTases, methyltransferases; NAD, Nicotinamide adenine dinucleotide; ROS, reactive oxygen species, RNS, reactive nitrogen species, SAH, S-adenosyl homocysteine; TCA, tricarboxylic cycle; THF, tetrahydrofolate.

Figure 2

Plant phytochemicals achieve hormesis through multifocal pathway inhibition. Our health strongly benefits from interactions of a large number of plant molecules in our diet with key regulators of mammalian physiology (adapted from [288]). Various plant-derived molecules are synthesized as secondary metabolites in response to stress. During adversity in the context of particular environmental stresses, animals have retained the ability to sense these stress signaling molecules synthesized by their distant ancestors, through enzymes and receptors which regulate inflammation-energy-metabolism pathways to protect and to increase the survival of the organism. Abbreviations used: PKC, protein kinase C; PKD, protein kinase D, IKK2, inhibitor of IkB kinase 2; ROS/RNS, reactive oxygen/nitrogen species; NR, nuclear receptor; AMPK, AMP-activated protein kinase; TSC, tuberous sclerosis complex mTOR, mammalian target of rapamycin; R6SK ribosomal S6 kinase; PI3K, phosphoinositide 3-kinase; PDK, pyruvate dehydrogenase kinase; AKT/PKB, protein kinase B; PGC1, peroxisome proliferator-activated receptor c coactivator 1; SIRT, sirtuin; FOXO, forkhead box O.

Figure 3

Activity of chromatin modifying writer-eraser enzymes depends on available concentrations of cofactor metabolites and environmental signals. (A) Schematic representation of a nucleosome with extruding histone tails with residues that can be modified by various chromatin writer (i.e., DNA methyltransferase (DNMT), histone methyltransferase (HMT), histone acetylase (HAT), ubiquitin ligase (L), kinase (K), glycosylase (G)) or chromatin eraser enzymes (i.e., DNA hydroxymethylase (TET), demethylase (HDMT), deacetylase (HDAC), proteasome (Pr), phosphatase (PP)), resulting in dynamic histone methylation (Me), acetylation (Ac), ubiquitination (Ub), phosphorylation (P), and glycosylation (Gly). These histone modifications have been associated with changes in chromatin organization, gene activation, silencing, and several other nuclear functions (adapted from [338]). (B) Hypothetical model of a glycolytic-oxidative metabolic switch and its possible influence on epigenetic modifiers and the epigenetic landscape (adapted from [339]).

Figure 4

Overview of the mechanisms and consequences of epigenetic regulation by nutritional compounds. Modulation of different classes of chromatin writers-erasers by phytochemicals (left panel). Genes encoding absorption, distribution, metabolism, and excretion (ADME) proteins can be epigenetically regulated and thereby determine individual nutritional responses. Epigenetic modification of disease-related genes can contribute to diagnosis (biomarker) as well as disease prevention or progression (right panel).