359 J Nutr Sci Vitaminol, 67, 359–365, 2021 Review The Ability of Nutrition to Mitigate Epigenetic Drift: A Novel Look at Regulating Gene Expression Raymond D. PALMER 1 , Veronica PAPA 2,3 and Mauro V ACCAREZZA 4,5 1 Helium-3 Biotech, South Perth, WA, Australia 2 Department of Motor Sciences and Wellness, University of Naples “Parthenope”, 80132 Napoli, Italy 3 FABAP Research Center, Avola (SR), Italy 4 Curtin Medical School, Faculty of Health Sciences, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Bentley, Perth, WA, 6102 Australia 5 Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy (Received May 19, 2021) Summary Epigenetic drift causes modification in gene expression during aging and a myriad of physiological changes that are mostly undesirable, remove youthful phenotype and are related to biological decay and disease onset. The epigenome is considered a stable regulator of genetic expression. Moreover, evidence is now accumulating that commonly available compounds found in foods can influence the epigenome to embrace a more youth- ful and therefore, more disease resistant state. Here we explore the correlation between nutriment and the epigenetic regulation through various types of alimentation. The aim is not to discuss specific chemicals involved in disease onset. Instead, we offer a brief glance at pathogens and offer a practical pathway into epigenetic regulation, hypothesizing that epi- genetic drift might be attenuated by several foods able to drive a more youthful and disease resistant phenotype. Key Words epigenetic drift, epigenetic diet, nutraceutical, gene expression, nutrigenom- ics, genomic diet, histones, methylation Senescence is the inability of organisms to rejuvenate tissues or mitigate damage, and as intracellular damage accumulates, exerting its deleterious effect, impaired cell function ensues and ultimately contributes to age- related disease and aging itself. The control of gene ex- pression and signaling processes involving the cell, its cellular matrix, and its surrounding environment ap- pear to be crucial in understanding the aging process and biological dysfunction that is associated with organ- ismal senescence (1). According to Issa (2), epigenetics can be defined as a stable mechanism of the regulation of gene expression that occurs regardless of the levels of the transcription factors that regulate the target genes in the cell. There- fore, it is crucial to distinguish between epigenetic silenc- ing and regulation of gene expression during aging, and differentiation from transient or dynamic changes that might involve chromatin remodeling or even de- oxyribonucleic acid (DNA) demethylation, which maybe induced in response to transcription factors or other sig- naling molecules. Many types of epigenetic processes have been identified such as modifications of chromatin structure or the regulation of transcription inside the promoter regions via methylation, acetylation, and phosphorylation (3). These regulation patterns mainly involve changes in DNA methylation and chromatin re- modeling which are encoded via the epigenome—a col- lection of methyl groups on DNA or on histone tails that are established during embryogenesis (4). During DNA methylation, DNA methyltransferase 1 (DNMT1) adds a methyl group (CH 3 ) covalently bonded to the symmetrical dinucleotide CG also known as CpG islands (areas of extreme methylation) that are embed- ded in the promoter region. Eventually, the 5-methylcy- tosine base can be further modified through sequential carboxylation by the ten-eleven translocation (TET) family of enzymes (5). Apart from telomere shortening, modification of his- tone tails provides another example of epigenetic regu- lation of gene expression (6). Until recently and for a long time, histones were thought to be structural pro- teins without any other cellular function apart from being the beads on a string around which DNA is wrapped. Enzymes known as “writers” were recently found to be able to add label groups such as acetyl or methyl groups to amino acids, ultimately protruding from the nucleosome leading to modifications of the histone structure. These labels serve as signaling mole- cules for downstream “reader” proteins which in turn repress or activate gene expression through chromatin E-mail: ray.palmer@helium3biotech.com Abbreviations: AGEs, advanced glycation end products; C. elegans, Caenorhabditis elegans; CpG, 5′-C-phosphate-G-3′; DNMT, DNA methyltransferases; EGCG, epigallocatechin-3-gallate; H3K9me3, histone 3 lysine 9 trimethylation; HAT, histone acetyl transferase; HDAC, histone deacetylase; HP1, hetero- chromatin protein 1; hTERT, human telomerase reverse tran- scriptase; miRNA, micro RNA; mtUPR, mitochondrial unfold- ed protein response; nDNA, nuclear DNA; NF-kappaB, nuclear factor kappaB; p53, tumor protein p53; PAHs, polycyclic aro- matic hydrocarbons; SASP, senescence-associated secretory phenotype.