Nutritional epigenetics denotes gene-diet interactions and highlights the modulatory role of nutrition in aging and age-related diseases such as cancer, CVD (cardiovascular disease), diabetes and neurodegenerative disorders. Nutrients are a source of epigenetic modification; they are able to regulate the placement of histone modifiers distinguishing phenotype from genotype. The energy status of the cells (fed or fasted) modulates the regulation of global DNA methylation via the S-adenosylmethionine (SAM), the methyltransferase inhibitor, S-adenosylhomocysteine (SAH) axis and whole blood histamine levels. Insulin resistance and hyperinsulinemia dysregulate cellular signals leading to metabolic inflexibility. Chronic elevations in insulin with long-standing impairments in glucose delivery are associated with profound changes in epigenetic patterns due to over-activation of the mTOR kinase pathway and repression of AMPK (adenosine monophosphate-activated protein kinase). Dietary ketosis is known to change the metabolic status of the cells by increasing the AMP/ATP (adenosine monophosphate/adenosine tri-phosphate) ratio. AMPK activation adapts rRNA (ribosomal ribonucleic acid) synthesis away from growth/biosynthesis and toward ATP availability and utilization, thereby, attenuating the progression of hypo-metabolic diseases in the body and the brain at the level of the genome.