Dietary Ketosis: Fatty Acids Activate AMPK Energy Circuits Modulating Global Methylation

Nutritional epigenetics denotes gene-diet interactions and highlights the modulatory role of cellular energy status in aging and age-related diseases like cancer, cardiovascular disease (CVD), diabetes and neurodegeneration. Nutrients are epigenetic modifiers; macro and micronutrients regulate the placement and distribution of DNA histone modifiers distinguishing phenotype from genotype. Cellular energy status (AMP/ATP) modulates the regulatory mechanics of DNA methylation via the SAM (S-adenosylmethionine) methlytransferase and the SAH (S-adenosyl homocysteine) methyltransferase inhibitor index. Whole blood histamine and homocysteine levels provide additional information on the status of methylation. Hyperinsulinemia and cellular insulin resistance dysregulate nutrient sensing pathways; perpetual fed-state signaling exacerbates systemic metabolic inflexibility. Chronic elevations in insulin with long-standing impairments in glucose delivery are associated with profound changes in epigenetic expression consequent of hyper-activation of mTOR and inhibition of AMPK kinase pathways. Dietary ketosis is known to govern adaptive mitonuclear energy availability by increasing cellular reduction potential via >AMP/ATP ratio. AMPK activation adapts rRNA synthesis away from fed-state growth/storage toward energy production/release, common to fasted-states. Research suggests that induced and controlled dietary ketogenesis, a fasting mimetic, transcriptionally modifies gene expression thereby attenuating metabolic diseases.

The study will explore whether early stage memory loss (SMC \& MCI) and comorbidity of Metabolic Syndrome are symptomatic of peripheral and cerebral hypo-metabolism resultant of sustained cellular insulin resistance. The investigators will attempt to show that consequent to systemic hyperinsulinemia, mitonuclear crosstalk dysregulates the energy sensing kinases, mTOR/AMPK, thereby modifying the intra/extracellular nutrient signaling pathways. The suppression of AMPK, coupled with chronic fed-state signaling, adapts rRNA synthesis away from nutrient availability toward ATP consuming processes. Increased biosynthesis of proteins, lipids and cholesterol with concurrent inhibition of fat oxidation, energy cofactors (NAD+, SAHH) and programmed apoptosis results in the epigenetic drift of methylation toward global gene activation with region-specific silencing of key regulatory/longevity genes, SIRTs (sirtuins), FOX03 and Nrf2. This global shift in energy is marked by suppression of the SAM/SAH methylation index and correlative jumps in whole blood histamine and/or homocysteine. The study explores whether the aforementioned shift in nutrient sensing pathways modulates metabolic inflexibility via energy shunts toward cytosolic, substrate level phosphorylation via activation of PDK (pyruvate dehydrogenase kinase). An insulin resistant energy surplus (\<AMP/ATP) fosters low cellular reduction potential, which triggers mitonuclear crosstalk inhibiting oxidative ATP via PDC (pyruvate dehydrogenase complex), the regulatory gateway between anaerobic glycolysis and oxidative mitochondrial respiration. The study will attempt to show that induced and controlled dietary ketosis initiates the spontaneous/favorable release of energy ( >AMP/ATP), activating the AMPK circuitry thereby inhibiting the synthesis/storage of protein, cholesterol and lipids. Thus, a shift in cellular energy from low reduction potential (ATP/NADH) to high reduction potential (AMP/NAD+) attenuates methylation drift evidenced by marked reductions in biosynthesis: fasting lipid profile (TRI., VLDL, LDL, HDL), LP-IR score (particle concentration/size), HgA1c, fasting insulin, HOMA-IR and epigenetic modification of DNA measured by improved methylation index (>SAM/SAH) with correlating reductions in whole blood histamine and/or homocysteine. The resultant change in cerebral glucose metabolism and correlative improvement in SMC/MCI will be assessed by valid clinical measures of cognition: Montreal Cognitive Assessment (MoCA), Brief Visual Memory Test-Revised (BVMT-R) and Rey Auditory Verbal Learning Task (RAVLT) administered at baseline and weeks 2/4/6/8/10/12.

Research Question: Are selective memory complaints (SMC), mild cognitive impairments (MCI) and comorbid Metabolic Syndrome symptomatic of peripheral/cerebral insulin resistance with a resultant epigenetic drift in methylation away from energy production toward anabolic synthesis/storage, initiated and sustained by metabolic inflexibility, aerobic glycolysis and PDK inhibition of oxidative phosphorylation?