Dietary Ketosis: Fatty Acids Activate AMPK Energy Circuits Modulating Global Methylation
Condition: Mild Cognitive Impairment; Metabolic Syndrome
MeSH terms: Metabolic Syndrome; Cognitive Dysfunction
Study type: Interventional

Summary: 
      The study explores whether selective memory complaints (SMC), mild cognitive impairment (MCI)
      and the comorbidity of Metabolic Syndrome symptomatic of peripheral and cerebral
      hypo-metabolism with corresponding epigenetic shifts in global DNA (deoxyribonucleic acid)
      methylation (away from nutrient availability and toward biosynthesis) are initiated by
      chronic metabolic inflexibility, over-activation of the mTOR (mammalian target of rapamycin)
      pathway, and the deregulation of neural oxidative phosphorylation.
    

Detailed description: 
      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?
    

Intervention name(s): Dietary intervention
Intervention type(s): Behavioral
Intervention description(s): Subjects in the experimental group will receive clinically regulated meal plans designed to facilitate prolonged benign dietary ketosis (BDK) in order to regulate glucose with restored insulin sensitivity focused at reversing the impaired capacity to switch between fat and carbohydrate oxidation.
Subjects in the control group will follow the their current dietary protocol (Standard American Diet-SAD).
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: To assess differences between the control and experimental groups, a mixed model will be fit for each variable separately using both baseline (week 0) and post program (week 12) values for each subject. Models will include week, group, and their interaction as fixed effects, gender as a covariate, and subject as a random effect. To assess significant differences, we will use the difference at week 12 adjusted for the baseline difference, and will report p-values, least squares means, and 95% confidence intervals. Further analysis of treatment effects over time will be examined by comparing the within-group differences over time.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Mild Cognitive Impairment; AMPK activation; DNA global hypo-methylation; Metabolic Syndrome; Ketogenic diet; SAM/SAH Index; S-adenosylmethionine (SAM); S-adenosylhomocysteine (SAH); Region-Specific hyper-methylation; mTOR kinase pathway; AMP/ATP ratio; Low Reduction Potential; High Reduction Potential; Delta G; Exergonic; Endergonic; Epigenetic Histone Modification; Montreal Cognitive Assessment (MoCA); Brief Visual Memory Test-Revised (BVMT-R); Rey Auditory Verbal Learning Task (RAVLT); HOMA-IR