Leah E. Jamerson, Tara Bradshaw, Patrick C. Bradshaw
Changes in brain [NADPH]/[NADP + ] and [NAD + ]/[NADH] may contribute to aging. Anti-aging dietary restriction (DR) and intermittent fasting (IF) alter redox states that may contribute to their longevity effects. Pyruvate/lactate and acetoacetate/beta-hydroxybutyrate are indicators of the cytoplasmic and mitochondrial [NAD + ]/[NADH], respectively, while the malate/pyruvate and isocitrate/alpha-ketoglutarate are indicators of the cytoplasmic [NADPH]/[NADP + ]. Using these metabolite-pair ratios as redox indicators, the C57BL/6J mouse brain showed opposite redox changes with aging to the C57BL/6N mouse brain and human brain in the cytoplasmic [NAD + ]/[NADH] and [NADPH]/[NADP + ]. Fasting caused universal reductive shifts in the brain cytoplasmic [NAD + ]/[NADH] and [NADPH]/[NADP + ] and mitochondrial [NAD + ]/[NADH]. The reductive shift in the cytoplasmic [NAD + ]/[NADH] with fasting was opposite to that occurring with anti-aging ketone ester supplementation or ketogenic diet, which have been shown to cause an oxidative shift of the cytoplasmic [NAD + ]/[NADH], but a reductive shift of the cerebral cortical cytoplasmic [NADPH]/[NADP + ]. Several pathways that influence redox metabolism and aging are discussed, including fatty acid and cholesterol synthesis, the citric acid cycle, fatty acid beta-oxidation, glutaminolysis, the malate-aspartate shuttle, the glycerol-3-phosphate shuttle, the citrate-pyruvate shuttle, and the citrate-alpha-ketoglutarate shuttle. Brain proteome, brain single-cell RNA-Seq, and brain-region-specific bulk RNA-Seq data sets of aging and DR were examined, focusing on the pathways listed above to determine how they might contribute to the redox changes. Intermittent fasting has been shown to induce cyclic metabolic switching that contributes to neuroprotection and other health benefits resulting in delayed aging, while cyclic reductive redox shifts, especially in mitochondria, may be a driver of the beneficial effects.