Effects of aging and anti-aging dietary restriction on regulators of the [NADPH]/[NADP+] in different neural cell types and brain regions

Dietary restriction (DR), which slows aging, increases the ratio of reduced glutathione (GSH) to oxidized glutathione disulfide (GSSG) in the brain. DR increases liver cytoplasmic [NADPH]/[NADP⁺] where much of the NADPH is generated by the folate cycle. This could also occur in astrocytes, the neural cell type with the highest folate cycle flux. Mice on a DR diet showed increased expression of folate cycle enzyme MTHFD1L in several brain regions and likely show increased astrocyte sarcosine catabolism increasing folate cycle cytoplasmic NADPH generation by ALDH1L1. Fasting also increases blood malate/pyruvate that increases tissue [NADPH]/[NADP⁺]. These events together with decreased NADPH-utilizing lipid synthesis during DR could lead to an increased brain cytoplasmic [NADPH]/[NADP⁺]. The more reduced NADP(H) pool, combined with the increased expression of brain glutathione disulfide reductase (GSR) and the decreased brain mitochondrial H₂O₂ generation, decreasing H₂O₂-induced oxidation of GSH, could lead to the increased brain GSH/GSSG. Aging also decreased the expression of mouse hippocampal NAD⁺ kinase (NADK) that was restored by DR. Studies that measure the [NADPH]/[NADP⁺], cysteine/cystine, and GSH/GSSG in different brain regions, subcellular compartments, and neural cell types, especially in astrocytes, during aging and DR are needed to establish effective targets and therapies for aging-related disorders.