The Effects of Aging and Anti-Aging Dietary Restriction on Brain Glutathione and Thioredoxin Redox Systems

Glutathione (GSH) is a cofactor for several enzymes including glutathione peroxidases (GPXs) that detoxify H2O2 and for glutaredoxins that catalyze protein cysteine deglutathionylation. Aging results in a decreased rate of brain GSH synthesis and an oxidation of brain GSH to glutathione disulfide (GSSG), which increases oxidative damage, but is delayed or reversed by anti-aging dietary restriction (DR). Fasting increases the hepatic synthesis and release of GSH, which is catabolized to its amino acids, possibly increasing their transport to the brain for the re-synthesis of GSH. Brain GSH synthesis is limited by cysteine availability. Some astrocytes may increase GSH synthesis during fasting and DR by increasing metabolic flux through the cysteine and H2S-synthesizing transsulfuration pathway. In contrast to the cytoplasm where the GPX1-GSH pathway for H2O2 detoxification is highly active, the mitochondrial matrix relies largely on peroxiredoxin 3 (PRDX3), which functions together with thioredoxin 2 and thioredoxin reductase 2. In contrast to the cytoplasmic and mitochondrial GSH/GSSG, the ER GSH/GSSG is more oxidized in young organisms and becomes reduced with aging and plays a more fundamental role in buffering protein disulfide bond isomerization than for providing GSH to ER GPXs. Studies addressing the aging and DR-induced redox changes in the cytoplasm, mitochondria, and ER in different neural cell types and brain regions are needed to establish effective therapies for aging-related disorders. This review further covers the brain cell-type and brain region-specific gene expression changes that occur with aging and DR for the major enzymes that maintain the cellular redox state.