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Age-related depletion of GSH levels and perturbations in its redox state may be especially deleterious to metabolically active tissues, such as the heart and brain. We examined the extent and the mechanisms underlying the potential age-related changes in cerebral and myocardial GSH status in young and old F344 rats and whether administration of (R)-α-lipoic acid (LA) can reverse these changes. Our results show that GSH/GSSG ratios in the aging heart and the brain declined by 58 and 66% relative to young controls, respectively (p<0.001). Despite a consistent loss in GSH redox status in both tissues, only cerebral GSH levels declined with age (p<0.01). To discern the potential mechanisms underlying this differential loss, the levels and the activities of γ-glutamylcysteine ligase (GCL) and cysteine availability were determined. There were no significant age-related changes in substrate or enzyme levels, or GCL …