Although low GSH levels in the elderly is associated with an increased morbidity, the mechanisms responsible for age-induced glutathione depletion remains unknown. We propose that the impaired GSH status of the elderly results from an imbalance between the rate of synthesis and the rate of consumption (irreversible loss) of glutathione. This imbalance is a direct result of the inability to maintain a rate of synthesis of GSH of sufficient magnitude to match consumption because of a shortage of glycine and cysteine, two of the amino acids used to synthesize GSH. Using stable isotope techniques, we will measure the rate of synthesis of glutathione and relate this measurement to the syntheses of cysteine and glycine and to oxidant stress in young controls and in old subjects. Twelve healthy young controls and 24 old adults (divided into 2 groups of 12 subjects aged 60-69 and 70-79 years) will be studied. The young subjects will be admitted once to the GCRC and the old subjects will be admitted on 4 occasions: after usual diet (no supplementation), after supplementation with cysteine, after supplementation with glycine, and after supplementation with both glycine and cysteine. During each occasion stable isotope and mass spectometry techniques will be used to determine cysteine, glycine and leucine kinetics as well as the rate of synthesis of erythrocyte and lymphocyte glutathione. These measurements will be repeated after dietary supplementation with glycine, cysteine, and glycine plus cysteine. Two subjects have completed all four studies and two have comleted at least one study. Analysis of the study is still pending.
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