Background: Aging is associated with oxidative stress, but under-lying mechanisms remain poorly understood. Objective: We tested whether glutathione deficiency occurs be-cause of diminished synthesis and contributes to oxidative stress in aging and whether stimulating glutathione synthesis with its pre-cursors cysteine and glycine could alleviate oxidative stress. Design: Eight elderly and 8 younger subjects received stable-isotope infusions of [ 2 H 2 ]glycine, after which red blood cell (RBC) gluta-thione synthesis and concentrations, plasma oxidative stress, and markers of oxidant damage (eg, F 2 -isoprostanes) were measured. Elderly subjects were restudied after 2 wk of glutathione precursor supplementation. Results: Compared with younger control subjects, elderly subjects had markedly lower RBC concentrations of glycine (486.7 6 28.3 compared with 218.0 6 23.7 lmol/L; P , 0.01), cysteine (26.2 6 1.4 compared with 19.8 6 1.3 lmol/L; P , 0.05), and glutathione (2.08 6 0.12 compared with 1.12 6 0.18 mmol/L RBCs; P , 0.05); lower glutathione fractional (83.14 6 6.43% compared with 45.80 6 5.69%/d; P , 0.01) and absolute (1.73 6 0.16 compared with 0.55 6 0.12 mmol/L RBCs per day; P , 0.01) synthesis rates; and higher plasma oxidative stress (304 6 16 compared with 346 6 20 Carratelli units; P , 0.05) and plasma F 2 -isoprostanes (97.7 6 8.3 compared with 136.3 6 11.3 pg/mL; P , 0.05). Precursor supplementation in elderly subjects led to a 94.6% higher glutathione concentration, a 78.8% higher fractional syn-thesis rate, a 230.9% higher absolute synthesis rate, and signif-icantly lower plasma oxidative stress and F 2 -isoprostanes. No differences in these measures were observed between younger subjects and supplemented elderly subjects. Conclusions: Glutathione deficiency in elderly humans occurs be-cause of a marked reduction in synthesis. Dietary supplementation with the glutathione precursors cysteine and glycine fully restores glutathione synthesis and concentrations and lowers levels of oxi-dative stress and oxidant damages. These findings suggest a practical and effective approach to decreasing oxidative stress in aging.
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