Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation

Abstract

Background: Aging is associated with oxidative stress, but underlying mechanisms remain poorly understood.

Objective: We tested whether glutathione deficiency occurs because of diminished synthesis and contributes to oxidative stress in aging and whether stimulating glutathione synthesis with its precursors cysteine and glycine could alleviate oxidative stress.

Design: Eight elderly and 8 younger subjects received stable-isotope infusions of [2H(2)]glycine, after which red blood cell (RBC) glutathione 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 ± 28.3 compared with 218.0 ± 23.7 μmol/L; P < 0.01), cysteine (26.2 ± 1.4 compared with 19.8 ± 1.3 μmol/L; P < 0.05), and glutathione (2.08 ± 0.12 compared with 1.12 ± 0.18 mmol/L RBCs; P < 0.05); lower glutathione fractional (83.14 ± 6.43% compared with 45.80 ± 5.69%/d; P < 0.01) and absolute (1.73 ± 0.16 compared with 0.55 ± 0.12 mmol/L RBCs per day; P < 0.01) synthesis rates; and higher plasma oxidative stress (304 ± 16 compared with 346 ± 20 Carratelli units; P < 0.05) and plasma F(2)-isoprostanes (97.7 ± 8.3 compared with 136.3 ± 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 synthesis rate, a 230.9% higher absolute synthesis rate, and significantly 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 because 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 oxidative stress and oxidant damages. These findings suggest a practical and effective approach to decreasing oxidative stress in aging.

FIGURE 1.

Mean (±SEM) glutathione (GSH) concentrations (A), GSH fractional synthesis rates (B), and GSH absolute synthesis rates (C) in young control (n = 8) and elderly (n = 8) subjects before and after supplementation with cysteine or glycine. Values are significantly different at P < 0.05 on the basis of 1-factor ANOVA and Bonferroni-corrected t tests. A: ^aSignificantly different from the elderly before supplementation, P < 0.05; ^bnot significantly different from the elderly after supplementation; ^csignificantly different from the elderly before supplementation, P < 0.05. B: ^aSignificantly different from the elderly before supplementation, P < 0.01; ^bnot significantly different from the elderly after supplementation; ^csignificantly different from the elderly after supplementation, P < 0.01. C: ^aSignificantly different from the elderly before supplementation, P < 0.01; ^bnot significantly different from the elderly after supplementation; ^csignificantly different from the elderly after supplementation, P < 0.01. RBC, red blood cells.