title: 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.
  
  
  METHODS
  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.
authors.affiliation: Translational Metabolism Unit, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Rajagopal V
authors.initials: RV
authors.lastname: Sekhar
authors.forename: Sanjeet G
authors.initials: SG
authors.lastname: Patel
authors.forename: Anuradha P
authors.initials: AP
authors.lastname: Guthikonda
authors.forename: Marvin
authors.initials: M
authors.lastname: Reid
authors.forename: Ashok
authors.initials: A
authors.lastname: Balasubramanyam
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: Farook
authors.initials: F
authors.lastname: Jahoor
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000502:physiology*; D003545:Cysteine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D019587:Dietary Supplements; D004912:Erythrocytes / Q000378:metabolism; D028441:F2-Isoprostanes / Q000097:blood; D005978:Glutathione / Q000096:biosynthesis* / Q000097:blood / Q000172:deficiency; D005998:Glycine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007554:Isotopes; D008659:Metabolic Diseases / Q000097:blood / Q000188:drug therapy*; D018384:Oxidative Stress / Q000187:drug effects*; D013194:Staining and Labeling
chemical_list: D028441:F2-Isoprostanes; D007554:Isotopes; D005978:Glutathione; D003545:Cysteine; D005998:Glycine