TitleDecline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid.
Publication TypeJournal Article
Year of Publication2004
AuthorsSuh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu R-M, Hagen TM
JournalProc Natl Acad Sci U S A
Date Published2004 Mar 09
KeywordsAging, Animals, Antioxidants, DNA-Binding Proteins, Glutamate-Cysteine Ligase, Glutathione, In Vitro Techniques, Liver, Male, NF-E2-Related Factor 2, Protein Subunits, Rats, Rats, Inbred F344, RNA, Messenger, Thioctic Acid, Trans-Activators, Transcription, Genetic

Glutathione (GSH) significantly declines in the aging rat liver. Because GSH levels are partly a reflection of its synthetic capacity, we measured the levels and activity of gamma-glutamylcysteine ligase (GCL), the rate-controlling enzyme in GSH synthesis. With age, both the catalytic (GCLC) and modulatory (GCLM) subunits of GCL decreased by 47% and 52%, respectively (P < 0.005). Concomitant with lower subunit levels, GCL activity also declined by 53% (P < 0.05). Because nuclear factor erythroid2-related factor 2 (Nrf2) governs basal and inducible GCLC and GCLM expression by means of the antioxidant response element (ARE), we hypothesized that aging results in dysregulation of Nrf2-mediated GCL expression. We observed an approximately 50% age-related loss in total (P < 0.001) and nuclear (P < 0.0001) Nrf2 levels, which suggests attenuation in Nrf2-dependent gene transcription. By using gel-shift and supershift assays, a marked reduction in Nrf2/ARE binding in old vs. young rats was noted. To determine whether the constitutive loss of Nrf2 transcriptional activity also affects the inducible nature of Nrf2 nuclear translocation, old rats were treated with (R)-alpha-lipoic acid (LA; 40 mg/kg i.p. up to 48 h), a disulfide compound shown to induce Nrf2 activation in vitro and improve GSH levels in vivo. LA administration increased nuclear Nrf2 levels in old rats after 12 h. LA also induced Nrf2 binding to the ARE, and, consequently, higher GCLC levels and GCL activity were observed 24 h after LA injection. Thus, the age-related loss in GSH synthesis may be caused by dysregulation of ARE-mediated gene expression, but chemoprotective agents, like LA, can attenuate this loss.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID14985508
PubMed Central IDPMC373470
Grant ListR01 AG17141A / AG / NIA NIH HHS / United States
R01 AG017141 / AG / NIA NIH HHS / United States
ES00210 / ES / NIEHS NIH HHS / United States
R01 ES 11831-01 / ES / NIEHS NIH HHS / United States
R01 ES011831 / ES / NIEHS NIH HHS / United States
P01 AT002034 / AT / NCCIH NIH HHS / United States
P01 AT002034-01 / AT / NCCIH NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States