Age-associated decline in gamma-glutamylcysteine synthetase gene expression in rats

Although glutathione (GSH) concentration has been reported to diminish with age, the mechanism underlying such age-associated decline in the GSH conte nt is not well understood. In this study, we compared the gene expression o f both subunits of gamma-glutamylcysteine synthetase (GCS), the rate-limiti ng enzyme in de novo GSH synthesis, in young, adult, and old Fisher 334 rat s. It was found that GCS activity was significantly decreased with increase d age in liver, kidney, lung, and red blood cells (RBC). Parallel with the decreased enzyme activity, the protein and mRNA contents of both GCS subuni ts also changed inversely with age in liver, kidney, and lung, implying a d ecreased GCS gene expression during aging. Such a reduced OCS gene expressi on was accompanied by a decline in total GSH content without any change in cysteine concentration. Furthermore, the decreased GCS gene expression in o ld rats was not associated with a decline in the plasma insulin or cortisol level. This study showed, for the first time, that the expression of both GCS subunit genes was decreased in some organs of old rats, which would res ult in a reduced rare of GSH biosynthesis. Such decline in GSH synthetic ca pacity may underlie the observed decrease in GSH content during aging. (C) 2000 Elsevier Science Inc.