Age and Cadmium as Modifiers of Metabolic and Thiol-Based Redox Homeostasis in Glutathione-Deficient Mice

The Nrf2 signaling pathway is one of the most important cellular defense and survival pathways, and the importance of Nrf2 signaling in aging has been well-documented. Intracellular levels of glutathione (GSH), a very important endogenous antioxidant, both governs and is governed by the Nrf2 pathway through expression of genes involved in its biosynthesis, including the subunits of the rate-limiting enzyme (glutamate cysteine ligase, GCL) in GSH production, GCLC and GCLM. Mice homozygous for the Gclm gene are severely deficient in GSH compared to wild-type controls, expressing approximately 10% of normal GSH levels (McConnachie et al., 2007). To compensate for reduced GSH, Gclm null mice have upregulated Nrf2-regulated genes, and, surprisingly, are less susceptible to certain types of oxidative damage. Young (