Plasticity of Antioxidant Defense Pathways in Response to Aging and Cadmium in Glutathione-Deficient Mice

Maintaining cellular homeostasis is an important determinant of health throughout the lifespan. The Nrf2 (NFE2L2) transcription factor is one of the most important for cellular defense and survival. Nrf2 and its orthologs have been shown to decrease aging associated pathology and increase longevity in a number of species. Two important Nrf2-regulated genes are glutamate cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, which are critical for the synthesis of the antioxidant glutathione (GSH). Gclm null mice are severely deficient in GSH compared to wild-type mice (~ 10% of WT). To compensate for low GSH, Gclm null mice have increased many Nrf2-regulated genes, and exhibit greater resistance to some but not all stressors. Young Gclm null mice also display a lean phenotype, resistance to high fat diet-induced diabetes and obesity, and improved glucose homeostasis. Since Nrf2 signaling has been reported to attenuate with aging, we hypothesized that older Gclm null mice would display greater susceptibility to exogenous stressors. We challenged Gclm WT, heterozygous and null mice with cadmium (Cd) because of its association with type 2 diabetes in several species, and its canonical role as an oxidative stress-inducing heavy metal. During aging and acute Cd administration, we unexpectedly found that Gclm null mice continue to maintain improved GSH redox, increased Nrf2 target gene expression and inducibility, and improved parameters of glucose homeostasis, relative to Gclm wild-type mice. These surprising findings suggest that chronic adaption to severely compromised GSH levels, likely due to continuous upregulation of Nrf2 mediated responses, persists throughout the lifespan in these mice. Dietary or other interventions that upregulate the Nrf2 pathway could thus improve late-life insulin sensitivity, glucose homeostasis, and promote an improved healthspan.