Limitations to adaptive homeostasis in an hyperoxia-induced model of accelerated ageing

The Nrf2 signal transduction pathway plays a major role in adaptive responses to oxidative stress and in maintaining adaptive homeostasis, yet Nrf2 signaling undergoes a significant age-dependent decline that is still poorly understood. We used mouse embryonic fibroblasts (MEFs) cultured under hyperoxic conditions of 40% O₂, as a model of accelerated ageing. Hyperoxia increased baseline levels of Nrf2 and multiple transcriptional targets (20S Proteasome, Immunoproteasome, Lon protease, NQO1, and HO-1), but resulted in loss of cellular ability to adapt to signaling levels (1.0 microM) of H₂O₂. In contrast, MEFs cultured at physiologically relevant conditions of 5% O₂ exhibited a transient induction of Nrf2 Phase II target genes and stress-protective enzymes (the Lon protease and OXR1) following H₂O₂ treatment. Importantly, all of these effects have been seen in older cells and organisms. Levels of Two major Nrf2 inhibitors, Bach1 and c-Myc, were strongly elevated by hyperoxia and appeared to exert a ceiling on Nrf2 signaling. Bach1 and c-Myc also increase during ageing and may thus be the mechanism by which adaptive homeostasis is compromised with age.