Aging effects on basal and lipopolysaccharide inducible expression of antioxidant and inflammatory genes in human blood monocytes

Forman, Henry Jay; Zhang, Jiuqi

doi:10.1016/j.freeradbiomed.2018.04.194

Cited by 1 publication

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“…However, the Nrf2-mediated adaptive increase is lost with the chronic oxidative stress of hyperoxic growth conditions. This finding mirrors earlier work showing a basal rise in Nrf2 levels in chronic diseases (including multiple forms of cancer) [68,69] and with age [14,70,71], accompanied by a loss of Nrf2 inducibility but are no longer inducible. This suggests that a new baseline is created that allows cells, tissues, or organisms to cope with an age-related increase in chronic oxidative stress; if an additional stress is encountered, however, the older organism is unable to further adapt or adjust.…”

Section: Discussionsupporting

confidence: 90%

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

Pomatto

Sun

et al. 2019

Redox Biology

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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% O 2 , 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 μM) of H 2 O 2 . In contrast, MEFs cultured at physiologically relevant conditions of 5% O 2 exhibited a transient induction of Nrf2 Phase II target genes and stress-protective enzymes (the Lon protease and OXR1) following H 2 O 2 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.

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