Limitations to adaptive homeostasis in an hyperoxia-induced model of accelerated ageing
Laura C.D. Pomatto,
Patrick Y. Sun,
Kelsi Yu,
Sandhyarani Gullapalli,
Conscience P. Bwiza,
Christina Sisliyan,
Sarah Wong,
Hongqiao Zhang,
Henry Jay Forman,
Peter L. Oliver,
Kay E. Davies,
Kelvin J.A. Davies
Affiliations
Laura C.D. Pomatto
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA
Patrick Y. Sun
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA
Kelsi Yu
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA
Sandhyarani Gullapalli
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA
Conscience P. Bwiza
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA
Christina Sisliyan
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA
Sarah Wong
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA
Hongqiao Zhang
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA
Henry Jay Forman
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA
Peter L. Oliver
Oxford Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK; MRC Harwell Institute, Harwell Campus, Didcot, Oxfordshire, OX11 0RD, UK
Kay E. Davies
Oxford Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK
Kelvin J.A. Davies
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA; Division of Molecular & Computational Biology, Department of Biological Sciences of the Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089-0191, USA; Department of Biochemistry & Molecular Medicine, Keck School of Medicine of USC, University of Southern California, University of Southern California, Los Angeles, CA 90089-0191, USA; Corresponding author. Leonard Davis School of Gerontology, The University of Southern California, Los Angeles, CA 90089-0191, USA.
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 μM) 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. Keywords: Adaptive homeostasis, Hyperoxia, Nrf2, 20S proteasome, Immunoproteasome, NQO1, Bach1, c-Myc, Lon protease, OXR1
