TY - JOUR
T1 - Adaptation of the master antioxidant response connects metabolism, lifespan and feather development pathways in birds
AU - Castiglione, Gianni M.
AU - Xu, Zhenhua
AU - Zhou, Lingli
AU - Duh, Elia J.
N1 - Funding Information:
The authors thank Lindsay Jacks and the volunteers at the Baltimore Bird Club Chapter of the Maryland Ornithological Society for their dedication to bird conservation and invaluable assistance in collecting and identifying bird specimens (http://www. lightsoutbaltimore.org/). The authors also thank Dr. Frances E. Hauser (University of Toronto Scarborough) for helpful comments regarding the manuscript. This work was supported by research grants from the National Institutes of Health (EY022383 and EY022683; to E.J.D.) and Core Grant P30EY001765, Imaging and Microscopy Core Module.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Birds (Aves) display high metabolic rates and oxygen consumption relative to mammals, increasing reactive oxygen species (ROS) formation. Although excess ROS reduces lifespan by causing extensive cellular dysfunction and damage, birds are remarkably long-lived. We address this paradox by identifying the constitutive activation of the NRF2 master antioxidant response in Neoaves (~95% of bird species), providing an adaptive mechanism capable of counterbalancing high ROS levels. We demonstrate that a KEAP1 mutation in the Neoavian ancestor disrupted the repression of NRF2 by KEAP1, leading to constitutive NRF2 activity and decreased oxidative stress in wild Neoaves tissues and cells. Our evidence suggests this ancient mutation induced a compensatory program in NRF2-target genes with functions beyond redox regulation—including feather development—while enabling significant metabolic rate increases that avoid trade-offs with lifespan. The strategy of NRF2 activation sought by intense clinical investigation therefore appears to have also unlocked a massively successful evolutionary trajectory.
AB - Birds (Aves) display high metabolic rates and oxygen consumption relative to mammals, increasing reactive oxygen species (ROS) formation. Although excess ROS reduces lifespan by causing extensive cellular dysfunction and damage, birds are remarkably long-lived. We address this paradox by identifying the constitutive activation of the NRF2 master antioxidant response in Neoaves (~95% of bird species), providing an adaptive mechanism capable of counterbalancing high ROS levels. We demonstrate that a KEAP1 mutation in the Neoavian ancestor disrupted the repression of NRF2 by KEAP1, leading to constitutive NRF2 activity and decreased oxidative stress in wild Neoaves tissues and cells. Our evidence suggests this ancient mutation induced a compensatory program in NRF2-target genes with functions beyond redox regulation—including feather development—while enabling significant metabolic rate increases that avoid trade-offs with lifespan. The strategy of NRF2 activation sought by intense clinical investigation therefore appears to have also unlocked a massively successful evolutionary trajectory.
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U2 - 10.1038/s41467-020-16129-4
DO - 10.1038/s41467-020-16129-4
M3 - Article
C2 - 32424161
AN - SCOPUS:85084881909
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2476
ER -