Oxidative stress is therefore a major constraint on animal performance 13, 14, 15, 16, yet the role of ROS in shaping the evolution of birds has often been overlooked.

In vertebrates, a consequence of high oxygen metabolism and intense aerobic activities (such as flight) is the generation of reactive oxygen species (ROS), which can cause extensive damage to cellular function if not counterbalanced by antioxidant enzymes 10, 11, 12, 13, 14. This is reflected in the extensive cardiovascular and pulmonary adaptations in birds relative to mammals 6, 7 and in their higher metabolic activity and oxygen consumption 5, 6, 8, 9. From a physiological standpoint, flapping flight deserves special attention as the most metabolically intense form of vertebrate locomotion 4, requiring high levels of oxygen and imposing a significant demand on oxygen transport systems 5, 6. Studies investigating the evolution of birds (Aves) have focused heavily on feather development and the skeletomuscular adaptations required for flight 1, 2, 3. The strategy of NRF2 activation sought by intense clinical investigation therefore appears to have also unlocked a massively successful evolutionary trajectory. 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.

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. 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. Although excess ROS reduces lifespan by causing extensive cellular dysfunction and damage, birds are remarkably long-lived.

Birds (Aves) display high metabolic rates and oxygen consumption relative to mammals, increasing reactive oxygen species (ROS) formation.

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