Adaptation of the master antioxidant response connects metabolism, lifespan and feather development pathways in birds

Abstract

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.

Bats host the most virulent—but not the most dangerous—zoonotic viruses

“…For example, bats have been found to host a suite of cellular-level anti-inflammatory adaptations-including enhanced cellular autophagy and downregulated signaling pathways linked to the induction of inflammatory antiviral defenses-which may both mitigate cellular damage induced by bat metabolism and inhibit immunopathology incurred upon viral infection (36,(42)(43)(44)(45)(46). On the other hand, birds may rely primarily on systemic antioxidant responses (47), which mitigate oxidative stress, but do not interact so tightly with cellular-level processes that impact viral pathology. Critically, birds appear to be missing anti-inflammatory protein tristetraprolin (TTP) (48), and immunopathology is often the cause of death in birds that die from viral infections such as HPAI and West Nile virus (40).…”

Bird evolution by insulin resistance

“…A series of gene losses may have taken place for adaptation to ROS leakage just after passage of the Cretaceous-Tertiary (KT) boundary (66 million years ago), with deletion of the C-terminal part of the Kelch-like ECH-associated protein (KEAP1), constitutively allowing NRF2 to activate antioxidant enzymes (Figure 3), the activation of which may have taken place during the early Tertiary period (Figure 4) [61,62]. Eventually, birds (Neoaves) have expanded up to the present time [7][8][9][10][11][12].…”

“…Associated with a further increase in oxygen concentration [63], Neoaves (swallow and crow) and Palaeognathae (chicken and ostrich) became separated [63]. Neoaves became equipped with constitutive NRF2 activation against reactive oxygen species (ROS) leakage and expanded over the surface of the whole earth [62]. Abbreviations: KT, Cretaceous-Tertiary; PT, Permian-Triassic.…”

“…basic trend of increasing [1,3], the NRF2 system, a master regulator of antioxidant enzymes, has become important among the vertebrates [61,62].…”

New Perspectives on Avian Models for Studies of Basic Aging Processes

“…Other clues to the protective mechanisms distinguishing longer-lived animals have come from examining membrane lipid composition (for a review, see [7]; see also [84][85][86]), as well as metabolic properties of avian cells in comparison to cell lines derived from mammals [55,80,86]. Finally, altered constitutive expression of NRF2 (nuclear factor erythroid 2-related factor), theconsequence of a mutation in Kelch-like ECH-associated protein 1 (KEAP-1) conserved within class Aves, has been proposed as a major factor in the evolution of long lifespan [87]. This, too, is consistent with findings for long-lived non-avian species [88].…”