Flight & Brains, Feathers & Hair

Adaptation to flight has a big impact on antioxidant defenses; recently this paper came up in my feed (thank Google):

Adaptation of the master antioxidant response connects metabolism, lifespan and feather development pathways in birds [2020] - https://www.nature.com/articles/s41467-020-16129-4

“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.

The physiological risks of constitutive NRF2 activation due to loss of KEAP1 binding have been demonstrated in vivo through KEAP1 knockout mice, which die from starvation shortly after birth from hyperkeratosis of the gastrointestinal tract, likely through overexpression of α-keratins and loricrins in squamous cells (ref. ³⁸; Fig. 4c). In addition to α-keratins, avian skin keratinocytes also express β-keratin genes, which combine with α-keratins to form avian skin appendages (feathers, scales, claws, beaks; ref. ³). ... 

This strongly suggests that the NRF2-mediated regulation of β-keratins we detected in Chicken skin has been compensated for by the loss of AREs and downregulation of ARE binding by NRF2 at Neoaves β-keratin loci. This pattern closely mirrors the loss of NRF2-mediated ARE-regulation in Neoaves GSTA2 (Fig. 4b). Together these analyses provide in vivo evidence that the evolution of NRF2-associated feather development genes may have been shaped by the constitutive activation of NRF2 in Neoaves.”

This reminded me of some work on the evolution of large brain size in humans & loss of body hair:

Hair for brain trade-off, a metabolic bypass for encephalization [2014] - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190188/

“Hair loss in humans is perplexing and raises many hypothetical explanations. This paper suggests that hair loss in humans is metabolically related to encephalization; and that hair covered hominids would have been unable to evolve large brains because of a dietary restriction of several amino acids which are essential for hair and brain development. We use simulations to imply that hair loss must have preceded increase in brain size & volume. In this respect we see hair loss as a major force in human evolution. We assume that hair reduction required favorable climatic conditions and must have been quick. Using evolutionary and ecological time scales, we pinpoint hair loss to a period around 2.2-2.4 million years ago. The dating is further supported by a rapid selection at that time of the sialic acid deletion mutation which may have protected growing human brains against calcium ion flux. In summary we view encephalization, in part, as a metabolic trade-off between hair and brain. Other biochemical changes may have intervened in the process too; and the deletion mutation of sialic acid hydroxylation may have been involved as well.

Human hair is composed of about 17% cysteine, a sulphuric amino acid noted for its ability to add rigidity to biological tissue (Table  3).”

Cysteine is also a major component of glutathione and a rate limiter for its synthesis; glutathione production is regulated through Nrf2. The Dror & Hopp 2014 paper mentions glutathione briefly; if the theory presented is correct, the increased need for glutathione synthesis is likely the major driver. In short, humans may have lost their body hair because of the increased demand for cysteine to produce glutathione which is needed to manage oxidative stress in the brain.

Birds upregulated glutathione synthesis by constitutive upregulation of Nrf2 and also avoided the problem of hyperkeratosis through downregulation of ARE binding by NRF2 at β-keratin loci. They have more glutathione, still have all their feathers, and no hyperkeratosis.

It is possible humans lost hair first, which freed up cysteine to be used for glutathione, which then allowed for encephalization. Hmmm...