Pelaez, D.; Moulin, C. M.; Chang, J.; Knechtel, K.

Regenerative capacity varies widely across the animal kingdom, yet adult mammals and birds exhibit limited ability to regenerate tissues such as the central nervous system (CNS). The evolutionary basis for this loss of regenerative competence remains unclear. Here we advance a Thermoregulatory Theory of Regenerative Scope, positing that the emergence and refinement of endothermic thermoregulation imposed energetic and molecular constraints that progressively limited regenerative potential in highly metabolic tissues. Comparative biology observations reveal that robust regeneration is retained in ectothermic vertebrates and in specific mammalian contexts where thermoregulation is developmentally immature or physiologically attenuated, including neonatal rodents and poikilothermic species. Notably, the developmental acquisition of endothermic capacity in mammals coincides with the decline of regenerative competence. We propose that this trade-off arises from both energetic competition and molecular interference between thermogenic pathways and injury-response programs. Central to this framework is calcium-dependent signaling associated with thermogenesis. Futile Ca2+ cycling across the sarco/endoplasmic reticulum through SERCA pumps contributes to heat generation but can also promote sustained intracellular Ca2+ elevations that activate inflammatory and fibrotic signaling pathways incompatible with functional regeneration. Proteomic analyses identifying NNAT and TRIM59 as candidate SERCA-associated regulators in the mammalian CNS suggest a molecular crosstalk linking thermogenic Ca2+ handling with regenerative failure. Together, these observations support a model in which the evolution of endothermy favored metabolic responsiveness and immune competence at the expense of regenerative capacity.