Thermoregulatory Constraints on Regenerative Competence: Evolutionary Trade-Offs Between Metabolic Homeostasis and Tissue Repair

Regenerative capacity varies widely across the animal kingdom, yet adult mammals and birds exhibit limited ability to regenerate complex tissues such as the central nervous system (CNS). The evolutionary basis for this loss of regenerative competence remains poorly understood. Here we advance a Thermoregulatory Theory of Regenerative Scope, proposing that the emergence and refinement of endothermic physiology shaped tissue-specific molecular architectures that can bias injury responses away from regeneration in highly metabolic organs. Rather than imposing a systemic energetic constraint, we suggest that endothermy provided the evolutionary context in which thermogenic calcium-handling systems became increasingly specialized in excitable tissues. In particular, futile Ca{superscript 2} cycling across the sarco/endoplasmic reticulum through SERCA pumps contributes to heat generation but may also promote sustained intracellular Ca{superscript 2} elevations that activate inflammatory and fibrotic/gliotic signaling pathways incompatible with functional regeneration. Comparative observations indicate that regenerative competence is retained in ectothermic vertebrates and in mammalian contexts where thermoregulatory systems are developmentally immature or physiologically attenuated. Importantly, regenerative outcomes differ substantially among tissues within endothermic organisms, suggesting that local calcium regulatory architectures, rather than metabolic intensity alone, may determine regenerative potential. This framework generates experimentally testable predictions linking thermogenic Ca{superscript 2} signaling to regenerative failure and provides an evolutionary lens through which disparate observations in regenerative biology may be unified.