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Why do many mammalian organs including the heart lose regenerative potential during the perinatal window remains enigmatic. Through phylogenetic analysis of non-model vertebrate species and mechanistic studies in zebrafish and mice, we provide evidence to support the critical roles of two major thermogenic neurohormonal pathways in suppressing heart regenerative capacity, and implicate that the limited regenerative capacity in various adult mammalian tissues may be a tradeoff for the acquisition of endothermy in ontogeny and phylogeny.