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This is controversially interpreted as a sign of immaturity or essential programming, increasing or decreasing the risk of sepsis, respectively. Here, combined transcriptomic, metabolic, and immunological studies in monocytes of healthy individuals reveal an inverse ontogenetic shift in metabolic pathway activities with increasing age. Neonatal monocytes are characterized by enhanced oxidative phosphorylation supporting ongoing myeloid differentiation. This phenotype is gradually replaced during early childhood by increasing glycolytic activity fueling the inflammatory responsiveness. Microbial stimulation shifts neonatal monocytes to an adult-like metabolism, whereas ketogenic diet in adults mimicking neonatal ketosis cannot revive a neonate-like metabolism. 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