Comparative lifespan trajectories of brain energy metabolism in human and macaque

Abstract

The brain's extraordinary energy demands are met by a suite of metabolic pathways that selectively appropriate glucose across development, yet how this metabolic strategy changes across the lifespan and whether it is conserved across species remains incompletely understood. We previously mapped five core energy metabolism pathways across the human cortex and lifespan, revealing a fundamental dichotomy between anabolic and energy-producing pathway expression: the pentose phosphate pathway, which contributes to biomass, peaks prenatally, while glycolysis, the TCA cycle, and oxidative phosphorylation rise postnatally. Here, we extend the analysis to the rhesus macaque and show that the prenatal-to-postnatal transition is similar across the two species. Using the MitoCarta3.0 annotation framework, we further identify two consistent mitochondria-specific programs: a progressive decline in mitochondrial genome maintenance pathways, and a postnatal rise in mitochondrial energy production and substrate utilization, replicated across human and macaque. Extending to mouse, rat, and chicken, we find this shifting metabolic strategy is a conserved feature of vertebrate brain development. Finally, we map the cortical expression of mitochondria-localized pathway genes in the adult human cortex, finding that the anabolic-oxidative dichotomy follows in the mature brain. Together, these findings provide a comparative transcriptomic framework for studying brain energy metabolism across the lifespan.