Brain metabolism is closely linked to systemic energy homeostasis, the central nervous system (CNS) playing a pivotal role in a whole-body energy partitioning and substrate availability for different organs. Glutamate dehydrogenase (GDH), encoded by Glud1, is a mitochondrial enzyme that catalyzes the oxidative deamination of glutamate to α-ketoglutarate, thereby coupling amino acid catabolism to mitochondrial energy production and neurotransmitter turnover in the CNS. Owing to this central position in neuronal metabolism, GDH has been recognized as a key regulator of brain neurometabolic homeostasis and is increasingly implicated in psychiatric and neurodegenerative disorders. While the peripheral functions of GDH in hepatic and pancreatic functions are well established, its central role in coordinating brain energy metabolism with systemic physiology, particularly during aging, remains poorly understood. This represents a critical gap in our understanding of how central metabolic enzymes integrate neuronal and whole-body energy demands. To address this, we investigated the impact of CNS-specific Glud1 deletion (Cns-Glud1⁻/⁻ mice) on brain-periphery communication, behavioral adaptation, and hippocampal metabolism across the lifespan. Multimodal analyses combining high-resolution enzymatic histochemistry, mass spectrometry imaging, and behavioral profiling revealed that loss of brain GDH reshapes systemic growth and tissue composition in a sex- and age-dependent manner, with preserved glycemic control. Under physiological conditions, GDH localized predominantly to astrocyte-rich synaptic layers of the hippocampus, and its expression declined with age. With central GDH deletion, hippocampal mitochondrial oxidative capacity and overall energy metabolism remained active, although lacking induction of compensatory pathways. Spatial metabolite profiling uncovered selective accumulation of glutamate, GABA- γ-aminobutyric acid and aspartate, reflecting disrupted glutamate oxidation and a shifted excitatory–inhibitory neurotransmitter balance. These neurochemical changes emerged with age and were accompanied by late-onset reductions in spontaneous locomotor and motivational behaviors, specifically in males. Together, these results identify brain GDH as a metabolic nexus that couples central neurotransmitter metabolism to systemic energy regulation. These findings bridge the gap between central amino acid metabolism and overall physiology, providing new insight into how the brain safeguards its energetic demands while reshaping peripheral metabolism across the lifespan.