Age-related neurodegenerative disorders, including dementia, are a major global health concern. This article describes the first comprehensive, data-driven molecular model of the neuro-glia-vascular system to explore the complex relationships between the aging brain, energy metabolism, blood flow, and neuronal activity. Comprising 16,800 interaction pathways, the model includes all key enzymes, transporters, metabolites, and circulatory factors vital for neuronal electrical activity. We found significant alterations in metabolite concentrations and differential effects on adenosine triphosphate (ATP) supply in neurons and astrocytes and within subcellular compartments in aged brains and identified reduced sodium/potassium adenosine triphosphatase (Na⁺/K⁺-ATPase) activity as the leading cause of impaired neuronal action potentials.