Shichkova, PolinaCoggan, Jay S.Boci, ElvisFavreau, Cyrille Pierre HenriAntonel, Stefano MaximilianoMarkram, HenryKeller, Daniel2023-09-222023-09-222023-09-22202310.1101/2023.08.30.555341https://infoscience.epfl.ch/handle/20.500.14299/200914Cognitive impairments and neurodegeneration in aging are linked to disrupted brain energy metabolism. We address this experimentally challenging problem with a computational molecular model that provides mechanistic insights and therapeutic predictions. This model encompasses key enzymes, transporters, metabolites, and other important factors, enabling the investigation of over 66,000 molecular interactions within and across cellular and subcellular compartments of neurons, glia, and blood vessels. During aging, action potential generation is primarily impaired due to reduced expression of the Na+/K+-ATPase pump and diminished ATP supply. The metabolic system loses flexibility, hindering its ability to effectively respond to stimuli or adapt to molecular damage. Astrocytes may defer to neuronal energy stability at their own expense. We identified potential strategies for rejuvenating the aged brain including supplying nutritional factors to the blood, increasing the NADH cytosol-mitochondria shuttle capacity and the expression of Na+/K+-ATPase. Transcription factor analysis implicated the estrogen related receptor alpha (ESRRA) as having the highest potential impact on aging, suggesting that dysregulated energy metabolism may be a transitional state between healthy aging and neurodegenerative disorders, rather than a hallmark of aging. This high-fidelity model serves as a foundation for future research on aging and cognitive health.aging brainneurodegenerationmolecular interactionstext::journal::journal article::research article