Reversing brain aging: Targeting energy metabolism in endogenous neural stem cells

Abstract Brain aging is a primary driver of human aging, and the decline of endogenous neural stem cells (eNSCs) is a central mechanism in this process. eNSCs, located in the subventricular zone and subgranular zone, are essential for neuronal regeneration and brain repair. Their aging process is closely associated with dysregulated energy metabolism, which is specifically manifested as homeostatic imbalances in key metabolic pathways, including the tricarboxylic acid cycle, glycolysis, oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism. This metabolic dysregulation serves both as a hallmark and a catalyst of brain aging and related disorders. Targeting eNSC energy metabolism is a promising strategy for counteracting brain aging. Interventions such as targeting mitochondrial function of eNSCs, modulating key metabolic pathways and therapeutic targets in eNSCs, and targeted activation of eNSCs, can activate eNSCs and promote nerve regeneration. Shifting brain senescence from an irreversible process to a modifiable process represents a transformative paradigm in aging research. Elucidating the molecular mechanism that regulates the changes in the metabolic lineage of eNSCs during brain aging will not only accelerate the cure of neurological diseases but also open up a new perspective for the development of advanced brain functions.