Targeting neural stem cell senescence for brain aging and neurodegeneration

Neural stem cells (NSCs) are central to maintaining adult brain plasticity through self-renewal and neurogenesis. However, aging induces profound morphological, functional, and molecular alterations in NSCs, including stem cell pool depletion, impaired activation, lineage bias toward gliogenesis, mitochondrial dysfunction, and dysregulated signaling pathways. These changes contribute directly to cognitive decline and the progression of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. This review summarizes advances in understanding the hallmarks of NSC aging, encompassing structural degeneration, impaired neurogenesis, and cascading dysregulation of metabolic, oxidative stress, inflammatory, and differentiation pathways. We also discuss promising therapeutic strategies aimed at delaying or reversing NSC aging. Pharmacological interventions, including senolytics, senomorphics, and bioactive compounds such as ginsenosides and polysaccharides, show potential in restoring NSC function. Cell transplantation and exosome-based therapies offer new means to replenish the neurogenic niche or deliver anti-aging signals. Furthermore, clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing provides unprecedented precision in rejuvenating aged NSCs by erasing “aging memory” and restoring proliferation. Lifestyle interventions, particularly exercise, also emerge as accessible approaches to enhance endogenous neurogenesis. Together, these advances reveal the dual scientific and clinical significance of targeting NSC aging: elucidating mechanisms of cellular senescence and offering strategies to delay brain aging and treat neurodegenerative diseases. By integrating molecular insights with translational progress, NSC-based interventions may pave the way for innovative anti-aging therapies and neuroregenerative medicine.