Background: Neural stem cells (NSCs) disrupt with aging, contributing to neurodegeneration. Ginsenoside Rg1 (Rg1), a compound found in Ginseng, is known for its anti-aging effects; however, its role in the progression of aging NSCs remains unclear. Therefore, this investigation explored the impact of Rg1 on the growth and maturation of aging NSC and elucidated its underlying molecular mechanisms. Methods: Initially, mouse models of brain aging were successfully established using D-galactose (D-gal) injection. Mice received Rg1 treatment along with D-gal administration. Brain tissues and NSCs were isolated and analyzed for pathological changes, gene expression, and cellular function. In vitro, experiments used aging NSCs treated with Rg1 to assess cell viability, proliferation, differentiation, and senescence markers. Results: D-gal triggered aging-related pathological alterations in mouse brains, elevated acetylcholinesterase levels, upregulated senescence genes, and inhibited NSC proliferation (p &lt; 0.05). However, Rg1 treatment mitigated D-gal-induced effects, delayed brain aging, and improved NSC function. In vitro, Rg1 significantly increased cell viability, promoted NSC proliferation and differentiation, reduced senescent neurons, and downregulated p53 and p21 genes (p &lt; 0.05). Conclusions: Rg1 demonstrates anti-aging properties in D-gal-induced mouse brain aging, promoting the proliferation and differentiation of NSCs, and downregulating the p53-p21 signaling pathway.

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