Adult hippocampal neurogenesis (AHN) deficits contribute to the progression of cognitive impairments during accelerated senescence, with the mechanistic causes poorly understood. Glycogen synthase kinase-3 beta (GSK-3 beta) is a critical regulator in prenatal neurodevelopment. The present study aims to study whether and how GSK-3 beta regulates AHN during the accelerated senescence. Methods: AHN and AHN-dependent cognition and GSK-3 beta were evaluated in 3- and 6-month senescence-accelerated mice prone 8 (SAM-P8) and senescence resistant 1 (SAM-R1) mice, respectively. GSK-3 beta was selectively overexpressed in wild-type mice using adeno-associated virus, or knocked-out by crossbreeding with GSK-3 beta floxed mice in the neural stem cells (NSCs) of Nestin-Cre mice, or pharmacologically inhibited with SB216763 in SAM-P8 mice. AHN was evaluated by BrdU-, DCX-staining and retrovirus-labeling. Results: AHN transiently increased at 3-month, but dramatically dropped at 6-month of age in SAM-P8 mice with a simultaneous activation of GSK-3 beta at 3-month. Selective overexpression of GSK-3 beta in hippocampal NSCs of wildtype mice induced long-term AHN deficits due to an accelerated depletion of NSC pool, although it transiently increased the proliferation and survival of the newborn neurons. Pharmacologically inhibiting GSK-3 beta by SB216763 efficiently preserved AHN and improved contextual memory in 6-month SAM-P8 mice, while conditional knock-out of GSK-3 beta in NSCs impaired AHN. Conclusion: Early-stage activation of GSK-3 beta in NSCs impairs AHN by accelerating the depletion of NSC pool, and pharmacological inhibition of GSK-3 beta is efficient to preserve AHN during the accelerated aging. These results reveal novel mechanisms underlying the AHN impairments during accelerated senescence and provide new targets for pro-neurogenic therapies for related diseases.