Sex-Specific neurogenic and cognitive responses in a murine model of accelerated aging

Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer’s disease-like neuropathology, and an initial increase in hippocampal neurogenesis that ultimately depletes the neural stem cell pool. Notably, most studies using murine models of aging or neurodegeneration have focused on males or mixed-sex cohorts, leaving sex-specific differences in neurogenesis and cognitive decline largely unexplored. Recent evidence indicates that diterpenoid treatment ameliorates cognitive decline and enhances neurogenesis in 6-month-old male SAMP8 mice. However, whether females exhibit similar responses remains unknown. In this study, we characterized sex differences in hippocampal neurogenesis in 6-month-old SAMP8 mice and examined potential sex-dependent effects of diterpenoid therapy. Our findings reveal marked sex differences in neurogenic capacity and treatment responsiveness. While diterpenoid treatment enhanced hippocampal neurogenesis and cognitive performance in males, these effects were largely absent in females. Overall, female SAMP8 mice exhibited reduced baseline neurogenesis and a diminished response to therapy, underscoring the importance of considering biological sex in the design of therapeutic strategies for age-related cognitive decline.