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 is associated with improved cognitive performance and enhanced 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 sex-specific differences in physiological and pathological hippocampal neurogenesis and in responsiveness to ER272 treatment. Male SAMR1 mice displayed higher baseline neurogenesis than females, while male and female SAMP8 mice followed distinct neurogenic aging trajectories. ER272 was associated with improved cognitive performance and preservation of multiple neurogenic parameters in males but showed limited effects in females. These results suggest sex-specific mechanisms of brain aging and indicate that mixed-sex analyses may mask biologically relevant differences, highlighting the importance of considering sex in aging studies and therapeutic development.