Chronic rapamycin treatment attenuates age-related motor deficits in sex-dependent manner in UM-HET3 mice

Interventions Testing Program identified rapamycin as a robust lifespan-extending agent at multiple testing sites and in both sexes, with particularly strong effects in females, making it a leading candidate in aging research. We used genetically heterogeneous UM-HET3 mice of both sexes to determine whether rapamycin can prevent or delay age-sensitive traits. Mice were supplemented with microencapsulated rapamycin at 14 ppm starting at 12 months of age. Chronic rapamycin supplementation prevented the age-related decline in motor function, with females benefiting more than males. We further determined that rapamycin attenuated the age-related increase in protein carbonyls, principally in the insoluble protein fraction of brain regions that subserve motor function. We also found increased protein expression of glial fibrillary acidic protein (GFAP) across several brain regions, surprisingly, rapamycin treatment further increased GFAP levels in the striatum of both sexes, however this increase is not supporting evidence for a decrease in oxidative stress. Age-related increase in ER stress has been reported to be associated with increased protein carbonyls. We observed that rapamycin reduced the expression of C/EBP homologous protein (CHOP), a marker of ER stress-mediated apoptosis, in the striatum region of female mice. Our data show a novel beneficial effect of rapamycin on age-related motor deficits that is not sex-specific and that these changes are associated with reduction in protein carbonyls in brain regions linked to motor function. Furthermore, our results are consistent with the idea that rapamycin's beneficial effects are mediated, at least in part, by reducing oxidative stress and ER stress-mediated apoptosis.