Geroprotective interventions preserve trabecular bone during ageing in female mice

Geroprotectors extend lifespan and improve several aspects of healthspan, yet their effects on skeletal ageing remain poorly understood. They hold potential advantages over current bone-targeted osteoporosis therapies, as they may simultaneously improve bone, neuromuscular function, and vision, thereby reducing the risk of falls, the major cause of fractures. Here we examined, for the first time, the long-term effects of rapamycin, acarbose, and 17α-estradiol, administered at lifespan-extending doses on trabecular and cortical bone architecture in male and female UM-HET3 mice measured with micro-computed tomography at 12 and 22 months of age. Bayesian modelling analysis reveals that all interventions produced responses in trabecular bone in females at 22 months. These effects were driven mainly by increases in trabecular number, with little evidence for changes in trabecular thickness. In contrast, treatment effects in males were generally negligible. Cortical responses were modest. Moderate increases in cortical area fraction were observed in females treated with rapamycin or 17α-estradiol at 22 months, whereas cortical thickness remained largely unchanged, suggesting a geometrical rather than anabolic effect. Interestingly, geroprotectors' strongest skeletal responses in females contrasts with the predominantly male-biased lifespan extension reported for acarbose and 17α-estradiol, suggesting differential mechanisms mediating lifespan extension and bone structure preservation.