Aging is associated with skeletal fragility driven by impaired bone remodeling, increased oxidative stress, and the accumulation of senescent cells. To determine whether ortho-vanillin (o-Vanillin) can alleviate age-related deficits in bone, we examined femoral bone microarchitecture, biomechanical properties, bone turnover, bone marrow adiposity, oxidative stress, DNA damage, osteocyte senescence, and femoral fracture healing in C57BL/6 J mice. DEXA was additionally used to assess bone mineral density and content at the femur, tibia, spine, and whole body. Aged mice displayed substantial deterioration in femoral trabecular and cortical structure, reduced mechanical strength, diminished osteogenic activity, enhanced osteoclastogenesis, and increased marrow adiposity. Aging also elevated oxidative stress, lipid peroxidation, and DNA damage, and induced significant osteocyte senescence with upregulation of SASP factors. o-Vanillin administration attenuated these changes, improving femoral bone microarchitecture and strength, restoring osteoblast function, suppressing osteoclast activity and adipogenesis, reducing oxidative stress and γH2AX accumulation, and decreasing osteocyte senescence and SASP expression. In a mid-diaphyseal femoral fracture model, aged mice exhibited impaired callus formation and delayed healing, whereas o-Vanillin partially improved early cartilage formation, osteoblast activity, and mechanical strength of the healing callus. These findings demonstrate that o-Vanillin mitigates multiple age-related impairments in the femur and partially restores fracture healing capacity, supporting its potential as a senescence-targeting approach to improve skeletal health during aging.
