Exercise is associated with attenuated aging-related osteoporosis through TMAO alpha Klotho inflammasome signaling.

Age-related osteoporosis is shaped by disrupted bone remodeling, metabolic stress, and inflammation. We combined an exploratory clinical comparison in adults aged 65 years and older with a D-galactose aging rat model and osteoblast-like cell experiments to examine exercise-associated changes in trimethylamine N-oxide (TMAO) and inflammasome signaling. Higher habitual activity in older adults was associated with higher hip T scores, lower serum and fecal TMAO, reduced IL-18 and IL-1β, and a turnover profile favoring bone formation. In aged rats, exercise lowered circulating and femoral marrow TMAO, preserved trabecular architecture, improved maximal load, and restrained TXNIP NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling while maintaining alpha Klotho. In osteoblast-like cells, TMAO promoted senescence and inflammasome assembly, whereas pathway modulation reduced these effects. These data support a gut bone inflammatory framework for exercise-associated skeletal protection in aging.