Study Links Higher Physical Activity With Lower TMAO and Better Bone Measures

Higher habitual physical activity was associated with healthier bone measures and lower levels of trimethylamine N-oxide (TMAO) in a study combining an exploratory comparison of older adults with experiments in aged rats and osteoblast-like cells.

In adults aged 65 and older, participants with higher activity levels had higher hip bone-density T scores, lower TMAO concentrations in serum and fecal samples, and reduced levels of the inflammatory molecules interleukin-18 and interleukin-1β. Their bone-turnover profile also favored bone formation over breakdown.

The human findings were observational, so they identified relationships rather than establishing that physical activity caused the changes. The study also did not demonstrate that lowering TMAO prevents osteoporosis or fractures.

The researchers examined TMAO because it is produced through a process involving gut microbial metabolism of dietary choline, phosphatidylcholine, and L-carnitine. The source material describes elevated TMAO as being linked with chronic low-grade inflammation and oxidative stress, and reports that earlier mechanistic work has implicated the compound in reduced osteogenic differentiation and increased osteoclast activity. Osteoblasts build bone matrix, while osteoclasts break it down; an imbalance favoring osteoclast activity contributes to bone loss.

The study focused on signaling involving α-Klotho, TXNIP, and the NLRP3 inflammasome. NLRP3 activation promotes maturation and release of interleukin-1β and interleukin-18, which can amplify inflammation and impair osteoblast function. The researchers hypothesized that exercise might reduce TMAO-associated stress while preserving α-Klotho’s restraint of the TXNIP/NLRP3 pathway.

The animal and laboratory experiments provided additional, but preclinical, evidence. In an aging rat model produced with D-galactose, exercise lowered TMAO in circulation and femoral bone marrow, preserved the architecture of trabecular bone, improved maximal load, and restrained TXNIP–NLRP3 signaling while maintaining α-Klotho. In osteoblast-like cells, TMAO promoted cellular senescence and inflammasome assembly, while changing the relevant pathway reduced those effects.

Taken together, the findings support what the researchers describe as a gut–bone inflammatory framework for exercise-associated skeletal protection during aging. The rat and cell results offer possible biological explanations for the human associations, but they do not establish that the same pathway produces a clinical benefit in people. The study also leaves unresolved whether changes in TMAO are a cause of activity-related bone differences, a consequence of other metabolic changes, or one part of a broader process.