Circulating Tsukushi Predicts Incident Sarcopenia and Functional Decline in Older Adults: A Prospective Cohort Study

BACKGROUND: Sarcopenia is a major age-related condition associated with functional decline, disability and mortality in older adults, yet reliable circulating biomarkers for early risk stratification remain limited. Tsukushi (TSK), a secreted hepatokine involved in systemic metabolic regulation, has recently been implicated in skeletal muscle homeostasis. However, prospective clinical evidence linking circulating TSK to sarcopenia development is lacking. We therefore investigated the association between serum TSK levels and incident sarcopenia in a community-based cohort of older adults. METHODS: A total of 1370 community-dwelling individuals aged ≥ 65 years were followed for 4 years. Baseline serum TSK levels were measured using enzyme-linked immunosorbent assay. Multivariable Cox proportional hazards models were used to assess the association between TSK and incident sarcopenia after adjustment for confounding factors. Restricted cubic spline analyses were applied to explore dose-response relationships, and predictive performance was evaluated using time-dependent receiver operating characteristic (ROC) curves. RESULTS: Lower baseline TSK levels were associated with a higher cumulative incidence of sarcopenia. In multivariable analyses, higher TSK levels were associated with a lower risk of incident sarcopenia (hazard ratio per SD increase = 0.64, 95% CI = 0.53-0.76, p < 0.001). Dose-response analyses demonstrated a non-linear association with overall sarcopenia risk, whereas associations with low muscle strength and low physical performance were more nearly linear. The association appeared more evident in women than in men. TSK alone showed moderate discrimination for incident sarcopenia (AUC = 0.700), while a combined clinical model improved discrimination (AUC = 0.808 at 4 years). CONCLUSIONS: Lower circulating TSK levels are associated with a higher risk of incident sarcopenia in older adults, particularly subsequent muscle-related functional decline. TSK may be a candidate biomarker for early sarcopenia risk stratification and may reflect systemic metabolic processes relevant to muscle health.