Total and regional fat-to-muscle ratio, frailty status, and multi-organ proteomic age-acceleration patterns: Evidence from the UK Biobank.

OBJECTIVES: Fat-to-muscle ratio reflects the imbalance between fat accumulation and estimated muscle mass, but its associations with frailty and multi-organ proteomic age acceleration remain unclear. STUDY DESIGN: This cross-sectional analysis included 445,317 UK Biobank participants, with 39,782 in proteomic analyses. Whole-body, trunk, leg, and arm fat-to-muscle ratios were derived from bioelectrical impedance. Sex-stratified multinomial logistic regression assessed associations with pre-frailty and frailty and incremental value beyond body mass index. MAIN OUTCOME MEASURES: Frailty status was defined using an adapted Fried phenotype. Organ-specific proteomic age-acceleration measures were derived using published ageing models, and concordance between fat-to-muscle ratio-related and frailty-related age-acceleration patterns was evaluated. RESULTS: Higher total and regional fat-to-muscle ratios were associated with greater odds of pre-frailty and frailty in both sexes, with arm ratio showing the most pronounced regional associations. Per one-standard-deviation higher arm ratio, the odds ratios for frailty were 1.86 (95% confidence interval 1.79-1.92) in men and 2.95 (95% confidence interval 2.75-3.18) in women. Adding arm ratio to body mass index-based models increased the area under the receiver operating characteristic curve by 0.0137 in men and 0.0068 in women. Higher fat-to-muscle ratios and frailty status were associated with multi-organ proteomic age acceleration, with the clearest concordance for arm ratio-related and frailty-related patterns. CONCLUSIONS: Regional fat-muscle imbalance, particularly in the arms, may provide complementary information on frailty-related body composition beyond body mass index and is associated with multi-organ proteomic age-acceleration patterns.