Predominant role of fat mass in the association between HMB and frailty

Background: β-Hydroxy-β-methylbutyrate (HMB) is a bioactive metabolite formed from the breakdown of leucine, which increases muscle protein synthesis and reduces muscle breakdown. Previous studies have shown an inverse association between HMB levels and frailty in older adults. This study aims to assess if body composition influences this association. Methods: A cross-sectional analysis was conducted using data from a cohort of adults ≥65 years from the Toledo Study of Healthy Aging. Body composition [total lean (TBLM) and fat mass (TBFM)] was assessed using dual-energy X-ray absorptiometry. Frailty was assessed with the Frailty Trait Scale (FTS-12). Six regression models were employed to examine HMB/body composition ratios and frailty, adjusting by age, sex, comorbidity, waist-to-hip ratio, nutritional status, and Mediterranean diet adherence. Results: Data from 1257 individuals (56.72% females, mean age 74.6±5.95 years) were analyzed. Significantly higher values of HMB levels were observed in men compared to women. HMB/body composition ratios were significantly associated with frailty in both sexes. Increased HMB/TBFM ratios occurred due to both higher HMB levels (Q1: 0.155±0.027 ng/mL vs Q4: 0.280±0.057 ng/mL) and lower fat mass (Q1: 19.11±3.12 kg/m² vs Q4: 11.34±2.44 kg/m²), whereas higher HMB/TBLM ratios were primarily driven by higher HMB levels (Q1: 0.149±0.023 ng/mL vs Q4: 0.292±0.05 ng/mL), whereas lean mass remained constant (Q1: 25.11±2.79 kg/m² vs Q4: 24.62±2.91 kg/m²). The protective effect of the HMB/TBFM ratio was independent of the lean mass ratio. Conclusion: The relationship between endogenous HMB and frailty is modified by body composition, with a stronger impact mediated by fat mass than lean mass. Future studies should explore the therapeutic implications of HMB supplementation in age-related changes in body composition and frailty.