AbstractBackgroundFrailty is a key element in healthy ageing in which muscle performance plays a main role. Beta‐hydroxy‐beta‐methylbutyrate (HMB) supplementation has shown favourable effects in modulating protein synthesis, improving muscle mass and function in interventional studies. Decreased age‐related endogenous HMB levels have been shown in previous studies. The aim of the present study is to assess whether there is an association between endogenous plasma HMB levels and frailty.MethodsData from 1290 subjects (56.98% women; mean ± standard deviation age 74.6 ± 5.95 years) from the Toledo Study for Healthy Aging were obtained. Participants had their frailty status qualified according to Fried's Frailty Phenotype (FFP) score and the Frailty Trait Scale in its 12‐domain version (FTS‐12). Plasma HMB levels were analysed by an ultrahigh‐performance liquid chromatography tandem mass spectrometry. Differences between groups (frail vs. non‐frail) were tested using Mann–Whitney U test, Kruskal–Wallis test and chi‐squared test. The association between HMB and frailty was assessed by multivariate linear and logistic regressions when frailty was analysed as continuous and binary, respectively. Models were adjusted by age, gender, comorbidity, body composition and protein intake.ResultsHMB levels were lower in those aged ≥75 years than in those aged 65–74 years, with an inverse linear relationship between age and HMB levels (β = −0.031; P = 0.018), mainly accounted by males (β = −0.062; P = 0.002). HMB levels were higher in men (0.238 ± 0.065 vs. 0.193 ± 0.051 ng/mL; P ≤ 0.001). HMB levels were significantly lower in frail than in non‐frail individuals: 0.204 ± 0.058 versus 0.217 ± 0.063 ng/dL (P = 0.001) according to the FFP and 0.203 ± 0.059 versus 0.219 ± 0.063 ng/mL (P < 0.001) according to FTS‐12. These differences showed a dose‐dependent profile when we compared them by quintiles of HMB (P for trend: 0.022; 0.012 and 0.0004, respectively, for FFP, FTS‐12 binary and FTS‐12 continuous). Variables associated with low HMB levels were body mass index, strength, exhaustion and weight loss. Frailty was associated with HMB levels in all the adjusted models, including the fully adjusted ones, no matter the tool used (odds ratio: 0.45 [0.26, 0.77] for FFP and 0.36 [0.20, 0.63] for FTS‐12 binary; β = −4.76 [−7.29, −2.23] for FTS‐12 score). This association was also observed when the analyses were done by quintiles, showing such association since Q4 (FFP), Q2 (FTS‐12 binary) and Q3 (FTS‐12 score). The associations were observed in the whole sample and in each gender.ConclusionsThere is an inverse association between HMB levels and frailty status. These findings support the design of targeted clinical trials to evaluate the effect of HMB supplementation in older frail people with low HMB levels.