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Beta\u2010hydroxy\u2010beta\u2010methylbutyrate (HMB) supplementation has shown favourable effects in modulating protein synthesis, improving muscle mass and function in interventional studies. Decreased age\u2010related 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data from 1290 subjects (56.98% women; mean\u00a0\u00b1\u00a0standard deviation age 74.6\u00a0\u00b1\u00a05.95\u00a0years) 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\u2010domain version (FTS\u201012). Plasma HMB levels were analysed by an ultrahigh\u2010performance liquid chromatography tandem mass spectrometry. Differences between groups (frail vs. non\u2010frail) were tested using Mann\u2013Whitney <jats:italic>U<\/jats:italic> test, Kruskal\u2013Wallis test and chi\u2010squared 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HMB levels were lower in those aged \u226575\u00a0years than in those aged 65\u201374\u00a0years, with an inverse linear relationship between age and HMB levels (<jats:italic>\u03b2<\/jats:italic>\u00a0=\u00a0\u22120.031; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.018), mainly accounted by males (<jats:italic>\u03b2<\/jats:italic>\u00a0=\u00a0\u22120.062; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.002). HMB levels were higher in men (0.238\u00a0\u00b1\u00a00.065 vs. 0.193\u00a0\u00b1\u00a00.051\u00a0ng\/mL; <jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.001). HMB levels were significantly lower in frail than in non\u2010frail individuals: 0.204\u00a0\u00b1\u00a00.058 versus 0.217\u00a0\u00b1\u00a00.063\u00a0ng\/dL (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.001) according to the FFP and 0.203\u00a0\u00b1\u00a00.059 versus 0.219\u00a0\u00b1\u00a00.063\u00a0ng\/mL (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) according to FTS\u201012. These differences showed a dose\u2010dependent profile when we compared them by quintiles of HMB (<jats:italic>P<\/jats:italic> for trend: 0.022; 0.012 and 0.0004, respectively, for FFP, FTS\u201012 binary and FTS\u201012 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\u201012 binary; <jats:italic>\u03b2<\/jats:italic>\u00a0=\u00a0\u22124.76 [\u22127.29, \u22122.23] for FTS\u201012 score). This association was also observed when the analyses were done by quintiles, showing such association since Q4 (FFP), Q2 (FTS\u201012 binary) and Q3 (FTS\u201012 score). The associations were observed in the whole sample and in each gender.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>There 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13394","type":"journal-article","created":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T08:08:43Z","timestamp":1702454923000},"page":"231-239","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Association between endogenous plasma beta\u2010hydroxy\u2010beta\u2010methylbutyrate levels and frailty in community\u2010dwelling older people"],"prefix":"10.1002","volume":"15","author":[{"given":"Bego\u00f1a","family":"Molina\u2010Baena","sequence":"first","affiliation":[{"name":"Hospital Universitario de la Princesa  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Antonio","family":"Carnicero","sequence":"additional","affiliation":[{"name":"Geriatric Research Group Biomedical Research Foundation at Getafe University Hospital  Madrid Spain"},{"name":"CIBER of Frailty and Healthy Aging (CIBERFES) Institute of Health Carlos III  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzette L.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Scientific &amp; Medical Affairs, Research &amp; Development Abbott Nutrition  Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Jos\u00e9","family":"Garc\u00eda\u2010Garc\u00eda","sequence":"additional","affiliation":[{"name":"CIBER of Frailty and Healthy Aging (CIBERFES) Institute of Health Carlos III  Madrid Spain"},{"name":"Department of Geriatrics Hospital Virgen del Valle  Toledo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Santos\u2010Fandila","sequence":"additional","affiliation":[{"name":"Scientific &amp; Medical Affairs, Research &amp; Development Abbott Nutrition  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Rueda","family":"Cabrera","sequence":"additional","affiliation":[{"name":"Scientific &amp; Medical Affairs, Research &amp; Development Abbott Nutrition  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6551-1333","authenticated-orcid":false,"given":"Leocadio","family":"Rodr\u00edguez\u2010Ma\u00f1as","sequence":"additional","affiliation":[{"name":"Geriatric Research Group Biomedical Research Foundation at Getafe University Hospital  Madrid Spain"},{"name":"CIBER of Frailty and Healthy Aging (CIBERFES) Institute of Health Carlos III  Madrid Spain"},{"name":"Department of Geriatrics Getafe University Hospital  Madrid 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