{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T14:13:13Z","timestamp":1780668793375,"version":"3.54.1"},"reference-count":81,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:00:00Z","timestamp":1726617600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013831","name":"Buck Institute for Research on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013831","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["K01AG078125"],"award-info":[{"award-number":["K01AG078125"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Frailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that interventions which target common underlying mechanism of aging could ameliorate frailty. Ketone bodies are metabolites produced during fasting or on a ketogenic diet that have pleiotropic effects on inflammatory and metabolic aging pathways in laboratory animal models. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate aging biology mechanisms and clinical outcomes relevant to frailty in older adults.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Objectives<\/jats:title>\n<jats:p>The primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a broad population of older adults (\u2265 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Community-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n = 30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>This study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of aging-related endpoints. This data will inform design of larger trials to rigorously test KE effects on aging mechanisms and clinical outcomes relevant to frailty.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0307951","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T17:26:57Z","timestamp":1726680417000},"page":"e0307951","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Rationale and protocol for a safety, tolerability and feasibility randomized, parallel arm, double-blind, placebo-controlled, pilot study of a novel ketone ester targeting frailty via immunometabolic geroscience mechanisms"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9566-9134","authenticated-orcid":true,"given":"Brianna J.","family":"Stubbs","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Alvarez Aza\u00f1edo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sawyer","family":"Peralta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie Roa","family":"Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wyatt","family":"Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Alexander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendie","family":"Silverman-Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thelma Y.","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Traci M.","family":"Blonquist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaibhav","family":"Upadhyay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Turnbaugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Newman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,9,18]]},"reference":[{"issue":"11","key":"pone.0307951.ref001","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1093\/gerona\/glw149","article-title":"Strategies and Challenges in Clinical Trials Targeting Human Aging","volume":"71","author":"JC Newman","year":"2016","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"11","key":"pone.0307951.ref002","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1093\/gerona\/glw126","article-title":"Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes","volume":"71","author":"J Justice","year":"2016","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"10206","key":"pone.0307951.ref003","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/S0140-6736(19)31785-4","article-title":"Management of frailty: opportunities, challenges, and future directions","volume":"394","author":"E Dent","year":"2019","journal-title":"Lancet"},{"issue":"11","key":"pone.0307951.ref004","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1093\/gerona\/glv133","article-title":"Frailty in Older Adults: A Nationally Representative Profile in the United States","volume":"70","author":"K Bandeen-Roche","year":"2015","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"4","key":"pone.0307951.ref005","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1007\/s11357-020-00208-x","article-title":"Poor mitochondrial health and systemic inflammation? 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