{ "abstract": "Importance: Midlife obesity affects nearly half of US adults and is a major risk factor for chronic diseases. Mitochondrial dysfunction contributes to obesity-related endothelial dysfunction and disease risk, highlighting the mitochondria as a potential intervention target. Urolithin A (UA), a polyphenol-derived microbial metabolite and mitophagy activator, is safe and benefits mitochondrial health in humans.\n\nObjective: To investigate whether supplementation with UA improved peripheral endothelial and cerebrovascular function in middle-aged adults with obesity.\n\nDesign, Setting, and Participants: This was a double-blind, placebo-controlled randomized clinical trial conducted at a single site (University of Oklahoma Health Campus) from October 2023 to May 2025. Middle-aged adults (40-64 years) with a body mass index of 30 or greater were eligible to enroll.\n\nIntervention: Enrolled participants were randomized 1:1 to receive 1000 mg of UA or placebo for 4 weeks.\n\nMain Outcomes and Measures: The primary outcome was change in brachial artery flow–mediated dilation (FMD) from baseline to end point comparing control and active groups. Secondary outcomes included complementary peripheral endothelial function measures (reactive hyperemia–induced perfusion fold change and acute reperfusion in the dorsal hand and reactive hyperemia index in the fingertips) and cerebrovascular function measures (task-evoked cerebrovascular hemodynamic responses and task performance). Primary analyses followed the intention-to-treat principle.\n\nResults: Overall, 50 participants were included (25 active and 25 control); mean (SD) age was 50.7 (7.1) years, mean (SD) BMI was 38.3 (7.0), and 37 (74%) were female. Mean (SD) follow-up duration was 28 (2) days. Seven participants were lost to follow-up (14% dropout rate). Change in mean (SD) FMD did not differ significantly based on group allocation (control: 0.3% [5.1%]; active: 1.3% [7.6%]). Similarly, there was no significant treatment effect on secondary peripheral endothelial function outcomes. T-contrast maps showed significantly greater task-evoked hemodynamic responses after supplementation with UA relative to placebo (control: mean [SD] β coefficient, −1.43 [5.26]; active: mean [SD] β coefficient, 15.53 [13.02]), while task performance remained unchanged.\n\nConclusions and Relevance: In this randomized clinical trial of 50 participants, 4 weeks of UA supplementation did not significantly improve peripheral endothelial function in middle-aged adults with obesity. However, supplementation was well tolerated and feasible, and its effect on task-evoked cerebrovascular hemodynamic responses warrants further investigation.\n\nTrial Registration: ClinicalTrials.gov: NCT05921266", "abstract_shown": true, "affiliations": [ "Department of Nutritional Sciences, College of Allied Health, University of Oklahoma Health Center, Oklahoma City", "Department of Neurosurgery, College of Medicine, University of Oklahoma Health Center, Oklahoma City", "Oklahoma Shared Clinical and Translational Resources, University of Oklahoma Health Center, Oklahoma City", "Now with: College of Dental Medicine, Kansas City University, Joplin, Missouri", "1893 Pharmacy, College of Pharmacy, University of Oklahoma Health Center, Oklahoma City", "Department of Biostatistics & Epidemiology, College of Public Health, University of Oklahoma Health Center, Oklahoma City", "Department of Nutritional Sciences, College of Education and Human Sciences, Oklahoma State University, Stillwater", "Now with School of Human Environmental Sciences, University of Arkansas, Fayetteville" ], "article_type": null, "arxiv": null, "author_total": 17, "authors": [ { "affs": [ 0 ], "name": "Ana Clara da Costa Pinaffi-Langley" }, { "affs": [ 1 ], "name": "Rafal Gulej" }, { "affs": [ 1 ], "name": "Zalan Kaposzta" }, { "affs": [ 1 ], "name": "Zsofia Szarvas" }, { "affs": [ 2, 3 ], "name": "Ali Shahriari" }, { "affs": [ 4 ], "name": "Henry Kinnard" }, { "affs": [ 4 ], "name": "Bryan Ticer" }, { "affs": [ 1 ], "name": "Camila B. Pinto" }, { "affs": [ 1 ], "name": "Peter Mukli" }, { "affs": [ 1 ], "name": "Mihaly Muranyi" }, { "affs": [ 1 ], "name": "Cheryl Adams" }, { "affs": [ 1 ], "name": "Jeng Kong" }, { "affs": [ 0 ], "name": "Leah Anderson" }, { "affs": [ 1 ], "name": "Stefano Tarantini" }, { "affs": [ 5 ], "name": "Yan Daniel Zhao" }, { "affs": [ 6, 7 ], "name": "Norman G. Hord" }, { "affs": [ 1 ], "name": "Andriy Yabluchanskiy" } ], "bibtex": "https://research.draconitic.com/paper/1p1ax88n7s7dk.bib", "cited_by": 0, "doi": "10.1001/jamanetworkopen.2026.38047", "fulltext_url": null, "id": "1p1ax88n7s7dk", "issns": [ "2574-3805" ], "landing_url": "https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2855121", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2737|Nitric Oxide and Endothelin Effects" ] ], "openalex": "W7221195238", "pdf_url": null, "pmcid": null, "pmid": null, "published": "2026-10-09", "publisher": "American Medical Association (AMA)", "ris": "https://research.draconitic.com/paper/1p1ax88n7s7dk.ris", "sources": [ { "first_seen": "2026-10-30T12:19:46Z", "native_id": "10.1001/jamanetworkopen.2026.38047", "source": "crossref", "url": "https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2855121" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2737|Nitric Oxide and Endothelin Effects", "subfield": "physiology" } ], "title": "Urolithin A and Endothelial and Cerebrovascular Function in Middle-Aged Adults With Obesity", "title_text": "Urolithin A and Endothelial and Cerebrovascular Function in Middle-Aged Adults With Obesity", "type": "peer-reviewed", "updated_at": "2026-10-30T12:19:46Z", "url": "https://research.draconitic.com/paper/1p1ax88n7s7dk", "venue": "JAMA Network Open", "versions": [] }