Urolithin A and Endothelial and Cerebrovascular Function in Middle-Aged Adults With Obesity: A Randomized Clinical Trial.

Authors

Ana Clara da Costa Pinaffi-Langley, Rafal Gulej, Zalan Kaposzta, Zsofia Szarvas, Ali Shahriari, Henry Kinnard, Bryan Ticer, Camila B Pinto, Peter Mukli, Mihaly Muranyi, Cheryl Adams, Jeng Kong, Leah Anderson, Stefano Tarantini, Yan Daniel Zhao, Norman G Hord, Andriy Yabluchanskiy

Published in

JAMA network open. Volume 9. Issue 10. Pages e2638047. Oct 01, 2026. Epub Oct 01, 2026.

Abstract

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.
To investigate whether supplementation with UA improved peripheral endothelial and cerebrovascular function in middle-aged adults with obesity.
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.
Enrolled participants were randomized 1:1 to receive 1000 mg of UA or placebo for 4 weeks.
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.
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.
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.
ClinicalTrials.gov: NCT05921266.

PMID:
42853569
Bibliographic data and abstract were imported from PubMed on 10 Oct 2026.

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