Urolithin A and Endothelial and Cerebrovascular Function in Middle-Aged Adults With Obesity

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