Urolithin A did not improve blood vessel function in a four-week trial of 50 adults with obesity

Urolithin A is sold in capsules and powders as a supplement for healthy aging, on the strength of research into how cells renew their energy supply. A small trial has now tested one of the hopes attached to it: that it might help blood vessels work better in people whose vessels are under strain.

It did not. In a study published on October 9 in JAMA Network Open, four weeks of urolithin A left blood vessel function in middle-aged adults with obesity no different from placebo. One secondary measure, of blood flow in the brain during a mental task, did move, and the researchers say it should be followed up.

What urolithin A is and why blood vessels were tested

Urolithin A is not eaten as such. A review published this year describes it as generated by specific gut bacterial species and absent from food in free form. The bacteria make it from ellagitannins and ellagic acid, which are plant compounds. Raspberries are a rich source of ellagitannins and anthocyanins, to take one food.

Interest in it centers on mitochondria, the structures inside cells that produce energy. Urolithin A prompts a process called mitophagy, in which cells break down worn-out mitochondria so that new ones can replace them. One research group calls it the recycling of faulty mitochondria during aging.

The connection to blood vessels runs through the endothelium, the thin layer of cells that lines every vessel and controls how it widens and narrows. The trial’s authors start from the scale of the problem: midlife obesity affects nearly half of US adults and is a major risk factor for chronic diseases. They argue that mitochondrial dysfunction contributes to obesity-related endothelial dysfunction and disease risk. Dysfunction means not working properly. If failing mitochondria are part of why vessels stop working well in obesity, a compound that renews mitochondria might help.

The stakes are set out in the team’s published protocol. Poorly working endothelium, it says, in turn contributes to the development of several diseases, such as cardiovascular disease and cognitive impairment. The same document was frank about the gap. Of urolithin A, it said, its potential to mitigate endothelial dysfunction in obese adults remains unknown.

How the urolithin A trial worked

The study was run at the University of Oklahoma, with Ana Clara da Costa Pinaffi-Langley as first author and Andriy Yabluchanskiy as senior author. It was a double-blind, placebo-controlled randomized clinical trial conducted at a single site between October 2023 and May 2025. Double-blind means neither the participants nor the staff assessing them knew who was taking what.

Middle-aged adults (40-64 years) with a body mass index of 30 or greater were eligible to enroll. Body mass index is weight in kilograms divided by the square of height in meters, and 30 is the usual threshold for obesity. The trial’s entry on ClinicalTrials.gov, the US government’s public register of trials, lists reasons for exclusion, among them uncontrolled high blood pressure or diabetes and a history of cognitive impairment.

The registry had planned for 54 people. In the end 50 participants were included (25 active and 25 control). Their average age was 50.7, their average body mass index was 38.3, and 37 of them (74%) were women.

The dose was the highest used in earlier human studies. The registry describes the active group as assigned to consume 1,000 mg of urolithin A daily in the form of softgel capsules, while the others took a placebo. This went on for four weeks.

Measurements were taken twice, at the start and after 28 days. The primary outcome was change in brachial artery flow-mediated dilation (FMD) from baseline to end point comparing control and active groups. The brachial artery is the main artery of the upper arm. In the test, a cuff briefly cuts off blood flow to the forearm. When it is released, blood surges back and a healthy artery widens in response. Ultrasound measures by how much. A primary outcome is the one result a trial is designed and sized to answer.

Secondary outcomes covered two further areas. One was the small vessels, tested by how blood flow rebounded in the back of the hand and in the fingertips. The other was the brain, which the paper lists as task-evoked cerebrovascular hemodynamic responses and task performance. Hemodynamic means relating to blood flow. In plain terms, the researchers recorded how blood flow in the brain responded while participants did a mental task, and how well they did on it.

The registered hypothesis was a positive one. In the registry’s words, researchers expect that urolithin A supplementation in middle-aged adults with obesity improves endothelial function and cerebral blood flow regulation.

What happened to blood vessel function

The main result was null. Flow-mediated dilation changed by an average of 0.3% in the placebo group and 1.3% in the urolithin A group, a gap the analysis could not tell apart from chance. Individual results varied widely around those averages. The spread, a measure of how far individuals sat from the average, was 5.1% in the placebo group and 7.6% in the urolithin A group.

The paper’s conclusion is that four weeks of the supplement did not improve peripheral endothelial function in middle-aged adults with obesity. Peripheral here refers to the body’s limbs, as opposed to the brain.

The small vessels told the same story. The authors report no treatment effect on secondary peripheral endothelial function outcomes.

Not everyone finished. Seven participants were lost to follow-up (14% dropout rate), which leaves 43 with measurements at both visits. The main analysis followed the intention-to-treat principle, meaning people were counted in the group they had been assigned to.

On safety, the paper says supplementation was well tolerated and feasible over the four weeks.

The brain blood flow result

One secondary measure did differ. During the mental task, the blood-flow response in the brain was larger after four weeks of urolithin A than after placebo. On the paper’s own index, which has no everyday units, the response averaged 15.53 in the urolithin A group and minus 1.43 in the placebo group.

The difference appeared, the paper notes, while task performance remained unchanged. People taking urolithin A did no better on the task itself.

The authors do not claim a benefit. Their wording is that the supplement’s effect on task-evoked cerebrovascular hemodynamic responses warrants further investigation.

There are reasons for that restraint. This was one of several secondary outcomes, and when a trial tests many things, one can come up positive by chance. A bigger blood-flow response is also not a benefit in itself. Performance did not improve, and the trial was not designed to say what the change means for thinking or memory.

The wider evidence on the brain is thin. A critical review published in July concluded that human studies so far establish safety and effects on muscle, with no completed trial yet evaluating cognitive or neurodegenerative disease-modifying outcomes. Neurodegenerative diseases are those, such as Alzheimer’s and Parkinson’s, in which nerve cells are gradually lost. The reviewers made a point of explicitly separating mechanistic plausibility from demonstrated clinical efficacy. A mechanism that makes sense in the laboratory, in other words, is a different thing from a measured benefit in people.

How this fits with other urolithin A trials

The new trial joins a short list. A systematic review from 2024 found five studies including 250 healthy individuals, lasting from 28 days to four months. The reviewers concluded that the supplement increased muscle strength and endurance but had no effect on anthropometrics, cardiovascular outcomes, and physical function. Anthropometrics are body measurements such as weight and waist size. Their closing line was that further research across more physiological systems and longer intervention periods is required.

So the blood vessel result agrees with what the earlier data on cardiovascular measures suggested.

The muscle trials show a pattern of their own. In Seattle, a total of 66 participants were randomized to 1,000 mg a day or placebo for four months. They were aged 65 to 90. The two primary measures were walking distance and energy production in a hand muscle. Neither improved more than with placebo: the distance walked in six minutes rose by 60.8 meters on urolithin A and 42.5 meters on placebo, a gap that could have been chance. Secondary measures of muscle endurance did improve, and the authors concluded that long-term urolithin A supplementation was beneficial for muscle endurance and plasma biomarkers.

A second trial, in middle-aged adults over four months, reported that muscle strength rose by about 12%. Its main target was something else, the peak power participants could produce. There the authors saw no clear improvement on peak power output (primary endpoint).

Several authors appear on both muscle papers, and the second names the product by its brand, Mitopure. The Oklahoma trial’s author list shares no names with them.

Across the three trials, then, each has missed its main target, while secondary measures have supplied the encouraging results.

Food studies had offered a hint about blood vessels. In 2018, a 3 arm double-blind randomized controlled crossover human intervention trial was conducted in 10 healthy males, who were given raspberry drinks. Crossover means that each participant receives every treatment in turn. Their flow-mediated dilation improved over the following day. Plasma ellagic acid, urolithin A-3-glucuronide and urolithin A-sulfate correlated with the improvements in FMD. The last two are forms urolithin A takes in the blood. But raspberries contain many compounds, and a correlation in 10 men could not show that urolithin A was responsible. The new trial gave the compound on its own, to a different group of people, and did not see the effect after four weeks.

What the urolithin A trial cannot show

Size and length. Fifty people started and 43 had complete measurements. With individual results varying as much as they did, a trial this size could have missed a modest effect. Four weeks is also short. Damage to blood vessels in obesity builds over years, and a longer course might behave differently.

A stand-in measure. Flow-mediated dilation is a test of how an artery responds. It is not a count of heart attacks or strokes, and the trial was not built to detect those.

The brain signal. It is a single secondary result with no change in performance. It may not hold up in a larger study.

Who took part. Participants had an average body mass index of 38.3, three quarters were women, and all were seen at one center. People with uncontrolled high blood pressure or diabetes were excluded. The results may not apply to older adults or to people without obesity.

One dose. Only 1,000 mg a day was tested, so the trial says nothing about other doses.

Dropout. One in seven participants was lost to follow-up, which is a sizable share in a trial of 50.

Safety over time. Being well tolerated for four weeks says little about years of use.

Whether a supplement makes sense for a particular person, including alongside prescribed medicines, is assessed by their doctor.

A month of urolithin A did not change how blood vessels performed, and the one result that did move is a question for a larger trial.