In 2005, a study identified a compound termed "Urolithin A," a metabolite of polyphenol metabolism created and absorbed in the colon. Given some of the momentum around polyphenols being potential anti-aging compounds, Urolithin A was subsequently studied more in-depth. Several early studies suggested a plethora of positive effects, including anti-aging, colon/endometrial/hepatocellular/pancreatic/prostate cancer protection (seemingly all via the conserved p53 pathway), anti-diabetes, anti-hyperuricemia, anti-inflammatory, anti-obesity, anti-oxidant, cardioprotection, improvement in degenerative disc disease, nephroprotection, and neuroprotection. More recent studies have suggested a positive effect on mitochondrial health, specifically something called "mitophagy," as well as possible improvements in muscle strength. As such, it is touted in longevity circles as the next best thing, as some physicians latch onto mitochondrial health as an allegedly important frontier in medicine.
Despite the momentum behind Urolithin A as a dietary supplement, there has only been one randomized controlled trial (RCT) done as of this writing. RCTs are the gold-standard of testing - they limit biases, account for the placebo effect, and are procedurally rigorous. All new drugs requesting FDA-approval typically have an RCT (or several) to support their safety and efficacy. However, compared to RCTs for FDA-approval of drugs, this RCT for Urolithin A was miniscule - only 66 patients, randomized to receiving either 1000mg of Urolithin A or a placebo daily for 4 months. The primary endpoints were 6-minute walk distance and change from baseline in ATP production in hand muscle. A 6-minute walk distance is self-explanatory; ATP production is difficult to measure since it's intracellular, however this study used a type of functional MRI called "phosphorus magnetic resonance spectroscopy" (P-MRS) to indirectly measure a signal of cellular metabolism.
After 4 months, there was no significant difference between the two groups in terms of these two primary outcomes. In other words, Urolithin A did not improve either 6-minute walking distance or ATP production. There are several potential causes for this: Urolithin A truly and actually doesn't improve muscle function or ATP generation; Urolithin A was given at an incorrect dose (too much/little, or too frequent/infrequent); Urolithin A wasn't given for a long enough duration of time; the study didn't include enough participants to see a meaningful difference.
Supporters of Urolithin A supplementation point to this last option as the most likely cause - they think there is an effect, but the study simply didn't have enough participants (termed "statistical power") to see this positive effect. But ignoring the results of a study that showed no effect of an intervention (a "null" result) based on the assumption of it being underpowered is a fallacy. Claiming a positive effect despite a null result is unjustified and illogical, unless there is strong prior evidence that the effect must exist. In other words, the "new" must justify itself, even if it is "natural." Mother nature (in this case, not supplementing with Urolithin A) wins by default unless the evidence of benefit is unequivocal.
This does not mean, however, that one RCT showing no effect should cause cessation of study--additional and larger studies, different dose/frequency, and longer duration are all reasonable additional steps to take in follow-up studies. Scientific studies frequently show changes in outcome based on changes in initial conditions. But again, without evidence of benefit, we can't just ignore a null result.
And while RCTs are the gold standard, additional studies need not necessarily be RCTs. Indeed there are other smaller studies that have been done on Urolithin A, showing mixed results at best:
This study was a review article published in 2024, which showed that Urolithin A caused a slight increase in muscle mass at 2 months with no change in muscle mass at 4 months.
This study showed that urolithin A supplementation caused an increase in mitochondrial gene expression, but no improvement in the primary outcome of athletic performance.
This study claims nonspecific benefits in several aspects of aging and longevity, but should largely be ignored since the authors have direct primary conflicts of interest with their company that sells urolithin A supplementation.
This study claims that some people cannot synthesize Urolithin A, but with supplementation (specifically pomegranate juice) patients can achieve "normal" levels of urolithin A. It is important to note that no claim is made that individuals who cannot synthesize Urolithin A are at risk of harm of any kind, so it is unclear that this supplementation contributes to any benefit. Moreover, the amount of pomegranate juice that patients were ingesting (8oz of POM pomegranate juice in under 10 minutes) contains 34g of sugar. This is metabolic poison, and the harms far outweigh any potential benefit to Urolithin A bioavailability.
But what about Urolithin A itself - what are the risks to higher levels of Urolithin A in the body? The short answer is that we don't really know. While studies done thus far haven't really shown much in terms of harm/risk, it is crucial to understand that absence of evidence of harm is not equal to evidence of absence of harm. In other words, just because we haven't found significant risk doesn't mean it isn't hidden. Again, the burden of proof is on the unnatural (Urolithin A supplementation) to provide direct evidence that it is not harmful.
The adverse effects yet discovered include decreased gut microorganism diversity, gastrointestinal discomfort, mild headaches or muscle aches, and cost (as of January 2026, Urolithin A supplementation will set you back ~$100 per month).
If patients truly want to be risk averse, it makes much more sense to simply eat foods that are rich in polyphenols, as these have a plethora of other benefits, have been consumed by humans for centuries without harm, are much cheaper than Urolithin A supplementation, and are more enjoyable to consume. These foods include raspberries, blackberries, walnuts, and pomegranate seeds (not juice).
Based on the current evidence and on basic longevity/healthspan principles, I do not recommend my patients consume Urolithin A supplementation.
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