Urolithin A for Mitochondrial Health and Muscle Function

Key takeaways:
~ Urolithin A is a compound made in the gut microbiome that helps to renew and optimize mitochondrial function.
~ Made by specific gut microbes, only about 40% of the population has this antioxidant and anti-inflammatory compound in their body naturally these days.
~ Dietary precursors for urolithin A are found in many ‘heart-healthy’ foods such as pomegranates, blueberries, and walnuts.
~ Genetic variants may help you determine if you are more likely to need and benefit from urolithin A.

What is urolithin A?

Urolithin A is a natural compound that gut bacteria produce by metabolizing specific polyphenols, called ellagitanins. These polyphenols are found in pomegranates, berries, almonds, and walnuts.

Researchers discovered more than a decade ago that urolithin A is one reason why eating pomegranates, berries, and nuts is beneficial for heart health, mitochondrial function, and more.[ref] It’s an excellent example of how diet–microbiome–metabolite synergy can be a powerful way to optimize health.

Urolithin A is now available as a supplement, and many recent studies and clinical trials show that it has many potential benefits.

Role of the gut microbiome:

Certain gut microbes convert ellagitanins to ellagic acid and then into urolithin A, which is then absorbed in the intestines.

Individual variation: Converters vs. non-converters
When eating foods containing the precursors for urolithin A, your gut microbiome composition determines whether you:[ref]

1. produce only urolithin A
2. produce urolithin B, isourolithin A, and urolithin A
3. do not produce any urolithins

Which microbes? 
A number of Enterocloster species, as well as Gordonibacter and Ellagibacter, are involved in the conversion of ellagitanins to urolithins. Some species convert it to intermediate urolithin metabolites, which can then be used by other gut bacteria to synthesize urolithin A.[ref]

About 40% of the population:
A 2022 study of an average population showed that about 12% had detectable levels of urolithin A from a standard diet. Adding pomegranate juice daily increased that number to about 40%.  Researchers also tested supplementing with 500 mg of urolithin A, which raised plasma levels 6-fold compared to the pomegranate juice.[ref]

Mechanism of action: Why Urolithin A can be beneficial

Mitophagy and mitochondrial health:
Mitochondrial autophagy – mitophagy – is the process by which damaged or defective mitochondria are broken down and recycled. This is a process that goes on constantly, and it keeps mitochondria functioning well. Promoting mitophagy, therefore, is beneficial to overall cellular health.[ref]

Mitochondrial energy production:
Animal studies show that urolithin A improves mitochondrial energy production when cells are under stress. Importantly, urolithin A does not appear to increase mitochondrial function under basal conditions but rather improves mitochondrial membrane potential when under physical stress.[ref] This is something to consider when deciding whether it is worthwhile to supplement with urolithin A — the benefits are greater for someone who is under stress, exercising a lot, or older.

Anti-inflammatory and immune regulation:
Urolithin A has been shown in multiple studies to regulate the inflammatory response. It can downregulate COX2 and decrease the response to IL-1β, which is a pro-inflammatory cytokine. It also prevents macrophages from transitioning to their pro-inflammatory form.[ref][ref]

Clinical trials and studies on urolithin A:

Note that many of the clinical trials were funded by manufacturers of urolithin A supplements.

Muscle function in older adults:
A study involving older adults aged 65-90 looked at the effect of 1,000 mg/day Urolithin A compared to a placebo. After 2 months, the results showed that 6-minute walk distance improved more in the urolithin A group, and that muscle endurance increased statistically significantly compared to placebo. In addition, CRP, a marker of inflammation, decreased in the urolithin A group.[ref]

Muscle strength and exercise performance, middle age:
In another study involving sedentary middle-aged adults, 500 mg of urolithin A was compared to a placebo. The results showed small but statistically significant improvements in muscle strength and clinically meaningful improvements in VO₂ and the 6-minute walk test.[ref]

In younger athletes:
Urolithin A supplements may give only a minor boost to people who are already in good shape. A study involving competitive male distance runners did not find a running performance benefit from urolithin A supplementation, although markers of post-exercise muscle damage were reduced. The conclusion was that in athletes, urolithin A may help facilitate recovery rather than giving a performance benefit.[ref]

A study in weight lifters showed that muscle mass and endurance increased slightly more in the group taking 1,000 mg of urolithin A for 8 weeks compared to the placebo group.[ref] Again, this is just a slight edge in healthy, younger individuals.

Cardiovascular health:
An animal model of atherosclerosis showed that urolithin A can promote plaque stability, which may help prevent heart attacks and strokes. In mice given urolithin A before the atherosclerosis-promoting diet, there was less plaque formed.[ref]

However, a clinical trial in older adults with heart failure found no statistical benefits from 500 mg/day of urolithin A.[ref]

Alzheimer’s (animal study):
A promising study in mouse models of Alzheimer’s showed that long-term urolithin A improved learning, memory, and olfactory function, as well as reducing amyloid beta and tau.[ref]

Osteoporosis (animal study):
In an animal model of osteoporosis, urolithin A reduced systemic bone loss. Cell studies then showed that urolithin A suppressed RANKL-triggered osteoclastogenesis and decreased inflammatory markers, including reducing NLRP3.[ref]

Related article: Osteoporosis, genetics, and personalized solutions

Pancreatitis (animal study):
In an animal model of pancreatitis, urolithin A helps to alleviate the inflammation.[ref]

Obesity-induced cardiomyopathy (animal study):
A study in mice with metabolic cardiomyopathy showed that mitochondrial dysfunction and oxidative stress were causal, and that urolithin A can protect against metabolic cardiomyopathy.[ref]

Age-related macular degeneration (animal and cell study):
Age-related macular degeneration (AMD) is a common cause of blindness in aging. The retina of the eye uses a lot of energy and contains a high number of mitochondria. Promoting mitophagy and improving mitochondrial function with urolithin A shows a lot of promise in animal models of AMD.[ref] Human clinical trials are needed here.

Safety and Side Effects:

In general, urolithin A is a natural substance produced by the gut microbiome and something that 40% of the population produces naturally. However, the safety and side effects of high doses need to be considered.

The clinical trial mentioned above, the one involving older adults and muscle function, also looked at safety and side effects. The results showed no difference in reported adverse effects at 1,000 mg/day compared to the placebo, and no significant changes in vital signs, hematology, or urinalysis were seen.[ref]

Talk with your doctor if you have any concerns about a supplement. Consult with your pharmacist, too, if you have questions on interactions with prescription drugs that you take.

Natural sources vs. supplementation:

Dietary options:
If your gut microbiome can convert ellagitannins into urolithin A, the following are good sources:

• pomegranate juice
• almonds and walnuts
• strawberries, raspberries, blueberries

Note that if you are going all in on drinking a lot of pomegranate juice, it can inhibit CYP3A4, which can alter the way some medications work. It also may mildly inhibit SLCO1B1, which is a transporter involved in response to statins and other medications.[ref] [ref]

Related article: Statins, SLCO1B1, and Muscle Pain

Microbiome component:
Without a microbiome test, you likely won’t know if the dietary sources of ellagitannins are providing any urolithin A. Currently, there are no probiotics on the market for directly providing the specific gut microbes needed.

However, you may not need a probiotic with the specific urolithin A bacteria. A study using a probiotic containing a high dose of multiple beneficial bacterial species, including Bifidobacterium and Lactobacillus species, along with a polyphenol supplement, found that urolithin A levels increased in all participants.

The study was small (16 participants in each arm of the trial), but the results did show that all of the participants receiving the probiotics plus polyphenols produced urolithin A by the end of 3 months. This was in contrast to the beginning of the study, when only half of the participants were urolithin A producers. The placebo arm had no change in urolithin A production.  The theory here is that supporting a healthy and diverse microbiome allows for the natural flourishing of the bacteria needed for urolithin A. The bifido and lactobacillus strains were producing precursors that the specific urolithin A bacteria needed for growth.

Supplemental urolithin A:
A number of companies are now selling urolithin A supplements.

A testing group, Healthy Longevity Medicine, tested urolithin A supplements in 2024  and found that some didn’t have the labeled amounts. One was 28% higher and another was 15% lower.[ref]

SuppCo testing company also tested urolithin A supplements from brands ordered off Amazon. They found four brands that met their labeling requirements – CodeAge liposomal, Timeline Mitopure, Pure Encapsulation Reunual, and Neurogan Health. You can read the full report and see the companies that had little to no urolithin A in their capsules.

Absorption of urolithin A:
Studies on urolithin A supplements show that they are absorbed and increase levels of urolithin in the body by 6-fold over diet.

Limitations on the research:

An overall picture emerges that urolithin A may be beneficial for older people or for middle-aged adults who aren’t in great shape. The studies in competitive athletes only show a slight benefit, so if you are young and healthy, you may not get as much value out of this supplement as someone who has mitochondrial dysfunction.

Notably, several of the clinical trials were funded by a urloithin A supplement manufacturer. This doesn’t make the results invalid, but it is something to consider when reading the studies.

Conclusion:

While large, independent clinical trials are needed in order to understand the scope, optimal dosing, and best practices for urolithin A, this molecule seems to hold a lot of potential as a natural way to improve mitochondrial function and prevent oxidative stress.

Importantly, restoring a healthy gut microbiome with diverse probiotic strains seems to be enough to promote the natural production of urolithin A from polyphenols. Our modern diet, exposure to antibiotics and pesticides, and reliance on ultraprocessed foods have caused shifts in the balance of bacteria in our guts. I’m struck by the fact that the specific foods, such as berries, almonds, and walnuts, that have long been associated with heart health and healthy longevity, contain the polyphenols used by the gut microbiome to create urolithin A.