Urolithin A Boosts Your Gains: A Human Randomized Trial

Looks like I'll be eating more walnuts and Iberian pork bacon. Here's why...

What if I told you that a natural compound, made by your gut from foods like walnuts, yellow raspberries, an often-overlooked portion of pomegranates, and even a specific type of bacon, could boost your strength, endurance, and cellular health? Okay, I’m being a bit sensational, I’ll admit. But there’s legitimate science here you won’t want to miss on a compound called urolithin A that’s making waves in the science world.

If you prefer a video breakdown, click below. Otherwise, keep reading!

Urolithin A is a gut microbe-derived natural metabolite made from complex polyphenols in foods called “ellagitannins.”

In the last 5 years alone, over 500 studies have explored urolithin A’s impact on everything from exercise performance and muscle strength to inflammation and brain health.

Don’t worry—I won’t subject you to all 500. Instead, we’ll dive into one of the most compelling human randomized controlled trials, published in Cell Reports Medicine, which tested Urolithin A’s effects on muscle strength and endurance and mitochondrial health.

Urolithin A for Muscle Strength

This study enrolled 88 overweight adults, mean BMI ~29 kg/m² , who were between the ages of 40 and 64 for a 4 month intervention where they were treated with one of two doses of urolithin A (500 mg or 1000 mg per day) or a placebo.

Strikingly, both doses of urolithin A improved leg muscle strength by 10-12% as compared to baseline, and improved leg muscle strength as compared to placebo.

Statistical aside: For randomized controlled trials you typically want to compare the intervention(s) to the control group. That’s considered more appropriate than change from baseline, since if the placebo control group also improves you might suspect another factor is responsible for the change. But, in this case, the placebo group actually got weaker over the 4-month period. So, I suppose, it’s extra striking that the two Urolithin A groups both improved in leg strength.

They also tested hand grip strength and, although the changes didn’t reach statistical significance, the higher dose of urolithin A was trending positively, with a 5% improvement. So, this might be a case of the study just being underpowered for this outcome, i.e. that there weren’t enough participants.

Table 2. Urolithin A supplementation at 500 mg and 1000 mg for 4 months improves leg muscle strength as compared to baseline and as compared to placebo. Supplementation at 1000 mg improves endurance as compared to baseline. (a) Indicates statistical significance, p <0.05, vs placebo. (b) Indicates trend, p 0.05 - 0.10, vs placebo. (c) Indicates statistical significance vs baseline. (c) Indicates trend, p 0.05 - 0.10, vs baseline.

Urolithin A for Endurance

In terms of endurance performance, peak power output similarly trended upwards in the Urolithin A groups, about ~4% from baseline, with no change from baseline in the placebo group, along with an increase from baseline in peak VO2 in the 1000 mg dose Urolithin A group, and improvements in cycling distance and a walking test that passed the threshold of what’s considered clinically significant, which basically means it was a pretty large effect size.

Quick Summary

All this is to say, in this randomized placebo-controlled trial, in just 4 months, Urolithin A dosed at 500 mg and 1000 mg per day showed improvements in strength at both doses with improvement in endurance performance at the 1000 mg dose group.

Urolithin A for Inflammation and Mitophagy

Now, how do the metabolic changes stack up? The researchers observed decreases in acylcarnitines, a metabolic change that suggests increased fat burning by mitochondria, and decreased inflammation, as measured by CRP and a cytokine panel. I won’t pretend these data strike me with shock and awe. However, I can see a clear signal and personally consider this a meaningful finding.

Figure 3. (B) Change in plasma levels of acylcarnitines. (C) Change in C-reactive protein. (D) Change in various indicated cytokines.

Additionally, they measured levels and markers of proteins related to mitophagy, which is the process by which old-damaged mitochondria are removed. Mitophagy is important for maintaining muscle and organ health. Interestingly, the researchers found increases in components of the Parkin system, which regulates mitophagy.

But these increases occurred only at the 500 mg dose (Figure 5E, below). It’s a bit hard to interpret these data in isolation in this paper. Being straight with you, this is sometimes just how data turns out. Science can be messy. However, taken in the context of other data, I’m placing my bet that that urolithin A does increase mitophagy in humans, and that this explains at least part of the functional muscular benefits observed in this study.

Of note, the Urolithin A treatment in this study also increased levels of key components of the mitochondrial electron transport chain and overall mitochondrial content. So, if you were to ask me if I’m impressed, I’d say, “ya. I am”

Again, as a high-level summary:

In just 4 months in this randomized controlled trial, urolithin A tended to improve strength and endurance performance, as well as inflammation and mitochondrial health.

Limitations

The adults included were overweight and sedentary. It’s not clear that these benefits would generalize to metabolically fit, active individuals. I think it’s fair to say one would expect bigger effect sizes in the more metabolically impaired with urolithin A supplementation. I could be wrong, but that’s my guess.

On the other hand, it’s possible that over a longer time course than 4 months, more positive results would manifest that we didn’t see in this study. And larger trials with more statistical power conducted in the future will likely reveal further significant results.

Dietary Sources of Ellagitannins

Now, where can you get ellagitannins, the precusor to urolithin A, in food? Well, I mentioned pomegranates, particularly the white portion.

Also berries, especially yellow raspberries, walnuts, and green and black teas.

Iberian pigs in Spain eat acorns rich in ellagitannins, leading to higher levels of urolithin A. I’ll be honest, I heard this bit of information from ~1 hour 1 min into a STEM Talks podcast with the first author of the study we just reviewed, although I was having trouble verifying the fact in the peer-reviewed literature myself, perhaps because the concentrations in this ham were never formally published.

But I’m still down to eat this special bacon and reap the rewards of a pork-cebo.

It's also notable that there’s a lot of variability in people’s ability to transform dietary ellagitannins into urolithins.

It’s generally thought the healthier your microbiome, the more likely you will have the capacity to turn the ellagitannins in your pomegranate or walnut into urolithins.

Those who don’t convert ellagitannins to urolithins are called “Metabotype 0”—which is a fancy way of saying your microbes are slacking on leg day. However, the good news is there’s some suggestion that with more exposure to ellagitannins, those Metabotype 0 non-converters may acquire the ability to make urolithins as their microbiome adapts. Here’s to hoping!

More on Urolithin A

Now, if all this interested you, I’ll recommend two podcasts with the first author of this research, on STEM-Talk and Metabolic Link, two podcasts I’ve been on (here and here) as well and I must say, that have great hosts.

Fermented Foods

Also, it’s worth raising the possibility that other gut health promoting behaviors, like eating fermented foods, can alter the microbiome in a manner that facilitates urolithin A production. Interestingly, the French, who eat a whole lot of fermented dairy as a population, have a particularly high rate of urolithin A producers: About 2.5-times that of Canadians. Bummer, Eh? I’m sorry.

My favorite fermented French cheese is – without question – Roquefort, the "King of Blue Cheese," “Cheese of Love,” and my tongue’s Achille’s Heel. It certainly fits my confirmation bias to speculate that combining Roquefort and Walnuts and Iberian Bacon is a super-star trio for gut and metabolic health. So, I’m going to run with that narrative.

For more on Fermented Foods, stay tuned for a upcoming Microbial Masterclass!