Gut Health and Aging: A Summary of Urolithin A

What are urolithins?

Urolithins are not found in food; however, their precursor polyphenols are. Polyphenols are abundantly found in many fruits and vegetables. When eaten, some of the polyphenols are directly absorbed by the small intestine, and others are degraded by digestive bacteria into other compounds, some of which are beneficial. For example, certain species of gut bacteria break down ellagic acid and ellagitannins into urolithins that may improve human health [1].

While urolithins as a class are still being investigated, urolithin A and urolithin B are well known in humans. Here, we focus on two human studies that measure plasma or urine levels for urolithin A, the most widely studied urolithin to date.

What is urolithin A good for?

Various tissues contain urolithin A, so it has been proposed to affect multiple organ systems in worms, cells, mice, and humans. In particular, there is significant cell, animal, and human data supporting the idea that urolithin A increases mitophagy. Mitophagy is a process by which damaged mitochondria are removed from the cell, thus promoting the growth and maintenance of healthy mitochondria.

Mitochondrial dysfunction is one of the hallmarks of aging. Unfortunately, aging causes mitophagy to decline in cells [2], which, in turn, causes damaged mitochondria to accumulate. As a result, reactive oxygen species can build up and promote inflammation. Additionally, as people age, they may convert fewer dietary precursors to urolithin A [3].

Dietary sources of urolithin A

So far, research has found that pomegranate, strawberries, blackberries, camu-camu, walnuts, chestnuts, pistachios, pecans, brewed tea, and oaken barrel-aged wines and spirits contain ellagic acid and/or ellagitannins [4, 5].

Urolithin A’s potential to improve mitophagy

A 2016 study showed that urolithin A improved muscle function in aged mice and extended lifespan in worms [6]. These promising results led to the same research group conducting human research studies. More studies are needed on supplemental urolithins to determine if they are beneficial for people who do not eat enough ellagic acid and ellagitannins. There are also concerns about low dietary production of urolithin A, which is dependent on health status, gut health, and age [7].

Urolithin A availability in food compared to supplements

Available in pill and powder forms, Urolithin A is marketed as a supplement that can decrease age-related cellular decline by improving mitochondrial health. The first Phase 1 clinical trial using a pure urolithin A supplement in 100 sedentary older adults was funded by Amazentis [8]. The paper released prior to this trial proved the safety and efficacy of urolithin A and showed a mitochondrial health benefit.

Participants in this recently published clinical trial were categorized in three groups based on their circulating urolithin A glucuronide levels and were asked to refrain from taking dietary supplements that could impact muscle or mitochondrial function [8].

The participants were asked to consume 8 ounces of 100% pomegranate or 500 milligrams of a urolithin A supplement at two separate intervals. This study examined the difference in pomegranate juice compared to the supplement for producing urolithin A in the gut. One fecal sample was collected during the screening period, and dried blood and plasma samples were collected before the participants consumed the pomegranate juice or supplement. Additional samples were then collected again at 6 and 12 hours after intake.

At the start of the study, only 12% of the participants had detectable urolithin A in their blood. The results showed that 27% of participants were poor converters of pomegranate juice to urolithin A. Additionally, 33% were unable to convert pomegranate juice to Urolithin A. The study also showed that plasma urolithin A was six times higher in the supplement group than the pomegranate group.

The researchers’ microbiome results showed that the gut bacteria composition was different between the non-producing and the low-producing urolithin A groups. The authors did note that the high-producing urolithin A group had an abundance of two specific bacteria types. However, there were no differences observed between the low-producing urolithin A group and the high-producing urolithin A group. Although other researchers have proposed possible candidates in analyzing human fecal samples [9, 10], it is not yet clear which bacteria in the gut produce urolithin A [7].

Due to the initial promising results in the human study, two additional clinical trials of urolithin A are underway: ENDURO and NOURISH.

More research is needed on the microbiome differences between the people that do produce sufficient urolithin from food versus those who do not sufficiently produce urolithin from food.

Human study on the Mediterranean diet

In 2020, an eight-week human study examined the effects of Mediterranean and Western diets on the gut microbiome [11]. Eighty-two males and females who were overweight or obese were instructed to eat a Mediterranean diet or to maintain their regular diets. The Mediterranean diet was matched to the participants’ current calorie and macronutrient intake to increase adherence. Participants documented their daily food consumption and physical activity, and they were assessed for compliance by study staff every 2 weeks.

The study showed higher levels of urolithin A glucuronides in the urine of the Mediterranean group as compared to the regular diet group. They also showed that increased urinary urolithin A production, including type A, B, C and their glucuronides, was associated with decreased high-sensitivity c-reactive protein, triglycerides, urinary carnitine, body fat mass, body weight, and BMI. The authors attribute the increase in urolithin A in the Mediterranean group to walnut intake because berries and pomegranate intake did not increase. Additionally, the Mediterranean diet group had significant decreases in low-density lipoprotein and high-density lipoprotein cholesterol at 4 weeks.

Microbiome results were intriguing as well. The authors integrated three different meta-omics databases [12] when comparing the two groups, and they noticed that microbiome diversity differed between the two diets. These results should not be surprising, as other studies have proven that changes in diet can alter microbiome diversity.

Microbiome considerations

Some people’s gut flora may not break down food sources to urolithin A or may do so only at low levels. This study suggested that urinary levels of urolithin were correlated with specific families of gut bacteria. More research is needed to elucidate the conversion of ellagic acid and ellagitannins to urolithin A from dietary precursors.

Urolithin A side effects

There are no observed side effects to date, although research suggests that Urolithin A may promote good mitochondrial health. Additional human studies are needed to fully explain its role in the hallmarks of aging.

Conclusion

The first study concluded that taking a pure urolithin A supplement can increase plasma levels of urolithin A better than pomegranate juice can. The second study showed that specific eating patterns, such as the one that resembles the Mediterranean diet as compared to a Western diet, increases urinary urolithin A.

Given the importance of preserving mitochondria health with aging, urolithin A may continue to gain more evidence as a geroprotector. If you do not commonly consume urolithin A in food, you may want to consider following this topic of research as more human data is published.

Disclaimer

This article is only a very brief summary. It is not intended as an exhaustive guide and is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use or any product or supplement vendor, and all discussion here is for scientific interest.

Source: Lifespan.io is a nonprofit advocacy organization and news outlet covering aging and rejuvenation research.

Author: Tovah

Literature

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[2] Sakellariou, G. K., Pearson, T., Lightfoot, A. P., Nye, G. A., Wells, N., Giakoumaki, I. I., … McArdle, A. (2016). Mitochondrial ROS regulate oxidative damage and mitophagy but not age-related muscle fiber atrophy. Scientific Reports, 6(1), 33944. https://doi.org/10.1038/srep33944

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[4] Arapitsas, P. (2012). Hydrolyzable tannin analysis in food. Food Chemistry, 135(3), 1708–1717. https://doi.org/10.1016/j.foodchem.2012.05.096

[5] Bakkalbasi, E., Mentes, Ö., & Artik, N. (2008). Food Ellagitannins–Occurrence, Effects of Processing and Storage. Critical Reviews in Food Science and Nutrition, 49(3), 283–298. https://doi.org/10.1080/10408390802064404

[6] Ryu, D., Mouchiroud, L., Andreux, P. A., Katsyuba, E., Moullan, N., Nicolet-Dit-Félix, A. A., … Auwerx, J. (2016). Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nature Medicine, 22(8). https://doi.org/10.1038/nm.4132

[7] Cortés-Martín, Adrián, Selma, M. V., Tomás-Barberán, F. A., González-Sarrías, A., & Espín, J. C. (2020). Where to Look into the Puzzle of Polyphenols and Health? The Postbiotics and Gut Microbiota Associated with Human Metabotypes. Molecular Nutrition and Food Research, Vol. 64. https://doi.org/10.1002/mnfr.201900952

[8] Singh, Anurag, D’Amico, D., Andreux, P. A., Dunngalvin, G., Kern, T., Blanco-Bose, W., … Rinsch, C. (2021). Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population. European Journal of Clinical Nutrition. https://doi.org/10.1038/s41430-021-00950-1

[9] Selma, M. V., Beltrán, D., García-Villalba, R., Espín, J. C., & Tomás-Barberán, F. A. (2014). Description of urolithin production capacity from ellagic acid of two human intestinal Gordonibacter species. Food and Function, 5(8). https://doi.org/10.1039/c4fo00092g

[10] Selma, M. V., Tomás-Barberán, F. A., Beltrán, D., García-Villalba, R., & Espín, J. C. (2014). Gordonibacter urolithinfaciens sp. nov., a urolithin-producing bacterium isolated from the human gut. International Journal of Systematic and Evolutionary Microbiology, 64(PART 7). https://doi.org/10.1099/ijs.0.055095-0

[11] Meslier, V., Laiola, M., Roager, H. M., De Filippis, F., Roume, H., Quinquis, B., … Ercolini, D. (2020). Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake. Gut, 69(7). https://doi.org/10.1136/gutjnl-2019-320438

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