October 14, 2022 7 min read
Getting older is a fact of life.
We may not want to face it but it is coming no matter how much we try to stop it.
In addition to the physical signs of aging, there are plenty of things going on inside our bodies that contribute to the aging process. One of the hallmarks is mitochondrial dysfunction, which is associated with many diseases, including cardiovascular, metabolic, and cancer[i].
However, a natural compound called urolithin A (UA), which is produced by gut microbes, could possess anti-aging properties due to its antioxidative effects[ii] and its ability to boost mitochondrial health[iii].
Research shows that the production of UA can vary between individuals because of differences in the microbiome responsible for breaking down ellagitannins. Ellagitannins are a type of polyphenol found in certain foods. When these foods like berries, pomegranates, and nuts are fermented by gut bacteria, they transform into UA. However, not everyone has a microbiome that can produce UA.
In this article, we are going to focus on a study by Singh et al. (2021), which studied the prevalence of UA producers in a healthy population and whether supplementation with UA can overcome the dietary and microbial barriers to its production and subsequent health benefits.
As we get older, the powerhouses of our cells, called mitochondria, become damaged, and their activity declines. Yet, a process called mitophagy enables your muscle cells to remove the damaged mitochondria and even stimulate the replacement of new, functioning ones. In other words, mitophagy can repair muscles and improve your health.
But if this is a natural process of getting older, how can we promote mitophagy?
That’s where urolithin A comes in. UA is a metabolite of the polyphenols ellagitannins. Ellagitannins are compounds that are naturally found in some foods, particularly fruit and nuts. Research has shown that UA has mitophagy-inducing effects[iv].
Ellagitannins are the precursor to urolithins, occurring in a variety of fruits and nuts. When you eat these foods, particularly pomegranate, berries, and walnuts, the ellagitannins produced are converted into ellagic acid (EA) in your duodenum (the first part of your small intestine). As EA moves through your lower gastrointestinal tract, it is converted further by gut bacteria into the intermediates urolithin E, urolithin M-6, and urolithin D. Urolithin E is then converted to urolithin M-7, giving rise to urolithin A, while urolithin M-6 and urolithin D further convert to urolithin C which is also converted to urolithin Aiv.
It has been proposed that eating a diet consisting of ET-rich foods is the best way to naturally boost your urolithin A levels. However, it has been shown that blood levels of UA vary in individuals after dietary consumption of ET-containing foods. Equally, further research has found there to be a significant difference in the final urolithins produced between individuals and the health benefits associated with foods containing ETs because of differing compositions in their gut microbiomes[v].
Because of microbial metabolism, humans can be sorted into 3 urolithin metabotypes:
The takeaway from this is that not everyone is capable of producing urolithin A, even if they eat foods that contain the precursor polyphenols needed. It’s important to note that as we get older, our ability to transform these into urolithin A also lessens. So far, there have been three strains of human gut bacteria that have been identified as urolithin producers. They are:
A study by Gaya et al. (2018) also identified Bifidobacterium pseudocatenulatumINIA P815 as a strain able to produce urolithin A and B from ellagic acid[vi].
As well as the mitophagy-inducing effects of urolithin A, various research has shown urolithin may:
The reason not all humans can produce UA is because of variations in the microbiome responsible for metabolising ellagic acid. Although the potential benefits of urolithin A are well documented, there has been little research published regarding the natural ability of healthy adult populations to produce UA from the conversion of ellagitannins and ellagic acid.
That’s what a study by Singh et al. (2022) aimed to do. The aims of the study were to determine the prevalence of urolithin A producers in a healthy adult population and if dietary supplementation of UA could overcome the microbiome and dietary barriers.
The study itself was a single-centre, two-period, crossover, randomized, open-label study and consisted of 100 participants. UA producers were determined through the consumption of a glass of pomegranate juice. Each participant was randomly assigned to a pomegranate juice or food product containing 500mg of urolithic A group. After a wash-out period, lasting for between eight and 14 days, subjects swapped over and started the next intervention.
To compare differences between those who could produce UA and those who couldn’t, researchers collected dietary questionnaires and faecal samples as well as blood samples to assess UA levels between the interventions.
The results of the study found that 12% of the study participants (n=100) had detectable levels of urolithin A at the start of the trial, known as a baseline. Those who were identified as UA producers were found to have a more diverse gut microbiome and a higher Firmicutes to Bacteroides ratio.
It was also found that the high-producer group had a significantly different abundance or prevalence of gut bacteria compared with the non-producing group. High UA producers were found to have a high abundance of species belonging to the Clostridiales and Ruminococcaceae families. What was of significance was that high producers of UA had an increased abundance of Akkermansia muciniphila.An increase in this bacterium in the presence of pomegranate ellagitannins was also seen in an earlier study by Henning et al[vii].
As part of the study, the participants were categorised into three groups based on their circulating UA glucuronide levels: non-producers (undetectable levels), low producers (<100 ng/mL), & high producers (>100 ng/mL)
The results showed that six hours after drinking pomegranate juice, most of the participants still hadn’t displayed any gut-mediated production of UA. After 24 hours, there was a marked increase, but still, only 40% of the study participants had circulating levels of UA that were above the threshold of 100 ng/mL. 33% of participants produced none, and 27% were poor converters.
In comparison, direct oral supplementation with UA increased blood plasma levels significantly and provided a >6-fold exposure to UA compared to pomegranate juice. The results of the two interventions can be seen below:
Table 1:Mean levels of UA at baseline, after 6 and 24 hours following dietary consumption of pomegranate juice or 500 mg direct oral supplementation.
Baseline UA glucuronide levels (ng/mL)
6-hour UA glucuronide levels (ng/mL)
24-hour UA glucuronide levels (ng/mL)
5.48 ± 19.97
12.84 ± 36.34
110.47 ± 131.6
Direct oral supplement
9.57 ± 47.78
480.75 ± 238.03
255.52 ± 129.38
Overall, the study showed that there are differences in the composition of the gut microbiomes in people who can and cannot produce urolithin A via bacterial metabolism. It was found that those who could produce UA had a higher Firmicutes to Bacteroidetesratio, which is often associated with obesity[viii].
Because not everybody has a gut microbiome composition that can metabolise urolithin A from its precursors, some people may be missing out on its potent health benefits. Therefore, the purpose of this study was to ascertain if drinking pomegranate juice which is rich in ellagitannins, or oral supplementation of UA could overcome the dietary and microbiome variations that may be contributing to the non-production of UA in some individuals.
The results showed that although there was gut microbiome-mediated transformation of the precursors found in the juice into UA, but not in all individuals. However, oral supplementation with 500mg of UA could overcome differences in gut microbiome composition and diet to boost plasma levels of UA in all individuals. The study also found a minimally invasive method of determining if someone was a natural UA producer using just a few drops of dried blood. In the future, this could mean that a similar method could be used to determine how much supplement someone needs based on their existing dietary nutrient levels.
The human gut microbiome plays a critical role in our health status, but some distinct variations may mean that you are simply not able to produce some beneficial metabolites. At present, this is the case for urolithic A. Singh et al. (2020) have demonstrated to get more UA, you can try:
Remember, it is essential to keep your microbiome diverse and abundant with health-promoting bacterial strains. As well as eating, a flavoursome, colourful, and (largely) natural diet and getting good exercise, you can give yours a boost with the PureHMO range from Layer Origin Nutrition.
Written By: Leanne Edermaniger, a science writer who enjoys writing about all things related to the gut microbiome.
[i] Zhunina, O., Yabbarov, N., Grechko, A., Starodubova, A., Ivanova, E., Nikiforov, N. and Orekhov, A., 2021. The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes. Frontiers in Molecular Biosciences, 8.
[ii] Liu CF, Li XL, Zhang ZL, Qiu L, Ding SX, Xue JX, Zhao GP, Li J. Antiaging Effects of Urolithin A on Replicative Senescent Human Skin Fibroblasts. Rejuvenation Res. 2019 Jun;22(3):191-200. doi: 10.1089/rej.2018.2066. Epub 2018 Oct 25. PMID: 30215291.
[iii] Liu, S., D’Amico, D., Shankland, E., Bhayana, S., Garcia , J., Aebischer, P., Rinsch, C., Singh, A. and Marcinek, D., 2022. Effect of Urolithin a Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults. JAMA Network Open, 5(1), p.e2144279.
[iv] Jayatunga DPW, Hone E, Khaira H, Lunelli T, Singh H, Guillemin GJ, Fernando B, Garg ML, Verdile G, Martins RN. Therapeutic Potential of Mitophagy-Inducing Microflora Metabolite, Urolithin A for Alzheimer's Disease. Nutrients. 2021 Oct 23;13(11):3744. doi: 10.3390/nu13113744. PMID: 34836000; PMCID: PMC8617978.
[v] Selma MV, Beltrán D, Luna MC, Romo-Vaquero M, García-Villalba R, Mira A, Espín JC, Tomás-Barberán FA. Isolation of Human Intestinal Bacteria Capable of Producing the Bioactive Metabolite Isourolithin A from Ellagic Acid. Front Microbiol. 2017 Aug 7;8:1521. doi: 10.3389/fmicb.2017.01521. PMID: 28824607; PMCID: PMC5545574.
[vi] Gaya, P., Peirotén, Á., Medina, M., Álvarez, I. and Landete, J., 2018. Bifidobacterium pseudocatenulatum INIA P815: The first bacterium able to produce urolithins A and B from ellagic acid. Journal of Functional Foods, 45, pp.95-99.
[vii] Henning SM, Summanen PH, Lee RP, Yang J, Finegold SM, Heber D, Li Z. Pomegranate ellagitannins stimulate the growth of Akkermansia muciniphila in vivo. Anaerobe. 2017 Feb;43:56-60. doi: 10.1016/j.anaerobe.2016.12.003. Epub 2016 Dec 7. PMID: 27940244.
[viii] Magne F, Gotteland M, Gauthier L, Zazueta A, Pesoa S, Navarrete P, Balamurugan R. The Firmicutes/Bacteroidetes Ratio: A Relevant Marker of Gut Dysbiosis in Obese Patients? Nutrients. 2020 May 19;12(5):1474. doi: 10.3390/nu12051474. PMID: 32438689; PMCID: PMC7285218.
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