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A Literature Review

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The Relationship between Urolithin A and Mitochondria


A Literature Review


Angela White


October 1, 2024



Introduction


There are a lot of marketing dollars being spent promoting Urolithin A (UA), a post biotic

compound naturally produced in the digestive tracts of humans. Social media ads claim that

supplementing UA results in increased energy, cellular renewal, increased muscle strength, and increased endurance, among other benefits. The most recent ad I saw claimed that supplementing UA while taking a GLP-1 inhibitor for weight loss is the answer to the known muscle loss that comes with these weight loss drugs.


Are these claims too good to be true? At first glance I assumed yes. However, the mechanism of action gave me pause. Upon further research I found that UA interacts with and promotes the health of our mitochondria. Dysfunctional mitochondria have been identified as a major factor in aging and in age related disease (1).


Mitochondria are organelles that are present in all cells of the body. Often referred to as the “powerhouses” of our cells, this is where energy, or ATP, is produced using the Kreb’s cycle and electron transport chain (2). The number of mitochondria in each cell depends on the energy demand for that cell type. We know that physical exercise places a higher demand on muscle and in turn, this increases the number and function of the mitochondria in muscle tissue. Whether we are talking about muscle tissue, digestive tract tissue, cardiac tissue, or brain tissue, all must have properly functioning mitochondria to maintain health (3).


Another piece of mitochondrial health is the clearing and elimination of old or dysfunctional mitochondria. Autophagy is a normal biological process in which damaged or dysfunctional cells are destroyed and removed from the body. When this happens in mitochondria it is called mitophagy. It is important that our body can identify and remove damaged cells. This allows for healthy cells to function properly and decreases the incidence of cellular degeneration, both of which support overall health (2,4).


We know that physical activity increases the number and function of mitochondria in various tissues. Decreasing inflammation and reducing oxidative stress also supports mitochondrial health. If we can identify other influencers of mitochondria, like UA, we could have another tool in improving people’s health outcomes. This literature review will discuss the

relationship between UA and mitochondria.


Sources of UA


Urolithin A is a metabolite produced endogenously in the human gut from classes of

foods known as ellagitannins (ETs) and ellagic acid (EA)(5,6). These foods include pomegranate, berries like strawberries, and nuts like walnuts and almonds. UA is the most common of the urolithins; this family of compounds produced in the gut (6).


It has been found that only 40% of people can convert food sources of ETs and EAs to

UA at significant levels (5). In one study, only 12% of participants had detectable levels of UA at baseline7. This conversion is dependent upon an individual’s microbiome and the bacteria present. We have not yet conclusively identified the specific bacteria needed for this conversion. Of note however in one study, higher levels of the Clostridiales and Ruminococcaceae family and Akkermansia muciniphiliain were seen with higher UA levels (7). More research is needed here. The conversion to UA is also dependent upon a person’s age and overall health (5).


Due to the variance and inconsistent levels produced from dietary sources, much of the

research on UA has utilized supplementation. Studies have found UA to be safe and well

tolerated in humans at both 500 mg and 1000 mg doses. Tests including vital signs, blood panels, and urinalysis all proved safe8. The safety of UA in humans was also confirmed in a study that did compare UA levels from food versus supplementation (7).


Clinical Research


UA improves cellular health by stimulating pathways that encourage mitophagy,

increasing mitochondrial function, and decreasing inflammation (2,4,5.)


In a study conducted by Singh et al., muscle strength and exercise performance were looked at alongside mitochondrial biomarkers in middle aged adults. Participants between the ages of 40 and 64 were divided into three groups and were given a placebo, 500 mg of UA, or 1,000 mg of UA for four months. There was no exercise regimen. While hand grip strength differences were not statistically significant, there was a significant increase in leg muscle strength in both UA groups. Exercise performance as measured by peak VO2 and VO2 max improved in the UA groups. Peak power output differences were improved but not significant. Mitochondrial efficiency, mitophagy via stimulation of the PINK1-Parkin pathways, and decreases in inflammatory markers were seen in plasma samples with these increases in muscle function (8).


Another study conducted by Liu et al, looked at the effects of UA supplementation on

muscle endurance and mitochondrial health in older adults, ages 65-909. At UA levels of 1000 mg, muscle endurance in both hands and legs was increased. There was not a significant increase in the six-minute walk test or in ATP production in hand skeletal muscles. However, there was a significant decrease in plasma levels of C-Reactive proteins (associated with inflammation) and in other biomarkers of mitochondrial health like ceramides and acylcarnitines (9).


This final study on osteoarthritis (OA) is interesting because mitochondrial dysfunction is

the primary culprit in OA (10). D’amico et al. found that UA again activated PINK1-Parkin

pathways, activating mitophagy, resulting in improved cellular respiration in chondrocyte tissue from both OA and healthy donors (10).


Conclusion


UA does seem to improve cellular health by stimulating pathways that encourage

mitophagy, increasing mitochondrial function, and decreasing inflammation. Much of the

research proving these mechanisms of action had been done in worms and mice. For instance, it was found that healthy mitochondria and mitophagy were established with UA in premature senescent auditory cells (11). UA was shown to support healthy mitophagy via specific pathways in nematodes (5).


However, there are more human studies being done that seem to support this influence of

UA on mitochondria. One limitation of this review is that many of these human studies have

been done by scientists selling a UA supplement to the public.


I am hopeful that more research will be done. Maintaining and improving our

mitochondrial health does seem to be integral in maintaining overall health. Even Alzheimer’s disease and cancer have been linked to mitochondrial and mitophagy dysfunction (3,6). There may be additional mechanisms of action at play in UA’s influence on cancer (6).


While exercise, an anti-inflammatory diet and lifestyle, and consumption of plenty of antioxidant rich foods are all important, having another effective tool in the toolbox to support our mitochondria could only be helpful.



References

1. Kothe B, Klein S, Petrosky SN. Urolithin A as a Potential Agent for Prevention of Age-Related

Disease: A Scoping Review. Cureus. 2023;15(7):e42550. Published 2023 Jul 27.

doi:10.7759/cureus.42550

2. Pradeepkiran JA, Hindle A, Kshirsagar S, Reddy PH. Are mitophagy enhancers therapeutic

targets for Alzheimer's disease?. Biomed Pharmacother. 2022;149:112918.

doi:10.1016/j.biopha.2022.112918

3. Fang EF, Hou Y, Palikaras K, et al. Mitophagy inhibits amyloid-β and tau pathology and

reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019;22(3):401-412.

doi:10.1038/s41593-018-0332-9

4. Zhao H, Song G, Zhu H, et al. Pharmacological Effects of Urolithin A and Its Role in Muscle

Health and Performance: Current Knowledge and Prospects. Nutrients. 2023;15(20):4441.

Published 2023 Oct 19. doi:10.3390/nu15204441

5. D’Amico D, Andreux PA, Valdes P, et al. Impact of the Natural Compound Urolithin A on

Health, Disease, and Aging. Trends in Molecular Medicine. 2021; 27(7): P687-699. DOI:

10.1016/j.molmed.2021.04.009

6. Al-Harbi SA, Abdulrahman AO, Zamzami MA, Khan MI. Urolithins: The Gut Based

Polyphenol Metabolites of Ellagitannins in Cancer Prevention, a Review. Front Nutr.

2021;8:647582. Published 2021 Jun 7. doi:10.3389/fnut.2021.647582

7. Singh, A., D’Amico, D., Andreux, P.A. et al. Direct supplementation with Urolithin A

overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to

achieve consistent levels across the population. Eur J Clin Nutr 76, 297–308 (2022).

8. Singh A, D'Amico D, Andreux PA, et al. Urolithin A improves muscle strength, exercise

performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged

adults. Cell Rep Med. 2022;3(5):100633. doi:10.1016/j.xcrm.2022.100633

9. Liu S, D'Amico D, Shankland E, et al. Effect of Urolithin A Supplementation on Muscle

Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial. JAMA Netw

Open. 2022;5(1):e2144279. Published 2022 Jan 4. doi:10.1001/jamanetworkopen.2021.44279

10. D'Amico D, Olmer M, Fouassier AM, et al. Urolithin A improves mitochondrial health,

reduces cartilage degeneration, and alleviates pain in osteoarthritis. Aging Cell.

2022;21(8):e13662. doi:10.1111/acel.13662

11. Cho SI, Jo ER, Song H. Urolithin A attenuates auditory cell senescence by activating

mitophagy. Sci Rep. 2022;12(1):7704. Published 2022 May 11. doi:10.1038/s41598-022-11894-2

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