A new star has been shining in the firmament of longevity supplements for several years now. It is called urolithin A and its light intensity increases a little every month. Reason enough to delve into this wonderful material – a job that we completed with intellectual pleasure. The more we learned about urolithin A, the more interesting this substance became.
By Willem Koert
Is urolithin A actually present in foods? When we researched this wonderful substance, we were unable to find the answer to that question. It could be that urolithin A is only being synthesized in the human body, thanks to probiotic bacteria such as Bifidobacterium and Eubacterium. When these organisms convert a group of polyphenols that biochemists call ellagitannins, found in foods such as tea, red grapes, walnuts, berries, raspberries, and pomegranate, urolithin A is formed.[1]
Of these foods, pomegranate is probably the best source. The polyphenols found in a glass of pomegranate juice consist mainly of ellagitannins.[2] These ellagitannins – better formulated: the metabolites of these ellagitannins – probably cause the increase in blood flow to the brain.[3] This improves the memory of forgetful people over sixty who drink a glass of pomegranate every day.
The basic chemical building block of ellagitannins is the polyphenol ellagic acid. When people ingest ellagitannins, bacteria in the intestines cut the molecules into pieces so that ellagic acid can be released. Ellagic acid is poorly absorbed.[4] After consuming ellagitannins, ellagic acid does appear in the blood, but only in negligible amounts. What does appear in blood are urolithins. These are biosynthesized by bacteria in the intestines that convert ellagic acid. Substances that are created in this way are called ‘postbiotics’.
Urolithins were discovered in the early 1980s when British scientists gave ellagic acid to laboratory animals.[5] Even then it became clear that urolithins not only circulated in relatively high concentrations but were also present for a considerably longer time than you would expect from polyphenols.
In humans the situation is somewhat more complicated.[6] In approximately 55 percent of people, after taking ellagitannins or ellagic acid, you will mainly find urolithin A in the blood. In 30 percent of people, the intestinal flora produces multiple urolithins. In this group, after ingestion of ellagitannins or ellagic acid, in addition to urolithin A, urolithin B and C also appear in the bloodstream. In the remaining 15 percent of people, the microflora is unable to produce any urolithins.
Biological effects
Because urolithins, unlike for example quercetin or resveratrol, are present in the body in relatively high concentrations for a long time, life scientists are studying their possible health effects with growing interest. For example, cancer researchers have discovered through in vitro research that urolithins can inhibit the effect of estradiol.[7] In petri dishes, but in animal studies as well, urolithin A and B appear to be able to inhibit muscle breakdown.[8] In vitro research suggests that urolithin A protects muscle from breakdown by switching on rejuvenating molecules such as SIRT1 and AMPK, increasing the activity of metabolites such as NAD+ and simultaneously stimulating the formation of capillaries that supply muscle cells with oxygen and nutrients.[9]
This is of course interesting, but in 2016 Swiss scientists at Swiss Federal Institute of Technology de Lausanne published a few animal studies that made urolithins – and especially urolithin A – even more interesting.[10] The researchers exposed nematodes to urolithin A for life and saw that their life span increased by 45 percent. When the researchers gave elderly mice a supplement with urolithin A every day for 6 weeks, their endurance increased by 40 percent. Moreover, they became more active. Old mice don’t move much. They prefer to spend their days sitting. However, when the animals were given urolithin A, they became more active.
If the mice had been adult humans, they would have been given about 400 milligrams of urolithin A daily. If those adult people had preferred not to use a supplement but a regular food, they could also have drunk one and a half liters of pomegranate juice every day. At least if they belong to the group that is able to convert ellagitannins into urolithin A.[11]
Mechanism
The most extraordinary discovery that the Swiss made concerned the mechanism of action of urolithin A. The researchers discovered that urolithin A forced cells to break down outdated and poorly functioning mitochondria and replace them with new ones.
Mitochondria convert nutrients into energy. They can be seen as separate small cells, with their own hereditary material, that are part of our cells and provide them with energy. During the aging process, mitochondria function less well due to an accumulation of genetic abnormalities. The mitochondria start to emit more and more potentially aggressive molecules that damage the cells and still have less energy available to them.[12] This has negative consequences for the cells, the tissues that make up the cells and of course for health in general.
Damaged mitochondria are a contributor to aging-related conditions and diseases,[13] clearing and replacing them is a strategy to slow aging. Cells act on their own to some extent and that process is called mitophagy.[14] Urolithin A was the first natural substance that stimulated mitophagy, according to the Swiss.
Amazentis
The Swiss found urolothin A so promising that they founded a company to finance further research into urolothin A and to market the substance themselves. This company is called Amazentis and now markets a supplement line of products with high concentrations of urolithin A. Amazentis uses the trade name Mitopure.
Amazentis has already acquired a respectable number of patents in a short time. They relate to the use of urolithin A against neurodegenerative diseases and cognitive disorders, neuromuscular diseases, and obesity, but also to the use of urolithin A in longevity supplements. In addition, Amazentis patented a process for producing limited amounts of urolithin A from ellagitannins.
More preclinical data
Time will tell to what extent urolithin A will be a success. However, recent animal studies are promising. They even suggest that urolithin A might be an interesting weight-loss drug. For example, Chinese researchers published in PLoS Biology an animal study in which fattened mice lost as much as 60 percent of their body fat after administration of urolithin A.[15] The human equivalent of the dose used was approximately 250 milligrams of urolithin A per day. As far as the Chinese could tell, urolithin A enhanced the effect of thyroid hormone on fat cells that could ‘brown’. Brown fat cells can burn their contents and convert them into heat. You must keep in mind that adult humans have significantly fewer of these types of fat cells than mice.
In other animal studies, urolithin A inhibits the early stages of Alzheimer’s disease,[16] improves muscle function in Duchenne’s disease[17] and urolithin A maintains the immune system of old laboratory animals.[18] In addition, in vitro studies suggest that urolithin A may inhibit the metastasis of colon cancer cells[19] and protect against hearing loss.[20]
Safety
Researchers affiliated with Amazentis have also published human research in recent years. Remarkable in these studies are the doses, which are always above the human equivalent of the doses given to laboratory animals. In the Amazentis trials, test subjects receive 500 or 1000 milligrams of urolithin A per day. In 2019, Amazentis published a trial in which inactive but healthy elderly people used these doses for 4 weeks, without any harmful side effects. Scientists have since assumed that urolithin A is safe in these doses.[21]
Rejuvenating muscles
In the Amazentis trials, test subjects do not respond as convincingly as laboratory animals. However, the trials do suggest that urolithin A can reverse aging symptoms in humans. This was, for example, the case with the trial that Amazentis published in 2022 and in which 88 test subjects participated. The subjects were middle-aged, healthy, had a sedentary lifestyle and were overweight or obese.[22]
The researchers divided their study subjects into 3 groups. One group took a placebo every day for 4 months. The other group took capsules every day in the morning, before breakfast, that provided a total of 500 milligrams of urolithin A. Yet another group took 1,000 milligrams of urolithin A every day.
Before the supplementation period started and at the end of it, the researchers determined the endurance and muscle strength of the test subjects. They saw that the 500 mg dose had increased muscle strength by 12 percent and that the 1000 mg dose had increased endurance capacity by 15 percent. The highest dose of utolithin A had improved the body’s ability to absorb oxygen by 10 percent. In a human study in which test subjects were not subjected to a challenging training schedule with strict supervision, this is a remarkable result.
In the blood of the test subjects, the researchers found indications that urolithin A supplementation had indeed improved the functioning of the mitochondria. Markers indicative of less complete conversion of fatty acids into energy were reduced.
Ongoing trials
Amazentis has conducted trials in which highly trained athletes were given urolithin A.[23] Although this trial has been completed, at the time of writing this blog we were unable to find any results. However, we did find anecdotes from older but passionate athletes who have experimented with urolithin A. For example, the Ageist website published the experiences of a 59-year-old well-trained fitness fanatic who used urolithin A. The man found that the time he needed to recover from his workouts drastically reduced.[24]
There is also interest in urolithin A outside Amazentis, as shown by the databases that register trials. The US government has set up a trial in which people over 55 with diabetes are given urolithin-A,[25] the University of Oklahoma in the US is studying the cardiovascular effects of urolithin A in obesity[26] and Canadian sports scientists from McMaster University are investigating whether the addition of urolithin A to protein shakes can prevent muscle breakdown during prolonged inactivity.[27] In yet other trials, oncologists give urolithin A to men with prostate cancer in the hope that it will slow their disease[28] and German researchers are studying the effects of urolithin A on the immune system.[29]
If a natural substance has such potential, it stands to reason that pharmaceutical companies will investigate whether they can synthesize a substance in their laboratories that does the same – and which they can then market lucratively as a drug. A group of pharmacologists from India and the United States have already created such a substance, studied it in preclinical research and patented it.[30] The researchers are provisionally calling the compound UAS03 and hope that the compound has an anti-inflammatory effect in acute inflammation in the intestinal tract.
No final verdict
Despite the high expectations, we cannot say much with certainty about how urolithin A performs as an anti-aging supplement. Perhaps urolithin A, when formulated and used properly, is as effective a longevity supplement as reveratrol, AKG, and NMN. Perhaps there will turn out to be some pitfalls with urolithin A. Or perhaps – and this is not at all impossible – urolithin A will exceed even the wildest expectations.
References
[1] Amakura Y, Okada M, Tsuji S, Tonogai Y. High-performance liquid chromatographic determination with photodiode array detection of ellagic acid in fresh and processed fruits. J Chromatogr A. 2000 Oct 27;896(1-2):87-93.
[2] Gil MI, Tomás-Barberán FA, Hess-Pierce B, Holcroft DM, Kader AA. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem. 2000 Oct;48(10):4581-9.
[3] Bookheimer SY, Renner BA, Ekstrom A, Li Z, Henning SM, Brown JA, Jones M, Moody T, Small GW. Pomegranate juice augments memory and FMRI activity in middle-aged and older adults with mild memory complaints. Evid Based Complement Alternat Med. 2013;2013:946298.
[4] Garcia-Muñoz C, Vaillant F. Metabolic fate of ellagitannins: implications for health, and research perspectives for innovative functional foods. Crit Rev Food Sci Nutr. 2014;54(12):1584-98.
[5] Doyle B, Griffiths LA. The metabolism of ellagic acid in the rat. Xenobiotica. 1980 Apr;10(4):247-56.
[6] Tomás-Barberán FA, García-Villalba R, González-Sarrías A, Selma MV, Espín JC. Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. J Agric Food Chem. 2014 Jul 16;62(28):6535-8.
[7] Adams LS, Zhang Y, Seeram NP, Heber D, Chen S. Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro. Cancer Prev Res (Phila). 2010 Jan;3(1):108-13.
[8] Rodriguez J, Pierre N, Naslain D, Bontemps F, Ferreira D, Priem F, Deldicque L, Francaux M. Urolithin B, a newly identified regulator of skeletal muscle mass. J Cachexia Sarcopenia Muscle. 2017 Aug;8(4):583-97.
[9] Ghosh N, Das A, Biswas N, Gnyawali S, Singh K, Gorain M, Polcyn C, Khanna S, Roy S, Sen CK. Urolithin A augments angiogenic pathways in skeletal muscle by bolstering NAD+ and SIRT1. Sci Rep. 2020 Nov 19;10(1):20184.
[10] Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, Aebischer P, Sandi C, Rinsch C, Auwerx J. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016 Aug;22(8):879-88.
[11] Singh A, D’Amico D, Andreux PA, Dunngalvin G, Kern T, Blanco-Bose W, Auwerx J, Aebischer P, Rinsch C. 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. 2022 Feb;76(2):297-308.
[12] Amorim JA, Coppotelli G, Rolo AP, Palmeira CM, Ross JM, Sinclair DA. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat Rev Endocrinol. 2022 Apr;18(4):243-58.
[13] Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest. 2013 Mar;123(3):951-7.
[14] Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011 Jan;12(1):9-14.
[15] Xia B, Shi XC, Xie BC, Zhu MQ, Chen Y, Chu XY, Cai GH, Liu M, Yang SZ, Mitchell GA, Pang WJ, Wu JW. Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice. PLoS Biol. 2020 Mar 27;18(3):e3000688.
[16] Esselun C, Theyssen E, Eckert GP. Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease. Int J Mol Sci. 2021 Aug 3;22(15):8333.
[17] Luan P, D’Amico D, Andreux PA, Laurila PP, Wohlwend M, Li H, Imamura de Lima T, Place N, Rinsch C, Zanou N, Auwerx J. Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy. Sci Transl Med. 2021 Apr 7;13(588):eabb0319.
[18] Girotra M, Chiang YH, Charmoy M, Ginefra P, Hope HC, Bataclan C, Yu YR, Schyrr F, Franco F, Geiger H, Cherix S, Ho PC, Naveiras O, Auwerx J, Held W, Vannini N. Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems. Nat Aging. 2023 Sep;3(9):1057-66.
[19] Zhao W, Shi F, Guo Z, Zhao J, Song X, Yang H. Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells. Mol Carcinog. 2018 Feb;57(2):193-200.
[20] Cho SI, Jo ER, Song H. Urolithin A attenuates auditory cell senescence by activating mitophagy. Sci Rep. 2022 May 11;12(1):7704.
[21] Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, Auwerx J, Singh A, Rinsch C. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab. 2019 Jun;1(6):595-603.
[22] Singh A, D’Amico D, Andreux PA, Fouassier AM, Blanco-Bose W, Evans M, Aebischer P, Auwerx J, Rinsch C. Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. Cell Rep Med. 2022 May 17;3(5):100633.
[23] NCT04783207.
[24] Stewart D. How Mitopure Improved My 59-Year-Old Endurance, Recovery, and Athletic Performance. Ageist. February 21, 2023.
[25] NCT06274749.
[26] NCT05921266.
[27] NCT05814705.
[28] NCT06022822.
[29] NCT05735886.
[30] Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG, Hiwale AA, Saiyed T, Patel P, Vijay-Kumar M, Langille MGI, Douglas GM, Cheng X, Rouchka EC, Waigel SJ, Dryden GW, Alatassi H, Zhang HG, Haribabu B, Vemula PK, Jala VR. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun. 2019 Jan 9;10(1):89.