UROLITHIN A

Urolithin A is produced from the breakdown of ellagic acid, which is high in foods like berries, nuts, pomegranate and is classed as a post-biotic. Its likely to be a significant contributor to the anti-cancer effects of tree nuts (see Walnuts in the Foods Library). Only about 40% of adults over 50 produce urolithin A from dietary sources, and this declines with age partly due to poor microbiome diversity.

With the emergence of the mitochondrial theory of cancer, this compound is gaining attention due to its ability to stimulate called mitophagy, or renewal of mitochondria the “engines” of cells. Mitochondrial dysfuntion is clearly and significantly seen in cancer, and is already verified as a dominant marker of glioblastoma, lung, colorectal and ovarian cancers. Importantly, urolithin A can suppress acylcarnitines, compounds that play a pivotal role in regulating lipid and sugar metabolism. High levels are linked closely with progression in several cancers including glioma, liver, prostate and breast cancer, . In kidney cancer, research shows 3 to 6X increases in these molecules in the tumor environment, and resulting upregulated fatty acid availabliity drives progression – high levels and are proposed as biomarkers for the disease. Studies in anti-aging find strongest effects at 500mg dose.

One study showed only 12% of adults around 50 had circulating levels of urolithin a and with that, they had good levels of key gut bactiera including Akkermansia muciniphilia. These bacteria play a crucial role in successful immunotherapy. There is a large volume of pre-clinical data in cancer research for urolithin A, and one result is the recent initiation of a multi-center phase II trial in early phase prostate cancer to establish its overall suitability (see References)

Pilot show systemic effects of urolithin A, noting significant anti-inflammatory actions in overweight adults, reducing c-reactive protein and IL-beta. 500 and 1000mg doses were used without any side effects and good absorption (highlight 1). Nestle is in trials of branded Mitopure for anti-aging.

TYPICAL ABSORPTION LEVELS

High

EXAMPLES OF IMPROVED OUTCOMES

PENDING

PRE-DIAGNOSIS OR PREVENTION

PENDING

Highlighted Studies

Together with its benefit on mitochondrial health, UA also reduced plasma biomarkers of inflammation. The reduction of the CRP [c-reactive protein] by UA is particularly relevant, as circulating CRP concentration is positively associated with an increased risk of age-related diseases and with poorer immune health…UA induction of mitophagy could potentially mediate its anti-inflammatory effect, as removing dysfunctional mitochondria reduces the production of reactive oxygen species (ROS)...

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in our study many differentially abundant taxa were also detected between the high UA producer group compared with the non-producer group. In particular, species belonging to the Clostridiales and Ruminococcaceae family were found in high abundance in the high UA producer group. Also, of particular interest is the species Akkermansia muciniphilia, a gut residing commensal bacteria often associated with health indicators such as lower BMI, low grade inflammation, and improved metabolic health....

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In this randomized clinical trial of 66 older adults, those who received supplementation with 1000 mg of urolithin A had a significant improvement in muscle endurance (number of muscle contractions until fatigue) for both hand and leg skeletal muscles compared with those who used placebo. Plasma levels of several acylcarnitines, ceramides (biomarkers of mitochondrial health), and C-reactive protein were decreased after urolithin A supplementation.

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The gut microbiota of the UA 50 mg/day group showed a significant increase in alpha diversity.. Four and nine microbial genera were significantly altered in the UA 10 mg/day and UA 50 mg/day groups, respectively.. Participants whose FMD scores improved with UA intake had poor baseline FMD values as well as a low Bacillota/Bacteroidota ratio.. Urolithin A intake alters the gut microbiota and improves their alpha diversity. In addition, the effect of UA on VEF correlated with the individual gu...

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TABLE OF REFERENCES

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URLRatingHighlightHighlight 2Visuals (click)
https://www.cell.com/cell-reports-medicine/pdf/S2666-3791(22)00158-6.pdf3C-reactive protein (CRP) is a well-established plasma biomarker of inflammation linked to aging34,35 and high BMI.36 As expected, middle-aged overweight ATLAS participants showed high average plasma CRP concentrations (approximately 3 mg/L; Figure S3B), which is associated with moderate to high risk of age-related chronic diseases.34,35 Administration of UA reduced plasma CRP levels at both doses, with results statistically significant at the 1,000 mg dose (Figure 3C). UA also led to an overall reduction of some pro-inflammatory cytokines, such as interferon gamma (IFN-g), interleukin-1 beta (IL-1b), and tumor necrosis factor alpha (TNF-a) Together with its benefit on mitochondrial health, UA also reduced plasma biomarkers of inflammation. The reduction of the CRP [c-reactive protein] by UA is particularly relevant, as circulating CRP concentration is positively associated with an increased risk of age-related diseases and with poorer immune health...UA induction of mitophagy could potentially mediate its anti-inflammatory effect, as removing dysfunctional mitochondria reduces the production of reactive oxygen species (ROS) and the release of mtDNA and cardiolipins, known triggers of inflammatory responses
https://www.nature.com/articles/s41430-021-00950-12.5 Likewise, in our study many differentially abundant taxa were also detected between the high UA producer group compared with the non-producer group. In particular, species belonging to the Clostridiales and Ruminococcaceae family were found in high abundance in the high UA producer group. Also, of particular interest is the species Akkermansia muciniphilia, a gut residing commensal bacteria often associated with health indicators such as lower BMI, low grade inflammation, and improved metabolic health [25,26,27]. A significantly increased abundance of Akkermansia muciniphilia was observed in high UA producers compared to the no producersOther examples of how foods can be metabolized differently based on gut microbiome include the generation of equol and short-chain fatty acids (SCFAs). Equol is a metabolite generated when gut microflora metabolizes dietary isoflavones such as daidzein [28, 29]. Studies have found that 30–40% of the population can naturally generate equol [30, 31]. Similarly, SCFAs are produced upon exposure to dietary fiber and an inability to produce SCFAs has been intricately linked to microbiome dysfunction that eventually leads to chronic disease development such as inflammatory bowel disease and age-related cognitive impairment
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/27882442.5Urolithin A supplementation led to a significant reduction in several acylcarnitines, primarily long-chain and polyunsaturated species, at both the 2-month and 4-month visits compared with baseline... plasma metabolomics showed a significant reduction from baseline measurement in the urolithin A group but not the placebo group.. To further test the effect of urolithin A on inflammation, we measured plasma levels of the inflammatory biomarker CRP. As for ceramides, a significant reduction from baseline in plasma CRP was observed in participants in the urolithin A group but not the placebo groupThe decrease in circulating biomarkers in this trial supports the improved mitochondrial health in participants who used the urolithin A supplement. Metabolomics data were consistent with findings from a previous clinical study that showed urolithin A decreased plasma acylcarnitines, which was indicative of improved mitochondrial metabolic efficiency, urolithin A reduced plasma CRP levels. Stable levels of CRP were associated with healthy aging outcomes in a large longitudinal study,28 and findings from this trial further support the benefits of urolithin A in this older population. However, CRP is a general biomarker of inflammation; thus, future studies should include additional measures, such as inflammatory cytokines, to test the anti-inflammatory activity of urolithin
https://link.springer.com/article/10.1007/s00216-018-1059-x2.5Hydroxybutyrylcarnitine, decanoylcarnitine, propanoylcarnitine, carnitine, dodecanoylcarnitine, and norepinephrine sulfate were found in distinctly higher concentrations in both cancer tissues and in urine of cancer patients compared with controls. In contrast, feature assigned to riboflavin and NAAG were present at significantly higher concentrations both in normal kidney tissue as compared with renal cancer tissue and in urine samples of healthy persons than in urine from the cancer patients. All eight mentioned compounds may be considered potential clear cell renal carcinoma biomarkers.Two features that were over-abundant in cancer tissue were putatively identified as carnitines (14, 15). In particular, acetylcarnitine (14) had a very high abundance in cancer tissue, while the abundance in normal renal tissue was two orders of magnitude lower. Decanoylcarnitine (15), was also over-expressed in the cancer tissue, though at much lower abundance. Similar observations have been made previously [23, 24] and attributed to fatty acid oxidation disorders (FAOD) and inhibition of the β-oxidation pathway. Several additional carnitines were putatively identified in this work
https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2022.1077534/full2.5The gut microbiota of the UA 50 mg/day group showed a significant increase in alpha diversity (Faith’s phylogenetic diversity). Four and nine microbial genera were significantly altered in the UA 10 mg/day and UA 50 mg/day groups, respectively (p < 0.05, not corrected). Participants whose FMD scores improved with UA intake had poor baseline FMD values as well as a low Bacillota/Bacteroidota ratio. Conclusion: Urolithin A intake alters the gut microbiota and improves their alpha diversity. In addition, the effect of UA on VEF correlated with the individual gut microbiota. Our results have practical implications for a new approach to providing healthcare that focuses on intestinal environment-based diet therapy. Upon analysis, Faith’s PD of the UA 50 mg/day group was significantly higher than that of the placebo group. As other alpha diversity indices did not show significant differences, it is likely that gut microbes with a low relative abundance and distant phylogenetic distance were enriched in the gut microbiota of the UA 50 mg/day group...This randomized controlled trial showed that UA has a modest effect on gut microbiota, such as increasing of Faith’s PD and Ruminiclostridium 5 in the 50 mg/day UA group. In addition, correlation analysis suggested that UA supplementation may be effective in UA non-producers.
https://www.researchgate.net/publication/351793268_Impact_of_the_Natural_Compound_Urolithin_A_on_Health_Disease_and_Aging2In humans, UA was shown to regulate mitochondrial function systemically and in skeletal muscle. Data from the first-in-human Phase I trial with UA administration showed a decrease in several plasma acylcarnitines [23], markers that reflect the efficacy of mitochondrial fatty acid oxidation at the level of theentirebody[24], and an increase in the expression of mitochondrial gene sets in the muscle no observed side effects following either single oral administration of UA up to 2000 mg or multiple oral dosing (28 days) of UA up to 1000 mg daily. UA also had a favorable pharmacokinetic profile, was bioavailable at all tested doses, and did not accumulate over time. It showed a relatively long-half life (t 1/2 =17–22 hours), most likely due to an active enterohepatic recirculation. UA was present in plasma, both as the parent UA and its glucuronide and sulfonated conjugated forms, and in skeletal muscle tissue, primarily in its parent form [23]. Subjects supplemented with UA showed increased markers of mitochondrial health
https://escholarship.org/content/qt9tw2s4v9/qt9tw2s4v9_noSplash_1ad7179c3d65ae13f78d2385428c249f.pdf1.5OMx was well-tolerated with no treatment-related withdrawals. There were no differences in baseline clinicopathological features between arms. Urolithin A was detected in 21/33 patient in the POMx group vs. 12/35 in the placebo group (p=0.031). Cancer pS6 kinase, NFκB, Ki67, and serum PSA changes were similar between arms. POMx prior to surgery results in pomegranate metabolite accumulation in prostate tissues. Our primary end-point in this modest-sized short-term trial was negative. Future larger longer studies are needed to more definitely test whether POMx reduces prostate oxidative stress as well as further animal testing to better understand the multiple mechanisms through which POMx may alter prostate cancer biology.The primary outcome was between arm differences in prostatic 8OHdG. This was assessed both in benign prostate tissue and PC tissue. In benign tissue, 8OHdG levels were 16% lower in the POMx treated arm, though this failed to reach statistical significance (p=0.095, table 2). Though 8OHdG expression in the benign tissue was significantly correlated with levels in cancer tissue (r=0.441, p=0.001), the overall expression was much lower in cancer tissue than in benign tissue (table 2). In cancer tissue, post-treatment 8OHdG levels were 23% lower in the POMx treated arm, though this difference did not reach statistical significance
https://www.cell.com/immunity/fulltext/S1074-7613(22)00508-81 In addition to this wide spectrum of potential applications covering the fields of neuro-degeneration, muscle disorders, and inflammatory diseases, we demonstrate here that UA induces a protective anti-tumor CD8+ T cell immunity strongly supporting its benefit for cancer therapy either in combination with immune checkpoint blockade or in the context of adoptive T cell therapy. Moreover, we suggested mitophagy in IEC as an important mechanism to enhance antigen presentation during early intestinal tumorigenesis. Our data here expanded upon this work and suggested that mitophagy induction represents an attractive option for therapy of established tumors as it promotes an adaptive T cell response via a dual mechanism: enhancing antigen presentation in tumor epithelia as well as directly affecting T cell fateConsidering the broad effects of UA and its systemic nature , and in vitro evidence of UA affecting macrophage polarization, we cannot exclude that other components that constitute the TME apart from CD8+ T cells and antigen-expressing tumor cells may also be affected by UA in a biologically relevant manner. Collectively, our study suggests that the orally available and well-tolerated mitophagy inducer UA confers CD8+ T cell-dependent anti-tumor effects in CRC [colorectal cancer]. The fact that UA induces a TSCM-associated phenotype in human leukocytes and CAR T cells ex vivo indicates that our findings can be translated into human disease and provide a solid rationale for future clinical trials to examine whether oral UA supplementation or in vitro treatment of leukocytes can be used for more effective tumor therapy
https://bjbas.springeropen.com/articles/10.1186/s43088-024-00492-y1Mitophagy enhances the cellular mitochondrial pool, is intimately linked to the formation of new organelles, and increases mitochondrial respiratory capacity. Uro-A first promotes mitophagy before favoring mitochondrial biogenesis. Uro-A triggers mitophagy and mitochondrial recycling in damaged cells, enhancing the mitochondria’s health. Mitophagy is impaired with age advancement and in many age-related disorders [5, 6]. Restoring proper levels of mitophagy is a promising method for halting the deterioration of organ function that comes with aging. Uro-A can trigger several routes that the process uses to progress. Once the phagophore membrane has cleared, the mitochondria, lysosomes, and mitochondria uniteWhile ellagic acid itself has been recognized for its antioxidant and anti-inflammatory properties, the metabolites, specifically urolithins, have garnered attention for their potential therapeutic effects. Recent research has shed light on the mechanisms by which urolithins exert their beneficial effects on various aspects of human health. It has been shown that urolithins have high bioavailability. Urolithins can travel to numerous regions of the body and influence a variety of biological processes, including those that are antiobesity, antibacterial, anti-inflammatory, and anticancer. However, further study is required to prove urolithins as a novel, broad-spectrum anticancer chemical for particular tumors.
https://journal-inflammation.biomedcentral.com/articles/10.1186/s12950-020-00242-81UA promoted the expression of anabolic factors including Sox-9, Collagen II, and Aggrecan while inhibiting the expression of catabolic factors such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) in rat chondrocytes. Protective effects of UA were also observed in ex vivo organ culture of articular cartilage. Mechanistically, IL-1β significantly activated and upregulated the expression of p-ERK 1/2, p-JNK, p-P38, and p-P65, while UA protected chondrocytes against IL-1β-induced injury by activating the mitogen-activated kinase (MAPK)/nuclear factor-κB (NF-κB) signaling pathwaysOur study further revealed that UA obviously inhibited the levels of MMP3 and MMP13 enhanced by IL-1β treatment. IL-1β also promotes the expression of iNOS and COX-2, which induces the production of nitric oxide (NO) and prostaglandin E2 (PGE2), respectively. NO is a well-known inflammatory mediator that can induce MMP secretion and activation and decrease Collagen II and proteoglycan synthesis. In the present study, we found that IL-1β-induced expression of iNOS and COX2 were also attenuated by UA. Sox-9 is a vital transcription factor that positively regulates Collagen II synthesis and is indispensable for chondrocyte differentiation [36]. Our study further pointed out that UA obviously restored the levels of SOX9 inhibited by IL-1β treatment.
https://connect.careboxhealth.com/en-US/trial/listing/453616N/AThis phase II randomized control trial assesses the effect of Urolithin A (Uro-A) supplementation compared to placebo in men with biopsy-confirmed prostate cancer undergoing radical prostatectomy (RP) progressive disease. A total of 90 men will be accrued and randomized 1:1 to receive a 1000 mg daily dose of Uro-A in two 250 mg capsules PO BID or two placebo capsules BID daily for 3 to 6 weeks prior to RP. The primary endpoint is to determine the effect of Uro-A on decreasing prostate tumor tissue oxidative stress (measured by 8-OHdG) compared to placebo.Measured by change from baseline to end-of-study, in comparison to changes from baseline to end-of-study in a control group receiving a placebo (except tissue levels, which will be compared between arms using end-of-tissue only). Will be analyzed using the same approach as the analysis of the primary endpoint. Changes in serum concentrations of Uro-A, urolithin sulfate and urolithin A glucuronide, from baseline to radical prostatectomy will be estimated and summarized
https://link.springer.com/article/10.1007/s11418-024-01821-21Mechanically, UC blocked the activation of the AKT/mTOR signaling pathway by decreasing the expression of Y-box binding protein 1(YBX1). The AKT agonist SC79 could reverse the suppression of cell proliferation in UC-treated CRC cells. In conclusion, our research revealed that UC could prevent the progression of CRC by blocking AKT/mTOR signaling, suggesting that it may have potential therapeutic values.The migration of CRC cells was greatly reduced in a dose-dependent manner with the treatment of UC (Fig. 3A). Besides, transwell experiments show that the invaded cells were greatly decreased in CRC cells when treated with UC (Fig. 3B), especially in the concentration of 30 µM. Overall, the result revealed that UC could effectively inhibit the migration of CRC cells.
https://www.cell.com/immunity/fulltext/S1074-7613(22)00508-8?1Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8+ T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer. UA-induced TSCM formation depended on Pink1-mediated mitophagy triggering cytosolic release of the mitochondrial phosphatase Pgam5. Cytosolic Pgam5 dephosphorylated β-catenin, which drove Wnt signaling and compensatory mitochondrial biogenesis. Collectively, we unravel a critical signaling pathway linking mitophagy to TSCM formation and suggest that the well-tolerated metabolic compound UA represents an attractive option to improve immune therapy.Collectively, our study suggests that the orally available and well-tolerated mitophagy inducer UA confers CD8+ T cell-dependent anti-tumor effects in CRC. The fact that UA induces a TSCM-associated phenotype in human leukocytes and CAR T cells ex vivo indicates that our findings can be translated into human disease and provide a solid rationale for future clinical trials to examine whether oral UA supplementation or in vitro treatment of leukocytes can be used for more effective tumor therapy.
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1503317/full3prostate markers

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