Prof. Stuart Phillips, Ph.D. (McMaster University) ‘Mitochondrial Health: A key to Aging & Recovering Well' presentation at the American College of Sports Medicine (ACSM) annual meeting 2022.
2:40 - Sarcopenia: the age-related decline in muscle mass, strength, and function 4:41 - Declines in mitochondrial function: Hallmarks of metabolic dysfunction and aging 5:16 - Mechanisms of skeletal muscle mitochondria involvement in sarcopenia 6:36 - The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial health 11:05 - Inactivity and disuse: when urolithin might exert an important effect? 13:20 - Mitigation of the decline in mitochondrial function attenuates disuse-atrophy and improves recovery
Urolithin A and its Impact on Muscle Health and Aging
Introduction
Speaker’s Background:
An affiliation with the company began in 2012, prior to Dr. Singh’s involvement. Initially invited by Amazentis CEO, Chris Rinch, to Switzerland to review data on the lifespan-extending effects of Urolithin A (UA) in C. elegans and mice. At the time, the company was a small team of just four people.
Initial Skepticism:
As a human physiologist, initial doubts about the translatability of the findings were mitigated by the robust scientific approach taken by Amazentis. Commendable progress has been made in translating research "from molecule to product" with strong scientific backing.
Research Context
Disclosures and Research Focus:
Funding comes from several agencies, and the presenter holds a patent unrelated to this work. The primary research focus is skeletal muscle and its response to aging, exercise, and disuse events such as bed rest or immobility.
Muscle Adaptation and Aging:
Exercise vs. Disuse:
Muscle hypertrophy occurs with exercise, while atrophy follows periods of disuse or immobilization.
Sarcopenia and Age:
Sarcopenia begins affecting muscle mass and function around 57 years old, although the exact onset varies.
About 25% of individuals over 60, and 60% of those over 80, experience sarcopenia (based on the European Working Group’s definition).
Key Insight: Sarcopenia might not be the primary issue. Instead, disuse events (e.g., hospitalization, illness) exacerbate the downward trajectory of muscle health.
Muscle Health, Aging, and the Role of Mitochondria
Muscle Loss: A Multifactorial Process:
Influenced by hormonal changes, microcirculation, exercise, and nutrition. The mitochondrial theory of aging posits that damaged mitochondria accumulate over time, reducing muscle function.
Mitophagy and Aging:
Mitophagy (the process of clearing damaged mitochondria) declines with age, leading to muscle dysfunction.
Blocking necessary processes like mitophagy or protein breakdown results in further damage. About 80% of proteins may be damaged or misfolded without proper turnover.
Urolithin A: A Promising Mitophagy Agent
Research Findings:
Urolithin A (UA) improves mitochondrial function by enhancing mitophagy and reducing circulating acylcarnitines, a biomarker of mitochondrial inefficiency.
Supplementation provides consistent benefits across age groups, overcoming gut microbiome variability.
Drinking pomegranate juice alone is insufficient to achieve effective UA levels due to the microbiome's role in UA production.
Functional Benefits:
Studies have shown improvements in hamstring strength, VO2 max, and walking distance with UA supplementation. For older individuals, these changes are clinically significant despite modest percentages (e.g., 10–12% improvements).
Safety and Efficacy:
UA has been shown to be safe, well-tolerated, and effective in improving strength and metabolic health.
Disuse Events and the Catabolic Crisis
The Impact of Disuse:
Events like hospitalization or surgery can lead to muscle loss that is difficult to recover from, particularly in older individuals.
Recovery after disuse in younger individuals is often more complete than in older adults, who may experience irreversible declines.
Catabolic Crisis:
Concept: Coined by the late Dr. Doug Patton Jones, this refers to the accelerated muscle loss during disuse events.
Trajectories: Older individuals often cannot fully recover muscle mass after such events, underscoring the importance of prehabilitation and targeted interventions.
Current and Future Research
Trials and Findings:
Ongoing collaboration with Nestlé Health Sciences and Amazentis involves trials in young individuals using disuse models like single-leg immobilization to test UA’s effectiveness.
Prior studies using omega-3 supplementation during disuse demonstrated that mitochondrial health is crucial for maintaining muscle mass.
Prehabilitation Strategies:
Prehabilitation with UA supplementation before elective surgeries (e.g., knee replacements) may prevent muscle loss and support faster recovery.
UA’s role as a mitophagy agent could be key to maintaining muscle function in aging populations.
Key Takeaways
Urolithin A’s Mechanism:
Acts as a pro-mitophagy agent, improving mitochondrial function by clearing damaged organelles.
Overcomes individual differences in gut microbiota to ensure consistent benefits.
Impact on Muscle Health:
Clinically significant improvements in strength and metabolic markers for older adults.
May be particularly effective in mitigating muscle loss during periods of disuse.
Future Applications:
UA shows promise as a prehabilitation and rehabilitation tool for elective surgeries and recovery from disuse events.
Conclusion
Urolithin A represents a breakthrough in muscle health research, with potential to combat sarcopenia, improve recovery after disuse events, and enhance quality of life in aging populations.
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Dr. Mark Tarnopolsky is a world-renowned expert in mitochondrial health, muscle function, and ageing science. As a clinician-scientist at McMaster University, he has dedicated his career to understanding how we can optimise our mitochondria - the tiny powerhouses in our cells - for better energy, performance, and longevity.
This is for you if you’ve ever asked yourself: Why does energy fade as I age? How can I boost my endurance, strength, and resilience whatever age I am? And what are the best ways to support...
Urolithins are metabolites produced by the gut microbiota from ellagitannins and ellagic acid, which are polyphenols found in foods like pomegranates, berries, and walnuts. Among the urolithins, **Urolithin A (UA)** has garnered significant attention for its health benefits, particularly in aging and cellular health.
## **Production and Bioavailability**
Urolithin A is not directly present in foods but is synthesized in the gut through microbial metabolism of ellagitannins. Its production depends on an individual's gut microbiota composition, as only certain bacteria can convert ellagitannins into urolithins. Variability in microbiota means not everyone produces UA efficiently. To overcome this limitation, direct supplementation of UA has been explored and shown to be effective[1][6][8].
## **Health Benefits**
### **1. Mitochondrial Health and Mitophagy**
Urolithin A enhances mitochondrial function by activating mitophagy, a process that clears damaged mitochondria, allowing healthy ones to thrive. This renewal improves energy production, particularly in tissues with high energy demands like muscles, brain, and heart. It also reduces oxidative stress and inflammation, which are key contributors to aging[2][3][4].
### **2. Muscle Health**
UA has demonstrated benefits for muscle strength and endurance, particularly in older adults. It promotes muscle protein synthesis, reduces inflammation during recovery from exercise, and enhances ATP production by improving mitochondrial efficiency. These effects help mitigate muscle atrophy and improve performance[3][5].
### **3. Anti-Aging Properties**
As a geroprotective agent, UA delays age-related decline by reducing oxidative stress, inflammation, and mitochondrial dysfunction. It activates pathways like AMPK and SIRT1 while inhibiting inflammatory signaling (e.g., NF-kB). These actions contribute to cellular resilience and longevity[2][4][9].
### **4. Cognitive and Joint Health**
UA has shown potential neuroprotective effects by reducing beta-amyloid plaques and tau protein accumulation associated with Alzheimer’s disease. It also supports joint health by improving mitochondrial respiration in cartilage cells[3][4].
### **5. Metabolic Benefits**
UA enhances insulin sensitivity, optimizes glucose uptake, and reduces fat accumulation in cells. These effects may help prevent metabolic disorders like type 2 diabetes and metabolic syndrome[2][7].
## **Safety**
Studies indicate that UA is safe for human consumption with no significant adverse effects reported. The U.S. FDA has classified it as a safe ingredient for food products at doses ranging from 250 mg to 1 gram per serving[1].
## **Conclusion**
Urolithin A represents a promising compound for promoting healthspan by targeting mitochondrial health, reducing inflammation, and improving muscle function. Its benefits extend to aging-related diseases, cognitive health, joint health, and metabolic regulation. While natural production depends on gut microbiota composition, direct supplementation offers a reliable way to harness its potential benefits[1][2][4].
In this upcoming one-hour webinar with Dr. Stuart Phillips, Professor of Kinesiology and a leading researcher in the field, he will share how strength training and protein intake can help older adults maintain muscle, improve mobility, and support overall well-being.
This session will offer evidence-based advice and simple strategies to help you age actively and confidently. Whether you're new to this form of exercise or curious about how much protein you really need as you age, you don't want to miss this opportunity to hear from one of Canada’s most...
In this upcoming one-hour webinar with Dr. Stuart Phillips, Professor of Kinesiology and a leading researcher in the field, he will share how strength training and protein intake can help older adults maintain muscle, improve mobility, and support overall well-being.
This session will offer evidence-based advice and simple strategies to help you age actively and confidently. Whether you're new to this form of exercise or curious about how much protein you really need as you age, you don't want to miss this opportunity to hear from one of Canada’s most...
### **4. Cognitive and Joint Health**
UA has shown potential neuroprotective effects by reducing beta-amyloid plaques and tau protein accumulation associated with Alzheimer’s disease. It also supports joint health by improving mitochondrial respiration in cartilage cells[3][4].
### **5. Metabolic Benefits**
UA enhances insulin sensitivity, optimizes glucose uptake, and reduces fat accumulation in cells. These effects may help prevent metabolic disorders like type 2 diabetes and metabolic syndrome[2][7].
## **Safety**
Studies indicate that UA is safe for human consumption with no significant adverse effects reported. The U.S. FDA has classified it as a safe ingredient for food products at doses ranging from 250 mg to 1 gram per serving[1].
## **Conclusion**
Urolithin A represents a promising compound for promoting healthspan by targeting mitochondrial health, reducing inflammation, and improving muscle function. Its benefits extend to aging-related diseases, cognitive health, joint health, and metabolic regulation. While natural production depends on gut microbiota composition, direct supplementation offers a reliable way to harness its potential benefits[1][2][4].
After some research on available products and questions regarding dosage, it appears there is a wide margin between different manufacturers. Time Line who offers the Mitopure ingredient is expensive at over $100.00 per month with a recommended dosage of 500 mg:
Dr. Russell J. Reiter said he’s taken melatonin for 27 years to protect his mitochondria. He thinks that this protection, and other effects of melatonin, are far superior to what it does for sleep. One of the most important things that it does is to detoxify Reactive Oxygen Species. It does this by three possible methods: 1) electron donation, 2) hydrogen atom donation, and 3) radical adduct formation (?). Melatonin is used by the mitochondria to protect us against free radicals because we need ATP.
Melatonin, as well as Vit C and Vit E, are free radical...
Urolithin A (UA), derived from ellagic acid-rich foods, extends healthspan and lifespan in animal models.
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In humans, UA shows a potential effect on decreasing inflammation and enhancing muscle strength and endurance.
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The impact of UA on human healthspan and lifespan requires further exploration.
Abstract
Urolithin A (UA) is a gut metabolite derived from ellagic acid. This systematic review assesses the potential geroprotective effect of UA in humans. In five studies including 250 healthy individuals, UA (10–1000 mg/day) for a duration ranging from 28 days to 4 months, showed a dose-dependent anti-inflammatory effect and upregulated some mitochondrial genes, markers of autophagy, and fatty acid oxidation. It did not affect mitochondrial maximal adenosine triphosphate production, biogenesis, dynamics, or gut microbiota composition. UA increased muscle strength and endurance, however, had no effect on anthropometrics, cardiovascular outcomes, and physical function. Unrelated adverse events were mild or moderate. Further research across more physiological systems and longer intervention periods is required.
2. Assessment of the potential geroprotective effect of UA: search criteria and methodology
2.1. Protocol registration and search strategy
The protocol of this systematic review was registered at PROSPERO international prospective register of systematic reviews (Reg #: CRD42022377812). Pubmed, Embase, Scopus, Web of Science and Cochrane databases were used for this search from inception until the 23rd May 2023. For detailed information on the search strategy and data extraction please refer to Supplementary Data.
2.2. Eligibility criteria
Articles were included based on the following criteria: 1) UA was given in any dosage form (capsule, powder, et cetera), dose, dosing interval, intervention duration, or route of administration, 2) human participants aged 18 years or older, 3) outcomes on age-related physiological changes or incidence of disease, 4) UA was administrated directly (not as a precursor form).
Articles were excluded if: 1) in vitro or animal models were utilized, 2) ellagic acid or any other precursors were tested, 3) records were conference abstracts, clinical study protocols, animal experiments, reviews, editorials, letters to the editor, or book chapters 4) they were published in a language other than English.
2.3. Study selection
Two review authors (ALYK and KXL) independently screened the titles and/or abstracts and the full-text articles retrieved using the search strategy. Any discrepancies between these authors over the eligibility for inclusion of studies were resolved by a third reviewer (LF). The articles were organized and managed using the Covidence 2020 (Veritas Health Innovation, Melbourne, Australia) screening tool (Covidence systematic review software, 2020).
2.4. Data extraction
Data extraction was conducted by two independent assessors (ALYK and KXL) and disagreement was resolved by a third assessor (AHK). The following data were extracted from articles: first author, year of publication, study location, study design, number of individuals per study group, dose, frequency, route, interval, and duration of UA administration, population characteristics (age and sex), health status (healthy or diseased) and any reported outcomes for the following groups: pharmacokinetics, biological and clinical outcomes, adverse events. If the statistical significance for outcomes was given, p-values of ≤0.05 and 0.05<p<0.10 were conserved as statistically significant and trend, respectively.
2.5. Registered human trials
To include all trials on UA research in humans, clinicaltrials.gov was searched for registered studies meeting the search criteria on 18th May 2023.
2.6. Risk of bias
The risk of bias was assessed by two reviewers (ALYK and KXL) using the revised Cochrane risk-of-bias tool v2.0. Any disagreements were resolved by a third reviewer (LF).
3. Pharmacokinetics of UA
After the exclusion of duplicates, 2700 articles were screened for title and abstracts. Twelve articles underwent full-text screening of which four were included (Andreux et al., 2019, Liu et al., 2022, Nishimoto et al., 2022; A. Singh et al., 2022). One article reported on two studies (Andreux et al., 2019), resulting in five included studies (Fig. 1). All five assessed studies were intention-to-treat studies and conducted among healthy adults (34.8 % males, mean age 40–85 years) in the United States, Canada, France, and Japan. The sample sizes ranged from 36 to 88 individuals, with a total of 250 individuals. The intervention duration ranged from 28 days to 4 months (Andreux et al., 2019, Liu et al., 2022, Nishimoto et al., 2022; A. Singh et al., 2022). None of the studies included a follow-up period after the intervention period. The study characteristics and cohort demographics are provided in Table 1.
†Empty stomach with water
#With water
Abbreviations: RCT: Randomized controlled trials, UA: Urolithin A, d: days, m: months, w: week, n: number of individuals.
*
Determined by vital signs, anthropometric measures, and absence of any chronic medical condition
3.1. Pharmacokinetic parameters
UA and its metabolites (UA glucuronide and UA sulfate) were detected in plasma after both single doses (ranging from 250 to 2000 mg) and the last administration of 250–1000 mg UA daily for 28 days (Andreux et al., 2019). UA was also detected in skeletal muscle after a single dose of 2000 mg (Andreux et al., 2019). The maximum plasma concentrations (Cmax), and total exposure, as indicated by the area under the curve (AUC), exhibited a dose-dependent increase. The time to maximal concentration (Tmax) of UA and its metabolites in plasma was 6 hours. The half-life (t1/2) of UA and UA-glucuronide and UA-sulfate in plasma was 17–22 hours and 25–58 hours, respectively. The concentrations of both UA and its metabolites reached a plateau after 7 days, maintaining consistency until 24 hours post-intervention. They were subsequently eliminated from plasma within the 72–96 hour period following the final administration of 250–1000 mg of UA daily over a 28-day period (Andreux et al., 2019).
The overview of the biological and clinical outcomes is shown in Fig. 2 (Key Figure) and Supplementary Table 1.
Fig. 2. Effect of Urolithin A on clinical and biological markers in human. ATP: Adenosine Triphosphate, BECN1: Beclin 1, CPT1B: Carnitine Palmitoyltransferase 1B, CRP: C-reactive protein, DXA: Dual X-ray Absorptiometry, ESRPA: Estrogen Receptor Subunit Alpha, FABP3: Fatty Acid-Binding Protein 3, FMD: Flow-Mediated Vasodilatation, FDI: First Dorsal Interosseus, GABA-RAPL1: Gamma-Aminobutyric Acid Receptor-Related RAP GTPase-Activating Protein-Like 1, Go: Gene Ontology, IFN-γ: Interferon γ, IL: Interleukin, LC3B: Microtubule-Associated Protein 1 A/1B Light Chain 3B, MFN2: Mitofusin 2, mtDNA/nuDNA ratio: Mitochondrial DNA to Nuclear DNA ratio, PARK2: Parkin RBR E3 Ubiquitin Protein Ligase, PGC1A: Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha, PPARA: Peroxisome Proliferator-Activated Receptor Alpha, PPO: Peak Power Output, PIK3C3: Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3, SQSTM1: Sequestosome 1, TA: Tibialis Anterior, TNF-α: Tumor Necrosis Factor α, ULK1: Unc-51 Like Autophagy Activating Kinase 1, VO2max: Maximum Oxygen Consumption.
4. Biological outcomes
4.1. Inflammatory markers
Four months of 500 mg UA significantly decreased the levels of interleukin-1 beta (IL-1ß), but not C-reactive protein (CRP), interferon-gamma (INF- γ), and tumor necrosis factor-alpha (TNF-α) (A. Singh et al., 2022). A higher dose of UA (1000 mg/day for 4 months) led to significant decreases in CRP, INF- γ, and TNF-α levels compared to placebo, but it did not affect the level of IL-1ß (A. Singh et al., 2022). Both doses did not affect the levels of IL-13 and IL-6 compared to placebo at 4 months (A. Singh et al., 2022). In another study, UA (1000 mg/day for 4 months) did not change the level of CRP as compared with placebo (Liu et al., 2022).
4.2. Mitochondrial function
4.2.1. Adenosine triphosphate (ATP) production
Treatment of UA (1000 mg/day for 4 weeks) did not affect the change in maximal ATP production from baseline to 4 months (Liu et al., 2022).
4.2.2. Gene enrichment
UA (500 or 1000 mg/day for 28 days) significantly enriched gene ontology (GO) Mitochondrial Matrix and GO Mitochondrion in the vastus lateralis, while higher dose of UA (1000 mg/day for 28 days) significantly enriched mitochondrial gene sets when compared to placebo (Andreux et al., 2019). UA (500 or 1000 mg/day for 28 days) did not affect mRNA levels of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 (PIK3C3), Unc-51 Like Autophagy Activating Kinase 1 (ULK1), Sequestosome 1 (SQSTM1), Microtubule-Associated Protein 1 A/1B Light Chain 3B (LC3B), when compared to placebo (Andreux et al., 2019).
4.2.3. Biogenesis and dynamics
While UA (500 mg/day for 28 days) did not have any significant effect on the mitochondrial biogenesis and dynamics markers, UA (1000 mg/day for 28 days) showed a trend towards improving the mRNA levels of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC1A), but not Peroxisome Proliferator-Activated Receptor Alpha (PPARA), Estrogen ReceptorSubunit Alpha (ESRPA) and Mitofusin 2 (MFN2), when compared to placebo (Andreux et al., 2019).
4.2.4. Autophagy/mitophagy
UA (500 mg/day for 28 days) significantly increased the mRNA levels of Gamma-Aminobutyric Acid Receptor-Related RAP GTPase-Activating Protein-Like 1 (GABA-RAPL1) and showed a trend of increasing mRNA levels of Beclin 1 (BECN1) compared to placebo without affecting the Parkin RBR E3 Ubiquitin Protein Ligase (PARK2) mRNA expression. UA (1000 mg/day for 28 days) also showed a trend in the improvement of mRNA levels of PARK2m but not BECN1 and GABA-RAPL1 compared to placebo (Andreux et al., 2019).
4.2.5. Fatty acid oxidation
While UA (500 mg/day for 28 days) did not have any significant effect on the fatty acid oxidation markers, UA (1000 mg/day for 28 days) increased the mRNA levels of Fatty Acid-Binding Protein 3 (FABP3) and showed a trend towards improvement of Carnitine Palmitoyltransferase 1B (CPT1B). Both doses did not affect the mitochondrial DNA to nuclear DNA ratio (mtDNA/nuDNA ratio) (Andreux et al., 2019).
4.3. Gut microbiome composition
Gut microbiota alpha diversity assessed by Faith’s phylogenic indices was higher in the UA (50 mg/day) treated group compared to placebo after 8 weeks of treatment. No differences were observed with the Shannon’s gut microbiome index, the number of Amplicon Sequence Variants (ASVs) beta diversity, assessed by the weighted and unweighted unique fraction metric. No significant changes were observed in the 195 genera identified by 16 S sequencing after correction for multiple testing (Nishimoto et al., 2022). The stool microbial metabolites formic acid was significantly higher, and propionic acid was significantly lower in UA (10 mg or 50 mg/day for 8 weeks) treated groups compared to placebo. No differences were observed for acetic, isobutyric, butyric, isovaleric, valeric, lactic, and succinic acids in any of the intervention groups compared to placebo (Nishimoto et al., 2022).
5. Clinical outcomes
5.1. Anthropometric measures
UA treatment (500 mg or 1000 mg/day for 4 months) did not change total lean or fat mass (measured by dual-energy X-ray absorptiometry (DEXA)) compared to placebo (A. Singh et al., 2022).
5.2. Cardiovascular capacity and function
While UA (10 mg/day for 8 weeks) showed a trend towards improvement of Flow-Mediated Dilatation (FMD), there was no change in FMD in other UA (10 mg or 50 mg/day for 4 weeks/8 weeks/12 weeks) treated groups compared to placebo (Nishimoto et al., 2022).
5.3. Physical function
UA (500 mg/day for 4 months) did not affect handgrip strength, gait speed, peak power output (PPO), peak oxygen consumption (VO2), estimated maximum oxygen consumption (VO2max), total cycling and 6-minute walk distance and time to fatigue (assessed on a stationary cycle ergometer) during exercise testing compared to placebo (Liu et al., 2022; A. Singh et al., 2022). While there was no significant effect of UA (500 mg/day for 4 months), a trend towards improvement in gait speed (6-minute walk test), VO2, VO2max, and total cycling distance, after the treatment with UA (1000 mg/day for 4 months). However, these test results were not reported at baseline (A. Singh et al., 2022).
5.4. Muscular strength, endurance and capacity
UA (500 or 1000 mg/day for 4 months) significantly increased muscle strength expressed as average peak torque in the hamstring muscle and the maximum torque during knee flexion when compared to placebo. UA had no significant effect on quadriceps strength compared to placebo (A. Singh et al., 2022). UA (1000 mg/day for 2 months) significantly improved muscular endurance in the right hand-first dorsal interosseus and leg tibialis anterior, as determined by the number of repeated isometric contractions until fatigue compared to placebo. This effect was not significant when the same dosing regimen was administrated for a longer period (4 months) (Liu et al., 2022).
5.5. Adverse events
There were no serious adverse events attributed directly to UA reported in any of the studies. Observed adverse events such as myalgia and headaches were classified as mild to moderate and assessed as unrelated to the interventions (Supplementary Table 2).
6. Risk of bias assessment
The risk of bias for human studies is presented in Fig. 3. There was a low overall risk of bias in three studies (Andreux et al., 2019, Liu et al., 2022) and an unclear risk of bias in the other two studies (Nishimoto et al., 2022; A. Singh et al., 2022). The studies’ selection of reported results [21], lack of details in describing the process of conducting and analysing the study [23], and dropout of participants with no specific reasons [22] contributed to the unclear risk of bias.
7. Current trends in UA research: insights from ongoing clinical trials
Five clinical trials were registered on clinicaltrials.com assessing the effect of UA on aging and aging-related diseases in humans as of 26.06.2023. Out of these, one is active but not recruiting, two are recruiting, and two are completed. Three studies included healthy individuals, and two included individuals with aging-related diseases. The primary outcomes were defined as: plasma levels over time of creatine kinase, 3000-meter track race performance, left ventricular ejection fraction, maximal mitochondrial respiration (rate of oxygen flux) and mitochondrial adenosine diphosphate sensitivity (Oroboros O2k), percentages of CD3+ T-cell immune cell population, mitochondrial activity in CD3+ T-cells and integumentary markers of aging (Supplementary Table 3, 4).
8. Discussion
The effect of UA has been studied in a few studies, including a small number of healthy participants. After oral intake, UA and its metabolites were detectable in plasma and skeletal muscle, showed anti-inflammatory properties, and improved muscle strength and endurance without serious side effects.
UA demonstrated a moderate absorption speed, with its concentration increasing in a dose-dependent manner without accumulation in plasma (Andreux et al., 2019). It has been reported that there were no differences in the bioavailability of UA when taken fasted and with high-protein yogurt. However, this data was not shown (Andreux et al., 2019).
While animal studies have indicated UA's presence in the blood and its distribution to various tissues (skeletal muscle in pigs (Espín et al., 2007), brain, lungs, stomach, small intestine, cecum, colon, kidney, bladder, spleen, and liver rats (M. A. Ávila-Gálvez et al., 2019; Gasperotti et al., 2015)), human data identified UA's presence in mammary tissue (M. Ávila-Gálvez et al., 2019) and muscle (Andreux et al., 2019). The question remains whether UA distributes in other human tissues.
After oral administration, UA undergoes metabolism by phase II enzymes such as glucuronosyl transferases and sulfotransferases, forming less active UA-glucuronides (Seeram et al., 2006). In in vitro studies, UA is typically tested in its aglycone form (Tomás-Barberán et al., 2017). Also, there are discrepancies in the expression and function of glucuronidation enzymes between different animal model species and humans (Fujiwara et al., 2018). This can explain the inconsistency between the UA concentrations used in in vitro and preclinical studies (5–50 μM) (Denk et al., 2022, Ginefra et al., 2024, Mehra et al., 2023) and the UA concentrations observed in human plasma or other organs (Andreux et al., 2019; M. Ávila-Gálvez et al., 2019).
Additional factors, including dietary habits, microbiota composition, and concurrent drug usage, may contribute to pharmacokinetic and pharmacodynamic interactions with UA, warranting further exploration. For example, when administered in vitro, UA inhibited the proliferation of LNCaPprostate cancer cells, however, its combination with bicalutamide (an antiandrogen drug that is primarily used to treat prostate cancer) mitigated the pro-apoptotic activity (Stanisławska et al., 2018). Another study reported that the concomitant use of UA and acarbose showed an additive inhibitory effect by non-competitively inhibiting alpha-glucosidase as determined by molecular docking analysis, which could potentially lead to the increased antihyperglycemic effect (Yin et al., 2023).
UA displayed a prolonged half-life (Andreux et al., 2019), supporting less frequent dosing regimens. Optimal dosing regimens should be explored further, taking into account blood concentrations that elicit clinically relevant responses for geroprotection.
The anti-inflammatory properties of UA are in line with the results reported in earlier preclinical investigations (Toney et al., 2021). The mechanism of UA anti-inflammatory effects lies in its capacity to inhibit nuclear factor-κB and Akt/mitogen-activated protein kinase signaling pathways and reduce both mRNA and protein levels of cyclooxygenase 2 (COX-2) (González-Sarrías et al., 2010, Larrosa et al., 2010). UA reduced the production of TNF-α while enhancing the synthesis of IL-10 and the expression of TGF-β1 in LPS-stimulated macrophages (Bobowska et al., 2021). Despite the effect of UA on interleukins in the included studies was inconsistent, UA exhibits pancreas protective effects by decreasing IL-1ß in diabetic mice (Tuohetaerbaike et al., 2020) and attenuates IL-1ß-induced inflammatory responses in rat articular chondrocytes (Ding et al., 2020).
The decline in mitochondrial activity during aging (Nguyen et al., 2013, Short et al., 2005), specifically, the ability of mitochondria to produce ATP in muscle (Amara et al., 2007), possibly leads to physical function decline indicated by a slower walking speed (Coen et al., 2013). In C57BL/6 mice, the administration of 10 mg/kg of UA over a period of 12–16 weeks led to an elevation in total ATP levels in skeletal muscle compared to the placebo (Ghosh et al., 2020). In humans, no significant increase in maximal ATP production mitochondrial biogenesis and dynamics was observed, however, higher doses significantly enriched most of the assessed mitochondrial genes showing an overall increase in the mitochondrial activity and fatty acid oxygenation (Andreux et al., 2019). The reason why some markers of autophagy were increased only at lower but not higher remains unclear and should be further explored with different dose rangers and treatment durations (Andreux et al., 2019, Ginefra et al., 2024, Girotra et al., 2023). A potential beneficial effect of UA on body composition, especially reducing fat mass, would be of immense relevance due to the associated effect on age-related diseases such as sarcopenia (Newman et al., 2005) and diabetes mellitus type 2 (Son et al., 2017). In male C57BL/6 mice on a high-fat diet, 30 mg/kg/day UA decreased the fat mass by more than 60 % and lowered the fat/body mass ratio by 70 % (Xia et al., 2020). Body composition was not affected by UA supplementation in the reported human study [23]. However, this study did not control for dietary patterns that could affect body composition (Gates et al., 2007).
Overall, UA did not change the gut microbiota in individuals who are not able to convert ellagic acid to UA, which might be due to the very low UA dosage given in the study (Nishimoto et al., 2022). It remains to be investigated if UA would affect the microbiota profile at higher doses reported in other studies when UA was detectable in plasma and muscle tissue. Since microbiota is responsible for the conversion of ellagic acid to UA it would be important to understand if natural producers would retain their ability to covert ellagic acid when supplemented with UA. Other oral intervention, metformin, significantly affected the gut microbiota composition after 2 and 4 months of treatment, which could be demonstrated with whole-genome shotgun sequencing (Wu et al., 2017), while the included UA study only used 16 S sequencing method.
Muscle strength is paramount for human health [18]. In studies involving UA supplementation, the evaluation of muscle health was more frequent compared to other clinical parameters. UA (50 mg/kg/day) incorporated into the chow diet for 10 weeks resulted in an approximately 25 % increased grip strength in a mouse model (3-weeks old male) of Duchenne muscular dystrophy when compared to placebo (Luan et al., 2021). UA supplementation in humans showed an overall positive effect on muscle strength tests and muscle endurance. However, no significant effect of UA on the handgrip strength was seen (A. Singh et al., 2022). The observed difference may be attributed to the mice's younger age and the extended treatment duration of 10 weeks, which would be equivalent to starting treatment in 10-year-old humans and lasting for 30 years (Schaum et al., 2020). This result indicates that the results from animal models should be interpreted with caution when extrapolated into human outcomes. UA did not affect gait speed or had any significant effect on cardiorespiratory fitness such as PPO, VO2, and VO2 max [23]. These findings are in accordance with other results reported in this review, such as a lack of the effect on ATP production and an inconsistent effect on the other markers of mitochondrial function and markers of autophagy that could have had a positive effect on physical performance (Grevendonk et al., 2021).
Taken together, current evidence does not support the beneficial effects of UA on physical function in healthy individuals. However, this conclusion should be considered in light of several limitations: small sample sizes, short intervention durations, and a wide participant age range (45–85 years), which includes both middle-aged and older individuals who may not be ideal candidates for geroprotection.
9. Concluding remarks
There is very limited evidence on the effect of UA in human aging. UA showed some improvement in mitochondrial activity and autophagy. It decreased inflammatory markers and increased muscle strength and endurance, however, it did not affect gut microbiota composition and physical function. Further research across a wider range of physiological systems, higher number of individuals and longer intervention periods is required.
Urolithin A (Uro A) is a dietary metabolite of the intestinal microbiota following the ingestion of plant-based food ingredients ellagitannins and ellagic acid in mammals. Accumulating studies have reported its multiple potential health benefits in ...
pmc.ncbi.nlm.nih.gov
Ameliorative Effects of Gut Microbial Metabolite Urolithin A on Pancreatic Diseases
Urolithin A (Uro A) is a dietary metabolite of the intestinal microbiota following the ingestion of plant-based food ingredients ellagitannins and ellagic acid in mammals. Accumulating studies have reported its multiple potential health benefits in a broad range of diseases, including cardiovascular disease, cancer, cognitive impairment, and diabetes. In particular, Uro A is safe via direct oral administration and is non-genotoxic. The pancreas plays a central role in regulating energy consumption and metabolism by secreting digestive enzymes and hormones. Numerous pathophysiological factors, such as inflammation, deficits of mitophagy, and endoplasmic reticulum stress, can negatively affect the pancreas, leading to pancreatic diseases, including pancreatitis, pancreatic cancer, and diabetes mellitus. Recent studies showed that Uro A activates autophagy and inhibits endoplasmic reticulum stress in the pancreas, thus decreasing oxidative stress, inflammation, and apoptosis. In this review, we summarize the knowledge of Uro A metabolism and biological activity in the gut, as well as the pathological features and mechanisms of common pancreatic diseases. Importantly, we focus on the potential activities of Uro A and the underlying mechanisms in ameliorating various pancreatic diseases via inhibiting inflammatory signaling pathways, activating autophagy, maintaining the mitochondrial function, and improving the immune microenvironment. It might present a novel nutritional strategy for the intervention and prevention of pancreatic diseases. Keywords: urolithin A, pancreas, autophagy, microbiota, diet
1. Introduction
Urolithin A (3,8-dihydroxy-dibenzoprranone, Uro A) and its glucuronic acid derivatives are the main urolithins in the blood and urine of mammals following the consumption of ellagitannins (ETs) and ellagic acid (EA). Urolithins are 6H-dibenzopyran-6-one derivatives (or aglycons) that were first isolated from natural sources (scent glands of beaver) in 1949 [1]. In vitro and in vivo experiments have shown that Uro A, as a natural active substance, has various health benefits, including antioxidant, anti-inflammatory, and cancer inhibition. Interestingly, these activities of Uro A are higher than those of Uro A precursor compounds (ETs and EA) for both disease prevention and treatment. Therefore, Uro A has broad prospects in clinical applications. For example, the benefits of Uro A supplementation in muscles have been supported by recent clinical trials in older adults [2,3]. Additionally, Uro A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in middle-aged adults [4]. Additionally, studies have demonstrated the safety of direct oral Uro A. The genotoxicity tests also show that Uro A is not genotoxic. Consistent with the results obtained by the population experiment, there was no significant systemic and tissue toxicity in rats after the continuous intragastric (i.g.) administration of Uro A for 90 days [5]. This study also revealed that the No Observed Adverse Effect Level (NOAEL) was determined to be 3451 mg/kg bw/day in male rats and 3826 mg/kg bw/day in female rats, which would be equivalent to a human-equivalent dose of approximately 557 mg/kg bw/day in males and 617 mg/kg bw/day in females [5]. Because of its effectiveness and safety, Uro A has been recognized as safe by the US Food and Drug Administration and was approved for use as a food ingredient. The pancreas is the center that regulates energy consumption and metabolism through secreting digestive enzymes and hormones [6]. The exocrine and endocrine glands form the morphologic and functional parts of the pancreas. A total of 95% of the exocrine pancreas consists of acinar cells and duct cells [7]. Endocrine cells are spherically clustered into the islet of Langerhans to form the endocrine pancreas [8]. Many pathophysiological conditions can hamper endocrine and exocrine pancreas functions, such as pancreatitis, pancreatic cancers, and diabetes mellitus (DM). In this review, we summarize the knowledge of Uro A metabolism and biological activity. Moreover, we discuss the pathological features and mechanisms of common pancreatic diseases. Finally, Uro A’s potential effect and mechanisms on the pancreas are further explored.
2. Urolithin A
2.1. Intestinal Microbial Metabolite Urolithin A
EA is a natural polyphenol that mainly exists in its condensed form—ETs. They are found in various berries, nuts, and seeds and are consumed in large quantities by mammals, including humans [9]. There is a correlation between ETs and health effects. However, EA is difficult to be absorbed directly by the gastrointestinal tract because it is a highly polar macromolecule. Thus, ET levels in tissues and plasma are insufficient to achieve the concentration required for its biological activity [10]. As shown in Figure 1, it has been shown that most ETs and EA react with the abundant gut microbiota to produce new metabolites with powerful health functions, such as urolithins. Urolithins are dibenzopyran-6-one derivatives with different hydroxyl substitutions, which can be considered a combination of coumarin and isocoumarin [11]. Natural urolithins were first isolated from the scent glands of beavers in 1949 and were gradually proved to be widespread in microbial, plant, animal, and human feces [1]. In terms of chemical structure, urolithins are produced from EA by lactone ring-opening and decarboxylation, and by gradually removing hydroxide radicals from various sites via dehydroxylase [12]. Common urolithins include Uro A, Uro B, iso-Uro A, iso-Uro B, Uro C, and Uro D. Uro A has attracted attention due to its mitochondrial autophagy activation, anti-aging and antioxidant properties, and other functions.
Uro A can travel through the bloodstream to peripheral tissues, including pancreas, brain, liver, and muscle tissue, and perform biological activities, such as preventing inflammation and increasing mitophagy. There were significant individual differences in the production and excretion of Urolithins [10]. Urolithin metabotypes (UMs) can be divided into three phenotypes (UM-A, UM-B, and UM-0) based on the different abilities of human subjects to excrete urolithins. UM-A produced Uro A; UM-B mainly produced iso-Uro A and Uro-B; and UM-0 did not produce Uro-A, iso-Uro A, or Uro B [13]. The distribution of UM-A and UM-B was affected by aging, with UM-A decreasing from 85% to 55% after adulthood [14]. Specific intestinal microflora can convert ETs and EA consumed by some people into urolithins [15]. Selma et al. reported that the abundance of Gordonibacter in the feces of UM-A individuals was higher than those of UM-B and UM-0 individuals [16]. In addition, two strains from the genus Gordonibacter with a Uro-C-producing ability were identified: G. urolithinfaciens and G. pamelaeae [17]. E. isourolithinifaciens was a strain from the genus Ellagibacter with the ability to produce iso-Uro A [18]. Additionally, Uro A could be produced by Bifidobacterium pseudocatenulatum from the genus Bifidobacterium [19]. The other studies consistently showed that Uro A and iso-Uro A could be found in fermentation broth inoculated with the fecal flora of two volunteers in vitro [12,20]. The Clostridium leptum group from the Firmicutes phylum was identified as the dominant flora in the fermentation broth, followed by Bacteroids and Prevotella [20]. These bacteria with the ability to produce urolithins can be used as novel probiotics in functional food and health products. To date, all the strains used to synthesize Uro A by fermentation in vitro are mixed strains without success with single strains. This may be because multiple bacteria are involved in the formation of intermediates during EA metabolism. Uro A prepared by biological fermentation is safe and has a wide range of raw materials. However, its purity is lower than chemical synthesis.
2.2. Pharmacokinetics of Urolithin A
The data suggested that, after the direct oral administration of Uro A (250–1000 mg) in healthy, older adults, its maximum plasma concentration (C max) and area under the curve (AUC) were dose-dependent. Furthermore, after oral administration, the highest C max was Uro A-glucuronide (1500–3000 nM), followed by Uro A-sulfate (200–400 nM) and Uro A (4–7 nM). All three substances exhibited similar kinetics, with peak concentrations in plasma at 6 h (T max) after dosing. The half-life (t 1/2) of Uro A and Uro A-glucuronide ranged from 17 to 22 h, while the t 1/2 of Uro A-sulfate was relatively long at 25–88 h. They were completely eliminated from plasma circulation within 72 to 96 h [2]. Animals were also treated by either i.g. or intravenous (i.v.) administration of 14C radiolabeled Uro A. After i.g. administration of Uro A, the majority of them were excreted via the feces. Total Uro A reached C max at around 3 h and then again around 6 or 7 h. In contrast, i.v. administration resulted in the urine as the main excretion route. Moreover, the results show that absorption after i.v. administration is higher than that after i.g. administration [5]. In conclusion, these pharmacokinetic data indicated that Uro A had favorable bioavailable profiles. In particular, after oral administration of EA (50 mg/kg) in rats, the plasma levels peaked at about 0.5 h, with a C max value of 93.6 ng/mL, showing that EA was poorly absorbed after oral administration. The pharmacokinetic profile of EA fitted to a two-compartment model with t 1/2 α 0.25 h and t 1/2 β 6.86 h, respectively [21].
Uro A-glucuronide is the main existing form of Uro A in blood circulation. Uro A-glucuronide is a macromolecule with many polar groups, making its transmembrane transport ability extremely low. However, a recent study showed the deconjugation of Uro-A glucuronide to Uro-A in the Sprague Dawley rat model of systemic inflammation induced by lipopolysaccharide (LPS). Therefore, the ratio of Uro A-glucuronide to Uro-A in the intestine, liver, kidney, bladder, spleen, lung, muscle, and urine was significantly decreased [22]. For instance, 8 h after a single oral administration of 2000 mg of Uro A, its parent state was mainly detected in skeletal muscle tissue (6 ng/g) [2].
2.3. Biological Activity of Urolithin A
Due to the strong biological activity of Uro A, studies on it have considerably increased in recent years. Many in vivo and in vitro experiments have shown that Uro A can improve oxidative stress, cognitive impairment, are anti-inflammatory and anti-aging, activate mitochondrial autophagy, and enhance intestinal barrier and other functions.
2.3.1. Anti-Inflammatory and Improved Oxidative Stress
Uro A can improve neuroinflammation, renal toxicity, and more. DaSilva et al. found that Uro A significantly improved LPS-induced BV2 cell inflammation [23]. Uro A reduces nitric oxide (NO) levels and down-regulates the expression of inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). This effect was achieved through the inhibition of nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), and activation of the Akt signaling pathway [23]. At the same time, Uro A reduced the expression of reactive oxygen species (ROS) in neuro-2a Cells induced by H2O2 by enhancing the activity of antioxidant enzymes [24]. Additionally, the study showed that Uro A significantly ameliorates cisplatin-induced nephrotoxicity in mice via modulating inflammation and oxidative stress [25]. To be specific, Uro A significantly reduced neutrophilic gelatinase-associated lipoprotein (NGAL), blood urea nitrogen (BUN), creatinine, and urinary kidney injury molecule-1 (KIM-1) in serum.
2.3.2. Anti-Aging
As a natural active substance, Uro A shows great anti-aging potential. Ryu et al. first demonstrated that Uro A improved mitochondrial function by inducing mitochondrial autophagy in C. elegans, thereby prolonging its lifespan and maintaining the normal activities of nematodes during senescence [26]. Furthermore, Uro A significantly inhibited the impaired autophagy in aging mice caused by D-galactose-induced overexpression of miR-34a [27]. They proved that Uro A upregulates the Sirt1 signaling pathway and down-regulates the mTOR signaling pathway to activate autophagy. In human skin fibroblasts, Uro A can reduce the expression of matrix metalloproteinase-1(MMP-1) and increase the expression of type-I collagen in senescent cells [28]. Uro A reduced ROS in senescent cells by activating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant system. Importantly, Uro A safeguarded against physiological decline, as illustrated by improving muscle function in young animals, demonstrating the benefits of Uro A in healthy environments [26,29]. However, whether Uro A can delay pancreatic aging or enhance pancreatic function in healthy people and its mechanism remains unclear.
2.3.3. Regulation of Metabolic Homeostasis
The incidence of metabolic diseases, such as insulin resistance (IR), obesity, metabolic syndrome, and DM increases. As a metabolite of foodborne EA via gut microbiota, Uro A was thought to have the activity of improving glucose and lipid metabolism disorders. In a high-fat-diet (HFD)-induced IR model, Uro A significantly reduced fasting blood glucose, serum triglycerides, free fatty acids, and increased adiponectin content [30]. Uro A interfered with cholesterol metabolism by regulating the expression of miR-33a and ERK/AMPKα/SREBP1 signaling pathways [31]. Xia et al. indicated that Uro A inhibited obesity induced by HFD via enhancing thermogenesis in brown adipose tissue and promoting the browning of white adipose tissue [32]. Overall, Uro A played an important role in weight control, glucose homeostasis, and lipid metabolism balance.
2.3.4. Improve Alzheimer’s Disease and Cognitive Impairment
Alzheimer’s disease (AD) has no good treatment in the world. Many pathogenic factors of AD exist, such as gene mutation, an unhealthy lifestyle, and brain trauma. Uro A is active against cognitive impairment and AD. Gong et al. proved that Uro A ameliorated cognitive impairment, attenuated neuronal apoptosis, promoted neurogenesis, and decreased accumulation of microglia and astrocytes in the APP/PS1 mouse AD model [33]. Impaired mitochondrial autophagy is one of the mechanisms resulting in AD. As an activator of mitochondrial autophagy, Uro A can inhibit Tau hyperphosphorylation through PINK-1, PDR-1, and DCT-1 signaling pathways, thereby restoring memory impairment in the AD model in C. elegans [34]. Long-term metabolic disorders also contribute to the development of AD. Lee et al. found that Uro A significantly reduced mitochondrial calcium overload and the accumulation of mt-ROS induced by high glucose and inhibited amyloid β-protein (Aβ)-related enzymes [35]. Studies have shown that Uro A also has other activities, such as protecting the intestinal barrier to maintain intestinal integrity, inducing cancer cell death, and improving cardiac dysfunction. It is well known that the function of gut microorganisms and gut barriers to human health are indisputable. Uro A exerted its barrier functions by activating aryl hydrocarbon receptor (AhR)-Nrf2-dependent pathways to upregulate epithelial tight junction proteins, which could reduce colon inflammation [36]. Moreover, the activities of Uro A in improving cerebral ischemia-reperfusion injury and Parkinson’s disease have also been reported. Uro A has solid biological activity both in vivo and in vitro. In most cases, Uro A played a role as an activator of mitochondrial autophagy. Uro A also played a role in improving endoplasmic reticulum (ER) stress and regulating gene expression. More possible biological activities and their specific mechanisms need to be further explored.
3. Pathogenic Mechanisms of Pancreatic Diseases
The pancreas is a primary target of free radicals due to its high synthetic and secretory activities, which result in oxidative damage [37]. In addition, pathophysiological changes, such as self-digestion, inflammatory response, intracellular Ca2+ overload, ER stress, mitochondrial dysfunction, and weakening of the immune system, can also impair endocrine and exocrine pancreas functions. The most common life-threatening pancreatic diseases include pancreatitis, DM, and pancreatic cancer.
3.1. Pancreatitis
Acute pancreatitis (AP), usually accompanied by acinar cell necrosis, is one of the most common diseases among gastroenterology disorders [38,39]. AP refers to intrapancreatic trypsinogen activation caused by gallstones, hypertriglyceridemia, metabolic abnormalities, obesity, and alcoholic intemperance, which is characterized by early local inflammatory damage of the pancreas and may progress to the serious systemic inflammatory response [40,41]. The global incidence in AP is 33.74 cases (95% confidence interval (CI): 23.33–48.81) per 100,000 individuals per year, and it is rising continuously at about 3.4% a year [42,43]. The incidence is not statistically significant between the sex, but increases with age [44]. Patients with mild AP have a good prognosis, but moderately severe AP or severe AP patients account for 15–20%, resulting in mortality rates as high as 30% because of persistent organ failure and pancreatic necrosis [45]. The pathogenesis of AP is associated with complex intra-acinar events, such as autophagy, oxidative stress, mitochondrial dysfunction, and ER stress [46]. Furthermore, inflammatory responses, including the recruitment of immune cells, activation of damage-related molecular patterns, and release of various inflammatory cytokines and chemokines, have been partly involved in the development of AP [47]. Based on recent studies on the effects of natural active substances on AP, three major signaling pathways, including NF-κB, Nrf2, and MAPK, have received great interest and attention from researchers and industries [47]. (1) During the development of AP, NF-κB is rapidly activated in pancreatic acinar cells, followed by significant increases in inflammatory cytokines and chemokines, which can affect vascular permeability and lead to thrombosis, bleeding, and tissue necrosis [48,49]. (2) Oxidative damage and inflammatory cascade amplification are essential factors that cause AP to evolve into severe AP [50]. Nrf-2 is a key factor of the endogenous antioxidant pathway, which is involved in a series of physiological activities of inflammatory response. Nrf-2 upregulates the expression of heme oxygenase 1(HO-1), quinone oxidoreductase 1 (NQO1), superoxide dismutase (SOD), and other antioxidant enzymes through the Nrf2/ antioxidant response element (ARE) signaling pathway [51]. These antioxidant proteins exert cytoprotective effects against pancreatic acinar cell injuries. It also down-regulates the expression and secretion of malonic dialdehyde (MDA), myeloperoxidase (MPO), C-reaction protein (CRP), and other inflammatory proteins. (3) Three predominant members of the MAPK family, c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPK, are upregulated to mitigate early AP progression by reducing pancreatic acinar cells damage and inhibiting inflammation [47]. Chronic pancreatitis (CP) is a complex disease characterized by a persistent or repeated inflammation of the pancreas that leads to progressive and irreversible morphologic changes causing impairment of pancreatic function [52]. Functional consequences include DM (endocrine insufficiency) and dyspepsia (exocrine insufficiency). CP develops in 36% (95% Cl: 20–53%) of patients with recurrent AP [40]. Similar to AP, CP mainly affects middle-aged and elder patients [44]. The crude mortality of CP is 0.09 (95% Cl: 0.02–0.47) per 100,000 individuals per year [42]. Additionally, the majority of patients with CP die from non-pancreatitis causes, such as cancer and cardiovascular disease [53]. Early CP is difficult to diagnose because the lesions are subtle and similar to other diseases [54]. The typical manifestations of later CP are focal necrosis, fibrosis, irregular enlargement of the pancreatic duct, pseudocysts, intraductal calculi, and calcifications [55]. CP’s potential causes include toxic factors (alcohol or smoking), metabolic abnormalities, genetics, impaired autoimmune, and disease [56]. The pathological changes of CP are quite complex, including acinar cell damage, acinar stress response, ductal dysfunction, and persistent or altered inflammation, but these mechanisms are not fully understood [57].
3.2. Pancreatic Cancer
Pancreatic cancer is a highly fatal disease with a 5-year survival rate of about 10% in the United States [58]. The most common and deadliest form of pancreatic cancer is referred to as pancreatic ductal adenocarcinoma (PDAC) [59]. Although the incidence of PDAC has been increasing year by year, the mortality rate has not decreased significantly due to late diagnosis, early metastasis, and limited response to chemotherapy or radiotherapy [60]. A major hallmark of PDAC is the presence of several activated oncogenic signaling pathways that contribute to the aggressiveness of disease and therapeutic resistance. For example, more than 90% of PDAC patients have K-RAS mutations that activate downstream pathways, such as phosphatidylinositol-3-kinase (PI3K)-Akt, to promote tumor genesis [61]. This pathway has been demonstrated in mice as well. Furthermore, in the pancreas of mice expressing PI3KCA mutations, acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasms (PanINs) progress to invasive PDAC [62]. PI3K-activated phosphorylation of Akt (the serine-threonine kinase of the AGC kinase family) also affects the expression of anti-apoptotic and cell-cycling-related proteins and transcription factors. Approximately 60% of PDAC patients experience increased Akt activity due to hyperphosphorylation, while Akt overexpression due to gene amplification is recorded in 10–20% of PDAC patients [63]. In addition, the complex PI3K signaling network plays a role in activating mTOR, NF-κB, GSK3β, p27, and Bad-Bax pathways [64]. Immune evasion is also a major obstacle to PDAC treatment. Common evasion mechanisms include impaired antigen presentation due to mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I) [65]. In PDAC, MHC-I is selectively degraded by lysosomes through an autophagy-dependent mechanism. PDAC can utilize its high basal autophagy levels to support its metabolism and maintain tumor growth. Notably, the inhibition of autophagy can restore MHC-I surface levels, improve antigen presentation, enhance anti-tumor T-cell responses, and reduce tumor growth [66]. What is more, the inhibition of autophagy also results in the loss of SLC7A11 on the plasma membrane and increases its localization at the lysosome in a mTORC2-dependent manner [67]. Metastatic PDAC has a lower infiltration of total T cells than resectable primary PDAC, proving that metastatic PDAC has poor immunogenicity. Furthermore, the number of CD68 (+) macrophages and VISTA (+) cells is significantly increased in the pancreatic stromal region of metastatic PDAC patients. Hence, VISTA may be a relevant immunotherapy target for the effective treatment of PDAC patients [68]. Ordinary care drugs, such as FOLFIRINOX and gemcitabine plus nab-paclitaxel, have limited clinical effects and are poorly tolerated by patients due to toxic side effects [69]. Therefore, there is an urgent need to develop new therapies to reduce the PDAC burden without significant off-target effects.
3.3. Diabetes Mellitus
Diabetes mellitus (DM) is a chronic metabolic disease characterized by elevated blood sugar levels over time leading to damage to the heart, vasculature, eyes, kidneys, and nerves [70]. According to the International Diabetes Federation, the global number of DM patients has increased in recent decades and is predicted to ascend to 642 million by 2040 [71]. Type 2 diabetes mellitus (T2DM) is the most common type of DM, accounting for about 90% of all cases [72]. T2DM is characterized by insufficient insulin secretion by β cells, IR, and inadequate compensatory insulin secretion [73]. Early on, when cells become IR, β cells secrete high amounts of insulin, leading to hyperinsulinemia. In later stages, with a gradual decline in β-cell function, insulin levels are insufficient to meet increased insulin requirements, which produce hyperglycemia [74]. The link between islet cell injuries and DM has been established for several years. Restricted islet cell proliferation and regeneration as well as reduced secretion capacity lead to a decline in the accurate management of glucose homeostasis. For example, many GWAS studies attested that SNPs adjacent to the CDKN2a/b gene is associated with T2DM [75]. This discovery suggests that β-cell-proliferation-related genetic defects might increase the susceptibility of T2DM. Many studies have shown the role of autophagy in β-cell function and survival. Autophagy can participate in the catabolic process of removing cytotoxic proteins and damaged organelles in cells under stress conditions to promote the survival of β cells under conditions conducive to cell death, including nutrient depletion, inflammation, hypoxia, and mitochondrial damage [76]. For example, Quan et al. showed that β-cell-specific autophagy-related 7 (Atg7)-null mice showed hypo-insulinemia and hyperglycemia, which induced DM [77]. In addition, the macrophage populations shift their polarity to a more inflammatory phenotype during islet inflammation, increasing the amplification of islet inflammation [78]; for instance, in many macrophage marker CD68+ cells near islets from DM patients, which is associated with decreased insulin immunoreactivity and increased amyloid deposits [79,80,81]. Hence, inflammation and immune damage play essential roles in the pathogenesis of DM and contribute to β-cell dysfunction in diabetes mouse models. In recent years, gut microbiota dysbiosis has been widely discussed as a driver of diabetes pathophysiology. Metformin, one of the most commonly used hypoglycemic agents, is known to alter the composition of gut bacteria [82]. In conclusion, DM, as a systemic metabolic disease, has complex pathophysiological driving factors. Therefore, we are supposed to fully consider the effect of islet cell injuries on DM.
4. Effects of Urolithin A on Pancreatic Diseases
4.1. Reduces the Expression of Pancreatic Inflammatory Factors
The inflammatory microenvironment of the pancreas led to pancreatitis and was the main reason for the decline in endocrine function [83]. Some researchers suggested that if β cells would express high levels of NF-κB signaling marking, cells’ proliferative and regenerative potential were reduced. The NF-κB-expressed β cells also emerged with a premature upregulation of socs2, a gene that inhibits proliferation [84]. It has been widely reported that EA can inhibit pancreatic inflammation (Table 1). In an experimental model of spontaneous chronic pancreatitis, male Wistar Bonn/Kobori rats were fed a diet supplemented with EA (100 mg/kg body weight/day) for ten weeks. They found that EA attenuated pancreatic inflammation and fibrosis by increasing pancreatic weight and decreasing MPO activity (a neutrophil infiltration index), collagen content, transforming growth factor-β1 (TGF-β1) expression, activated pancreatic stellate cells (PSCs), and ED-1-positive cells [85]. Masamune et al. also reported that EA inhibited the production of monocyte chemoattractant protein-1 (MCP-1) and activation of activator protein-1 (AP-1) and MAPK in PSCs, all induced by interleukin (IL)-1β and TNF-α [86]. Meanwhile, EA inhibited PDGF-BB-induced tyrosine phosphorylation of PDGF P-receptors and the downstream ERK and Akt activation in PSCs. In particular, EA inhibited ROS production in PSCs in response to TGF-β1 or platelet-derived growth factor (PDGF) [87].
Table 1.
Potential effects and mechanisms of urolithin A and its precursor compounds EA on pancreatic diseases.
[th]
Disease Model
[/th][th]
Treatment
[/th][th]
Metabolic Response
[/th][th]
Ref.
[/th]
[td]
Spontaneous CP in male Wistar Bonn/Kobori rats
[/td][td]
100 mg/kg BW/day orally administered with EA for 10 weeks
Although EA had many promising developments, it was poorly absorbed in the human gut, limiting its anti-inflammatory effects. As mentioned above, EA was metabolized by microorganisms into a series of downstream compounds, such as Uro A [5]. A well-known effect of preclinical models exposed to Uro A was the attenuation of harmful inflammatory responses [94]. Uro A showed more potent anti-inflammatory properties than EA or ETs, suggesting that it might be the main compound for treating AP or CP (Table 1). The anti-inflammatory effects were first reported to reduce the mRNA and protein levels of inflammatory marker COX-2 in rats with acute colitis [95]. Zhang et al. had firstly reported that Uro A inhibited the thioredoxin-interacting protein (TXNIP)/Nod-like receptor family pyrin domain containing 3 (NLRP3)/IL-1β inflammation signal in MIN6 β cells by modulating AMPK (Figure 2) [88]. Finally, they testified that Uro A also down-regulated the protein kinase RNA (PKR)-like ER kinase (PERK) and promoted AMPK phosphorylation [96]. The latest research showed that Uro A can attenuate the severity of alcohol-associated chronic pancreatitis (ACP) in C56BL6/J mice by regulating the PI3K/AKT/mTOR signaling axis [89].
Uro A is metabolized by gut microbiota after ingestion of ETs and EA in mammals and has multiple potential health benefits. Uro A can attenuate pancreatic diseases by inhibiting inflammatory signaling pathways, activating autophagy, maintaining the mitochondrial function, and improving the immune microenvironment. Nevertheless, studies on reducing pancreatic inflammation by Uro A had only been verified in animals and cells without clinical studies. The upstream mediators of Uro A’s anti-inflammatory effects, including the NF-κB and AhR-Nrf2 pathways, were mainly studied in vitro [36]. Nevertheless, the mechanisms of Uro A action in the context of inflammation seemed to vary with tissues and conditions. Hence, the differences in Uro A’s mitigation degree and mechanism on AP and CP need to be further explored.
4.2. Activates Autophagy and Maintains Mitochondrial Function in the Pancreas
Mitochondrial damage, such as the loss of mitochondrial DNA (mt DNA) integrity, the alteration of mitochondrial morphology, and dysfunction, can lead to cellular senescence and apoptosis [97]. On the one hand, mitochondria acted as both nutrient sensors and signal generators for insulin secretion in β cells. Moreover, nutrients can inhibit the ATP-sensitive K+ (KATP) channel and then enhance insulin secretion either by acting as substrates for mitochondrial ATP synthesis (the triggering pathway) or by regulating Ca2+ channels (the amplifying pathway). On the other hand, mitochondria were the primary source of reactive oxygen species (ROS) at the level of the electron transport chain so that mitochondria might be the main targets of ROS damage [98]. Additionally, many studies have revealed a causal relationship between pancreatic diseases and dysregulation of mitochondrial dynamics (including fusion and fission) [97,99,100]. Thus, mitochondrial damage gave rise to decreased pancreatic function. The most consistent effect of Uro A across species, including cells, worms, mice, and humans, was improved mitochondrial health [94]. This benefit was driven by the clearance and recycling of dysfunctional mitochondria, known as selective autophagy [101]. For example, Uro A increased the expression of mitochondrial autophagy genes lgg-1, pink-1, and pdr-1, encoding for LC-3B, and formation of autophagosome vesicles in C. elegans [29]. Interestingly, Pink1 knockdown in microglia eliminated Uro A-mediated reductions in TNF-α and increased IL-10, suggesting that Uro A reduces neuroinflammation by inducing mitochondrial autophagy [34]. Zhang et al. also proved that Uro A inhibited glucolipotoxicity-induced ER stress and the TXNIP/NLRP3/IL-1β inflammation signal in MIN6 β cells by modulating autophagy [88]. Remarkably, the inhibitory effects of Uro A on p62 were stronger than TXNIP-inhibitor verapamil (p < 0.05) [102]. Uro A promoting PINK1/Parkin-mediated mitophagy was also reported in pancreatic cells of diabetic mice [90]. Therefore, Uro A restoring the correct level of mitochondrial autophagy to maintain normal mitochondrial function is highly likely to be the mechanism of Uro A reducing pancreatic diseases (Figure 2).
4.3. Inhibits Endoplasmic Reticulum Stress in the Pancreas
The misfolding and inhibition of protein folding in the endoplasmic reticulum (ER) lead to the aggregation of unfolded proteins, resulting in ER stress [103]. Li et al. showed that the ER stress and unfolded protein response (UPR) accompanied by the accumulation of protein aggregates emerged as a significant pathway affected by aging, specifically in β cells. Simultaneously, the transcriptomic dysregulation of UPR components was linked to activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1) signaling pathways [8]. ER stress-related apoptosis lead to a reduction in β-cell proliferation and regeneration, ultimately resulting in reduced insulin secretion and increased T2DM morbidity [104]. Therefore, maintaining transcriptional stability and reducing protein homeostasis loss during aging was crucial to recovering pancreatic function. It has been reported that Uro A suppresses glucolipotoxicity-induced ER stress in pancreatic beta cells [88]. However, more studies are needed on Uro A’s upstream and downstream pathways in the pancreas to improve ER stress.
4.4. Inhibits the Occurrence and Development of Pancreatic Tumors
High intakes of berries rich in ETs, including strawberries, pomegranates, and blueberries, were inversely associated with PDAC incidence [105]. EA, an intestinal metabolite of ellagic tannins, inhibited multiple carcinogenic pathways activated in PDAC, such as COX-2, NF-κB, and Wnt signaling, so that EA successfully arrested cell cycles and reversed epithelial to mesenchymal transition in PDAC [106]. As a downstream compound of EA, Uro A showed more potent antioxidant and anti-inflammatory properties, improving bioavailability and anti-tumor effect [107]. It has been demonstrated that the S473 phosphorylation site of AKT is activated by PI3K [108]. Uro A treatment resulted in a dose-dependent reduction in phospho-AKT (p-AKT) expression in PDAC cell lines, leading to a significant down-regulation of phospho-p70 S6 kinase (p-PS6K) expression regulated by the mTORC1 complex. Therefore, Uro A inhibited the proliferation and migration of PDAC cells and enhanced apoptosis by down-regulating the PI3K/AKT/mTOR pathway [109] (Figure 2). Furthermore, Uro A treatment also down-regulated PDK1 (the upstream target of AKT) and p-GSK3β and p-4E-BP1 (the downstream targets of AKT), suggesting that Uro A effectively inhibited the PDK1/AKT/mTOR [110]. Uro A treatment also reduced immunosuppressive tumor-associated macrophages (TAMs) and regulatory T cells in the engineered PKT mouse model of PDAC. It meant that Uro A treatment attenuated tumor growth and prolonged survival in mice by inducing changes in the immunosuppressive microenvironment of PDAC [91]. Srinivasan et al. also pointed out that Uro A inhibited AKT, PS6K, and STAT3 signaling, thereby reducing the Ki67-positive tumor cells and increasing cleaved caspase-3 expression in the pancreatic tissues of PDAC mice [92]. These results suggest that Uro A is a novel inhibitor/regulator for multi-signal pathways in PDAC and has potential in the prevention and treatment of pancreatic cancer (Table 1).
4.5. Protects Pancreatic β Cells
There have been many studies on the ameliorative effect of Uro A on DM and its complications. Specifically, Savi et al. first showed that Uro A recovered cardiomyocyte contractility and calcium dynamics in diabetic cardiomyopathy (DCM) rats [111]. Albasher et al. further demonstrated that Uro A prevents streptozotocin (STZ)-induced DCM in rats by activating SIRT1 expression and deacetylase activity [112]. Xiao et al. suggested that Uro A can attenuate DM-related cognitive impairment by ameliorating systemic inflammation and intestinal barrier dysfunction through the N-glycan biosynthesis pathway [113]. This conclusion was also supported by Lee et al. They pointed out that Uro A prevented DM-associated AD by reducing transglutaminase type 2 (TGM2)-dependent mitochondria-associated ER membrane (MAM) formation and maintaining mitochondrial calcium and ROS homeostasis [35]. Xu et al. indicated that Uro A ameliorated diabetic retinopathy by activating the Nrf2/HO-1 pathway to inhibit inflammation and oxidative stress [114]. Zhou et al. found that Phyllanthus emblica L. facilitated vascular function in STZ-induced hyperglycemia rats by regulating Akt/β-catenin signaling, mediated by the ETs metabolites [115]. Insulin resistance is one of the core mechanisms of DM. However, as a complex systemic metabolic disease, insulin resistance alone is not enough to cause DM. Islet dysfunction caused by the decrease in the total amount of islet β cells is also the key to the pathogenesis of DM. Studies have shown that β cells in T2DM can be divided into three main states: susceptibility, adaptation, and failure [116,117,118]. During insulin resistance, β cells compensate for the dysfunction by increasing insulin demand through insulin secretion [90]. When β cells fail to compensate for glucose homeostasis, hyperglycemia occurs. More importantly, EA from Phyllanthus emblica L. increased the size or number of β cells in diabetic rats. EA also directly increased glucose-stimulated insulin secretion from isolated islets, suggesting that EA acted directly on pancreatic β cells to exert anti-diabetic activity, thereby stimulating insulin secretion and reducing glucose intolerance [93]. Histopathological results showed that Uro A had protective effects on β cells, such as improving the pancreatic structure and increasing islet size and number. Ultrastructural damages in DM mice pancreas after Uro A treatment, including ER expansion, mitochondria swelling, cristae fracture, and myelin sheath formation, were also significantly improved [90]. We also discussed earlier that Uro A prevented β-cell apoptosis in T2DM model mice by activating autophagy and regulating the AKT/mTOR signal [88,90,102]. However, the specific mechanisms of Uro A improving β-cell structure and function to mitigate DM risk need to be explored further. In summary, the metabolism and the roles of Uro A in ameliorating pancreatic diseases have been extensively discussed in this section (summarized in Figure 2). By clarifying Uro A’s metabolism in vivo and Uro A’s mechanisms for protecting the pancreas, it might shed new light on managing pancreatic injuries via plant-based foods rich in ETs and EA.
5. Conclusions
Uro A is metabolized from ETs and EA in mammals by gut bacteria and is significantly associated with systemic beneficial effects [119]. This review introduced the metabolic process of Uro A through intestinal floras and discussed the benefits of Uro A in vivo and in vitro models of health decline linked to inflammation, oxidative stress, aging, metabolic disorders, AD, and cognitive impairment. In particular, we focused on the Uro A’s mechanisms in attenuating pancreatic diseases by inhibiting inflammatory signaling pathways, activating autophagy, maintaining the mitochondrial function, and improving the immune microenvironment. Since EA is insoluble and the gastrointestinal tract absorbs only a mere portion of it, the intestinal microbiota metabolizes most EA into urolithins, which are more easily absorbed and circulated through the bloodstream to cells and tissues [120]. However, due to the differences in age, health status, and composition of intestinal floras, the types and concentrations of produced urolithins can vary among individuals. Individuals also respond differently to exposure to urolithins or EA. Uro A has attracted attention due to its solid biological activity in the past decade. Uro A’s bioaccessibility was proven in an in vitro digestive simulation test, and toxicological studies have shown that Uro A has a good safety profile [2,121]. Moreover, there are many studies on the ameliorative effect of Uro A on DM and its complications, and most of them are mainly achieved by improving insulin resistance [112,113]. However, the effects and mechanisms of Uro A directly acting on β cells to boost glucose metabolism disorders were not discussed in detail. In addition, Uro A can also act on the pancreatic exocrine system to relieve pancreatitis or PDAC [89,92]. Several key factors support the improvement of pancreatic disease by Uro A. At first, Uro A inhibited ER stress and the TXNIP/NLRP3/IL-1β inflammation signal in β cells by modulating autophagy [88]. Uro A promoting PINK1/Parkin-mediated mitophagy to maintain mitochondrial function was also reported in pancreatic cells of diabetic mice [90]. Meanwhile, Uro A attenuates tumor growth and prolonged survival in mice by inducing changes in the immunosuppressive microenvironment of PDAC [91]. Uro A has beneficial effects in many tissues and is closely linked to gut microbes [122]. Intestinal microbial composition regulates the ability of ETs and EA to produce Uro A [15]. Future studies should clarify the bacterial species responsible for the urolithins conversion and investigate the relationship between Uro A, gut bacteria, and pancreatic diseases. This may shed light on the protective effects of Uro A on the pancreas, especially the exocrine pancreas. Meanwhile, considering the safety and wide sources of Uro A prepared by biological fermentation, we are supposed to look for strains that can efficiently transform ETs and EA into high-purity Uro A. We advocate for the nutritional supplementation of Uro A as an innovative way to ameliorate the function of the damaged pancreas. However, whether Uro A can delay pancreatic aging or enhance normal pancreatic function in healthy people and its mechanism remain unclear. Therefore, further studies are required to exploit the roles and mechanisms of using Uro A to protect the pancreas.
Taking into consideration the half-life of Urolithin A, which is 17 to 22 hours, dosing would appear to be best taken daily. Recommended dosages range from 250 mg to 1000 mg. Most of the studies indicate that the ideal dose is age dependent.
As a younger person, a dose of 250 mg might be ideal. Older individuals would appear to benefit from the higher doses.
This sounds like a great addition to anyone taking Rapamycin (Sirolimus)
After some research on available products and questions regarding dosage, it appears there is a wide margin between different manufacturers. Time Line who offers the Mitopure ingredient is expensive at over $100.00 per month with a recommended dosage of 500 mg:
This is why there IMO needs to be a private version of the FDA to test things and see if the low-priced one is the real thing. Also, this is also why the promotion of very over-priced supps whose effects are very hard to detect is a big problem with "biohackers" these days. The people who report benefit from Urolithin A (e.g. Dr Gundry) seem to be people who were not in very good shape to begin with, so whether the benefit would apply to someone who is in good shape is very unclear, and a likely better approach is to do all the basics first.
This is why there IMO needs to be a private version of the FDA to test things and see if the low-priced one is the real thing. Also, this is also why the promotion of very over-priced supps whose effects are very hard to detect is a big problem with "biohackers" these days. The people who report benefit from Urolithin A (e.g. Dr Gundry) seem to be people who were not in very good shape to begin with, so whether the benefit would apply to someone who is in good shape is very unclear, and a likely better approach is to do all the basics first.
Not trying to hijack thread or tread on anyone just posting what I found on GROC4
See new posts
Is Mitopure a brand name and does other version work as good
Yes, Mitopure is a brand name for a proprietary, highly pure form of Urolithin A—a postbiotic compound produced by gut bacteria from foods like pomegranates, nuts, and berries—that's clinically shown to support mitochondrial health, muscle strength, and endurance by promoting mitophagy (the recycling of damaged mitochondria).It's developed by Timeline Nutrition (formerly Amazentis) and is the first Urolithin A supplement to undergo extensive human clinical trials, with GRAS (Generally Recognized as Safe) status from the FDA, NSF for Sport certification, and Clean Label Project verification for purity.Do Other Versions Work as Well?Other Urolithin A supplements exist as alternatives (e.g., VIVALIFER Naturals, Topffy, Aeternum UA, or various Amazon generics), often at lower prices, but they may not perform equivalently to Mitopure for several reasons:
Clinical Evidence: Mitopure is the specific form used in most peer-reviewed studies showing benefits like a 12-25% increase in muscle strength after four months of use. Other brands lack comparable human trial data, so their efficacy is less substantiated.
Purity and Dosage: Mitopure delivers a standardized 500mg dose of pure Urolithin A per serving, backed by third-party testing. Some alternatives have been found to contain little to no actual Urolithin A or use unverified precursors, potentially reducing effectiveness. Timeline has publicly questioned the authenticity of many Amazon-listed products.
Bioavailability and Safety: Mitopure's patented formulation ensures better absorption and safety, with no reported side effects in trials. Cheaper options might include fillers or inconsistent sourcing, leading to variable results or risks.
In summary, while alternatives could provide similar benefits if they truly contain high-quality Urolithin A at effective doses, Mitopure has the strongest evidence for reliability and results.
Not trying to hijack thread or tread on anyone just posting what I found on GROC4
See new posts
Is Mitopure a brand name and does other version work as good
Yes, Mitopure is a brand name for a proprietary, highly pure form of Urolithin A—a postbiotic compound produced by gut bacteria from foods like pomegranates, nuts, and berries—that's clinically shown to support mitochondrial health, muscle strength, and endurance by promoting mitophagy (the recycling of damaged mitochondria).It's developed by Timeline Nutrition (formerly Amazentis) and is the first Urolithin A supplement to undergo extensive human clinical trials, with GRAS (Generally Recognized as Safe) status from the FDA, NSF for Sport certification, and Clean Label Project verification for purity.Do Other Versions Work as Well?Other Urolithin A supplements exist as alternatives (e.g., VIVALIFER Naturals, Topffy, Aeternum UA, or various Amazon generics), often at lower prices, but they may not perform equivalently to Mitopure for several reasons:
Clinical Evidence: Mitopure is the specific form used in most peer-reviewed studies showing benefits like a 12-25% increase in muscle strength after four months of use. Other brands lack comparable human trial data, so their efficacy is less substantiated.
Purity and Dosage: Mitopure delivers a standardized 500mg dose of pure Urolithin A per serving, backed by third-party testing. Some alternatives have been found to contain little to no actual Urolithin A or use unverified precursors, potentially reducing effectiveness. Timeline has publicly questioned the authenticity of many Amazon-listed products.
Bioavailability and Safety: Mitopure's patented formulation ensures better absorption and safety, with no reported side effects in trials. Cheaper options might include fillers or inconsistent sourcing, leading to variable results or risks.
In summary, while alternatives could provide similar benefits if they truly contain high-quality Urolithin A at effective doses, Mitopure has the strongest evidence for reliability and results.
Good information. Obtaining the patent and FDA approval was an expensive endeavor. That allows for statements to be made as to efficacy, which is a major part of their marketing. Also, being in sales for most of my life, a higher priced product has a certain appeal in that it makes it appear to be something special.
There is a study done using MitoPure, I didn't post it because I felt it was likely biased. It is here:
Targeting mitophagy to activate the recycling of faulty mitochondria during aging is a strategy to mitigate muscle decline. We present results from a randomized, placebo-controlled trial in middle-aged adults where we administer a postbiotic ...
pmc.ncbi.nlm.nih.gov
It is true that it's a jungle out there with untested products, a lot of garbage exists. I do however believe a lower priced alternative exists. Finding it is the tricky part.
This is why there IMO needs to be a private version of the FDA to test things and see if the low-priced one is the real thing. Also, this is also why the promotion of very over-priced supps whose effects are very hard to detect is a big problem with "biohackers" these days. The people who report benefit from Urolithin A (e.g. Dr Gundry) seem to be people who were not in very good shape to begin with, so whether the benefit would apply to someone who is in good shape is very unclear, and a likely better approach is to do all the basics first.
I believe that some European countries have strict supplement guidelines. I agree that we should have that as well. Just as long as it doesn't become corrupt like the FDA.
I also agree that the basics should be paramount to any supplement or drug. But I can see real potential in this one for most everyone.
Predict estradiol, DHT, and free testosterone levels based on total testosterone
⚠️ Medical Disclaimer
This tool provides predictions based on statistical models and should NOT replace professional medical advice.
Always consult with your healthcare provider before making any changes to your TRT protocol.
ℹ️ Input Parameters
Normal range: 300-1000 ng/dL
Predicted Hormone Levels
Enter your total testosterone value to see predictions
Results will appear here after calculation
Understanding Your Hormones
Estradiol (E2)
A form of estrogen produced from testosterone. Important for bone health, mood, and libido.
Too high can cause side effects; too low can affect well-being.
DHT
Dihydrotestosterone is a potent androgen derived from testosterone. Affects hair growth,
prostate health, and masculinization effects.
Free Testosterone
The biologically active form of testosterone not bound to proteins.
Directly available for cellular uptake and biological effects.
Scientific Reference
Lakshman KM, Kaplan B, Travison TG, Basaria S, Knapp PE, Singh AB, LaValley MP, Mazer NA, Bhasin S. The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men. J Clin Endocrinol Metab. 2010 Aug;95(8):3955-64.
