Urolithin A: The Next Big Thing Or the Next Forgotten Fad?

Dec 4 / Drs. Bryan & Julie Walsh

Introduction

The supplement market is an ever-changing landscape, constantly evolving—or perhaps devolving—with the steady introduction of new molecules and substances touted as miracle solutions for various health concerns. One recent standout is Urolithin A, a gut microbiome metabolite derived from ellagitannins found in foods like pomegranates and walnuts. This compound has caught the attention of the scientific community, sparking the usual cascade of interest in the nutritional and functional medicine industries, alongside a frenzy among overzealous biohackers, health enthusiasts, and social media influencers.


But before diving headfirst into the hype surrounding Urolithin A, it's worth pausing to reflect on the history of supplement trends—many of which initially dazzled with potential only to fall short of expectations. History has a habit of repeating itself, after all.

Historical Context: Promises of the Past

Depending on ones age and time spent in this industry, the following brief list may ring some bells of familiarity in supplements gone by:

  1. Resveratrol: Once hailed as an anti-aging wonder, resveratrol's clinical outcomes failed to match the initial hype. While in vitro and animal studies showed promising results, human trials have been largely inconclusive [1].
  2. Beta carotene: Initially touted for cancer prevention, beta carotene supplements were later found to potentially increase lung cancer risk in smokers [2].
  3. Chromium picolinate: Claims of metabolism-boosting effects were largely debunked after extensive research showed minimal impact on weight loss or muscle gain [3].
  4. Conjugated linoleic acid (CLA): Despite initial promises of significant weight loss benefits, long-term studies have shown only modest effects, if any [4].
  5. DHEA: The anti-aging effects of DHEA proved less impressive in human studies than initially hoped, with potential side effects outweighing benefits for many individuals [5].
  6. And there are so many more littering the graveyard of once hopeful and promising supplements. 

These examples serve as a cautionary tale as we delve into the potential of Urolithin A—or any new supplement that captures the attention of practitioners and the public alike. This article aims to provide a balanced exploration of Urolithin A, examining its mechanism of action, current research landscape, and broader context within gut health and metabolism. We'll consider both supplementation and whole food approaches, offering nutritional and functional medicine practitioners a comprehensive perspective to inform clinical decisions.

"While Urolithin A represents an exciting area of nutritional research, its place in clinical practice should be considered as part of a comprehensive approach to health that prioritizes dietary quality, gut health, and overall lifestyle factors."

The Chemical Structure and Properties of Urolithin A

Urolithin A, chemically known as 3,8-dihydroxy-urolithin, is a dibenzopyran-6-one compound. Its molecular formula is C13H8O4, and it has a molecular weight of 228.2 g/mol. The structure of Urolithin A is characterized by two phenolic hydroxyl groups, which contribute to its antioxidant properties.
This chemical structure allows Urolithin A to interact with various biological targets, potentially explaining its diverse range of reported health effects.

Metabolism and Bioavailability

The metabolism and bioavailability of Urolithin A in the body are complex processes that involve several steps:
  1. Gut Microbiota Metabolism: The production of Urolithin A is largely dependent on the metabolic activities of gut microbiota. Different bacterial species play roles in this conversion process, with some being more efficient than others [30].
  2. Absorption: Once produced, Urolithin A is absorbed in the colon and enters the bloodstream.
  3. Liver Metabolism: In the liver, Urolithin A undergoes phase II biotransformation, resulting in various conjugated forms, primarily glucuronides and sulfates [28].
  4. Distribution: The conjugated forms of Urolithin A are then distributed throughout the body via the bloodstream.
  5. Excretion: Urolithin A and its metabolites are eventually excreted in urine and feces.
The bioavailability of Urolithin A can vary significantly among individuals due to differences in gut microbiome composition, diet, and other factors. This variability has led to interest in direct supplementation with Urolithin A as a potential way to ensure consistent levels across populations. But more on all of that in a moment.

Foods Rich in Ellagitannins and Ellagic Acid

While coming up with a list of foods with specific quantities for ellagitannins and ellagic acid is an attractive concept, it can also be misleading given a number of different factors that can impact the quantity of these molecules in food. Such factors include:
  • Growing conditions
  • Ripeness
  • Storage conditions
  • Processing methods
  • Variety of the fruit/nut
  • Analytical methods used to measure the compounds
The ranking of foods in the following list is accurate in that pomegranates generally contain the most ellagic acid, followed by certain berries (especially raspberries, blackberries, and cloudberries), and nuts (particularly walnuts). Cloudberries are notably rich in ellagitannins, though their exact content can vary. Oak-aged wines are also included here, as ellagitannins can be extracted from oak barrels during aging, though we think there are better ways of consuming Urolithin A promoting substances than in wine. Therefore, keep in mind that this represents a greatest-to-least ellagic acid containing food list, and the specific quantities are subject to the factors listed above.  
  1. Pomegranates
    • Amount: 150-300 mg of ellagic acid per 100g of fresh pomegranate seeds; high in punicalagins.
  2. Raspberries
    • Amount: ~270 mg of ellagic acid per 100g of fresh raspberries; seeds are particularly high.
  3. Strawberries
    • Amount: ~150-190 mg of ellagic acid per 100g of fresh strawberries.
  4. Blackberries
    • Amount: ~150 mg of ellagic acid per 100g of fresh blackberries.
  5. Walnuts
    • Amount: ~59 mg of ellagic acid per 100g of walnuts.
  6. Pecans
    • Amount: ~33 mg of ellagic acid per 100g of pecans.
  7. Almonds
    • Amount: ~33 mg of ellagic acid per 100g of almonds.
  8. Grapes (especially Muscadine)
    • Amount: ~20-55 mg of ellagic acid per 100g of Muscadine grapes.
  9. Oak-aged wines
    • Amount: Varies widely depending on the type and aging process, but generally lower than in fresh fruits.
  10. Guava
    • Amount: ~20 mg of ellagic acid per 100g of guava.
  11. Cloudberries
    • Amount: ~500 mg of ellagitannins per 100g; particularly sanguiin H-6.
  12. Persimmons
    • Amount: ~20 mg of ellagic acid per 100g.

Urolithin Metabotypes

The variability in Urolithin A production has led researchers to classify individuals into different "urolithin metabotypes" based on their ability to produce various urolithins [19]. Three main metabotypes have been identified:
  1. Metabotype A: Individuals who efficiently produce Urolithin A as the main end-product of ellagitannin metabolism.
  2. Metabotype B: Individuals who produce Urolithin B and/or isourolithin A, with little or no Urolithin A production.
  3. Metabotype 0: Individuals who produce little to no urolithins.
The distribution of these metabotypes varies across populations. For example, a study by Tomás-Barberán et al. found that approximately 40% of individuals belonged to metabotype A, 10% to metabotype B, and 50% to metabotype 0 in a Western population [29].

The Role of Gut Microbiome in Urolithin A Production

As previously mentioned, the ability to produce Urolithin A varies significantly among individuals due to differences in gut microbiome composition. Selma et al. conducted a study that shed light on this variability and its potential health implications [26].

Key findings from this study included:
  1. The researchers identified two main urolithin metabotypes based on the gut microbiota's ability to metabolize ellagitannins.
  2. These metabotypes correlated with cardiometabolic risk biomarkers, suggesting a potential link between urolithin production capacity and overall health.
  3. The study found differences in urolithin metabotypes among individuals with different body weight statuses (normal weight, overweight-obese, and metabolic syndrome).
This research underscores the importance of considering individual gut microbiome composition when discussing the potential benefits of ellagic acid-rich foods or Urolithin A supplementation.

Urolithin A Mechanism of Action

Urolithin A's primary mechanism of action centers on its role as a potent activator of mitophagy, the process by which cells remove damaged or dysfunctional mitochondria. This process is crucial for maintaining cellular health and energy production. Keep in mind, however, this information was gleaned from pre-clinical studies in animals, not humans. 

Lifespan Extension and mitophagy in C. elegans

One of the most striking early findings came from studies in Caenorhabditis elegans, a tiny nematode worm often used in aging research due to its short lifespan and well-characterized genetics. Ryu et al. reported that Urolithin A treatment extended the lifespan of C. elegans by more than 45%[6]. This dramatic effect was attributed to Urolithin A's ability to induce mitophagy, thereby improving mitochondrial function and cellular health.

Urolithin A has been shown to stimulate mitophagy through the activation of specific cellular pathways, including PINK1/Parkin signaling [6]. This activation leads to improved mitochondrial function and increased ATP production, potentially enhancing overall cellular energy metabolism. The importance of this mechanism cannot be overstated, as mitochondrial dysfunction is implicated in various age-related diseases and conditions [7].

Anti-inflammatory Properties

In addition to its effects on mitophagy, Urolithin A exhibits anti-inflammatory properties, possibly through the modulation of NF-κB signaling pathways [8]. This anti-inflammatory action may contribute to its potential benefits in various chronic diseases associated with low-grade inflammation.

Antioxidant Effects

Urolithin A has also demonstrated antioxidant effects, though these may be secondary to its mitophagy-enhancing properties rather than direct free radical scavenging [9]. By promoting the removal of damaged mitochondria, which are a significant source of cellular reactive oxygen species (ROS), Urolithin A indirectly reduces oxidative stress.

Muscle Function Enhancement

In muscle tissue, Urolithin A has been observed to improve muscle cell function and potentially enhance muscle strength and endurance in humans [10]. This effect is thought to be related to improved mitochondrial health in muscle cells, leading to more efficient energy production and utilization.

Gut Health Impact

In the gut, Urolithin A may contribute to improved barrier function and reduced inflammation, though the exact mechanisms are still under investigation [11]. This potential benefit is particularly intriguing given Urolithin A's origin as a gut metabolite.

The gut health effects of Urolithin A are particularly intriguing, given its origin as a gut metabolite. Some research suggests it may improve gut barrier function and reduce inflammation, but these findings are primarily from preclinical studies [18]. The potential for Urolithin A to positively influence the gut microbiome and overall digestive health warrants further investigation in human trials.

Cardiovascular Effects

Cardiovascular effects have also been noted, with some studies suggesting improvements in endothelial function and potential cardioprotective properties [12]. These effects may be related to Urolithin A's anti-inflammatory and antioxidant properties.

Neuroprotective Potential

Another area of research focus has been on Urolithin A's potential neuroprotective effects, with animal studies suggesting benefits in models of neurodegenerative diseases [16]. However, human data in this area is virtually non-existent, highlighting a significant gap in our understanding of Urolithin A's effects on brain health.

Paucity of Human Trials

It's important to note that many of the effects listed above, thus far, have been primarily observed in vitro or in animal models, with human studies still very limited in scope and duration, or possible bias due to sponsorship and funding. The translation of these mechanistic findings to clinically relevant outcomes in humans remains an area of active research and debate.

Current Research Landscape

The research landscape for Urolithin A is still in its early stages, with a limited number of human clinical trials completed to date. Most studies have been small-scale, short-term, and perhaps most problematic, often funded by companies with a vested interest in Urolithin A supplementation. While these studies have shown promising results in areas such as muscle function and mitochondrial health, their limited scope and potential bias call for cautious interpretation.

Key Human Studies

A notable study published in JAMA Network Open in 2022 found improvements in muscle endurance in older adults supplementing with Urolithin A, but the primary endpoint of improved walking distance was not met [13]. This highlights the complex nature of translating cellular mechanisms to whole-body outcomes.
Study Participants Duration Key Findings Limitations
Liu et al. (2022)[13] 66 older adults 4 months Improved muscle endurance, no significant change in walking distance Small sample size, short duration
Andreux et al. (2019)[14] 60 elderly individuals 4 weeks Improved mitochondrial gene expression in muscle Short duration, limited functional outcomes
Singh et al. (2022)[15] 88 middle-aged adults 4 months Improved muscle strength and exercise performance Industry-funded, limited long-term data

Funding and Bias Concerns

When examining the research landscape surrounding Urolithin A, it's crucial to note that a significant portion of the published literature comes from researchers affiliated with Amazentis, the company that has commercialized synthetic Urolithin A. This includes several key papers that form the foundation of our current understanding of Urolithin A's effects on mitochondrial function and muscle health. While industry-sponsored research isn't inherently problematic, this concentration of research from a single commercial entity warrants careful consideration when evaluating the totality of evidence. This heavily dominated funding by specific industry players raises concerns about potential bias and the need for more independent, publicly funded studies to provide a balanced view of its efficacy and safety. 

While the studies themselves appear methodologically sound and have passed peer review in reputable journals, the relative scarcity of independent replication studies creates an important gap in our scientific understanding as well as makes one wonder why other researchers aren't quite as interested in Urolithin A as this body of researchers working with Amazentis. This doesn't invalidate the findings but suggests that practitioners should maintain a balanced perspective until more independent research groups validate these results through non-industry funded studies. Particularly noteworthy is the absence, thus far, of studies showing null or negative results, which could be subject to publication bias - a common phenomenon in industry-sponsored research where unfavorable results may not reach publication.

Limitations of Current Human Clinical Evidence

While these studies provide intriguing preliminary evidence, several limitations should be considered:
  1. Small Sample Sizes: Most of the available human studies have involved relatively small numbers of participants, limiting the generalizability of their findings.
  2. Short Duration: Many of the studies have been relatively short-term, ranging from a few weeks to a few months. The long-term effects of Urolithin A supplementation remain unclear.
  3. Limited Population Diversity: Most studies have focused on older adults or middle-aged individuals. The effects of Urolithin A in younger populations or those with specific health conditions are less well-studied.
  4. Potential Conflicts of Interest: As discussed above, a significant portion of the human clinical research on Urolithin A has been sponsored by companies that produce Urolithin A supplements, which could potentially introduce bias.
  5. Lack of Diverse Health Outcomes: While muscle health and mitochondrial function have been relatively well-studied, there is a lack of human clinical evidence for many of the other potential benefits suggested by preclinical research, such as neuroprotective effects or anti-cancer properties.
  6. Variability in Dosage and Duration: The optimal dosage and duration of Urolithin A supplementation remain unclear, with studies using varying protocols.
Given these limitations, while the existing human clinical evidence is promising, it is not yet sufficient to draw firm conclusions about the efficacy of Urolithin A supplementation for various health outcomes. More extensive, long-term, independently funded clinical trials are needed to fully elucidate the potential benefits and risks of Urolithin A supplementation in humans.

Beyond Urolithin A

While Urolithin A has garnered significant attention, it's crucial to consider the broader context of ellagitannin metabolism and the complete profile of bioactive compounds found in whole food sources. Ellagitannins are metabolized into various urolithins, including Urolithin B, C, and D, each with potentially distinct biological activities.

Urolithin Metabolites

Some research suggests that the combination of these metabolites may offer synergistic benefits not seen with Urolithin A alone [21]. For instance:
  • Urolithin B has shown promise in some studies for its anti-inflammatory and antioxidant properties [22].
  • Urolithin C has demonstrated potential anticancer effects in preclinical models [23].
  • The parent compound, ellagic acid, also possesses biological activities that may contribute to the overall health benefits of ellagitannin-rich foods [24].

Whole Food Complexity

Foods high in ellagitannins, such as pomegranates, berries, and nuts, contain a complex array of other bioactive compounds including flavonoids, lignans, and other polyphenols. These compounds may work together to produce health benefits that extend beyond what can be achieved with isolated Urolithin A supplementation alone [25]. Table 1 expounds on some of the additional compounds available in certain whole foods and the effects they may have on the human body.
Food Source Key Bioactive Compounds Potential Health Benefits
Pomegranate Punicalagins, anthocyanins, ellagic acid Antioxidant, anti-inflammatory, cardioprotective
Walnuts Ellagitannins, omega-3 fatty acids, vitamin E Cognitive function, heart health, anti-inflammatory
Strawberries Ellagitannins, vitamin C, anthocyanins Antioxidant, immune support, cardiovascular health
Raspberries Ellagitannins, anthocyanins, quercetin Anti-cancer, anti-inflammatory, metabolic health

Table 1: Bioactive Compounds in Ellagitannin-Rich Foods

Prebiotic Effects

The fiber content in these whole foods contributes to their prebiotic effects, potentially enhancing the gut environment that facilitates Urolithin production[26]. This highlights the importance of considering the entire food matrix when evaluating the potential health benefits of ellagitannin-rich foods.

Matrix Effect

The matrix effect of whole foods, where the combination of nutrients and bioactive compounds may enhance bioavailability and efficacy, is another factor to consider [27]. This complexity underscores the potential limitations of a reductionist approach focused solely on Urolithin A supplementation.

Comparative Analysis

To better understand the pros and cons of supplementation versus dietary sources, consider the following table:
Aspect Urolithin A Supplementation Dietary Sources of Ellagic Acid
Dosage Control High Variable
Concentration Potentially Higher Generally Lower
Convenience High Moderate
Whole Food Benefits No Yes
Synergistic Effects Limited Potentially High
Cost Generally Higher Generally Lower
Safety Profile Limited Long-Term Data Well-Established
Gut Microbiome Support Limited Potentially High
Other Beneficial Compounds Limited Abundant

Given these considerations, a balanced approach might involve focusing on a diet rich in ellagic acid-containing foods while simultaneously supporting overall gut health, rather than simply jumping to the latest isolated relatively untested molecule.

Personalized Approach

The variability in individual responses to ellagitannin-rich foods, due to differences in gut microbiome composition, suggests that a personalized approach to dietary recommendations may be more effective than universal supplementation [28]. Understanding the full spectrum of ellagitannin metabolites and their interactions with other dietary components provides a more comprehensive view of the potential health benefits associated with these foods.

Gut Health Optimization

The production of Urolithin A is intrinsically linked to gut health, specifically the composition and function of the gut microbiome. This connection underscores the importance of a holistic approach to gut health optimization when considering the potential benefits of Urolithin A.

Certain bacterial species, for example, particularly those belonging to the Gordonibacter genus, have been identified as key players in the conversion of ellagitannins to Urolithin A [30]. However, the presence of these bacteria alone does not guarantee efficient Urolithin A production. Factors such as overall microbial diversity, the presence of competing bacteria, and the overall gut environment all play roles in determining Urolithin A production efficiency.

This complexity suggests that strategies aimed at optimizing overall gut health may be more effective than targeted supplementation in maximizing the potential benefits of Urolithin A. Approaches to improve gut health and potentially enhance Urolithin A production include:
  1. Increasing dietary diversity: Particularly focusing on plant-based foods rich in fiber and polyphenols [31].
  2. Regular consumption of fermented foods: To introduce beneficial bacteria and support microbial diversity [32].
  3. Stress reduction and adequate sleep: Which have been shown to positively impact gut microbiome composition [33].
  4. Regular physical activity: Which can enhance microbial diversity and overall gut health [34].
  5. Minimizing exposure to negative factors: Such as excessive alcohol consumption and certain medications that can disrupt gut health [35].

Strategies for Gut Health Optimization

It's also important to consider the bidirectional relationship between Urolithin A and gut health. While a healthy gut microbiome is necessary for Urolithin A production, some research suggests that Urolithin A precursors may have prebiotic-like effects, potentially promoting the growth of beneficial bacteria and improving gut barrier function [36]. This creates a positive feedback loop where improved gut health enhances Urolithin A production, which in turn further supports gut health.
Given the evidence presented in this article, we personally recommend that clinicians advise their clients to consume Urolithin A precursor foods and support optimal gut function, rather than advocating for supplementation with an isolated bacterial metabolite that has limited independent clinical validation. While human trials exist, they are predominantly industry-sponsored. Furthermore, the Urolithin A precursor foods likely contain additional beneficial metabolites and bioactive compounds that may work synergistically to promote health outcomes beyond what an isolated compound can do by itself.

Conclusion 

As we navigate the complex story of Urolithin A research and its potential applications, it's important to maintain a balanced perspective that considers both the promise of targeted supplementation as well as the holistic benefits of a whole food approach. While Urolithin A has demonstrated intriguing potential in areas such as mitochondrial health, muscle function, and anti-inflammatory effects, current research leaves a lot to be desired and is largely industry-driven. The historical context of once promising supplements reminds us to approach the next shiny supplement on the block with a certain amount of caution.

The best and most reasonable approach appears to be a whole food approach that emphasizes ellagitannin-rich foods like pomegranates, berries, and nuts, while also supporting gut health. This approach offers several advantages. First, it provides not only the precursors for Urolithin A but also a complex array of other beneficial compounds and nutrients that may work together synergistically. Second, this approach also aligns with broader principles of gut health optimization, which has wide reaching benefits, as well as being crucial for optimal Urolithin A production.

Ultimately, while Urolithin A represents an exciting area of nutritional research, its place in clinical practice should be considered as part of a comprehensive approach to health that prioritizes diet quality, gut health, and overall lifestyle factors. As research continues to evolve, maintaining a critical and evidence-based perspective will be essential in determining whether Urolithin A truly represents the next big thing in nutritional science or if it will join the ranks of past supplement trends that failed to live up to their initial promise.

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Chris

"This should be 101 level teaching for anyone studying to be a healthcare practitioner. I tremendously appreciate the insights presented here." 

Dr Kang

“Extremely helpful. I have been wondering what could be the balancing pivot for especially older adults who should be ingesting slightly higher amounts of protein but yet be able to mitigate age-related bone loss risks. This clinical content session answered the question. Dr. Walsh has done it again, by translating evidence-based insights into practical clinical implementation that we could use immediately.”

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Sadie

"I LOVE everything about these presentations. It makes me excited to practice. 😊"

Carrie

"This is incredible information Dr Walsh."

Fernando

"Another outstanding presentation...
Thank you!"

Khaled

"You ground me from all the FM Hype out there, which is mostly messy, biased, and FOMO driven. Please keep doing what you're doing. Your work is benefiting so many patients around the globe. Truly blessed to be amongst your students. Much love ❤️"