#41

@RobTuck Based on my interview with Mark Tarnopolsky MD PhD, mitochondria expert, I wouldn’t bother. He says exercise is the only reliable mechanism to build healthy mitochondria.

Edit: he also said don’t bother with Urolithin A.

3 Likes
#42

If you really want it, liftmode seems like a trusted brand on reddit.

1 Like
#43

Thanks for the replies. I had wondered myself whether it was worth it given that I maintain decent exercise protocols with hiking and weightlifting. My speculative reason for considering Urolithin A was to see if it might reduce my recovery interval. Now approaching 80, I find that it takes at least two full days and sometimes three to recover from a strenuous one-hour mountain hike. I can hike more often but the returns appear to me negative.

1 Like
#44

It seems to me that Urolithin is a poor man’s Rapamycin, except that Rapamycin has much more data and actually costs less per year. Am I missing something?

1 Like
#45

I forgot about this, but it increases lifespan similarly as rapamycin in Koh Tong Wey?

can-we-get-urolithin-a-in-2024-update-v0-0di36oy6ncic1
can-we-get-urolithin-a-in-2024-update-v0-0di36oy6ncic11920×1053 83.1 KB

3 Likes
#46

@RobTuck I would think lowering inflammation in general would help with recovery. Also making sure you are getting enough nutrients to repair and adapt. Plus be sure to ramp up slowly so the recovery isn’t so long that you lose the adaptation benefit. Once in a while for an adventure is worth it no doubt.

#47

My inflammatory markers are about as low as they go @约瑟夫_拉维尔. I have experimented for several years to find ways to shorten beneficial exercise increased recovery time. The results have been modest. (This has been quite a contrast to my competitive running days where I trained from 20 to 60 miles a week.)

I think the length of my beneficial recovery cycles is dictated by at least one factor for certain and perhaps others I am unaware of. My LDH levels have been subnormal (95 IU/L is a typical reading) going back to my first test of it in the 1980’s. I have about 20 readings over that time span. I think low LDH and/or its genetic causes plays a role, including that my Type I muscles are atypically stronger at the end of intensive exercise than at the beginning. It is believed that intense exercise temporarily increases LDH.

As for the impacts, my experiences conform to the empirical research on men 70 years and older. The effort to benefit curve is described by an inverted-U; get to the right side of the tail and the net benefits drop. This is very different than we see in younger men. Even more depressing is that training doesn’t seem to shorten the recovery interval much. And not just in my case; others my age have reported similar experiences.

Perhaps others in my age group will report other findings and help us all figure this out. I love strenuous lower body exercises, especially hiking steep mountains and would love to be able to do more of it.

2 Likes
#48

Doesn’t that imply that Urolithin is cheaper? I don’t think it is? And it assumes that Urolithin actually works.

2 Likes
#49

Koh Tong Wey is a scientist :wink:. I believe this was a study in Killifish …?

3 Likes
#50

I’m going to blame the placement of that text. :melting_face:

2 Likes
#51

By chance, I came across several sources of `Urolithin-A at Amazon which look to be legitimate. Have the patent issues been resolved?

Given the improvements in LLMs, I submitted this question to 4o to obtain a good review.

Identify, analyze, and synthesize the theoretical, clinical and related research on the impact of Urolithin A human health, wellness, and longevity. Separate the findings and generalizations according to degree of certainty.*

ChatGPT said:

Urolithin A (UA), a metabolite derived from ellagitannins found in foods such as pomegranates, berries, and nuts, has gained significant attention for its potential impact on human health, wellness, and longevity. The research on UA spans preclinical and clinical studies, with varying degrees of certainty and direct evidence. The following breakdown categorizes the findings based on the strength of evidence:

1. Preclinical and Mechanistic Evidence (High Certainty in Cellular and Animal Models)

  • Mitochondrial Biogenesis and Function: One of the most robust findings in preclinical research is UA’s role in enhancing mitochondrial health. Studies have shown that UA induces mitophagy, a selective degradation of damaged mitochondria, leading to improved mitochondrial function and biogenesis. This mechanism was demonstrated through in vitro studies and rodent models, where UA supplementation enhanced muscle function and extended the healthspan of aged mice.
  • Antioxidant and Anti-inflammatory Effects: UA has been shown to exert strong antioxidant and anti-inflammatory properties. It reduces reactive oxygen species (ROS) and modulates inflammation through pathways involving the Nrf2 signaling and downregulation of pro-inflammatory cytokines like IL-6 and TNF-α.
  • Cellular Senescence: Research has highlighted that UA can influence cellular senescence by reducing senescence-associated secretory phenotype (SASP) factors. This effect, observed in cell cultures and animal studies, is relevant for slowing age-related tissue damage and chronic inflammation.

2. Early-Stage Clinical Evidence (Moderate Certainty)

  • Muscle Health and Physical Performance: Initial human trials have provided promising results. A key randomized, double-blind, placebo-controlled study demonstrated that oral UA supplementation improved muscle endurance in older adults. This outcome is tied to enhanced mitochondrial function, which aligns with preclinical findings. These trials, while well-conducted, are still limited in sample size and duration.
  • Safety and Tolerability: Clinical trials have confirmed that UA is generally safe and well-tolerated in healthy populations at doses used in research settings. Adverse effects reported have been minimal, though long-term safety data are still under investigation.

3. Potential Cardiometabolic and Cognitive Benefits (Preliminary and Emerging Evidence)

  • 心血管健康: UA’s anti-inflammatory and mitochondrial-boosting properties may theoretically contribute to improved cardiovascular health. Animal models have suggested reductions in markers of vascular aging and improved endothelial function. However, direct clinical evidence in humans remains limited to indirect markers rather than long-term cardiovascular outcomes.
  • Cognitive Function: Some preclinical studies have suggested that UA’s role in enhancing mitochondrial function could be beneficial for neuroprotection, potentially mitigating cognitive decline. This hypothesis is supported by animal models showing reduced neuroinflammation and improved cognitive behavior, but robust clinical trials in human subjects have yet to validate these findings.

4. Longevity and Lifespan Extension (Speculative but Supported by Mechanistic Insight)

  • Lifespan Studies: UA’s ability to promote mitophagy and delay cellular senescence has led to speculation about its potential to extend lifespan. In Caenorhabditis elegans, UA supplementation has been associated with a significant increase in lifespan, which supports its potential as a geroprotective agent. However, direct evidence for lifespan extension in humans is lacking, and extrapolations from animal studies should be approached with caution.
  • Systemic Impact on Aging Pathways: The impact of UA on key aging pathways, such as AMPK activation and sirtuin modulation, lends theoretical support for its inclusion in longevity research. These pathways are well-established in aging biology, suggesting UA could exert broad systemic effects. Still, long-term human studies to directly test its effects on aging biomarkers and lifespan are in progress.

5. Synthesis and Recommendations for Future Research

  • Strengths of Current Findings: The strongest evidence supports UA’s role in improving mitochondrial health and muscle function, with clinical trials in older adults providing a reasonable level of confidence. The mechanistic evidence in animal models robustly supports its role in mitophagy and anti-inflammatory action.
  • Gaps and Future Directions: While UA shows promise for improving healthspan and potentially impacting longevity, critical gaps remain, particularly regarding long-term human trials and studies focused on clinical outcomes related to chronic diseases, cardiovascular health, and cognitive function. Large-scale, longitudinal studies would be essential to confirm these broader effects.
  • Emerging Research Areas: Combining UA with other interventions such as caloric restriction or known metabolic modulators may provide synergistic effects. This avenue warrants further exploration, especially for understanding its potential in personalized or integrative medicine strategies targeting aging and metabolic health.

Conclusions by Degree of Certainty

  • High Certainty: Mitochondrial health improvement, muscle endurance enhancement, safety and tolerability.
  • Moderate Certainty: Anti-inflammatory effects, potential benefits for physical performance in aging populations.
  • Preliminary Evidence: Cardiometabolic and cognitive benefits, systemic aging impact.
  • Speculative/Needs Further Research: Lifespan extension, long-term impacts on chronic disease and aging.

UA stands as a compelling candidate for promoting healthspan and wellness, particularly through mitochondrial support and anti-inflammatory mechanisms. However, its full potential in longevity and chronic disease prevention awaits more rigorous, long-term human research.

4o

What doses have been employed in human research on Urolithin A ?***

ChatGPT said:

Human clinical trials investigating Urolithin A (UA) have employed various dosing regimens to assess its safety and efficacy:

  • Single Ascending Dose Study: In a phase 1 clinical trial, healthy elderly participants received single doses of UA ranging from 250 mg to 2,000 mg. The study aimed to evaluate safety and pharmacokinetics, finding UA to be well-tolerated across all doses.

InfoScience

  • Multiple Ascending Dose Study: The same phase 1 trial included a multiple-dose segment where participants were administered daily doses of 250 mg, 500 mg, or 1,000 mg of UA over a 28-day period. This study also reported good tolerability and provided insights into the compound’s pharmacokinetic profile.

InfoScience

  • Four-Month Supplementation Study: A randomized clinical trial involving older adults (aged 65 to 90 years) assessed the effects of daily supplementation with 1,000 mg of UA over four months. The study observed improvements in muscle endurance and mitochondrial health, with UA being well-tolerated.

JAMA Network

  • Middle-Aged Adults Study: Another study focused on middle-aged adults (aged 40 to 64 years) who received daily doses of 500 mg or 1,000 mg of UA for four months. Results indicated significant improvements in muscle strength and endurance, with both dosages being well-tolerated.

Longevity Technology

These studies collectively suggest that daily doses of UA ranging from 250 mg to 1,000 mg are safe and well-tolerated in human populations, with doses of 500 mg and 1,000 mg commonly used to evaluate efficacy in enhancing muscle function and mitochondrial health.

2 Likes
#52

Additional possibly helpful information:

Is it known which probiotics in the gut are required to convert ellagitannins and ellagic acid into Urolithin-A?

ChatGPT said:

Yes, certain gut bacteria have been identified as key players in the conversion of ellagitannins and ellagic acid into Urolithin A (UA). The microbial conversion process involves specific bacterial species capable of metabolizing these polyphenols. Notably, the presence and activity of these bacteria can vary widely among individuals, which can impact the efficiency of UA production. The main bacterial genera and species associated with this conversion include:

1. Gordonibacter Species

  • Gordonibacter urolithinfaciens and Gordonibacter pamelaeae are among the most well-documented bacteria involved in UA production. These species are capable of metabolizing ellagic acid into intermediate urolithins, which are further processed into UA.
  • These bacteria are considered to play a critical role in the initial breakdown of complex ellagitannins into smaller, absorbable molecules that can then be further converted into UA.

2. Akkermansia and Bacteroides

  • Some studies suggest that Akkermansia muciniphila, known for its beneficial role in gut health, may support the process indirectly by maintaining a healthy gut environment conducive to the activity of UA-producing bacteria.
  • Bacteroides species, commonly found in the gut, may also participate in the breakdown of dietary polyphenols, though their specific role in the direct synthesis of UA is less defined.

3. Lactobacillus and Clostridium Strains

  • Certain strains of Lactobacillus and Clostridium have been associated with the metabolic pathways involved in polyphenol breakdown, potentially contributing to the generation of UA intermediates.
  • These bacteria help deconjugate and hydrolyze complex tannins and polyphenols, facilitating the process that leads to UA formation.

4. Ellagitannin-Metabolizing Microbial Consortia

  • UA production often requires a consortium of microbes working sequentially. For instance, some bacteria break down ellagitannins into ellagic acid, which is then processed by other gut bacteria into intermediate and final urolithins.
  • The presence of a balanced and diverse gut microbiota can thus enhance the conversion rate of dietary ellagitannins to UA.

Individual Variability

  • Inter-individual differences: The composition of the gut microbiome varies significantly between individuals, influencing how effectively ellagitannins and ellagic acid are converted into UA. Some people, termed “urolithin producers,” harbor the right bacterial profile for efficient conversion, while “non-producers” may have lower or negligible UA production.
  • Diet and microbiome modulation: Factors such as diet, antibiotic use, and lifestyle can impact the abundance and activity of UA-producing bacteria. Including prebiotic-rich foods and a diverse range of fiber sources can support a gut environment conducive to these microbial populations.

Probiotic and Prebiotic Considerations

While direct supplementation of specific probiotic strains for UA production is not well-established, fostering a diverse and balanced gut microbiome through broad-spectrum probiotics, prebiotics, and a polyphenol-rich diet could help enhance the chances of efficient UA conversion. Research into targeted probiotics capable of enhancing UA production is still developing, and there is potential for future advances in microbiome-targeted therapies aimed at boosting UA synthesis.

Overall, Gordonibacter species are the most directly linked to UA conversion, but the process involves a complex interplay of gut microbial communities.

4o

2 Likes
#53

And Perplexity did a pretty good job of summarizing the patent situation - unless it made stuff up. It has access to this forum and it quotes us in the “Sources” at the end.

Nestlé’s patent coverage on Urolithin A is complex and has significant implications for other companies looking to sell the compound as a supplement. Here’s an overview of the situation:

Patent Coverage

Nestlé Health Science, through its partnership with Amazentis, has secured several patents related to Urolithin A:

  1. Composition Patents: These cover specific formulations containing Urolithin A, including combinations with other compounds like nicotinamide riboside[2].

  2. Method Patents: These patents cover various uses of Urolithin A, such as:

    • Enhancing immune responses[2]
    • Treating muscle-related conditions[2]
    • Addressing neurodegenerative and mitochondrial diseases[2]

  3. Production Methods: Patents have been granted for methods of preparing Urolithin A and its salts, particularly for large-scale production[2].

Implications for Other Companies

The patent situation creates challenges for other companies wanting to sell Urolithin A as a supplement:

  1. Limited Freedom to Operate: While Urolithin A itself is a naturally occurring compound, Nestlé’s patents on specific uses and formulations restrict other companies’ ability to market it for certain purposes[3][4].

  2. Legal Challenges: Nestlé has shown willingness to pursue legal action against competitors. For example, DoNotAge.org was forced to stop selling Urolithin A due to legal pressure from Nestlé[3][4].

  3. Narrow Marketing Claims: Companies may be able to sell Urolithin A but might be restricted in making certain health claims, particularly related to muscle function[3].

  4. Research and Development Constraints: The patents may limit other companies’ ability to conduct research or develop new products using Urolithin A without risking infringement[5][6].

Potential for Sales by Other Companies

Despite these challenges, there may still be opportunities for other companies to sell Urolithin A as a supplement:

  1. Different Formulations: Companies might develop unique formulations or combinations not covered by Nestlé’s patents[2].

  2. Alternative Applications: Exploring uses of Urolithin A not specifically claimed in Nestlé’s patents could provide avenues for product development[5].

  3. Geographic Considerations: Patent coverage may vary by country, potentially allowing sales in regions where certain patents are not in force[7].

  4. Licensing Agreements: Companies might negotiate licensing agreements with Nestlé or Amazentis to use the patented technology[5][7].

  5. Patent Expiration: As patents expire, opportunities for generic versions of Urolithin A products may emerge[6].

In conclusion, while Nestlé’s patents create significant barriers, they do not completely prevent other companies from selling Urolithin A as a supplement. However, such companies would need to carefully navigate the patent landscape and potentially face legal challenges from Nestlé[3][4]. The situation underscores the complex interplay between intellectual property rights and the dietary supplement market.

Sources
[1] Nestlé invests in mitochondrial health ingredient - Food Dive Nestlé invests in mitochondrial health ingredient | Food Dive
[2] Patents Assigned to Amazentis SA Patents Assigned to Amazentis SA - Justia Patents Search
[3] Nestle sues DoNotAge : r/NMN - Reddit https://www.reddit.com/r/NMN/comments/13xkgg2/nestle_sues_donotage/
[4] Sad news about Urolithin A, Nestle Blocking Sales by Competitors Sad news about Urolithin A, Nestle Blocking Sales by Competitors
[5] Nestlé Health Science invests in global strategic partnership with … Nestlé Health Science invests in global strategic partnership with Amazentis to develop its new cellular nutrient Urolithin A | Markets Insider
[6] Nestle takes an equity stake in cellular nutrition company | 2019-04-02 Nestle takes an equity stake in cellular nutrition company | 2019-04-02 | Baking Business
[7] Nestlé Health Science Invests Amazentis’ Cellular Nutrient Urolithin A Nestlé Health Science Invests Amazentis' Cellular Nutrient Urolithin A
[8] Nestlé invests in Amazentis to leverage anti-aging technology Nestlé invests in Amazentis to leverage anti-aging technology
[9] Nestle invests in Urolithin A cellular nutrition technology Nestle invests in Urolithin A cellular nutrition technology
[10] One of the most undervalued companies of our generation? (part 2) One of the most undervalued companies of our generation? (part 2)
[11] Nestle enters nutritional-health partnership with local technology … https://www.just-food.com/news/nestle-enters-nutritional-health-partnership-with-local-technology-firm-amazentis/
[12] US10695320B2 - Compositions comprising urolithin compounds US10695320B2 - Compositions comprising urolithin compounds - Google Patents
[13] WO2017036992A1 - Compositions comprising urolithin compounds WO2017036992A1 - Compositions comprising urolithin compounds - Google Patents
[14] Urolithin-A promotes CD8+ T cell-mediated cancer - AACR Journals https://aacrjournals.org/cancerrescommun/article-pdf/doi/10.1158/2767-9764.CRC-24-0022/3442736/crc-24-0022.pdf
[15] Everything You Need To Know About Urolithin A - Timeline Longevity Everything You Need To Know About Urolithin A - Timeline Longevity
[16] Does Nestlé Own a Patent on Urolithin A? : r/urolithin_a - Reddit https://www.reddit.com/r/urolithin_a/comments/1ese0ul/does_nestlé_own_a_patent_on_urolithin_a/
[17] Sad news about Urolithin A, Nestle Blocking Sales by Competitors Sad news about Urolithin A, Nestle Blocking Sales by Competitors
[18] Introducing Celltrient™ Cellular Nutrition | Nestlé Health Science Introducing Celltrient™ Cellular Nutrition | Nestlé Health Science
[19] “What to do about the leaky gut” - PMC - PubMed Central “What to do about the leaky gut” - PMC
[20] WO2014111580A1 - Urolithin b for muscle growth - Google Patents WO2014111580A1 - Urolithin b for muscle growth - Google Patents
[21] Timeline raises questions about Urolithin A supplements on Amazon Timeline raises questions about Urolithin A supplements on Amazon
[22] Société des Produits Nestlé S.A. - IPqwery Société des Produits Nestlé S.A.
[23] US10442784B2 - Compositions comprising an urolithin compound US10442784B2 - Compositions comprising an urolithin compound - Google Patents
[24] EP3278800B1 - Google Patents EP3278800B1 - Compositions and methods for improving mitochondrial function and treating muscle-related pathological conditions - Google Patents
[25] Nestlé Health Science and Amazentis partner on a new class of … Nestlé Health Science and Amazentis partner on a new class of “breakthrough” cellular nutrients
[26] Partnerships and investments | Nestlé Health Science https://www.nestlehealthscience.co.za/partners
[27] Anyone have a read on Urolithin A? : r/PeterAttia - Reddit https://www.reddit.com/r/PeterAttia/comments/1do37py/anyone_have_a_read_on_urolithin_a/
[28] [PDF] Meaningful innovation to boost growth - Nestlé https://www.nestle.com/sites/default/files/2022-11/investor-seminar-2022-innovation.pdf
[29] Nestlé and L’oréal Are Betting on Urolithin a, a Longevity Supplement https://www.businessinsider.com/nestle-and-loreal-are-betting-on-urolithin-a-longevity-supplement-2024-10

1 Like
#54

I think the real issue with UA is that it is not that effective according to my N=1 experimentation.

Rapamycin, however, hits the spot as do other molecules.

1 Like
#55

I’ve posted this before, this seems legitimate (iHerb own brand). But isn’t there not that much good evidence for urolithin a?
https://www.iherb.com/pr/super-nutrition-urolithin-a-250-mg-60-liquid-veggie-capsules/142031

Confirmed!

1 Like
#56

Pretty hard to get any supplements where the base compounds do not come from offshore.

I buy all my base compounds from reputable Chinese manufacturers, just like all the other supplement companies do.

1 Like
#57

The product is called “Urolithin A,” and the label says it contains 500 mg UA per 2 capsules. However, the analysis doesn’t quantify UA, but urolithins. That could be a mix rich in urolithin-B or -G, which are reported to have pharmacological effects in mice but no the specific mitophagy activation.

3 Likes
#58

What’s a mitophagy activation? I swear supplement sellers create new buzzwords all the time, by making them known and placing weight on them rather than the hard endpoints that matter in the end.

1 Like
#59

I agree with you that hard endpoints are what matters in the end. If I call a product “Rapamycin” and its CoA measures the amount of macrolide antimicrobials in the product without specifying the amount of rapamycin, someone looking for an mTOR inhibitor will not be swayed by the fact that other macrolide antimicrobials also benefit some hard outcomes.

1 Like
#60

I already understood your point, I have no disagreement with it. Good find.

I never said any of the other Urolithins were efficacious. Mitophagy activation sounds like marketing to me, that was my point. So you can look for a supplement with Urolithin A CoA, and it might not make a difference either way.

1 Like