Urolithin A – Mitochondrial rejuvenation and positiv Immunmodulation

My brain is a joke – I wrote an article about Anti-aging for the immune system with Urolithin A three weeks ago and simply forgot about it because so much is happening right now:

I’m barely getting any sleep – Petros and I were on the phone until 5 a.m. last night, and I’m spending all Sunday in front of the computer preparing for the next lectures in early December, reviewing 250 lab results, and… and… and…

This is exactly how I imagined early retirement! “Thanks Petros!!”

OK, enough complaining, here’s the article from three weeks ago:

oh well, its not yet translated to English!! So use this google-translation Link to read this other posting of mine about Urolithin A in proper English.

AntiAging für das Immunsystem: Urolithin A

And here’s today’s article on the same topic

Because the drug tests very well in our patients , I’ve been wanting to share this with my colleagues for weeks. Since I’ve already spent so much time on this article today, writing and researching everything, here’s the information again, presented in a slightly different format.

Problem: Immune Senescence

Since 2021, we’ve been seeing an increasing number of patients with complete loss of part of the immune system. In the example graphic, NK1 and NK2 cells are missing—these are killer cells that target bacteria and viruses.

In this case, we would naturally expect the patient to show signs of a weakened immune system, such as herpes zoster, EBV, CMV, etc.

Thankfully, the patient does not have an NK3 immunodeficiency, as these mediate the anti-cancer immune response. This would be disastrous for a cancer patient; we see this in cases of highly advanced cancer.

… Therefore, I am always on the lookout for treatment options for this specific form of AIDS (acquired immunodeficiency syndrome).

So ​​far, I have found:

Utilin and Recarcin

—Utilin, by the way, is an extract of Bacillus subtilis, which ferments natto and then releases nattokinase. I’ve written two good articles about it:

OK, also not yet translated – wonderful posting because I show some darkfield-microscopy-videos of real cancer patient – use this google translation link please

Utilin und Recarcin – Killerzell Induktoren

our best natural-killer cell stimulation protocol

Anktiva = IL-15 antibody – approved for bladder cancer

could be something like this, it activates the killer cells against cancer. The fact that it was only approved for bladder cancer is a political decision; its effectiveness will be independent of cancer. It also significantly improved the health of an ME/CFS/long-COVID patient within a few days.

Nattokinase – Spike Clearance, Endothelitis

Natto is responsible for the fact that people in Kyoto Prefecture, Japan, live 10 years longer than the rest of Japan – because they eat 30-50g of natto daily. The main active ingredient is nattokinase.

In the post-COVID era, nattokinase has proven effective as a spike clearance agent and a treatment for endothelitis: persistently elevated D-dimer levels in laboratory tests indicate inflammation of the inner lining of blood vessels due to COVID virus persistence or sustained spike expression from mRNA-transfected endothelial cells. We only see a reduction in D-dimer at 4000 IU of nattokinase, and it also takes a very long time (many months) for the D-dimer level to normalize. N-ACC or glutathione is helpful; this is also part of the McCullough Anti-Spike Protocol.

Link to the McCullough Anti-Spike Protocol

But what is Urolithin A?

I came across it in a tweet: “Anti-aging for the immune system”

The subsequent research was then great

Urolithin A (UA) is a postbiotic metabolite produced in the large intestine by gut bacteria from ellagitannins and ellagic acid. These polyphenols are found primarily in pomegranates, walnuts, raspberries, strawberries, blackberries, etc. (PubMed)

Important:

• Only a portion of the population (roughly 30–40%) produces significant amounts of UA from food, depending on the individual microbiome.
• Therefore, dietary supplements contain synthetically produced urolithin A, chemically identical to the naturally occurring metabolite. (Cell)

Production / Formation

1. In the body (physiological)
   • Ellagitannins from food pass through the stomach and small intestine largely unchanged.
   • In the colon, they are gradually converted by certain bacteria (including Enterocloster species) into various urolithins, including Urolithin A, which is then absorbed and becomes systemically available. (Nature)
2. Industrially (Supplements)
   • UA is chemically synthesized and offered in standardized form (often 250–500 mg per capsule).
   • Branded supplements (e.g., Mitopure, etc.) use purified UA that has been used in clinical trials. (JAMA Network)

Mechanisms of Action – Focus on the Immune System / Mitochondria

The central property of Urolithin A is the activation of mitophagy – that is, the selective removal of damaged mitochondria – and thus a kind of “mitochondrial cleansing”: (Cell)

• Activation of the PINK1-Parkin signaling pathway → marks defective mitochondria and leads to their degradation.
• Activation of AMPK and inhibition of mTOR → promotes autophagy and energy metabolism. (Differential Role of Active Compounds in Mitophagy and …” MDPI)Activation of Nrf2 → antioxidant response, reduction of oxidative stress. ((PDF) Urolithin as a Metabolite of Ellagitannins and Ellagic …” href=”https://www.researchgate.net/publication/390467936_Urolithin_as_a_Metabolite_of_Ellagitannins_and_Ellagic_Acid_from_Fruits_and_Nuts_Produced_by_the_Gut_Microbiota_Its_Role_on_Non-Communicable_Diseases?utm_source=chatgpt.com”>ResearchGate)

For the immune system, this means:

• T cells
  • UA can promote T memory stem cells (T_SCM) with high mitochondrial fitness and proliferation capacity; In preclinical models, this resulted in enhanced anti-tumor T-cell responses. (Expansion of T memory stem cells with superior anti-tumor …” ScienceDirect)Myeloid cells / macrophages

    Data suggest a shift towards a more anti-inflammatory phenotype and a reduction in pro-inflammatory cytokines (TNF-α, IL-6, etc.). (Pharmacological Effects of Urolithin A and Its Role in …)

• Microbiome / Gut Barrier
  • UA influences the composition of the microbiome, supports the integrity of the gut barrier and reduces endotoxin-mediated inflammation. (Wiley Online Library)

Net effect: more like immunomodulating (mitochondrial rejuvenation, dampening effect on inflammaging), not classically immunosuppressive.

Clinical trials in humans – overview

Most human studies focus on muscle function / aging, and increasingly on the immune system:

1. Older adults (sarcopenia-prone)g)
   • Randomized trial (JAMA Network Open, 2022): 60–90-year-olds received 500 or 1000 mg UA/day for 4 months.
   • Result: Significant improvement in muscle endurance (e.g., leg extension), positive changes in mitochondrial health biomarkers; no safety concerns. (JAMA Network)
2. Middle Age (Muscle Performance)
   • Randomized trial in middle-aged adults (Cell Journal): 500–1000 mg UA/day led to:
     • improved muscle strength and endurance
     • improved biomarkers of mitochondrial function (ATP production, acyl-carnitine profiles, etc.). (Cell)
3. Systematic Reviews / Sports Nutrition
   • Systematic Review 2024: UA shows Consistent effects on mitochondrial biomarkers, muscle endurance, and some functional outcomes, with good tolerability. (Targeting aging with urolithin A in humans: A systematic …” ScienceDirect)Review 2025 (Sports Nutrition): emphasizes benefits for muscle quality, fatigue reduction, and mild anti-inflammatory effects – suitable for younger and older individuals, with no relevant side effects reported in studies to date. (Emerging evidence of Urolithin A in sports nutrition) Frontiers)

1. Immune System – New Data 2025
   • Nature Aging Study 2025 (Denk et al.): 28 days of UA in healthy middle-aged individuals:
     • Improvement of mitochondrial fitness in immune cells
     • “rejuvenation” of immune cell phenotypes (including improved function of T cells, NK cells) compared to placebo
     • No differences in clinically relevant side effects compared to placebo. (News-Medical)

1. 1. Ongoing / Further StudiesSeveral ongoing trials (Mitopure, etc.) on mitochondrial quality, muscle function, and metabolic health; Previous safety data confirm good tolerability. (ClinicalTrials)

To date, there is very limited human data on oncological endpoints; much of what is interesting regarding T-cell boost/tumor immunity comes from preclinical models. (ScienceDirect)
…ScienceDirect)

Typical Dosage in Studies / Practical Applications

In human studies, the following dosages were primarily used:

• 250–1000 mg urolithin A per day orally, usually:
  • 500 mg once daily or
  • 500 mg twice daily (total 1000 mg/day).(JAMA Network)

   

… Some key points:

Minimum effective dose: Several studies have shown that even 500 mg/day has measurable effects on mitochondrial biomarkers; 1000 mg/day resulted in sometimes stronger or more consistent effects on muscle performance and inflammatory markers. (nad.com)

Method of administration: usually once daily with food. The time of day appears to be less critical than continuous intake over weeks or months.

Important legal/medical information:

Urolithin A Side Effects, Benefits, and Dosage is (as of now) not a licensed drug.It is not a food supplement; there is no officially recommended medical dose for specific conditions.

Side Effects and Safety

Human studies (over 4–12 weeks, in some cases up to 4 months) show:

• Well tolerated, no serious adverse events compared to placebo.
• Laboratory monitoring (liver, kidney, hematology, lipid profile, cardiac parameters) remained unremarkable. (JAMA Network)

… Reported side effects (mostly mild, not consistently more frequent than with placebo):

Gastrointestinal discomfort

Mild nausea, bloating, abdominal pressure, occasional loose stools. (Meto health)

Muscle discomfort

Isolated reports of muscle soreness; not clearly causal, but mentioned in review articles. nad.com)

Upper respiratory tract infections

• • occurred with similar frequency in the treatment and placebo groups in a study (including COVID-19 infections) and are not considered a specific side effect. (Nature)

Contraindications / Caution:

1. 1. • So far, there is little data on pregnancy, breastfeeding, children, and severe liver or kidney disease – use is generally discouraged in these cases.
      • Interactions with conventional medications have not been described as significant so far, but systematic data are still limited.

Overall, current literature classifies UA at 250–1000 mg/day as safe and well tolerated, based on several randomized controlled trials and reviews. (ScienceDirect)

Long-term use

1. 1. • Solid human data available

It is currently primarily used for periods of up to approximately 4 months of continuous intake, with good tolerability. (JAMA Network)

Recent reviews and sports/longevity literature also report on long-term use in real-world settings, but formal studies over several years are still lacking. (Targeting aging with urolithin A in humans: A systematic study) ScienceDirect)

Practical implications for medical use:

• UA can be considered a relatively safe mitochondrial and immunomodulating supplement, with particularly good data in:
  • older patients with muscle weakness/sarcopenia
  • middle-aged people with declining performance / “mitochondrial fatigue”. (ScienceDirect)
• For oncological issues and targeted immuno-oncology, the evidence is currently predominantly preclinical; here, UA would at most be considered an adjuvant mitochondrial support supplement, not an oncological therapeutic agent. (PMC)