Urolithin A for Healthy Adults

Overseen By Josephine M Egan, M.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: National Institute on Aging (NIA)

Must not be taking: Glucose lowering drugs

Disqualifiers: Diabetes, Autoimmune disease, Cancer, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 8 weeks

180 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Background: As people age, the cells in the pancreas that produce insulin begin to release less of this hormone, and levels of blood glucose (sugar) rise. This can lead to illnesses such as diabetes. Urolithin A (UA) is a natural nutritional supplement that may improve how the body controls blood glucose. Objective: To learn if UA improves levels of insulin and other hormones that help control blood glucose. Eligibility: People aged 55 years and older with a body mass index of 27 or higher. Design: Participants will have 6 clinic visits over 8 weeks. Participants will be screened. They will have a physical exam with blood and urine tests and a test of their heart function. UA gelcaps are taken by mouth every morning at home. Half of participants will take UA. The other half will take a placebo. The placebo looks like the study drug but does not contain any medicine. Participants will not know which they are taking. Participants will have tests during the study including: Oral glucose tolerance: Participants will drink a sweet liquid. Blood will be drawn at intervals over the next 3 hours. Continuous glucose monitor: A sensor with a needle that goes just under the skin will be placed on the upper arm. Participants will wear this sensor throughout the study. Exercise. Participants will walk on a treadmill while their heart rate, hearth rhythm, and blood pressure are monitored. They will walk in a hallway at normal and fast paces. Imaging scans of the thigh; scans of the brain are optional....

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on glucose-lowering drugs, you cannot participate. Also, you should not be on any investigational drugs or require long-term treatment with antibiotics, corticosteroids, or immunosuppressors.

Is Urolithin A safe for humans?

Research on Urolithin A, a compound found in foods like pomegranates and nuts, shows it is not toxic in animal studies, with no harmful effects observed at high doses. It has been tested in rats without causing any health issues, suggesting it is generally safe. ^{1 2 3 4 5}

How is the drug Urolithin A unique compared to other treatments?

Urolithin A is unique because it is a natural compound produced by gut bacteria from foods like pomegranates and berries, and it enhances cellular health by improving mitochondrial function and reducing inflammation. Unlike other treatments, not everyone can naturally produce Urolithin A due to gut microbiome differences, making direct supplementation a novel approach to ensure consistent benefits across individuals. ^{2 6 7 8 9}

What evidence supports the effectiveness of the treatment Urolithin A for healthy adults?

Research shows that Urolithin A, a compound from foods like pomegranates and berries, can improve cell health and reduce inflammation, which may help with aging and related conditions. It has shown benefits in muscle health in older adults and may help prevent diseases like Alzheimer's and type 2 diabetes by reducing inflammation. ^{2 6 8 10 11}

Who Is on the Research Team?

Josephine M Egan, M.D.

Principal Investigator

National Institute on Aging (NIA)

Are You a Good Fit for This Trial?

This trial is for healthy adults aged 55 or older with a body mass index (BMI) of 27 or higher. Participants will be involved in the study for about 8 weeks, which includes taking gelcaps daily and undergoing various tests such as blood draws after drinking a sweet liquid, wearing a glucose monitor, exercising on a treadmill, and having imaging scans.

Inclusion Criteria

Provision of signed and dated informed consent form

Able to speak and read English (We do not have ready access to interpreters of different languages at the NIA Clinical Unit)

In good general health, as evidenced by medical history/physical exam/laboratory results

Exclusion Criteria

Fasting glucose >= 126 on screening visit

Is on treatment with an investigational drug or other intervention within 8 weeks of enrollment

On average, consumes more than 1 alcoholic drink per day

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Urolithin A or placebo for 8 weeks with various tests including oral glucose tolerance, continuous glucose monitoring, and exercise tests

8 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Urolithin A

Trial Overview The trial is testing whether Urolithin A (UA), taken as gelcaps every morning, can improve insulin levels and help control blood sugar compared to a placebo. Half of the participants will receive UA while the other half will get a placebo that looks identical but contains no medicine.

How Is the Trial Designed?

Group I: Urolithin A Active Control 1 Intervention

50% of participants

Group II: Placebo Placebo Group 1 Intervention

50% of participants

Urolithin A is already approved in United States, European Union for the following indications:

Approved in United States as Urolithin A for:

• Generally Recognized as Safe (GRAS) for dietary supplement use

Approved in European Union as Urolithin A for:

• No specific therapeutic indications approved; available as a dietary supplement

Who Is Running the Clinical Trial?

National Institute on Aging (NIA)

Lead Sponsor

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

Urolithins, which are metabolites derived from ellagic acid, are better absorbed in the body and may be responsible for the health benefits associated with foods containing ellagitannins.

This study successfully developed a new method to synthesize specific urolithin glucuronides, which are important for understanding their mechanisms of action in human cells, and confirmed their presence in different human metabotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Regioselective Synthesis of Urolithin Glucuronides─Human Gut Microbiota Cometabolites of Ellagitannins and Ellagic Acid. Villalgordo, JM., Trulli, L., García-Villalba, R., et al.[2022]

Urolithin A (UA), derived from gut bacteria processing ellagitannins found in foods like pomegranate and berries, has been shown to enhance cellular health by promoting mitophagy and improving mitochondrial function while reducing inflammation.

Recent clinical trials indicate that UA supplementation can provide benefits for muscle health in elderly individuals, suggesting its potential as a nutritional intervention to combat aging and age-related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of the Natural Compound Urolithin A on Health, Disease, and Aging. D'Amico, D., Andreux, PA., Valdés, P., et al.[2021]

Urolithin A (UroA), derived from foods like pomegranates and walnuts, shows promise as a therapeutic agent due to its ability to reduce inflammation in various tissues, which may help prevent diseases like Alzheimer's and type 2 diabetes.

Research indicates that UroA's anti-inflammatory effects could be harnessed through dietary sources or as a pharmaceutical treatment, highlighting its potential role in managing immunometabolic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory Role of Urolithin A on Metabolic Diseases. Toney, AM., Fox, D., Chaidez, V., et al.[2021]

Urolithins, which are metabolites from berries and pomegranates, exhibit a range of health benefits including anti-inflammatory, anti-oxidative, and anti-aging properties, as well as potential anti-SARS-CoV-2 and anticancer effects.

Recent modifications to urolithins have improved their solubility and metabolic stability, enhancing their potential as therapeutic agents by targeting various signaling pathways involved in tumor suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Synthesis of Urolithins and their Derivatives and the Modes of Antitumor Action. Xu, X., Liu, Z., Yao, L.[2023]

Four new urolithins were identified in human feces after pomegranate extract intake, occurring in only 19% of subjects, indicating variability in gut microbiota metabolism.

The new urolithins require specific bacterial activity for their production, which differs from previously known urolithins, suggesting a potential for stratifying individuals based on their gut microbiome's metabolic capabilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of Novel Urolithin Metabolites in Human Feces and Urine after the Intake of a Pomegranate Extract. García-Villalba, R., Selma, MV., Espín, JC., et al.[2019]

Urolithin A (UA), a metabolite from foods like pomegranates, was found to be non-genotoxic in a series of tests, indicating it does not damage genetic material.

In a 90-day study with rats, UA showed no adverse effects on health at doses up to 5% of their diet, suggesting it is safe for consumption at high levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety assessment of Urolithin A, a metabolite produced by the human gut microbiota upon dietary intake of plant derived ellagitannins and ellagic acid. Heilman, J., Andreux, P., Tran, N., et al.[2018]

Urolithin A (UroA) effectively inhibits the growth of both androgen receptor-positive (AR+) and androgen receptor-negative (AR-) prostate cancer cells, with AR+ cells being more sensitive to its effects, indicating its potential as a targeted therapy for castration-resistant prostate cancer (CRPC).

Oral administration of UroA significantly reduced the growth of AR+ C4-2B xenografts in animal models without causing toxicity, and it works by downregulating androgen receptor signaling, suggesting its promise as a safe and effective treatment option for CRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer. Dahiya, NR., Chandrasekaran, B., Kolluru, V., et al.[2020]

In a study involving 94 participants with varying BMI and health statuses, specific urolithin metabolites (UMs) were found to correlate with cardiometabolic risk factors, suggesting they could serve as potential biomarkers for assessing cardiovascular health.

Urolithin-A was associated with positive lipid profiles in overweight-obese individuals, while Urolithin-B was linked to higher cholesterol levels, indicating that the type of urolithin produced may influence cardiometabolic disease risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The gut microbiota metabolism of pomegranate or walnut ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers: Comparison between normoweight, overweight-obesity and metabolic syndrome. Selma, MV., González-Sarrías, A., Salas-Salvadó, J., et al.[2019]

Urolithin A, derived from foods like pomegranate and nuts, shows significant anti-inflammatory effects in microglial cells by reducing harmful substances like TNF-α and IL-6, indicating its potential as a neuroprotective agent.

The neuroprotective effects of urolithin A are linked to the activation of SIRT-1 and the induction of autophagy, as these processes are essential for its efficacy in protecting brain cells from damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of Autophagy and Activation of SIRT-1 Deacetylation Mechanisms Mediate Neuroprotection by the Pomegranate Metabolite Urolithin A in BV2 Microglia and Differentiated 3D Human Neural Progenitor Cells. Velagapudi, R., Lepiarz, I., El-Bakoush, A., et al.[2019]

In a study of 100 healthy participants, only 12% had detectable levels of Urolithin A (UA) from their diet, but after consuming pomegranate juice, about 40% converted the precursor compounds into UA, indicating that dietary intake can influence UA production.

Direct supplementation with UA significantly increased plasma levels, providing over six times the exposure compared to pomegranate juice, suggesting that UA supplementation can effectively overcome individual differences in gut microbiome and dietary intake.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population. Singh, A., D'Amico, D., Andreux, PA., et al.[2022]

Urolithins, which are produced by gut bacteria from ellagitannins and ellagic acid found in foods like berries and nuts, are better absorbed by the body and may be responsible for the health benefits associated with these foods.

The review highlights the variability in how different individuals produce urolithins, which can affect their health outcomes, and discusses the need for further research to understand the mechanisms of action and health effects of these metabolites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Urolithins, the rescue of "old" metabolites to understand a "new" concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Tomás-Barberán, FA., González-Sarrías, A., García-Villalba, R., et al.[2018]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Novel Regioselective Synthesis of Urolithin Glucuronides─Human Gut Microbiota Cometabolites of Ellagitannins and Ellagic Acid. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Impact of the Natural Compound Urolithin A on Health, Disease, and Aging. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Immunomodulatory Role of Urolithin A on Metabolic Diseases. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

The Synthesis of Urolithins and their Derivatives and the Modes of Antitumor Action. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Identification of Novel Urolithin Metabolites in Human Feces and Urine after the Intake of a Pomegranate Extract. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Safety assessment of Urolithin A, a metabolite produced by the human gut microbiota upon dietary intake of plant derived ellagitannins and ellagic acid. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer. [2020]

8. England pubmed.ncbi.nlm.nih.gov

The gut microbiota metabolism of pomegranate or walnut ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers: Comparison between normoweight, overweight-obesity and metabolic syndrome. [2019]

9. Germany pubmed.ncbi.nlm.nih.gov

Induction of Autophagy and Activation of SIRT-1 Deacetylation Mechanisms Mediate Neuroprotection by the Pomegranate Metabolite Urolithin A in BV2 Microglia and Differentiated 3D Human Neural Progenitor Cells. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population. [2022]

11. Germany pubmed.ncbi.nlm.nih.gov

Urolithins, the rescue of "old" metabolites to understand a "new" concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. [2018]