Urolithin A

Urolithin A (UA) is a dibenzofuranone polyphenol produced in the human colon from dietary ellagitannins (present in pomegranate, walnuts, and certain berries) by gut bacteria including Gordonibacter urolithinfaciens. Because only approximately 40% of adults harbor sufficient microbial capacity to convert ellagitannins to UA from food — and just 12% carry detectable baseline plasma levels — most research has focused on direct oral supplementation rather than dietary modification.

UA's central mechanism is the induction of mitophagy, the selective autophagy of dysfunctional mitochondria. The primary pathway activated by UA is PINK1-Parkin independent: UA elevates mitochondrial BNIP3 (BCL2/adenovirus E1B 19 kDa interacting protein 3), a mitophagy receptor that binds directly to the autophagosomal scaffold protein LC3, targeting impaired organelles for lysosomal degradation. UA additionally activates AMPK and suppresses mTOR signaling, and upregulates PGC-1alpha, stimulating parallel mitochondrial biogenesis to replenish the cleared organelles.

• Mitophagy induction: BNIP3-LC3 axis (PINK1-Parkin independent) • Bioenergetic signaling: AMPK activation, mTOR inhibition • Mitochondrial renewal: PGC-1alpha upregulation, increased biogenesis • Immune signaling: UA enhances cGAS-STING pathway activation in innate immune cells, increasing phosphorylated STING and IRF3 nuclear translocation, an effect that contrasts with NAD+ precursors such as nicotinamide riboside

By clearing mitochondria with impaired membrane potential, UA is proposed to shift cells toward a phenotype characterized by higher respiratory efficiency, lower reactive oxygen species burden, and reduced inflammatory signaling.

Multiple randomized, placebo-controlled human trials have evaluated UA, providing the strongest clinical evidence base among mitophagy-targeting supplements, though several primary endpoints have not reached statistical significance.

The first-in-human trial (Andreux et al., Nature Metabolism, 2019; PMID 32694802; n=60 healthy sedentary elderly, ages 61-85) established safety and bioavailability at 250, 500, and 1000 mg/day over four weeks. Doses of 500 and 1000 mg/day modulated plasma acylcarnitines and upregulated skeletal muscle mitochondrial gene expression, demonstrating a molecular signal of improved mitochondrial health.

The JAMA Network Open trial (Liu et al., 2022; PMID 35050355; n=66, ages 65-90, mean 71.7 years; 1000 mg/day for four months) found that primary endpoints — six-minute walk distance and maximal ATP production — were not significantly improved. Secondary endpoints showed large and statistically significant gains in muscle endurance: hand muscle contractions to fatigue averaged 95.3 with UA versus 11.6 with placebo (p less than 0.01), and leg muscle 41.4 versus 5.7 (p less than 0.01). Plasma acylcarnitines, ceramides, and C-reactive protein were significantly reduced. No serious adverse events occurred.

The ATLAS trial (Singh et al., Cell Reports Medicine, 2022; n=88, overweight middle-aged adults; 500 or 1000 mg/day for four months) reported approximately 12% improvement in muscle strength, clinically meaningful gains in peak VO2 and six-minute walk distance, and reductions in CRP and plasma acylcarnitines. The primary endpoint — peak power output — did not reach statistical significance.

A 2025 trial published in Nature Aging (Denk et al., MitoImmune study; n=50, ages 45-70, mean 53 years; 1000 mg/day for 28 days) found UA significantly expanded naive-like, less exhausted CD8+ T cells (treatment difference 0.50 percentage points, 95% CI 0.16-0.83, p=0.044) and improved CD8+ fatty acid oxidation capacity (treatment difference 14.72 percentage points, p=0.006), suggesting a benefit for immune aging.

A 2024 systematic review (Kuerec et al., Ageing Research Reviews; PMID 39002645; 5 RCTs, n=250 total; 10-1000 mg/day, 28 days to four months) concluded UA produced dose-dependent anti-inflammatory effects, upregulated mitochondrial and autophagy marker genes, and improved some muscle strength and endurance outcomes, but did not significantly affect mitochondrial maximal ATP production, biogenesis dynamics, gut microbiota, anthropometrics, or cardiovascular function. The authors called for larger, longer studies. Preclinical evidence in Alzheimer's transgenic mouse models is promising but not yet replicated in human trials.

Typical dosage: 250-500 mg (daily).

Oral UA has been studied in purified supplemental form across a narrow dose range. The majority of clinical trials have used 500 mg or 1000 mg per day, taken as a single daily dose, typically with food. The 2019 first-in-human trial included a 250 mg/day arm alongside 500 and 1000 mg arms; both 500 and 1000 mg produced detectable mitochondrial gene expression changes. Most efficacy data comes from the 1000 mg/day dose over four months.

A 2021 pharmacokinetic study in 100 healthy adults (Singh et al., European Journal of Clinical Nutrition; PMID 34117375) demonstrated that a single oral 500 mg dose of purified UA achieves more than six-fold higher circulating exposure compared to an equivalent serving of pomegranate juice, and delivers consistent plasma levels regardless of individual gut microbiome composition — an important consideration given that roughly 60% of adults are poor or non-converters from dietary sources.

Commercial formulations (notably Mitopure, the form used in most published trials) are available as 500 mg softgels or powdered sachets. The manufacturer recommends 500-1000 mg once daily. The ATLAS trial found similar directional trends at both 500 and 1000 mg, though the larger dose produced more consistent effects on biomarkers.

Trial durations have ranged from four weeks (immune endpoints) to four months (muscle and metabolic endpoints). No published controlled trials have evaluated UA for longer than four months.

This information reflects dosing reported in published clinical research and is provided for educational purposes only. It does not constitute medical advice. Speak with a qualified healthcare provider before starting any supplement regimen.

No compound-specific stability data has been identified for this peptide. The general lyophilized-peptide handling framework applies — see Storage & handling for temperature, reconstitution diluent, and beyond-use dating principles.

No published human clinical trials have examined UA in combination with other supplements. The following is based on preclinical data and mechanistic inference; any proposed synergy in healthy adults is anecdotal.

UA and NAD+ precursors (NMN, NR): Both compound classes are studied for mitochondrial support, but a 2024 human microglial cell study (Madsen et al., Frontiers in Aging Neuroscience; PMID 39665042) found directly opposing effects on innate immune signaling — UA enhanced cGAS-STING pathway activation while NR suppressed it. Both improved maximal respiratory capacity. Community users frequently report combining UA with NMN or NR, but whether combined use produces additive, neutral, or opposing effects in vivo is unknown. This combination is anecdotal.

UA and caloric restriction mimetics (berberine, rapamycin analogs, spermidine): All share AMPK activation and mTOR inhibition as overlapping mechanisms, suggesting theoretical complementarity. No human combination data exists; this is speculative.

UA and resistance exercise: Several published trials note that UA was tested in sedentary or lightly active adults. Smaller trials in athletes have evaluated recovery biomarkers. Whether UA adds benefit on top of structured exercise-induced mitophagy is not established in controlled studies.

UA and omega-3 fatty acids or antioxidants (quercetin, vitamin E): Sometimes discussed in longevity supplement stacks; no mechanistic rationale specific to UA combination has been established, and evidence is entirely anecdotal.

Urolithin A is not currently FDA-approved for any indication. It is generally classified as a research compound. Regulatory status varies by country.

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Reported side effects: Well-tolerated

Across all published clinical trials, UA has demonstrated a favorable safety profile. No serious adverse events attributed to UA have been reported at doses of 500-1000 mg/day for periods up to four months. Liver function tests, kidney function markers, hematological parameters, and electrocardiogram findings have not shown clinically significant changes in treated participants.

In the JAMA Network Open trial (n=66, four months), 31 treatment-emergent adverse events were recorded across both arms combined; rates did not differ statistically between UA and placebo, and no event was classified as serious or drug-related. Myalgia (muscle aches) has been cited in one trial as a mild adverse event with possible relationship to UA. In topical formulation studies, mild skin irritation was reported by a small number of participants.

UA has received Generally Recognized As Safe (GRAS) notification status in the United States for use as a food ingredient, based on submissions by the manufacturer.

Important safety considerations: • No clinical data exist for pregnancy or breastfeeding; use in these populations should be avoided without specific healthcare provider guidance. • UA is metabolized hepatically; theoretical interactions with cytochrome P450 inducers (rifampicin, carbamazepine) may accelerate UA clearance, while inhibitors (clarithromycin, azithromycin) may increase exposure. No formal drug-interaction studies have been published. • All trials were conducted in predominantly healthy adult populations; safety in individuals with significant hepatic, renal, or immunologic disease is not established. • UA has been identified as an aryl hydrocarbon receptor (AhR) antagonist in preclinical work; clinical significance is unknown. • Controlled safety data beyond four months is lacking. Long-term tolerability has not been formally evaluated in an RCT.