Urolithin A (UA) is gaining attention as a next-generation postbiotic—a compound produced not directly by foods but by the metabolism of dietary polyphenols by gut microbiota. The underlying science is a compelling example of the microbiome’s pivotal role in mediating the health effects of nutrition. Specifically, UA results from the biotransformation of ellagitannins and ellagic acid, which are abundant in pomegranates, walnuts, raspberries, and some other berries. However, as shown in a 2016 study published in Nature Communications by researchers from the Spanish National Research Council (CSIC) at the University of Murcia, only about 12% to 40% of individuals possess the specific gut bacteria—such as Gordonibacter urolithinfaciens—required to convert these dietary precursors into UA (Selma et al., 2016, Nature Communications, Spanish National Research Council, University of Murcia). This has direct implications for the feasibility of acquiring UA’s benefits from diet alone, as most people are non-producers or “low-producers” regardless of their food intake.
At the molecular level, UA belongs to the class of dibenzo-α-pyrones and has been shown in laboratory and animal models to activate mitophagy, the selective autophagic removal of dysfunctional mitochondria. Notably, a 2016 paper published in Nature Medicine by a team led from Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland demonstrated that UA supplementation extended lifespan in C. elegans and improved muscle function in rodents by triggering mitophagy and enhancing mitochondrial health (Ryu et al., 2016, Nature Medicine, EPFL, Switzerland). Impaired mitophagy and the accumulation of damaged mitochondria are hallmarks of aging and a wide spectrum of degenerative diseases, including sarcopenia, neurodegeneration, and metabolic syndrome.
The unique aspect of UA, compared to many other bioactive compounds, is its successful translation into human clinical trials. For instance, the ENERGIZE Study, a double-blind, randomized controlled trial published in Cell Reports Medicine in 2022, was conducted by researchers from Amazentis and the École Polytechnique Fédérale de Lausanne. In this study, older adults (mean age 71) with low muscle function received 1,000 mg of UA (Mitopure®) daily for four months. The results showed that the UA group had significant improvements in muscle strength (up to 12% increase in leg muscle peak torque) and walking distance (an average increase of 33 meters in the six-minute walk test). These improvements reflected not only functional gains but also measurable cellular changes, including reduced plasma acylcarnitine levels and upregulation of genes involved in mitochondrial biogenesis and mitophagy (Singh et al., 2022, Cell Reports Medicine, Amazentis and EPFL, Switzerland).
Further supporting these findings, a 2019 randomized clinical trial published in Nature Metabolism by Andreux and colleagues (Amazentis and EPFL, Switzerland) evaluated healthy but sedentary elderly participants who received either 500 mg or 1,000 mg of UA daily for 28 days. The researchers found dose-dependent increases in plasma UA concentrations and significant upregulation of mitochondrial gene expression in muscle biopsies, with the supplement showing excellent safety and tolerability (Andreux et al., 2019, Nature Metabolism, Amazentis and EPFL, Switzerland).
Additional work in 2024, published in Frontiers in Nutrition and led by researchers from Amazentis and partner institutions, further confirmed the safety and pharmacokinetics of UA. This study found that daily UA dosing reliably maintained steady plasma levels due to a plasma half-life of 17–22 hours and up to 58 hours for its conjugated forms, making once-daily supplementation practical and effective (Guimaraes et al., 2024, Frontiers in Nutrition, Amazentis and collaborators).
UA’s physiological effects extend beyond muscle. A 2019 study in Aging Cell by Fang and colleagues at the University of Oslo and collaborating institutions showed that UA supplementation in a mouse model of Alzheimer’s disease improved cognitive performance, enhanced mitophagy, and reduced markers of neuroinflammation and tau pathology (Fang et al., 2019, Aging Cell, University of Oslo). Human data for neuroprotection are forthcoming, but clinical trials are already in progress.
Cardiometabolic and anti-inflammatory effects are also supported by preclinical and emerging clinical studies. Ryu and colleagues in the aforementioned Nature Medicine paper found that UA supplementation in rodents improved endurance, reduced visceral fat, and enhanced insulin sensitivity, primarily by supporting mitochondrial function and fatty acid oxidation (Ryu et al., 2016, Nature Medicine, EPFL, Switzerland). In human studies, lower inflammatory markers, such as C-reactive protein (CRP), have been observed after UA supplementation, indicating possible systemic anti-inflammatory effects.
Because the ability to convert dietary ellagitannins to UA is limited to a minority of adults, direct UA supplementation is emerging as a reliable strategy. Clinical trials have generally used 500–1,000 mg of pure UA (such as Mitopure®) daily. The compound is produced through pharmaceutical-grade organic synthesis, ensuring both purity and high bioavailability (Andreux et al., 2019, Nature Metabolism; Guimaraes et al., 2024, Frontiers in Nutrition). UA was granted generally recognized as safe (GRAS) status by the FDA in 2018, and a comprehensive scientific review by the Alzheimer’s Drug Discovery Foundation in 2023 confirmed the absence of toxicity or adverse effects at relevant doses.
A practical supplementation protocol, reflecting these human studies, is 500–1,000 mg of UA daily with a meal, continued for at least 4–16 weeks to see benefits in mitochondrial function and muscle performance. Stacking UA with exercise and other lifestyle interventions, such as NAD+ boosters, omega-3 fatty acids, and adequate sleep, may further enhance its effects.
While animal and observational studies suggest broader benefits for hepatic, immune, and even anti-cancer health, more rigorous human trials are still needed to confirm these effects. An example is the PREDIMED-Plus trial, conducted in Spain and published in Molecular Nutrition & Food Research in 2020, which indicated that higher urinary UA levels correlated with improved metabolic and inflammatory profiles in adults on a Mediterranean diet (Garcia-Mantrana et al., 2020, Molecular Nutrition & Food Research, PREDIMED-Plus, Spain).
Across all clinical studies—including those by Andreux (2019), Singh (2022), and Guimaraes (2024)—UA has shown a consistent safety profile, with adverse events rare and generally limited to mild gastrointestinal symptoms. There have been no significant effects on liver, kidney, or hematologic function. Because UA is a downstream metabolite of ellagitannins, it avoids the drug–nutrient interactions sometimes seen with whole pomegranate products.
In summary, Urolithin A represents a scientifically validated, next-generation postbiotic with unique benefits for mitochondrial renewal and muscle function. The research base, anchored by leading institutions such as the University of Murcia, EPFL, Amazentis, and others, provides a strong foundation for UA’s use as a dietary supplement for cellular health and healthy aging.
SAFAK LAB 