--- topic: "Urolithin A" title: "Mitochondrial Health and Aging" order: 1 description: "What research shows about urolithin A, a gut-made compound from pomegranates and nuts that triggers mitophagy, and what the first human trials found for muscle strength and endurance" question: "Can urolithin A supplements improve muscle strength and endurance?" answer: "Urolithin A may improve muscle endurance in older adults and leg strength in middle-aged adults, but both 2022 trials missed their primary endpoints." actions: - "Eat pomegranate, walnuts and berries for ellagitannins, but your gut microbiome decides how much urolithin A you make [5]." - "If you supplement, trials used 500–1,000 mg a day of purified urolithin A for four months; other products were not tested [4]." cautions: - "The trials were funded by the supplement's maker, lasted four months, and do not show it prevents falls, disability or disease [3][4]." - "Both 2022 trials missed their primary endpoints (walk distance and muscle ATP; peak power), so benefits come from secondary results [3][4]." - "Animal results in worms, mice and rats show a mechanism, not a proven benefit for people [1]." confidence: 2 confidenceNote: "Two company-funded RCTs (66 and 88 people) improved only secondary measures; a first-in-human trial showed safety and biomarker changes; the rest is animal data." evidenceSummary: rctCount: 2 observationalCount: 0 metaAnalysisCount: 0 totalParticipants: "150+" replicated: false newestStudyYear: 2022 references: - id: "1" pmid: "27400265" title: "Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents" authors: "Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, Aebischer P, Sandi C, Rinsch C, Auwerx J" year: 2016 journal: "Nature Medicine" - id: "2" pmid: "32694802" title: "The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans" authors: "Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, Auwerx J, Singh A, Rinsch C" year: 2019 journal: "Nature Metabolism" - id: "3" pmid: "35050355" title: "Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial" authors: "Liu S, D'Amico D, Shankland E, Bhayana S, Garcia JM, Aebischer P, Rinsch C, Singh A, Marcinek DJ" year: 2022 journal: "JAMA Network Open" - id: "4" pmid: "35584623" title: "Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults" authors: "Singh A, D'Amico D, Andreux PA, Fouassier AM, Blanco-Bose W, Evans M, Aebischer P, Auwerx J, Rinsch C" year: 2022 journal: "Cell Reports Medicine" - id: "5" pmid: "35118817" title: "Urolithins: a Comprehensive Update on their Metabolism, Bioactivity, and Associated Gut Microbiota" authors: "García-Villalba R, Giménez-Bastida JA, Cortés-Martín A, Ávila-Gálvez MÁ, Tomás-Barberán FA, Selma MV, Espín JC, González-Sarrías A" year: 2022 journal: "Molecular Nutrition & Food Research" --- Urolithin A is not something you eat directly — your gut bacteria make it from ellagitannins, polyphenols found in pomegranates, walnuts, and certain berries. [1][5] In animals the compound was found to induce mitophagy, the cellular process that identifies and removes damaged mitochondria so they can be replaced with healthy ones. [1] Researchers believe this quality-control mechanism becomes less effective with age and that this contributes to muscle weakness, fatigue, and cellular aging. [1] Two randomized trials published in 2022 found better muscle endurance in older adults [3] and better muscle strength in middle-aged adults [4] taking urolithin A, although neither trial improved on placebo for its primary endpoint. People differ in how well their gut microbiome makes urolithin A from food, which is one reason direct supplementation has become an active area of research. [5] ## How Urolithin A Is Made — and Why That Matters Pomegranates, walnuts, and some berries (strawberries are one example) contain a class of polyphenols called ellagitannins. When you eat these foods, your gut bacteria break the ellagitannins down into ellagic acid and then into a series of compounds called urolithins; urolithin A is the one that has attracted the most research. [5] The critical variable is your gut microbiome. Only some people's bacterial communities can complete this conversion. Researchers sort people into "urolithin metabotypes" — UM-A, UM-B, and UM-0, the last producing little or no urolithins — and this variation is one reason studies of ellagitannin-rich foods often show inconsistent effects. [5] The benefit of eating pomegranate may depend on who can actually convert its polyphenols into the active compound. ## The Mitophagy Mechanism Mitochondria, the energy-producing organelles in your cells, accumulate damage over time — from oxidative stress, environmental toxins, and normal metabolic wear. Healthy cells continuously run a quality-control process called mitophagy: damaged mitochondria are tagged with specific protein signals, then engulfed and recycled. This keeps the mitochondrial pool functional and limits the cellular damage that degraded mitochondria can cause. With age, mitophagy is thought to slow down. Damaged mitochondria then accumulate, producing more reactive oxygen species, triggering more inflammation, and generating less energy efficiently. This mitochondrial dysfunction is believed to underlie part of what we call "aging" at the cellular level, and it has been linked to sarcopenia (age-related muscle loss) and reduced physical performance. [1] In the 2016 *Nature Medicine* study, urolithin A was identified as a first-in-class natural compound that induces mitophagy both in cells and in living animals after oral consumption. In *C. elegans* roundworms it prevented the accumulation of dysfunctional mitochondria with age, extended lifespan, and prolonged normal activity (mobility and pharyngeal pumping). In two mouse models of age-related decline in muscle function, and in young rats, it improved exercise capacity. [1] These are animal results; they show a mechanism, not a proven benefit for people. ## What Human Trials Show Three human trials have now been reported. Each included authors from Amazentis, the company that makes the Mitopure supplement (see the limitations in the evidence section). **First-in-human safety and biomarker trial (2019):** Healthy, sedentary older adults received urolithin A as a single dose or as multiple doses over four weeks. The primary outcome was safety, and the compound was safe and was bioavailable in plasma at every dose tested. After four weeks at 500 mg or 1,000 mg a day, plasma acylcarnitines (markers of mitochondrial fat processing) and the expression of mitochondrial genes in skeletal muscle had changed. [2] These were secondary biomarker outcomes, not measures of how people felt or functioned. **Older adult RCT (2022):** Sixty-six adults aged 65–90 were randomized to 1,000 mg urolithin A or placebo daily for 4 months. The two primary endpoints — change in 6-minute walk distance and maximal muscle ATP production — did not differ significantly from placebo. The secondary endpoint, muscle endurance, did: at 2 months, the number of contractions until fatigue rose by about 95 in a hand muscle and about 41 in a leg muscle with urolithin A, compared with about 12 and 6 with placebo. Plasma acylcarnitines, ceramides, and C-reactive protein were also lower with urolithin A. [3] **Middle-aged adult RCT (2022):** Eighty-eight adults aged 40–64 were randomized to 500 mg of urolithin A, 1,000 mg, or placebo daily for 4 months. Leg muscle strength (hamstring peak torque) rose about 12% from baseline with 500 mg and about 10% with 1,000 mg, a significant difference from placebo, where it fell by about 10%. Aerobic endurance (peak oxygen consumption) and 6-minute walk performance showed clinically meaningful improvements. But the primary endpoint, peak power output, did not improve significantly. Plasma acylcarnitines and C-reactive protein were lower with urolithin A, and muscle biopsies showed higher levels of proteins linked to mitophagy and mitochondrial metabolism. [4] ## Who the Evidence Covers, and Practical Guidance The trials enrolled healthy middle-aged and older adults, and reported no safety problems; the 2022 older-adult trial found no statistical differences in adverse events between urolithin A and placebo. [2][3] They do not show that urolithin A prevents falls, disability, or disease, and they did not test people selected for being poor urolithin producers. Doses used in the trials: single doses and 500–1,000 mg a day. [2][4] The branded form "Mitopure" (used in the middle-aged adult trial [4]) is purified urolithin A, which bypasses the gut conversion step. Other urolithin A supplements exist, but they have not been tested in these trials. **Food sources** of the ellagitannin precursors include pomegranate, walnuts, and strawberries and other berries. [1][5] Whether eating them produces enough urolithin A to matter depends on your gut microbiome. Urolithin A is sometimes paired with other mitochondria-supportive compounds. See our [CoQ10 page](/coq10/coq10-basics) for the role of ubiquinol in the mitochondrial electron transport chain, and [PQQ](/pqq/mitochondrial-health-and-cognition) for a compound studied for mitochondrial biogenesis. For the broader context of cellular aging, see our [autophagy page](/autophagy/cellular-recycling) and [NAD+ page](/nad-plus/nad-plus-basics). ## Evidence Review ### Foundational Preclinical Work: Ryu et al. 2016 The study that put urolithin A on the scientific map was published in *Nature Medicine* (PMID 27400265). Ryu and colleagues identified urolithin A as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. [1] In *C. elegans*, urolithin A prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. It also prolonged normal activity during aging, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where urolithin A improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. The authors concluded that the findings highlight the potential of urolithin A to improve mitochondrial and muscle function. [1] ### First Human Trial: Andreux et al. 2019 The transition to humans was published in *Nature Metabolism* (PMID 32694802). It was a first-in-human clinical trial in which urolithin A was given to healthy, sedentary elderly individuals either as a single dose or as multiple doses over a 4-week period. [2] The main findings: - Urolithin A had a favorable safety profile (the primary outcome) - It was bioavailable in plasma at all doses tested - After 4 weeks at 500 mg and 1,000 mg a day, it modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression (secondary outcomes) This was the proof of concept that oral urolithin A reaches the bloodstream in humans and changes mitochondrial biomarkers. It was not designed to detect changes in function. ### Older Adult RCT: Liu et al. 2022 Liu and colleagues (PMID 35050355) conducted a 4-month double-blind, placebo-controlled RCT in 66 adults aged 65–90 (33 per group; mean age 71.7; 75.8% women) at a medical center and a cancer research center in Seattle. [3] Participants took 1,000 mg of urolithin A or placebo daily. The primary end points were the change in 6-minute walk distance and the change in maximal ATP production in hand muscle (measured with magnetic resonance spectroscopy). The secondary end points were muscle endurance in a hand muscle (first dorsal interosseus) and a leg muscle (tibialis anterior). Neither primary end point showed a significant difference. The 6-minute walk distance rose by 60.8 m with urolithin A and 42.5 m with placebo, and the change in maximal ATP production was similar in the two groups. Muscle endurance, a secondary end point, improved significantly at 2 months: the number of contractions until fatigue rose by 95.3 (hand) and 41.4 (leg) with urolithin A, versus 11.6 and 5.7 with placebo. Plasma levels of several acylcarnitines, ceramides, and C-reactive protein were lower with urolithin A at 4 months. Adverse events did not differ between groups. The authors concluded that urolithin A was safe and well tolerated and that, although the walk distance and ATP results were not significant, long-term supplementation was beneficial for muscle endurance and plasma biomarkers, and that future work is needed to confirm this. ### Middle-Aged Adult RCT: Singh et al. 2022 This trial (PMID 35584623) enrolled middle-aged adults (aged 40–64; 88 randomized) in a randomized, double-blind, placebo-controlled study and compared placebo, 500 mg a day, and 1,000 mg a day of urolithin A (Mitopure) for 4 months. [4] The primary endpoint was peak power output during an aerobic cycling test, and it did not improve significantly. Among the secondary and exploratory results: - **Muscle strength:** average peak torque of the hamstring improved by about 12% with 500 mg (p = 0.027 versus placebo) and about 9.8% with 1,000 mg (p = 0.029), while it fell by about 9.8% in the placebo group - **Aerobic endurance:** peak oxygen consumption (peak VO2) rose about 10% from baseline with 1,000 mg (placebo: about −1%), and the authors describe the improvements in peak VO2 and 6-minute walk performance as clinically meaningful - **Biomarkers:** plasma acylcarnitines and C-reactive protein were significantly lower with urolithin A - **Muscle biopsies:** expression of proteins linked to mitophagy and mitochondrial metabolism increased significantly The two doses did not clearly differ in the strength results, and hand-grip strength did not improve significantly. The study was funded by Amazentis SA, which sponsored the trial and employs several of the authors; its product was the one tested. ### Metabolism and Microbiome Review: García-Villalba et al. 2022 This comprehensive update (PMID 35118817) reviews the metabolism, bioactivity, and associated gut microbiota of urolithins, emphasizing the last five years of literature. [5] To date, 13 urolithins and their conjugated metabolites (glucuronides, sulfates) have been described and detected in human fluids and tissues, including urine, blood, feces, breast milk, prostate, colon, and breast tissue. The review describes progress in identifying the microorganisms that make urolithins and the gut microbiota profiles associated with the three metabotypes (UM-A, UM-B, and UM-0). It cautions that many in vitro studies have not used physiologically relevant forms and concentrations, which makes some reported urolithin activities questionable. In contrast, it notes remarkable progress in research on the safety, bioactivity, and mechanisms of urolithin A, including the first human interventions. ### Overall Evidence Assessment The urolithin A evidence base is unusual for a supplement: the preclinical work is substantial, urolithin A has a plausible mechanism (mitophagy), and the three human trials found it safe and found consistent changes in mitochondrial biomarkers. Functional effects are mixed. In older adults, the trial missed both primary endpoints but found better muscle endurance; in middle-aged adults it missed its primary endpoint but found better hamstring strength and some exercise measures. The main limitations are the modest sample sizes (66 and 88 participants in the two efficacy trials), the sponsorship (both 2022 trials were funded by Amazentis SA, the maker of Mitopure, and several authors are its employees), and the lack of long-term (beyond 4 months) data. Independent replication is needed, along with trials that measure outcomes people care about, such as falls, mobility, and disability. The mechanistic grounding and the consistency across the three trials place urolithin A among the better-studied supplements for muscle aging, but the clinical benefit remains unproven.