Urolithin A, A Gut Microbiome Derived Compound Improves Mitochondrial Health And Muscle Performance

Urolithin A (UA) is a natural gut microbiome derived metabolite generated upon consumption of foods rich in the ellagitannins such as berries, pomegranates, and walnuts. UA can naturally be produced only by 30-40% of the population who have the appropriate gut microflora needed to convert dietary precursors into UA. UA has been shown to stimulate mitophagy and improve muscle function in pre-clinical models and to improve mitochondrial health in older adults. PURPOSE: To determine the effects of UA supplementation on physical performance and mitochondrial health in middle-aged healthy adults. METHODS: Healthy middle-aged adults (n = 88, between 40-64 years) were randomly assigned to 3 different supplementation groups. Each group was provided with either UA (500 mg/day), UA (1000 mg/day) or a placebo for 4 months. The effect of supplementation was investigated on muscle strength (isokinetic peak torque), physical performance (six-minute walk test), exercise capacity (peak VO2) and biomarkers of mitochondrial health (from muscle biopsies and blood plasma). Long term safety and compliance were also assessed. RESULTS: The average age of participants in each group was not significantly different; 51 + 7 yrs in UA 500 mg/day group vs. 52 + 6 yrs in UA 1000 mg/day group vs. 54 + 6 yrs in placebo group. Average peak torque in the knee flexors was significantly increased in both UA 500 mg/day (+12.0%, p < 0.05 compared with placebo) and UA 1000 mg/day groups (+9.8%, p < 0.05 compared with placebo). At the highest dose of 1000 mg/day, UA increased peak VO2 (~10%, p = 0.058) compared to placebo. The UA 1000 mg/day group showed a significant increase from baseline in physical performance during the six-minute walk test, with an increased mean distance of 33.43 m (p < 0.05). Muscle proteomics showed UA elevated levels of protein involved in mitophagy and oxidative phosphorylation, markers of improved mitochondrial quality and respiratory capacity. In the plasma, UA reduced acylcarnitines and C-reactive protein levels, indicating higher mitochondrial efficiency and reduced inflammation at the systemic level. CONCLUSION: Direct calibrated supplementation with UA is an appealing nutritional strategy to deliver health benefits on muscle function, physical performance, and mitochondrial health.