Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults.

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• Mitochondrial dysfunction is associated with ageing and linked to deterioration of skeletal muscle and sarcopenia. Improving mitochondrial health may therefore help to improve muscle health as we age.
• Previous studies have demonstrated improvements in muscle endurance with long term UA intake in older adults (1) and the study by Singh et al. supports these findings in middle-aged adults.
• For middle-aged clients who are noticing a decline in muscle strength, exercise performance, or a general increase in fatigue, taking 500-1,000 mg UA daily for two to four months could lead to noticeable improvements in symptoms.
• The compounds from which UA is derived are also found in polyphenol-rich plant foods including pomegranates, berries and walnuts, therefore consuming these foods may be useful dietary additions for the same purpose.
• These findings are likely to be relevant for younger populations too, as mitophagy, which is part of the action of UA, contributes to the removal and recycling of dysfunctional mitochondria, allowing healthier intact mitochondria to take their place.

• Urolithin A (UA) is a microbiome metabolite – known as a postbiotic - of elligitannins and polyphenolic compounds found in some plant foods including pomegratate, berries and walnuts.
• In animal models, UA has previously been shown to have a range of potential health benefits involving induction of mitophagy and on mitochondrial function, as well as on disease states including osteoarthritis, inflammatory bowel disease, cardiovascular disease, and neurodegenerative disorders.
• The current study sought to establish proof-of-concept of the efficacy and safety of long-term UA supplementation on physiological endpoints in middle-aged adults.
• The primary outcome was peak power output and secondary outcomes included a range of clinical and physiological parameters linked to muscle strength, exercise tolerance and physical performance.
• The study tested UA in 500mg and 1000 mg doses against placebo in a 3-arm randomized-controlled trial in n= 88 subjects aged 40-64y who were healthy, overweight (BMI 25.0-34.9 kg/m2), sedentary, and who had a low VO2max at study inclusion. 79 subjects completed the study.
• Subjects were assessed at baseline, midpoint (2 months) and endpoint (4 months). In addition to the UA intervention, subjects were asked to maintain low physical activity status for the duration of the trial, and avoid pomegranates and supplements known to influence muscle performance (high protein, CoQ10m vitamin B3 or L-carnitine).
• Though a difference in peak power output (primary outcome) was not observed, muscle strength improved by up to c. 12% with 500 mg daily UA (p=0.027). With 1000 mg UA daily, aerobic endurance improved by up to 15% (p=0.03), gait speed increased by 7% (p=0.004), and in the 6-minute walk test subjects improved by 7% (p=0.008) and walked on average more than 30 additional meters, indicating a clinically meaningful difference in mobility.
• In addition, subjects in the UA groups had improved biomarkers of cellular health. With 1000 mg UA daily, inflammation was reduced (CRP, p<0.05; IFN-γ and TNF-α, both p<0.05). In addition, biomarkers of mitochondrial efficiency were also improved with 500 mg UA daily, Iing increased protein levels related to improved mitophagy, and expression of genes belonging to mitochondria.
• UA was deemed as safe and well tolerated at both 500 mg and 1000 mg doses for 4 months’ administration.
• A strength of the study was that the groups were balanced for all physiological parameters at baseline. However, the ratio of females was 2:1, and ethnicity was mainly western European. This may limit interpretation of the findings.
• All authors except one are either employees, board members or members of the scientific advisory board of Amazentis SA, who both manufacture Mitopure, the UA supplement used, and who funded this trial.

• Mitophagy is an important step in improving mitochondrial health. This study demonstrates the potential of UA to activate this pathway.
• In healthy middle-aged adults who are overweight or obese, sedentary and with low physical performance, oral UA supplementation at a sufficient dose and duration may:
• increase muscle strength
• increase mitophagy proteins in human skeletal muscle, as well as various other mitochondrial markers
• increase exercise performance and aerobic exercise
• be a valuable intervention to consider in clients who are suffering from mitochondrial dysfunction

• This study was exploratory and the sample size for some of the outcomes was very small and inadequate to demonstrate true statistical significance. Future studies of similar design are needed to confirm the findings
• Nevertheless, the study was well-structured with carefully elaborated markers. It could be used as a template for future studies.