Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial

Abstract

Importance: Aging is associated with a decline in mitochondrial function and reduced exercise capacity. Urolithin A is a natural gut microbiome-derived food metabolite that has been shown to stimulate mitophagy and improve muscle function in older animals and to induce mitochondrial gene expression in older humans.

Objective: To investigate whether oral administration of urolithin A improved the 6-minute walk distance, muscle endurance in hand and leg muscles, and biomarkers associated with mitochondrial and cellular health.

Design, setting, and participants: This double-blind, placebo-controlled randomized clinical trial in adults aged 65 to 90 years was conducted at a medical center and a cancer research center in Seattle, Washington, from March 1, 2018, to July 30, 2020. Muscle fatigue tests and plasma analysis of biomarkers were assessed at baseline, 2 months, and 4 months. Six-minute walk distance and maximal ATP production were assessed using magnetic resonance spectroscopy at baseline and at the end of study at 4 months. The analysis used an intention-to-treat approach.

Interventions: Participants were randomized to receive daily oral supplementation with either 1000 mg urolithin A or placebo for 4 months.

Main outcomes and measures: The primary end point was change from baseline in the 6-minute walk distance and change from baseline to 4 months in maximal ATP production in the hand skeletal muscle. The secondary end points were change in muscle endurance of 2 skeletal muscles (tibialis anterior [TA] in the leg and first dorsal interosseus [FDI] in the hand). Cellular health biomarkers were investigated via plasma metabolomics. Adverse events were recorded and compared between the 2 groups during the intervention period.

Results: A total of 66 participants were randomized to either the urolithin A (n = 33) or the placebo (n = 33) intervention group. These participants had a mean (SD) age of 71.7 (4.94) years, were predominantly women (50 [75.8%]), and were all White individuals. Urolithin A, compared with placebo, significantly improved muscle endurance (ie, increase in the number of muscle contractions until fatigue from baseline) in the FDI and TA at 2 months (urolithin A: FDI, 95.3 [115.5] and TA, 41.4 [65.5]; placebo: FDI, 11.6 [147.4] and TA, 5.7 [127.1]). Plasma levels of several acylcarnitines, ceramides, and C-reactive protein were decreased by urolithin A, compared with placebo, at 4 months (baseline vs 4 mo: urolithin A, 2.14 [2.15] vs 2.07 [1.46]; placebo, 2.17 [2.52] vs 2.65 [1.86]). The mean (SD) increase from baseline in the 6-minute walk distance was 60.8 (67.2) m in the urolithin A group and 42.5 (73.3) m in the placebo group. The mean (SD) change from baseline to 4 months in maximal ATP production in the FDI was 0.07 (0.23) mM/s in the urolithin A group and 0.06 (0.20) mM/s in the placebo group; for the TA, it was -0.03 (0.10) mM/s in the urolithin A group and 0.03 (0.10) mM/s in the placebo group. These results showed no significant improvement with urolithin A supplementation compared with placebo. No statistical differences in adverse events were observed between the 2 groups.

Conclusions and relevance: This randomized clinical trial found that urolithin A supplementation was safe and well tolerated in the assessed population. Although the improvements in the 6-minute walk distance and maximal ATP production in the hand muscle were not significant in the urolithin A group vs the placebo group, long-term urolithin A supplementation was beneficial for muscle endurance and plasma biomarkers, suggesting that urolithin A may counteract age-associated muscle decline; however, future work is needed to confirm this finding.

Trial registration: ClinicalTrials.gov Identifier: NCT03283462.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Liu reported receiving grants from drugs at no cost for research use from Stealth BioTherapeutics and supplements at no cost for research use from AstaReal outside the submitted work. Dr D'Amico reported being an employee of Amazentis SA during the conduct of the study and receiving personal fees from Amazentis SA outside the submitted work. Dr Shankland reported receiving drugs at no cost for research use from Stealth BioTherapeutics and supplements at no cost for research use from AstaReal outside the submitted work. Ms Bhayana reported receiving drugs at no cost for research use from Stealth BioTherapeutics and supplements at no cost for research use from AstaReal outside the submitted work. Dr Garcia reported being a full-time employee of the US government during the conduct of the study. Dr Aebischer reported being the chair of the board and a shareholder of Amazentis SA during the conduct of the study. Dr Rinsch reported being the founder, the chief executive officer, and a board member of Amazentis SA during the conduct of the study; holding a patent for US 9,872,850 issued, a patent for US 10,028,932 issued, a patent for US 10,485,782 issued, a patent for US 11,020,373 issued, a patent for US 10,906,883 issued, a patent for US 20180256538 pending, and a patent for US 20180256539 pending. Dr Singh reported being an employee of Amazentis SA during the conduct of the study and holding a patent for US 20180256538 pending and a patent for US 20180256539 pending. Dr Marcinek reported receiving drugs at no cost for research use from Stealth BioTherapeutics, grants from Boehringer Ingelheim, and supplements at no cost for research use from AstaReal outside the submitted work.

Figures

Figure 1.. CONSORT Diagram of Participant Flow Through the Study

Figure 2.. Effect of Urolithin A Supplementation on the 6-Minute Walk Distance and Maximal Adenosine Triphosphate (ATP) Production in Hand Muscles and Muscle Endurance

Data were analyzed using an analysis of covariance with 95% CIs for treatment differences. The center horizontal line represents the mean and the top and bottom lines represent the SEM. FDI indicates first dorsal interosseus; TA, tibialis anterior. aP <.01 with post hoc 2-sided Wilcoxon 2-sample test. bP = .05. cP = .07 with post hoc 2-sided Wilcoxon 2-sample test.

Figure 3.. Effect of Urolithin A on Biomarkers of Mitochondrial Health and Inflammation

A-F, Data represent geometric mean (95% CI). A 2-way repeated-measures analysis of variance was used. G, Data represent mean (95% CI). An analysis of covariance model was used. BL indicates baseline; CRP indicates C-reactive protein. Light gray circles indicate change in plasma levels in the control group at 2 months; dark blue circles, change in plasma levels in the control group at 4 months; orange circles, change in plasma levels in the urolithin A group at 2 months; bright blue circles, change in plasma levels in the urolithin A group at 4 months. aP <.05. b.05 is less than P < .10.