The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans

Abstract

Urolithin A (UA) is a natural dietary, microflora-derived metabolite shown to stimulate mitophagy and improve muscle health in old animals and in preclinical models of aging1. Here, we report the results of a first-in-human clinical trial in which we administered UA, either as a single dose or as multiple doses over a 4-week period, to healthy, sedentary elderly individuals. We show that UA has a favourable safety profile (primary outcome). UA was bioavailable in plasma at all doses tested, and 4 weeks of treatment with UA at doses of 500 mg and 1,000 mg modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression in elderly individuals (secondary outcomes). These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.

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Fig. 1: UA phase 1 study design, pharmacokinetic analysis and impact on plasma acylcarnitines in elderly individuals.
Fig. 2: UA impacts markers of mitochondrial function after 28 d of treatment.

Data availability

The gene expression data are deposited at the European Genome-phenome Archive under accession code EGAS00001003638 and can be accessed subject to signing a data access agreement.

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Acknowledgements

We would like to thank the volunteers for their participation in the study and Eurofins Optimed study staff for subject recruitment, data collection and processing, and S. Houten for his insight on the acylcarnitine data. Grant support by the Fondation Suisse de Recherche sur les Maladies Musculaires and the Fondation Marcel Levaillant is acknowledged.

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A.S., W.B., P.A.A., P.A. and C.R. contributed to the design of the study. P.A.A., A.S., C.R. and J.A. wrote the manuscript with the help of the other co-authors. A.S., W.B., P.A.A. and C.R. collected all the ex vivo data. P.A.A. and D.R. analysed the metabolomics data. F.B., M.I. and P.A.A. analysed the microarray data. All authors reviewed the manuscript.

Corresponding author

Correspondence to Chris Rinsch.

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Competing interests

The authors declare the following competing interests: A.S., P.A.A., W.B. and C.R. are employees; P.A. and C.R. are board members; and J.A. and P.A. are members of the Scientific Advisory Board of Amazentis SA, the sponsor of this clinical study. The other authors declare no competing interests.

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Supplementary Figs. 1 and 2 and Supplementary Tables 1–5

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Andreux, P.A., Blanco-Bose, W., Ryu, D. et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab 1, 595–603 (2019). https://doi.org/10.1038/s42255-019-0073-4

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