Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Ryu, D. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879–888 (2016).

    Article  CAS  Google Scholar 

  2. Choi, A. M., Ryter, S. W. & Levine, B. Autophagy in human health and disease. N. Engl. J. Med. 368, 651–662 (2013).

    Article  CAS  Google Scholar 

  3. Drake, J. C. & Yan, Z. Mitophagy in maintaining skeletal muscle mitochondrial proteostasis and metabolic health with ageing. J. Physiol. 595, 6391–6399 (2017).

    Article  CAS  Google Scholar 

  4. Coen, P. M. et al. Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults. J. Gerontol. A 68, 447–455 (2013).

    Article  Google Scholar 

  5. Zane, A. C. et al. Muscle strength mediates the relationship between mitochondrial energetics and walking performance. Aging Cell 16, 461–468 (2017).

    Article  CAS  Google Scholar 

  6. Heilman, J., Andreux, P., Tran, N., Rinsch, C. & Blanco-Bose, W. Safety assessment of Urolithin A, a metabolite produced by the human gut microbiota upon dietary intake of plant derived ellagitannins and ellagic acid. Food Chem. Toxicol. 108, 289–297 (2017).

    Article  CAS  Google Scholar 

  7. Keefe, D. M. GRAS Notice No. GRN 000791 (Food and Drug Administration, 2018).

  8. Yoshimura, Y. et al. Interventions for treating sarcopenia: a systematic review and meta-analysis of randomized controlled studies. J. Am. Med. Dir. Assoc. 18, 553 e551–553.e516 (2017).

    Article  Google Scholar 

  9. Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products EMEA/CHMP/SWP/28367/07 (European Medicines Agency, 2007).

  10. Yang, H. et al. Phase 1 single- and multiple-ascending-dose randomized studies of the safety, pharmacokinetics, and pharmacodynamics of AG-348, a first-in-class allosteric activator of pyruvate kinase R, in healthy volunteers. Clin. Pharmacol. Drug Dev. 8, 246–259 (2019).

    Article  CAS  Google Scholar 

  11. Chandorkar, G., Zhan, Q., Donovan, J., Rege, S. & Patino, H. Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers. BMC Pharmacol. Toxicol. 18, 24 (2017).

    Article  Google Scholar 

  12. Guideline on Bioanalytical Method Validation EMEA/CHMP/EWP/192217/2009 (European Medicines Agency, 2011).

  13. Guidance for Industry: Bioanalytical Method Validation (US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research and, Center for Veterinary Medicine, 2001).

  14. Tomas-Barberan, F. A. et al. Urolithins, the rescue of ‘old’ metabolites to understand a ‘new’ concept: metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Mol. Nutr. Food Res. 61, 1500901 (2017).

    Article  Google Scholar 

  15. Schooneman, M. G., Vaz, F. M., Houten, S. M. & Soeters, M. R. Acylcarnitines: reflecting or inflicting insulin resistance? Diabetes 62, 1–8 (2013).

    Article  CAS  Google Scholar 

  16. Mitochondrial Medicine Society’s Committee on Diagnosis et al.The in-depth evaluation of suspected mitochondrial disease. Mol. Genet. Metab. 94, 16–37 (2008).

    Article  Google Scholar 

  17. Lum, H. et al. Plasma acylcarnitines are associated with physical performance in elderly men. J. Gerontol. A 66, 548–553 (2011).

    Article  Google Scholar 

  18. Felder, T. K. et al. Specific circulating phospholipids, acylcarnitines, amino acids and biogenic amines are aerobic exercise markers. J. Sci. Med. Sport 20, 700–705 (2017).

    Article  Google Scholar 

  19. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  Google Scholar 

  20. Mahoney, D. J., Parise, G., Melov, S., Safdar, A. & Tarnopolsky, M. A. Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exercise. FASEB J. 19, 1498–1500 (2005).

    Article  CAS  Google Scholar 

  21. Lammers, G. et al. Expression of genes involved in fatty acid transport and insulin signaling is altered by physical inactivity and exercise training in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 303, E1245–E1251 (2012).

    Article  CAS  Google Scholar 

  22. Robinson, M. M. et al. Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans. Cell Metab. 25, 581–592 (2017).

    Article  CAS  Google Scholar 

  23. Andreux, P. A. et al. Mitochondrial function is impaired in the skeletal muscle of pre-frail elderly. Sci. Rep. 8, 8548 (2018).

    Article  Google Scholar 

  24. Gong, Z. et al. Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice. J. Neuroinflammation 16, 62 (2019).

    Article  Google Scholar 

  25. Fang, E. F. et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci. 22, 401–412 (2019).

    Article  CAS  Google Scholar 

  26. Singh, R. et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat. Commun. 10, 89 (2019).

    Article  Google Scholar 

  27. Olesen, J., Kiilerich, K. & Pilegaard, H. PGC-1alpha-mediated adaptations in skeletal muscle. Pflugers Arch. 460, 153–162 (2010).

    Article  CAS  Google Scholar 

  28. Jeppesen, J. et al. Enhanced fatty acid oxidation and FATP4 protein expression after endurance exercise training in human skeletal muscle. PLoS ONE 7, e29391 (2012).

    Article  CAS  Google Scholar 

  29. Laker, R. C. et al. Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat. Commun. 8, 548 (2017).

    Article  Google Scholar 

  30. Vainshtein, A., Tryon, L. D., Pauly, M. & Hood, D. A. Role of PGC-1alpha during acute exercise-induced autophagy and mitophagy in skeletal muscle. Am. J. Physiol., Cell Physiol. 308, C710–C719 (2015).

    Article  Google Scholar 

  31. Harrigan, J. A., Jacq, X., Martin, N. M. & Jackson, S. P. Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat. Rev. Drug Discov. 17, 57–78 (2018).

    Article  CAS  Google Scholar 

  32. Spendiff, S. et al. Mitochondrial DNA deletions in muscle satellite cells: implications for therapies. Hum. Mol. Genet. 22, 4739–4747 (2013).

    Article  CAS  Google Scholar 

  33. Milburn, M. V. & Lawton, K. A. Application of metabolomics to diagnosis of insulin resistance. Annu. Rev. Med. 64, 291–305 (2013).

    Article  CAS  Google Scholar 

  34. Fried, L. P. et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 56, M146–M156 (2001).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Ethics declarations

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.

Additional information

Journal peer review information: Primary Handling Editor: Christoph Schmitt.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

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

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-019-0073-4

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research