Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents

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Abstract

The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans, UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function.

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Figure 1: UA improves fitness and extends lifespan.
Figure 2: UA alters mitochondrial functions in C. elegans.
Figure 3: Mitophagy is required for UA-mediated longevity phenotype.
Figure 4: UA induces mitophagy in muscle and intestinal mouse cell lines.
Figure 5: UA shifts mitochondria from CI- to CII-driven respiration.
Figure 6: UA improves exercise capacity in rodent models via the induction of mitophagy.

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Acknowledgements

We thank P. Gönczy (Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne) for sharing reagents and equipment, the Caenorhabditis Genetics Center for providing worm strains and the Auwerx team members for discussions. We thank the team of the Phenotyping Unit, Center of PhenoGenomics, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL) for their technical and scientific expertise in the mouse experiments. We thank K.H. Kim (Yonsei University College of Medicine) for providing mRFP-GFP-LC3B reporter and for discussion. We thank G. Yellen (Department of Neurobiology, Harvard Medical School) for providing mitochondrial pHRed-expressing plasmid and D. Kaiserlian (INSERM) for the Mode-K cell line. J.A. is the Nestlé Chair in Energy Metabolism. Work in the Auwerx laboratory is supported by the Ecole Polytechnique Fédérale de Lausanne and Systems X (SysX.ch 2013/153), and was co-financed by the Commission for Technology and Innovation (CTI) (15171.1 PFLS-LS). L.M. was supported by a fellowship from Fondation Médicale pour la Recherche (FRM).

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L.M., P.A.A., D.R., P.A., C.S., C.R. and J.A. conceived and designed the project. L.M., P.A.A., D.R., E.K., A.A.N.-d.-F., P.J., G.L.S., N.M., E.G.W. and D.H. performed the experiments. L.M., C.R., P.A.A. and J.A. wrote the manuscript, with contributions from all of the other authors.

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Correspondence to Chris Rinsch or Johan Auwerx.

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Competing interests

P.A.A. and C.R. are employed by Amazentis; C.R. and P.A.A. are board members of Amazentis; and J.A. and C.S. are consultants to Amazentis.

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Ryu, D., Mouchiroud, L., Andreux, P. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med 22, 879–888 (2016). https://doi.org/10.1038/nm.4132

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