Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents
Open accessAbstract
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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Supplementing old mice with urolithin A for 27-31 weeks increased their grip strength and endurance.
“a recent study has shown that supplementing old mice with urolithin A for 27–31 weeks increased their grip strength and endurance (Ryu et al. 2016).”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Ryu et al. 2016
Park2 was one of the most upregulated genes upon urolithin A treatment.
“Park2 (i.e. the gene coding for Parkin) was one of the most upregulated genes upon urolithin A treatment (Ryu et al. 2016).”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Ryu et al. 2016
Reactivation of autophagy in aged mice by expressing Atg7 in skeletal muscle or treating with Urolithin A ameliorates muscle mass.
“Reactivation of autophagy in aged mice both by expressing Atg7 in skeletal or by treating mice with Urolithin A, a compound that promotes mitophagy, ameliorate muscle mass51,56.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [56]
Urolithin A selectively activates mitophagy in muscle and improves muscle function in aging.
“Recently, urolithin A, a metabolite of ellagitannins that are abundant in pomegranate fruit, as well as in nuts and berries was shown to selectively activate mitophagy in muscle and improve muscle function in aging.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [56]
Urolithin A activates mitophagy via PINK1/parkin and BNIP3 pathways.
“Urolithin A was found to activate mitophagy via PINK1/parkin and BNIP3 pathways56.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [56]
Exposure to mitophagy modulators increases lifespan in worms.
“exposure to mitophagy modulators increases lifespan in worms23,24.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [24]
Urolithin A supplementation stimulates Parkin-mediated mitophagy and prolongs lifespan in C. elegans.
“Recently, Dr Auwerx’s research group reported that urolithin A supplementation, a natural dietary microflora-derived metabolite from ingested ellagitannins and ellagic acid, stimulates Parkin-mediated mitophagy and prolongs lifespan in C. elegans [160], and improves muscle function and running performance in old rodents while increasing Parkin expression [160].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [160]
Urolithin A improves muscle function and running performance in old rodents while increasing Parkin expression.
“and improves muscle function and running performance in old rodents while increasing Parkin expression [160]”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [160]
The concentration of serum urolithins can reach up to micromolar levels without displaying toxicity in certain populations.
“The concentration of serum urolithins can reach up to micromolar levels without displaying toxicity in certain populations.132,134,138,144,145”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [134]
Among urolithins, urolithin A displays potent anti-inflammatory, antioxidative, and antiaging properties.
“Among urolithins, urolithin A (UroA) displays potent anti-inflammatory, antioxidative, and antiaging properties.130,133, 134, 135”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [134]
In C. elegans, urolithin A extends lifespan and improves muscle health.
“In C. elegans, urolithin A, as an autophagy inducer, extends lifespan and improves muscle heath [95].”
From Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy (2021) · cites this paper as [95]
In in vitro and in vivo models, urolithin A induces mitophagy and improves grip strength and overnight running distance.
“In both in vitro (C2C12 myoblasts and Mode-K intestinal cells) and in vivo (aging and HFD-fed C57BL/6J mice) models, urolithin A induces mitophagy and improves grip strength and overnight running distance [95].”
From Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy (2021) · cites this paper as [95]
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- Authors
- Ryu, D., Mouchiroud, L., Andreux, P. A., Katsyuba, E., Moullan, N., Nicolet-dit-Félix, A. A., Williams, E. G., Jha, P., Lo Sasso, G., Huzard, D., Aebischer, P., Sandi, C., Rinsch, C., & Auwerx, J.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- Amazentis (Switzerland) (CH)
- Corresponding author
- Rinsch, Chris
- Auwerx, Johan
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-07-11
- Volume
- 22
- Issue
- 8
- Pages
- 879-888
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2470574011
- Cited by
- 1,105
- References
- 64
- Citations by year
- 2026: 163 · 2025: 138 · 2024: 138 · 2023: 113 · 2022: 125 · 2021: 118 · 2020: 115 · 2019: 87 · 2018: 41 · 2017: 54 · 2016: 10
- FWCI
- 34.64
- Type
- journal article
- Language
- en
- Open access
- green
- infoscience.epfl.ch
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Nursing › Nutrition and Dietetics › Pomegranate: compositions and health benefits
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- urolithin A, mitophagy, ellagitannins, Punica granatum, lifespan extension, aging, mitochondrial dysfunction, muscle function, exercise capacity, mitochondrial respiratory capacity, natural compounds, dietary polyphenols
- MeSH terms
- Animals, Coumarins, DNA, Mitochondrial, Fertility, Longevity, Mitochondria, Oxygen Consumption, Pharynx, RNA, Messenger, Caenorhabditis elegans, Muscle, Skeletal, Microscopy, Confocal, Myoblasts, Mice, Rats, Real-Time Polymerase Chain Reaction, Mitophagy
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