Editors' ChoiceAging

A mitochondrial Pac-man drug to tackle aging

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Science Translational Medicine  17 Jul 2019:
Vol. 11, Issue 501, eaay3574
DOI: 10.1126/scitranslmed.aay3574

Abstract

Urolithin A, an activator of mitophagy, is safe to use and increases skeletal muscle mitochondrial gene expression in elderly individuals.

A hallmark of aging is the loss of cells’ ability to remove nonfunctioning organelles and proteins by a quality control process called autophagy. The inability of energetically active skeletal muscle to turnover mitochondria via autophagy (called mitophagy) is related to the decline in muscle strength and performance seen in older people. Tackling mitophagy could be a therapeutic approach to address the decline in skeletal muscle health associated with aging.

In a phase I clinical trial, Andreux et al. investigated whether urolithin A (UA), a microflora-derived metabolite reported to initiate autophagy in animal models of aging, could be safely given to healthy but sedentary elderly subjects. The clinical trial comprised two parts. The first part tested the safety and pharmacokinetics of the compound by orally administering the subjects single escalating doses of UA. The second part studied mitochondrial gene expression and function by giving the subjects set doses of UA for four weeks, followed by analysis of skeletal muscle biopsies and plasma samples. The study reported that UA was safe to use in all of the subjects when given in doses ranging from 250 mg to 1000 mg. UA and its metabolites also appeared in plasma samples of these subjects, demonstrating the bioavailability of the compound.

To further assess the effect of UA in the mitochondria, the investigators analyzed the gene expression profiles of skeletal muscle biopsies from the subjects taking UA for four weeks. Transcriptomic analysis showed dose-dependent up-regulation of genes associated with mitochondrial biogenesis, mitophagy, and fatty acid oxidation—a key aspect of mitochondrial function. The authors also reported that the same gene sets were down-regulated in sedentary prefrail subjects with low skeletal muscle strength versus age-matched healthy individuals. This finding indirectly supports the hypothesis that UA improves the declining mitochondrial function in the aging skeletal muscle. The team also assessed plasma acylcarnitines in the patient cohorts as an indirect measurement of mitochondrial function. Patients given UA had decreased serum acylcarnitines, suggesting improved fatty acid oxidation and therefore mitochondrial function.

Future studies should investigate the consequences of improving the function of skeletal muscle mitochondria in elderly subjects given UA through skeletal muscle performance and exercise tests. Considering its favorable safety profile and bioavailability, UA could be used as a dietary supplement and potentially be useful in diseases associated with muscle weakness and loss, which currently lack effective therapies.

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