Urolithin A is one of a number of molecules regulated as supplements that is known to modestly improve mitochondrial function. A number of companies are working on deriving drugs from modified forms of urolithin A, while the research community is more focused on trying to understand how exactly it improves mitochondrial function. The effect size is not large, as is the case for better understood approaches to improve mitochondrial function in aged tissues, such as the various ways to increase NAD+ in mitochondria, and delivery of forms of mitochondrially targeted antioxidant. These various molecules tend to produce results that are smaller than those resulting from greater exercise and greater physical fitness, where there is data to compare directly, and have collectively failed to move the needle on diseases in a range of clinical trials. Nonetheless, there remains considerable interest in all of these approaches, largely because they cost little and are immediately available for use.
Urolithin A (UA) is a natural compound produced through a multi-step metabolic process by gut microbiota, derived from dietary precursors such as ellagitannins (ETs) and ellagic acid (EA). These polyphenols are abundant in foods like pomegranates, berries, and tea. Extensive preclinical research highlights UA's diverse biological effects, including anti-inflammatory, antioxidant, anti-senescence, anti-apoptotic, and promoting mitophagy. Randomized clinical studies further validate UA's ability to upregulate proteins linked to mitophagy and oxidative phosphorylation (OXPHOS) in muscle tissue while reducing plasma inflammatory markers, such as C-reactive protein (CRP).
Regarding safety, clinical trials have confirmed UA's tolerability at doses up to 1000 mg daily, with no serious adverse effects reported in interventions lasting up to four months. Notably, UA is the first compound shown in human trials to induce mitochondrial-related gene expression without significant side effects. The U.S. FDA has granted UA Generally Recognized as Safe status as a food additive.
UA has been extensively investigated in preclinical models of various central nervous system (CNS) disorders. This review systematically integrates preclinical evidence for UA's therapeutic potential in CNS disorders and elucidates its biosynthesis, pharmacokinetic properties, key bioactivities, and recent clinical trials involving UA. Although clinical trials targeting UA treatment for CNS disorders have not yet been initiated, multiple clinical trials have demonstrated that UA possesses favorable safety and pharmacokinetic profiles and have validated some of the biological effects observed in in preclinical studies. Importantly, this review provides an in-depth analysis of the challenges encountered in the clinical translation of UA for the treatment of CNS disorders.
Link: https://doi.org/10.3390/biomedicines13071553
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