Urolithin A is the most abundant type of urolithin produced by the human microbiota. This nutritional compound is derived from ellagitannins and ellagic acid commonly found in berries, nuts, and pomegranate. Urolithin A (UA) has a powerful influence on mitochondrial function, as it reduces inflammation, promotes antioxidant mechanisms that result in anti-aging effects. Indeed, these mechanisms associated with urolithin A prevent age-related conditions that affect muscle, brain, and joint tissues. Lamentably, studies have reported that only 40% of healthy individuals can produce UA from food, and this is coincidental with changes in the gut microbiota due to aging and health status. Understanding the mechanisms of how UA can be applied to counteract age-related conditions is the cornerstone to implement its supplementation.
UA molecular mechanisms
Urolithin A is metabolized from polyphenols, ellagitannins, and ellagic acids by the microbiota in the large intestine. Therefore, this conversion depends on specific bacterial strains that seem less abundant in the elderly population.
UA supports mitochondrial function by recycling dysfunctional mitochondria through a mechanism called mitophagy. An increased level of UA in feces is consistent with an improvement in mitochondrial health. Indeed, this benefit can be seen across different species like humans, worms, and mice.
Nevertheless, mitophagy, a highly selective autophagy process, is impaired by aging, which can lead to age-related diseases. Indeed, UA seems to be the answer to improving levels of mitophagy and counteract age-related organ dysfunction.
This selective autophagy process occurs ins the presence of damaged mitochondria or the exposure of mitophagy inducers.
For example, the UA activated PTEN-induced kinase 1 (PINK1)/Parkin-dependent mitophagy promotes ubiquitination of dysfunctional mitochondria. The process starts when the mitochondrial proteins get phosphorylated by PINK1, which functions like docking sites for adaptor proteins like microtubule-associated protein LC3. These proteins act like phagocytic membranes that engulf the mitochondria and then merge with lysosomes, promoting the clearance of the mitochondria remnants.
Besides this, other PINK1–Parkin independent mitophagy pathways function with the activation of mitochondrial proteins, such as BNIP3, NIX, and FUNDC1. However, these mitochondria proteins also recruit LC3 and upregulate an autophagosome complex.
After the mitophagy mechanism takes place, there is a reduced mitochondrial abundance. On the other hand, studies report an increased quality of the cellular mitochondria and improved mitochondrial activity.
Clinical research in mouse models reports that UA exposure is consistent with an increased mitophagy, followed by mitochondrial biogenesis in muscle and muscle. In addition, UA supplementation in humans is consistent with an upregulation of mitochondrial function in muscle. Also, UA increases the use and efficacy of fatty acids by the mitochondria and the expression of mitochondrial gene sets in muscle tissue.
Urolithin A in aging
Most of the studies regarding the anti-aging effects of UA have been made in animal models, but those same effects can be extrapolated to humans.
Research reports a 45% higher effectiveness anti-aging of UA compared to their precursors EA and ellagitannins. Researchers extracted this result from a study comparing EA to UA and their effectiveness in extending wild-type worms’ lifespan.
Other research made to observe UA’s effects on skeletal muscle function in C. elegans resulted in improved integrity of muscle fibers and increased motility. On mouse models, UA supplementation in middle-age and old-age mice for six weeks resulted in better aerobic performance, better hand-grip strength, and enhanced skeletal muscle strength. Another significant benefit from UA supplementation was an increment of angiogenesis markers in the skeletal muscle of middle-aged mice (16 weeks).
Current research shows the effectiveness of UA in animal models and how it can potentially benefit humans. The overall effects of UA supplementation reflect on longevity, better gut barrier integrity, higher muscular strength, endurance, and minor age-related muscle dysfunction. However, the main question is, “am I a UA producer or a non-UA- producer?”. Most research is consistent with the lesson that UA supplementation will work better than EA or ellagitannins. In addition, it is safe to mention that having the UA- producing bacteria is needed to enable these anti-aging benefits.- Ana Paola Rodríguez Arciniega, MS
D’Amico, Davide et al. “Impact of the Natural Compound Urolithin A on Health, Disease, and Aging.” Trends in molecular medicine vol. 27,7 (2021): 687-699. doi:10.1016/j.molmed.2021.04.009
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