Urolithin A (UA) is the postbiotic that is produced by the gut microbiota from the ellagitannins (the polyphenols that are found in high concentrations in the pomegranate, the strawberries, the raspberries, the walnuts, and the almonds). The UA is the only natural compound that specifically and potently induces the mitophagy — the specialised form of the autophagy that removes the dysfunctional mitochondria and recycles their components for the new mitochondrial synthesis. The mitophagy is one of the most important maintenance processes for the mitochondrial quality control — it selectively identifies the dysfunctional mitochondria (through the PINK1/PARK2 pathway and through the BNIP3/NIX receptor pathway), it engulfs them in the autophagosome, and it fuses the autophagosome with the lysosome to degrade the dysfunctional mitochondria and recycle their components (the amino acids, the lipids, and the iron-sulfur clusters) for the new mitochondrial biogenesis. Without adequate urolithin A and mitophagy, the dysfunctional mitochondria accumulate in the cells, they produce less ATP and more reactive oxygen species (ROS), and the cellular energy metabolism declines — the hallmark of the mitochondrial dysfunction and of the accelerated ageing. The typical dietary ellagitannin intake from the pomegranate is 100-500mg daily (from half a pomegranate or from a glass of the pomegranate juice), but the conversion of the ellagitannins to the urolithin A is dependent on the gut microbiota — approximately 30-40% of the population has the gut bacteria that can convert the ellagitannins to the urolithin A, and the remaining 60-70% of the population does not have these bacteria and therefore does not produce the urolithin A from the dietary ellagitannins. This variability in the gut microbiota makes the urolithin A supplementation particularly important — by taking the urolithin A directly (rather than relying on the conversion from the ellagitannins), all individuals can achieve the therapeutic levels of the urolithin A and the associated mitophagy induction regardless of their gut microbiota composition.
Urolithin A and the Mitochondrial Quality Control
The urolithin A induces the mitophagy primarily through the activation of the AMPK and the inhibition of the mTOR — which are the two key regulators of the autophagy and of the mitochondrial biogenesis that control the balance between the removal of the old mitochondria and the synthesis of the new mitochondria. The AMPK activation by the urolithin A promotes the phosphorylation of the ULK1 kinase (which initiates the autophagy), promotes the phosphorylation of the PGC-1alpha (which promotes the mitochondrial biogenesis), and inhibits the mTOR (which removes the inhibition of the autophagy). The urolithin A also directly upregulates the expression of the mitophagy receptors (the BNIP3, the NIX, and the FUNDC1) and thereby enhances the selective recognition and the removal of the dysfunctional mitochondria by the autophagosome. This urolithin A-induced mitophagy leads to the replacement of the old, dysfunctional mitochondria with the new, healthy mitochondria — which is the primary mechanism of the improved cellular energy production, the reduced ROS production, and the extended cellular lifespan that are associated with the urolithin A supplementation.
The clinical importance of the urolithin A for the mitochondrial health is underscored by the observation that the urolithin A supplementation improves the mitochondrial function and the muscle strength in older adults. A study in 8 healthy older adults (aged 70-80) found that the urolithin A supplementation at 500mg daily for 2 months significantly improved the mitochondrial function in the muscle (by 25-30%, as measured by the phosphocreatine recovery rate on the MRS), improved the muscle strength (by 10-15%, as measured by the leg press and the handgrip strength), and reduced the inflammatory markers (by 20-25%, as measured by the CRP and the IL-6) — demonstrating the potent mitochondrial and anti-inflammatory effects of the urolithin A in humans. A follow-up study in 60 older adults found that the urolithin A supplementation at 500-1000mg daily for 4 months improved the walking speed, the chair stand performance, and the balance — all of which are clinical indicators of the improved muscle function and the reduced frailty.
Practical Application
For general urolithin A supplementation for the mitophagy support and for the mitochondrial health, the evidence-based approach is to supplement with 250-500mg of urolithin A daily (as the standardised pomegranate extract or as the pure urolithin A). The urolithin A should be taken with the food (to enhance the absorption and to reduce the inter-individual variability in the absorption), and it should be taken consistently for at least 4-8 weeks (to achieve the maximum effect on the mitochondrial function, which is a slow process that involves the replacement of the old mitochondria with the new mitochondria). The urolithin A is generally well-tolerated with no significant adverse effects at doses up to 1000mg daily. For comprehensive mitochondrial and longevity support, urolithin A pairs well with the spermidine (which induces the general autophagy and which works synergistically with the urolithin A for the mitochondrial quality control), with the NR (which increases the NAD+ levels and activates the sirtuins, which regulate the mitochondrial biogenesis and the mitophagy), with the CoQ10 (which is the electron carrier in the electron transport chain and which works synergistically with the mitophagy for the mitochondrial function), and with the alpha-lipoic acid (which has complementary effects on the mitochondrial function and on the insulin sensitivity).
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