Pomegranates, Urolithin A, Mitophagy, Mitochondrial cleanup – (part 1)

Last week a publication in Nature Medicine from the École Polytechnique Fédérale de Lausanne (EPFL) about Urolithin A improving mitochondrial and muscle function led to a large amount of news articles (for example here and here). The Swiss EPFL institute was also recently in the news with finding that “NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice” and is starting to build a reputation as an anti-aging research leader.

Pomegranates, nuts, berries have varying degrees of health benefits like anti-inflamation and anti-cancer effects. These benefits have been partly linked to ellagitannins which are precursors of substances called urolithins. Despite various research and the wide-spread human exposure via dietary consumption of their precursors, urolithin’s effects are still not well understood. What is known is that during intestinal metabolism by bacteria, the ellagitannins are converted to urolithins. One of the complications measuring the effects in human’s is that urolithin production is dependent on the composition of the gut microbiome. Individuals producing urolithins show a much higher abundance of the certain bacteria groups. Having the wrong type of microbiome can result in no production of urolithins at all. 

To overcome this the researchers in this study used pre-prepared urolithin A (UA) that was orally fed to worms and rodents (mice and rats). In the worms the chronic feeding with UA led to significantly longer lifespan. But significantly longer lifespan in worms has been demonstrated with a whole range of compounds which later failed to have effects in humans. However an interesting  finding in the study with worms was that the researchers managed to confirm that UA activates mitophagy throughout the duration of the treatment (and that UA had no effect on ROS production thus excluding that as mechanism). The researchers noted that UA activation of mitophagy prevented the accumulation of dysfunctional mitochondria with age and as result extended lifespan.

When the team gave the chemical to elderly mice, they observed they could run 42 per cent further. Analyses showed that the improvement occurred in the mice without them building any more muscles, which suggests that UA improves muscle-cell quality, rather than quantity. Similar to the observations in worms, when the researchers looked closer, they found that UA appeared to improve muscle cells by triggering them to eliminate damaged mitochondria – the powerhouses of the cell. When these are removed, the remaining healthy mitochondria divide and multiply resulting in more energy production and increased efficiency. Similar effect were observed in rats. While the study mentioned specifically improvements in muscle it was not entirely clear whether UA has similar cleanup effects in other tissue, likely this will be topics of future research.

A clinical trial of the compound in people has started to see whether it will show similar effects on muscle and whether it can reduce frailty as they age.

The rodents received 50 mg/kg/d of UA for a period of upto 8 months. Using FDA specified guidelines  we can calculate the Human Equivalent Dose (HED) for the UA diet given to the mice. 50mg/kg dosing in mice translates into a HED of approx. 4mg/kg. Or into approximately 280mg daily UA dosing for a person weighing 70kg.

While this daily dose sounds reasonable there is a major challenge. As of now there is no UA supplement on the market. The compound can be bought for research purposes for example here but at an astronomical price – a daily dose would cost 2000USD. It is very likely of-course that in the future companies will bring out low cost supplements.

But for those interested, in the upcoming part 2 a summary about the possibilities (if any) to induce the own body to make urolithin A. In the mean time if you fancy pomegranates there is now even more reason to keep eating them or drinking the juice as it may to boost those muscle mitochondria.

 

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