In uncovering a compound's potential anti-aging properties, researchers reveal a fascinating result of the co-evolution of plants, bacteria, and animals over millions of years. They show the compound enables muscle cells in animals to protect themselves against one of the major causes of aging. The compound - called urolithin A - is naturally produced in the gut when a molecule that is present in pomegranates is digested by intestinal bacteria.
Tests of urolithin A's effect in humans are not yet complete, say researchers from the École Polytechnique Fédérale in Lausanne (EPFL), Switzerland, who report promising results from studies using nematodes and rodents in the journal Nature Medicine.
There have been many claims about the health benefits of pomegranates - including their supposed anti-aging properties. However, the authors note that a lack of conclusive evidence - plus controversial marketing - has led to much skepticism. So they decided to take a closer look.
As we age, an important process that our cells rely on for energy slows down and begins to malfunction. This process - called "mitophagy" - recycles worn-out mitochondria, the tiny powerhouses inside cells that make the chemical units of energy that fuel their work.
If worn-out mitochondria are not recycled, they and their decomposing components build up inside cells, eventually causing problems in many tissues, including muscle, which gradually becomes weaker.
There is also evidence that build-up of faulty or worn-out mitochondria plays a role in the diseases of aging, such as Parkinson's disease. Scientists have also found that defects in the Parkinson's gene Fbxo7 also disrupt mitophagy.
Urolithin A is the only molecule that can relaunch mitophagy
In the new study, the EPFL team establishes that urolithin A can restore mitophagy in cells where the process has become sluggish. Co-author Patrick Aebischer, a professor in neuroscience and president of EPFL, says urolithin A is unique in this respect:
"It's the only known molecule that can relaunch the mitochondrial clean-up process, otherwise known as mitophagy. It's a completely natural substance, and its effect is powerful and measurable."
He and his colleagues first tested the effect of urolithin A in the nematode worm Caenorhabditis elegans, a very useful model for studying human biology at the cell level for several reasons: it is multicellular, its cells have many features in common with human cells, and it develops from a fertilized egg.
For these reasons, and the fact that at 8-10 days of age, C. elegans is considered elderly, scientists also find the worm very useful for studying the process and effects of aging.
The researchers found that when they exposed C. elegans to urolithin A, the worms lived on average more than 45 percent longer.
The team also observed that urolithin A prevented the accumulation of dysfunctional mitochondria as the worms aged.
Urolithin A improved endurance in elderly mice
The researchers then repeated the tests with rodents. They found, like they did with the worms, that urolithin A led to a significant reduction in faulty mitochondria. Also, older mice - around 2 years old - showed 42 percent better endurance while running than other mice of the same age that had not been exposed to the compound.
In further tests with young rats, the team also found that exposure to urolithin A improved exercise capacity.
These tests showed that a robust cellular recycling of mitochondria - mitophagy - was taking place, the authors conclude.
However, while the study results appear promising, the researchers are by no means suggesting people should start consuming pomegranates to slow aging or preserve muscle strength on the basis of their findings.
The team points out it is not urolithin A that is present in pomegranates, but a precursor, a molecule in a family called the ellagitannins. When the molecule mixes with water in the gut, it breaks down into ellagic acid, which is further processed by gut bacteria to produce urolithin A.
Because of the number of steps involved in its natural production, and because of the role of the bacteria, the amount of urolithin A produced can vary widely. In fact, the necessary bacteria may be absent altogether in some individuals.
Human trials of urolithin A under way
If you happen to be one of the people whose gut bacteria do not produce urolithin A, then it is possible that pomegranates and pomegranate juice will not give you the benefits seen in the study.
To try and overcome this, the team has launched a start-up biotechnology company, Amazentis, which has developed a way to deliver finely calibrated doses of urolithin A. Human trials have already started on testing the effects of urolithin A delivered this way.
The authors are optimistic that they will find urolithin A has similar results in humans. In evolutionary terms, C. elegans and rodents are quite distant, which is a good sign that the study has revealed a mechanism that is essential to living organisms.
"Precursors to urolithin A are found not only in pomegranates, but also in smaller amounts in many nuts and berries."
Chris Rinsch, co-author and CEO of Amazentis
The following video from EPFL, and introduced by Prof. Auwerx, explains mitophagy, the role of urolithin A, and the team's hopes about its application to diseases linked with aging: