Longevity Briefs: Can This Gut Metabolite Slow Ageing?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Urolithin A is a molecule produced by microbes in the gut, and can also be taken as a dietary supplement. This anti-inflammatory compound has generated some excitement after studies showed it could extend animal lifespan and improve various aspects of health in animal models. For example, a study last year showed that urolithin A could improve cognitive function in a mouse model of Alzheimer’s disease, and also significantly extended the lifespan of normally ageing mice.

In this study, which was just published in preprint and has not yet been peer reviewed, researchers make some new findings about how urolithin A works, suggesting that it may protect against the pro-ageing influence of senescent cells. Senescent cells are cells that are no longer able to divide, either because they have reached their replicative limit or because they have been badly damaged. Senescent cells build up with increasing age, and are thought to contribute to ageing largely through the release of harmful signalling molecules known as SASP factors (senescence-associated secretory phenotype). 

The discovery:

Researchers started by taking human foetal lung cells and used them to produce two types of senescent cells – cells that had become senescent due to damage from chemotherapy, and cells that had become senescent after dividing too many times. They then treated the cells with urolithin A, and found that while markers of cellular senescence weren’t affected, the inflammatory SASP factors they released were reduced, as was the expression of their corresponding genes. When the researchers exposed healthy cells to media collected from senescent cells treated with either urolithin A or a control, they found that the media from the urolithin A-treated cells caused less senescence in the healthy cells.

Looking further into the mechanism, researchers found that treating cells with urolithin A significantly reduced levels of cytosolic DNA – DNA fragments floating freely within the cell. DNA should remain contained within the nucleus or the mitochondria, and so DNA outside of these locations is indicative of severe damage or the presence of pathogens. Consequently, the cell responds to free DNA by triggering an inflammatory response. Urolithin A has previously been shown to enhance the clearance of damaged mitochondria, which may help to explain why it reduced cytosolic DNA.

The implications:

Urolithin A might help suppress the harmful signals released by senescent cells, thereby reducing their impact and preventing the spread of senescence. Mitochondria, the power plants of the cell, become increasingly dysfunctional and damaged with age, leaking their DNA. Urolithin A appears to mitigate this by clearing damaged mitochondria. While this study has not yet been peer reviewed and was only in cultured cells, there is some evidence for human health benefits of urolithin A supplementation, such as improved muscle strength. Urolithin A is also produced by gut bacteria when they metabolise ellagitannins, which are found in foods such as pomegranates and walnuts. Unfortunately, this is dependent on gut microbiome composition, with some research suggesting that only 40% of people can synthesise urolithin A in meaningful quantities.