Intestinal bacteria and their metabolites contribute directly to vascular aging

The aging of the innermost cell layer of blood vessels leads to cardiovascular diseases. Researchers at UZH have now shown for the first time that intestinal bacteria and their metabolites contribute directly to vascular aging. As people age, the bacterial composition in their gut changes, resulting in fewer "rejuvenating" and more harmful substances in the body.

Cardiovascular diseases are the most common cause of death worldwide. Even if known traditional risk factors such as diabetes or high blood pressure are treated, the disease worsens in half of all cases, especially in older patients. Researchers at UZH have now shown for the first time that intestinal bacteria and their metabolites can accelerate the ageing of blood vessels and trigger cardiovascular disease.

Phenylacetic acid triggers cell aging

The human body consists of around 30 to 100 trillion bacteria that reside in our organs. Ninety percent of these bacteria live in the intestine, processing the food we eat into metabolic products, which in turn affect our bodies. "Half of these substances have not yet been recognized," says Soheil Saeedi. His research group at the Center for Translational and Experimental Cardiology is investigating how the microbiota composition changes with age and whether this affects the cardiovascular system.

Using data from more than 7,000 healthy individuals aged between 18 and 95 as well as a mouse model of chronological aging, the researchers found that the breakdown product of the amino acid phenylalanine - phenylacetic acid - accumulates with age. In several series of experiments, Saeedi's team was able to prove that phenylacetic acid leads to senescence of endothelial cells, in which the cells that line the inside of blood vessels do not proliferate, secrete inflammatory molecules, and exhibit aging phenotype. As a result, the vessels stiffen up and their function is impaired.

Responsible bacterium found

By conducting a comprehensive bioinformatic analysis of the microbiome of mice and humans, the researchers were able to identify the bacterium Clostridium sp.ASF356, which can process phenylalanine into phenylacetic acid. When the researchers colonized young mice with this bacterium, they subsequently showed increased phenylacetic acid levels and signs of vascular aging. However, when the bacteria were eliminated with antibiotics, the concentration of phenylacetic acid in the body decreased. "We were thus able to show that the intestinal bacteria are responsible for the increased levels," explains Saeedi.

The body's own fountain of youth

However, the microbiome in the gut also produces substances that are beneficial to vascular health. Short-chain fatty acids such as acetate, which are produced by fermentation of dietary fibers and polysaccharides in the intestine, act as natural rejuvenating agents. The research group used in-vitro experiments to show that adding sodium acetate can restore the function of aged vascular endothelial cells. When analyzing intestinal bacteria, they found that the number of bacteria that produce such rejuvenating agents decreases with age.

"The aging process of the cardiovascular system can therefore be regulated via the microbiome," says Saeedi. The pharmacologist and his team are now investigating which diet has a positive influence on the complex interaction between bacteria and humans. Dietary fibers and foods with antioxidant and anti-inflammatory properties boost the body's own "fountain of youth". In contrast, intake of food and drinks that are rich in phenylalanine, e.g. red meat, dairy products and certain artificial sweeteners, should be limited to slow down vascular aging. The researchers are also working on ways to reduce phenylacetic acid in the body through medication. Initial attempts to curb the formation of phenylacetic acid with the help of genetically modified bacteria have been promising.