Older Gut Microbiomes Can Drive Vascular Aging

Over half of the human body is not even human. Everyone carries almost 40 trillion bacterial cells, forming their microbiome, which play various roles in different organs, including affecting digestion, mental wellbeing, immune function, and cardiovascular health.¹ However, certain members of this invisible ‘organ’ can also cause problems, especially as individuals age.

Age detrimentally affects all cells—human and bacterial—of the body. Experiments in mice have revealed that age alters the composition of the gut microbiota.² This disturbance can throw off the balance of essential metabolites, elevating the risk of diseases such as cardiovascular disorders.

Two such bacterial metabolites are phenylacetic acid (PAA) and its derivative phenylacetylglutamine (PAGln); higher levels of both are strongly associated with heart disease in humans.³ But do these microbial metabolites drive cardiovascular aging? And if yes, how?

Jürg Beer, a cardiologist at the University of Zürich, was curious to find out. In a study published in Nature Aging, Beer and his colleagues showed that PAA and PAGln accelerate senescence in mice and human blood vessel cells, which reduces vascular function.⁴ These findings provide a foundation for further exploring the gut-vascular crosstalk and potential therapeutics in humans for treating age-related diseases.

“It's an exciting step forward in terms of understanding how microbial metabolites biologically affect host processes,” said Ami Bhatt, a hematologist at Stanford University who was not involved in the study. “I suspect that some of these findings may also extend to endothelial cell function in other compartments, such as the blood-brain barrier.”

The innermost layer of cells in blood vessels—endothelial cells—shows various signs of aging: DNA instability, epigenetic modifications, cell cycle arrest, and secretion of inflammatory molecules.⁵ Such dysfunctional endothelial cells are major contributors to cardiovascular diseases.

Beer and his team first investigated if PAA and PAGln could cause these cellular changes in an aging animal. They measured plasma levels of the molecules in mice and observed a higher abundance in older animals as compared to the young ones. Many of the older mice had poor endothelial function, making the blood vessels less pliable than those in their younger counterparts. Genomic analysis of fecal samples showed increased levels of PAA- and PAGln-producing microbial genes in aged mice, with the Clostridium species ASF356 emerging as the only possible synthesizer. The researchers also analyzed metabolite levels using data from a human cohort with over 7,000 people and observed enrichment of Clostridrium species and higher levels of PAA and PAGln in older persons.

“With age, one narrows down the microbiome by nutrition and antibiotics,” Beer said. “The idea is one could reseed the right microbiome as a therapy, which is quite simple technically and promising prognostically.”

For their experiment, Beer and his colleagues tried the opposite. They hypothesized that if the Clostridrium species was in fact contributing to a decline in vascular function in aging mice, it could do so in young ones as well. To test this, they wiped out the gut microbiota of young mice and introduced the Clostridrium species. Levels of PAA and PAGln in these animals shot up significantly as compared to young mice that were left undisturbed. Moreover, their endothelial cells aged rapidly and became stiffer.

One of the established drivers of endothelial aging is oxidative stress, caused by excess production of free radicals in the body.⁶ Beer and his team speculated that PAA and PAGln could modulate this process to induce vascular senescence. They treated human endothelial cells with PAA and a fluorescent detector of free radicals and observed higher levels of oxidative molecules compared to untreated cells.

“What remains to be explored is how to potentially suppress these detrimental metabolites and see whether the reduction impacts clinical outcome,” said Arash Haghikia, a cardiologist at Ruhr University Bochum, who was not involved in the study.

Despite the substantial ill-effects of a single species, there are numerous other bacteria that produce beneficial short-chain fatty acids that could counteract vascular senescence. One such metabolite is acetate, which the researchers found in low levels in aged mice. Treating young, Clostridium-colonized mice with acetate restored the function of aged endothelial cells in the animals.

Haghikia noted that translating these findings to the clinic is still ways away, but Beer suggested there may still be valuable overarching lessons to consider. Diets rich in processed red meat and lower vegetable content are strongly associated with higher levels of plasma PAGln, while those rich in dietary fiber stimulate production of short-chain fatty acids.⁷ “It currently boils down to the right nutrition,” said Beer.

Bhatt is excited for what this could mean for early diagnoses of diseases and treatment. “Maybe down the road, in addition to having blood tests that measure things like cholesterol, we will have fecal metabolite tests that measure a handful of important molecules, and treatments that try to modulate their levels.”