Chronic inflammation and oxidative stress disrupt the function of smooth muscle cells in blood vessel walls. This is one of the contributing causes of vascular stiffness with age, alongside cross-links, calcification, and loss of elastin, all of which alter the structural properties of blood vessel tissue to produce a reduction in elasticity. There is the question of the relative importance of these contributions, a question that exists for most aspects of aging at the present time, lacking easy ways to remove only one contributing factor to assess the outcome. Nonetheless, the research results noted here suggest that smooth muscle dysfunction is the most important factor in vascular stiffness, and that - in mice, at least - changes in gut bacteria populations are the cause of this issue. This might make us more optimistic about the prospects for near term therapies in humans.
Stiffening of blood vessels is important because it results in hypertension; the feedback mechanisms controlling blood pressure are disrupted by this type of damage and dysfunction. That in turn produces tissue damage throughout the body due to rupture of capillaries and other pressure-related issues. Hypertension also accelerates the progression of atherosclerosis, and makes it more likely for fatal structural failures in large blood vessels to occur in the later stages of that condition.
Why do blood vessels naturally stiffen and degrade as we age, boosting cardiovascular disease risk? Researchers gave young mice and old mice broad-spectrum antibiotics to kill off the majority of bacteria living in their gut, aka their gut microbiome. Then they assessed the health of their vascular endothelium (the inner lining of their blood vessels) and the stiffness of their large arteries. They also measured blood levels of inflammatory compounds, tissue-damaging free-radicals, antioxidants, and the blood-vessel-expanding compound nitric oxide in both groups. After three to four weeks of the treatment, the young mice saw no change in vascular health. The old mice, however, saw vast improvements on all measures. "When you suppressed the microbiome of the old mice, their vascular health was restored to that of young mice. This suggests there is something about those microorganisms that is causing vascular dysfunction."
To assess what that something may be, the researchers then took fecal samples from another set of mice and had them genetically sequenced, comparing the gut bacteria living in the old mice with that in the young. In the old mice, the researchers saw an increased prevalence of microbes that are pro-inflammatory and have been previously associated with diseases. For instance, the old mice hosted significantly more Proteobacteria, a phyla that includes Salmonella and other pathogens, and pro-inflammatory Desulfovibrio. To drill down further, the researchers measured blood levels of metabolites - small molecules produced by the gut microorganisms and absorbed into the bloodstream - in old and young mice. Old mice had three times as much TMAO (trimethylamine N-oxide), a metabolite shown in previous studies to be linked to increased risk of atherosclerosis, heart attack, and stroke.
"We have long known that oxidative stress and inflammation are involved in making arteries unhealthy over time, but we didn't know why arteries begin to get inflamed and stressed. Something is triggering this. We now suspect that, with age, the gut microbiota begins producing toxic molecules, including TMAO, which get into the blood stream, cause inflammation and oxidative stress and damage tissue." The researchers recently launched a human trial to explore how different diets impact the gut and, in turn, cardiovascular disease risk. They are also studying a compound called dimethyl butanol, which blocks the bacterial enzyme required to produce TMAO. Ultimately, it could be developed into a dietary supplement.