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The Aging Gut Microbiome Produces More Trimethylamine, Harming Arterial Function


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Posted 08 July 2020 - 08:22 PM


In recent years academic interest has grown in the study of the gut microbiome. Researchers are making inroads into understanding the considerable influence of these microbial populations over the progression of health and aging. The gut microbiome may be as influential as physical activity in these matters. The balance of microbial populations shifts unfavorably over time, for reasons that are yet to be fully mapped and understood. This leads to greater numbers of inflammatory microbes, or those that produce harmful byproducts, and fewer microbes that produce beneficial metabolites. Researchers have identified some of the more important beneficial metabolites that decline with age, such as indoles, butyrate, and propionate. In the research materials I'll point out today, the authors note a harmful metabolite, trimethylamine, that is produced in greater amounts in older individuals.

What to do about these issues? It is possible in principle to supplement missing metabolites, as they are identified. Removal of harmful metabolites is more challenging as a general rule, for all that it seems plausible in the specific case of trimelthylamine. A better approach to the problem is to fix the age-related disruption of the microbiome. Various options exist: fecal microbiota transplants, for example, are already used in human medicine, and transplanting young microbes into old individuals has been shown to be beneficial in animal studies, a method to reset the balance of microbial populations. Equally, less comprehensive methods such as innoculation against flagellin, to rouse the immune system into destroying more of the harmful microbes present in the gut, are also possible. It is also the case that very aggressive use of probiotics might work, though not yet all that well explored at the high doses likely required.

What makes arteries age? Study explores new link to gut bacteria, diet

Eat a slab of steak or a plate of scrambled eggs, and your resident gut bacteria get to work immediately to break it down. As they metabolize the amino acids L-carnitine and choline, they churn out a metabolic byproduct called trimethylamine, which the liver converts to trimethylamine-N-Oxide (TMAO) and sends coursing through your bloodstream. Previous studies have shown that people with higher blood levels of TMAO are more than twice as likely to have a heart attack or stroke and tend to die earlier. But to date, scientists haven't completely understood why.

The researchers measured the blood and arterial health of 101 older adults and 22 young adults and found that TMAO levels significantly rise with age. (This falls in line with a previous study in mice, showing the gut microbiome - or your collection of intestinal bacteria - changes with age, breeding more bacteria that help produce TMAO). Adults with higher blood levels of TMAO had significantly worse artery function, the new study found, and showed greater signs of oxidative stress, or tissue damage, in the lining of their blood vessels. When the researchers fed TMAO directly to young mice, their blood vessels swiftly aged.

Preliminary data also show that mice with higher levels of TMAO exhibit decreases in learning and memory, suggesting the compound could also play a role in age-related cognitive decline. On the flip side, old mice that ate a compound called dimethyl butanol (found in trace amounts in olive oil, vinegar and red wine) saw their vascular dysfunction reverse. Scientists believe that this compound prevents the production of TMAO. Everyone - even a young vegan - produces some TMAO. But over time, eating a lot of animal products may take a toll.

Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans

Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. In healthy humans, plasma trimethylamine-N-oxide was higher in middle-aged/older (64±7 years) versus young (22±2 years) adults (6.5±0.7 versus 1.6±0.2 µmol/L) and inversely related to brachial artery flow-mediated dilation.

In young mice, 6 months of dietary supplementation with trimethylamine-N-oxide induced an aging-like impairment in carotid artery endothelium-dependent dilation to acetylcholine versus control feeding (peak dilation: 79±3% versus 95±3%). This impairment was accompanied by increased vascular nitrotyrosine, a marker of oxidative stress. Trimethylamine-N-oxide supplementation also reduced activation of endothelial nitric oxide synthase and impaired nitric oxide-mediated dilation. Acute incubation of carotid arteries with trimethylamine-N-oxide recapitulated these events.

Next, treatment with 3,3-dimethyl-1-butanol for 8 to 10 weeks to suppress trimethylamine-N-oxide selectively improved endothelium-dependent dilation in old mice to young levels (peak: 90±2%) by normalizing vascular superoxide production, restoring nitric oxide-mediated dilation, and ameliorating superoxide-related suppression of endothelium-dependent dilation.

Lastly, among healthy middle-aged/older adults, higher plasma trimethylamine-N-oxide was associated with greater nitrotyrosine abundance in biopsied endothelial cells, and infusion of the antioxidant ascorbic acid restored flow-mediated dilation to young levels, indicating tonic oxidative stress-related suppression of endothelial function with higher circulating trimethylamine-N-oxide.


View the full article at FightAging




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