Why do arteries age? Study explores link to gut bacteria, diet

July 1, 2020

Science Daily/University of Colorado at Boulder

Eat a slab of steak and your resident gut bacteria get to work immediately to break it down. But new research shows that a metabolic byproduct, called TMAO, produced in the process can be harmful to the lining of arteries, making them age faster.

A compound produced in the gut when we eat red meat damages our arteries and may play a key role in boosting risk of heart disease as we get older, according to new University of Colorado Boulder research.

The study, published this month in the American Heart Association journal Hypertension, also suggests that people may be able to prevent or even reverse such age-related decline via dietary changes and targeted therapies, like novel nutritional supplements.

"Our work shows for the first time that not only is this compound directly impairing artery function, it may also help explain the damage to the cardiovascular system that naturally occurs with age," said first author Vienna Brunt, a postdoctoral researcher in the Department of Integrative Physiology.

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.

Drawing on animal and human experiments, Brunt and her team set out to answer three questions: Does TMAO somehow damage our vascular system? If so, how? And could it be one reason why cardiovascular health gets worse -- even among people who exercise and don't smoke -- as we get older?

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.

"Just putting it in their diet made them look like old mice," said Brunt. She noted that 12-month-old mice (the equivalent of humans about 35 years old) looked more like 27-month-old mice (age 80 in people) after eating TMAO for several months.

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.

Brunt notes that everyone -- even a young vegan -- produces some TMAO. But over time, eating a lot of animal products may take a toll.

"The more red meat you eat, the more you are feeding those bacteria that produce it," she said.

Senior author Doug Seals, director of the Integrative Physiology of Aging Laboratory, said the study is an important breakthrough because it sheds light on why our arteries erode with age, even in the healthiest people.

"Aging is the single greatest risk factor for cardiovascular disease, primarily as a result of oxidative stress to our arteries," said Seals. "But what causes oxidative stress to develop in our arteries as we age? That has been the big unkown. This study identifies what could be a very important driver."

The research team is now further exploring compounds that might block production of TMAO to prevent age-related vascular decline.

For now, they said, a plant-based diet may also keep levels in check.

https://www.sciencedaily.com/releases/2020/07/200701100019.htm

Study links frequent red meat consumption to high levels of chemical associated with heart disease

Findings reveal tripling of blood levels of TMAO from red meat diet, but dietary effects can be reversed

December 11, 2018

Science Daily/NIH/National Heart, Lung and Blood Institute

Researchers have identified another reason to limit red meat consumption: high levels of a gut-generated chemical called trimethylamine N-oxide (TMAO), that also is linked to heart disease. Scientists found that people who eat a diet rich in red meat have triple the TMAO levels of those who eat a diet rich in either white meat or mostly plant-based proteins, but discontinuation of red meat eventually lowers those TMAO levels.

TMAO is a dietary byproduct that is formed by gut bacteria during digestion and is derived in part from nutrients that are abundant in red meat. While high saturated fat levels in red meat have long been known to contribute to heart disease -- the leading cause of death in the United States -- a growing number of studies have identified TMAO as another culprit. Until now, researchers knew little about how typical dietary patterns influence TMAO production or elimination.

The findings suggest that measuring and targeting TMAO levels -- something doctors can do with a simple blood test -- may be a promising new strategy for individualizing diets and helping to prevent heart disease. The study was funded largely by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health. It will be published Dec. 10 in the European Heart Journal, a publication of the European Society of Cardiology.

"These findings reinforce current dietary recommendations that encourage all ages to follow a heart-healthy eating plan that limits red meat," said Charlotte Pratt, Ph.D., the NHLBI project officer for the study and a nutrition researcher and Deputy Chief of the Clinical Applications & Prevention Branch, Division of Cardiovascular Sciences, NHLBI. "This means eating a variety of foods, including more vegetables, fruits, whole grains, low-fat dairy foods, and plant-based protein sources such as beans and peas."

"This study shows for the first time what a dramatic effect changing your diet has on levels of TMAO, which is increasingly linked to heart disease," said Stanley L. Hazen, M.D., Ph.D., senior author of the study and section head of Preventive Cardiology & Rehabilitation at the Cleveland Clinic. "It suggests that you can lower your heart disease risk by lowering TMAO."

Hazen estimated that as many as a quarter of middle-aged Americans have naturally elevated TMAO levels, which are made worse by chronic red meat consumption. However, every person's TMAO profile appears to be different, so tracking this chemical marker, Hazen suggested, could be an important step in using personalized medicine to fight heart disease.

For the study, researchers enrolled 113 healthy men and women in a clinical trial to examine the effects of dietary protein -- in the form of red meat, white meat, or non-meat sources -- on TMAO production. All subjects were placed on each diet for a month in random order. When on the red meat diet, the participants consumed roughly the equivalent of about 8 ounces of steak daily, or two quarter-pound beef patties. After one month, researchers found that, on average, blood levels of TMAO in these participants tripled, compared to when they were on the diets high in either white meat or non-meat protein sources.

While all diets contained equal amounts of calories, half of the participants were also placed on high-fat versions of the three diets, and the researchers observed similar results. Thus, the effects of the protein source on TMAO levels were independent of dietary fat intake.

Importantly, the researchers discovered that the TMAO increases were reversible. When the subjects discontinued their red meat diet and moved to either a white meat or non-meat diet for another month, their TMAO levels decreased significantly.

The exact mechanisms by which TMAO affects heart disease is complex. Prior research has shown TMAO enhances cholesterol deposits into cells of the artery wall. Studies by the researchers also suggest that the chemical interacts with platelets -- blood cells that are responsible for normal clotting responses -- in a way that increases the risk for clot-related events such as heart attack and stroke.

TMAO measurement is currently available as a quick, simple blood test first developed by Hazen's laboratory. In recent published studies, he and his colleagues reported development of a new class of drugs that are capable of lowering TMAO levels in the blood and reducing atherosclerosis and clotting risks in animal models, but those drugs are still experimental and not yet available to the public.

https://www.sciencedaily.com/releases/2018/12/181211084948.htm