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
Antioxidant compound from soybeans may prevent marijuana-induced blood vessel damage
July 30, 2019
Science Daily/American Heart Association
Marijuana exposure damages cells of the inner lining of blood vessels throughout the heart and vascular system. In studies with human cells and arteries from mice, a compound found in soybeans blocked the damage and may have potential in preventing cardiovascular side effects of marijuana use.
In laboratory tests, a compound found in soybeans blocked damage to the lining of blood vessels in the heart and circulatory system and may someday provide a way to prevent the cardiovascular side effects of recreational and medical marijuana use, according to preliminary research presented at the American Heart Association's Basic Cardiovascular Sciences 2019 Scientific Sessions.
Marijuana is the most widely used illicit drug worldwide and is increasingly being made legal for recreational and medicinal purposes. However, there have been studies that link marijuana smoking to an increased risk of heart attack and stroke.
There can also be cardiovascular side effects, including changes in heart rate and blood pressure, when people take FDA-approved medications containing a synthetic version of delta-9-tetrahydrocannabinol (THC) -- the main compound in marijuana that gives the sensation of being high.
"These medications are prescribed to reduce the nausea and vomiting induced by chemotherapy and to increase appetite in certain people with acquired immune deficiency syndrome," said Tzu-Tan "Thomas" Wei, Ph.D., the study's lead author and assistant professor of pharmacology in the College of Medicine at National Taiwan University in Taipei City. "The goal of our studies is to investigate the mechanisms of marijuana-induced damage and discover new drugs to prevent those side effects."
The effects of THC occur after it binds to one of two cannabinoid receptors (CB1 and CB2) that are found throughout the brain and body and are also acted on by naturally occurring cannabinoids.
In the current study, the researchers used endothelial cells (like those that line blood vessels) derived from the stem cells of five healthy people. Exposing the cells to THC, they found that:
THC exposure induced inflammation and oxidative stress, which are known to affect the inner linings of blood vessels and are associated with the development of heart disease.
Lab techniques that block access to the CB1 receptor by THC eliminated the effects of THC exposure on endothelial cells.
Treatment with JW-1, an antioxidant compound found in soybeans, eliminated the effects of THC exposure.
In addition, the researchers used a laboratory technique called wire myography to examine the response of mouse arteries to THC, finding that JW-1 blocked THC's negative effects on the function of the inner lining.
An earlier attempt to gain health benefits from blocking the CB1 receptor proved problematic.
"Previously, a drug that blocked CB1 was approved in Europe for the treatment of obesity, but it had to be withdrawn because of severe psychiatric side effects," Wei said. "In contrast, as an antioxidant, JW-1 may have neuroprotective effects. Discovering a new way to protect blood vessels without psychiatric side effects would be clinically important with the rapid growth of cannabis use worldwide."
The researchers are currently extending their research by testing cells derived from regular marijuana users and those who smoke both cigarettes and marijuana. In addition, they are looking at the impact of THC along with the other main component of marijuana, cannabidiol.
"Meanwhile, if you have heart disease, talk to your doctor before you use marijuana or one of the synthetic THC-containing medications," Wei said. "Marijuana may cause more severe effects on the cardiovascular system in those with pre-existing heart disease."
https://www.sciencedaily.com/releases/2019/07/190730182430.htm
More than just jaundice: Mouse study shows bilirubin may protect the brain
Researchers have found bilirubin plays a unique role in protecting the brain
August 12, 2019
Science Daily/Johns Hopkins Medicine
In studies in mice, Johns Hopkins Medicine researchers report they have found that bilirubin, a bile pigment most commonly known for yellowing the skin of people with jaundice, may play an unexpected role in protecting brain cells from damage from oxidative stress.
Bilirubin is commonly measured in lab tests as a marker for liver or blood health, and high levels may indicate disease. However, whether it has a role in healthy people has remained unclear.
The Johns Hopkins Medicine team says its interest in the compound's function in the brain arose from testing which tissues in the mouse body produced bilirubin. Surprisingly, the researchers found "exceptional levels" of the stuff in mouse brains -- five to 10 times higher production than in rodents' livers.
"Bilirubin is normally considered a waste product, but this level of production takes a lot of metabolic energy, and it seemed bizarre for bilirubin to not have a function," says Bindu Paul, Ph.D., faculty research instructor at the Johns Hopkins University School of Medicine's Solomon H. Snyder Department of Neuroscience, and a member of the research team.
The new study, described in a report published July 25 in Cell Chemical Biology, set out to find the purpose for harboring so much bilirubin in the brain. The team noted that past studies proposed that bilirubin might be an important antioxidant. Since the brain is so metabolically active and vulnerable to oxidative damage, the research group considered the possibility that bilirubin might be particularly important to protecting the brain against oxidative stress.
For their experiments, the team used mouse neurons grown in the laboratory that were genetically engineered to not produce bilirubin. As the cells grew, the researchers exposed them to various sources of oxidative stress by introducing reactive molecules to their environment.
When compared with normal mouse brain cells, the researchers found that the genetically modified mouse neurons were far more vulnerable to these stressors -- particularly at the hand of a harmful form of oxygen called superoxide.
Chirag Vasavda, an M.D./Ph.D. student in Solomon Snyder's laboratory and first author on the study, notes that superoxide is an important chemical cell messenger linked to learning, memory and development in the brain.
However, excessive brain cell activity can lead to uncontrolled superoxide levels, which can trigger oxidative stress and initiate a series of harmful reactions that cause damage to the brain. "Our initial experiments hinted to us that bilirubin might play an important role in controlling the levels of superoxide in the brain," says Vasavda.
The research team suspected that bilirubin's ability to regulate superoxide originated in its chemical structure, which allows it to grab on to and neutralize the harmful molecule in a way that other antioxidants, such as glutathione and cysteine, cannot.
To test this, the researchers stimulated excessive brain cell activity in normal brains and brains engineered to lack bilirubin. They found that brains lacking the bilirubin-production gene accumulated excessive superoxide. Then they stimulated brain activity in normal mice and mice lacking bilirubin to test whether removing bilirubin worsens brain damage or cell death.
The researchers found that mice that lacked bilirubin had about two to three times more brain damage as their normal counterparts, suggesting that bilirubin protected normal brains against harmful superoxide reactions.
This discovery, the investigators say, advances scientific understanding of bilirubin's role in the brain and elsewhere and could lead to novel treatments for neurodegenerative diseases such as Huntington's and Parkinson's that are marked by excessive superoxide levels and oxidative stress.
https://www.sciencedaily.com/releases/2019/08/190812094502.htm