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How much protein do you eat daily? At first glance, this question may seem straightforward considering protein's outsized influence on our contemporary lifestyles — from foodies throwing back plates of juicy fried chicken, fitness enthusiasts chugging whey shakes for gains, and carnivore diet followers chomping on red meat.
But as it turns out, we’re consuming far more than is recommended. About 75 percent of Americans “meet or exceed the recommendation for meats, poultry, and eggs,” according to a 2020 report by the U.S. Department of Agriculture and the Department of Health and Human Services.
Indulging in a wee bit more protein can spell disaster for our cardiovascular health, particularly in abetting debilitating diseases like atherosclerosis, as a variety of animal-based studies to date have found. However, the exact biological mechanism connecting atherosclerosis — where sticky plaques, or fatty deposits, accumulate in and damage the arteries — with extra proteins from dietary meat wasn’t well understood.
In a study published in 2024 in the journal Nature, researchers used mice to identify a potential culprit: an essential amino acid called leucine. Researchers led by the University of Pittsburgh Medical Center and Washington University School of Medicine in St. Louis found leucine turns on a biochemical pathway in mice called the mechanistic target of rapamycin (or mTOR) in immune cells called macrophages, which are involved in atherosclerosis. In male mice, this switch happened when there were 25 extra grams of dietary protein in a meal or when consuming 22 percent of all dietary needs from protein.
“It’s not considered new information that the macrophage is a big part of atherosclerosis,” Babak Razani, a cardiologist and professor of medicine at the University of Pittsburgh, who led the new study, tells Inverse. “What’s important is what are the mechanisms by which it starts wreaking havoc [in the arteries] and becoming part of the problem.”
Uncovering leucine’s role, he says, offers insight into how diet can be finely adjusted to optimize an individual’s health outcomes and enhance overall well-being with specific advice based on their biochemical makeup — part and parcel of the emerging science of personalized or precision nutrition.
The protein-heart connection
Atherosclerosis is a relatively common inflammatory condition, especially in Western countries where in the U.S., for instance, half of Americans over the age of 40 have plaques building up in their arteries and just don’t know it, according to the National Institutes of Health. Since atherosclerosis underlies other serious cardiovascular conditions and events like peripheral vascular disease, heart attack (about 75 percent occur when plaque-ridden arteries burst), and stroke, it’s also the major cause of death in the U.S. and the rest of the industrialized world.
When there’s a lot of cholesterol swimming around in the blood, these fat-like molecules combine to form waxy substances in the middle layer of a blood vessel, eventually catching the eye of the immune system. Macrophages, a type of white blood cell circulating through our blood vessels, try to remove this build-up by gobbling away at the plaque. But at some point, says Razani, these well-intentioned immune cells become part of the problem.
“Sometimes I give talks where I say the macrophage [becomes] a firefighter turned arsonist,” he explains. “It comes in there to save the day and starts doing bad things. The cells get overcome, and a lot of them start dying. When a cell dies, something else has to retrieve that cell. It turns out that another ‘firefighter’ has to come in there, another macrophage to eat the dead macrophage, and then it gets overcome. All you get is a big graveyard of cells, and that’s really part of the problem for atherosclerosis.”
In 2020, Razani, then at Washington University School of Medicine in St. Louis, and colleagues discovered that high-protein diets appeared to be involved with plaque formation, at least in mice. In that study, the researchers saw that when mice genetically prone to atherosclerosis were fed meals rich in protein and fat, they developed 30 percent more plaque in their tiny arteries than other mice on the high-fat but low-protein diet.
Examining mousy macrophages in Petri dishes, the pressure point appeared to be amino acids — the building blocks of protein. (Among mammals, there are 21 amino acids that form proteins, nine of those are essential, meaning they can only be obtained from the diet and not made by the body itself.) In macrophages, excessive amounts of amino acids were flipping on the mTOR pathway, which regulates a cell’s growth and survival in response to nutritional and environmental cues. In the case of atherosclerosis, this biochemical pathway was preventing macrophages from cleaning up the toxic dump of plaque, contributing to that unrelenting cellular graveyard.
Finding the tipping point
Razani and his colleagues had a few hunches as to which amino acids were diddling with the mTOR switch. Leucine and another essential amino acid called arginine were strong candidates since, in the 2020 study, they both were more potent in activating the biochemical pathway in macrophages than other amino acids.
To flush out their suspect, the researchers ran two experiments in healthy human volunteers to see which amino acids were elevated in the blood after eating a meal containing varying amounts, or “doses,” of protein. The first involved 14 participants consuming an animal protein-based smoothie (containing whey), one with a recommended amount of protein and the other with higher amounts, about one to two weeks apart. The second experiment had participants eating a meal of animal-based protein meant to mimic a real-world scenario.
“When [those meals] get absorbed, all types of amino acids flood the circulation, and we measured each of the 20 amino acids and looked at the levels — saw which ones were the highest, moderate, or low,” says Razani.
From nearly two dozen, the researchers whittled it down to seven amino acids and sprinkled them, in accordance with their dosage in the graded protein meals, on human-derived macrophages in a Petri dish. As it did during the 2020 study, one amino acid stood out yet again in activating mTOR: leucine.
Next, the researchers wanted to see if these results actually yielded atherosclerosis. In humans, it takes decades for the condition to develop, so not exactly timely enough (or ethical) to study. But in certain mouse models, it can take as little as two months when the animals are placed on a high-fat, high-protein diet.
Playing around with different amounts of protein, Razani and his colleagues saw that moderate levels of protein cause atherosclerosis while higher amounts cause more. There was no atherosclerosis if you subtracted out leucine, but feeding the mice leucine-only protein sources did it big time.
It seemed there was a certain threshold to how much leucine in dietary protein is required to activate the mTOR pathway. In mice, that tipping point came out to 25 extra grams of dietary protein in a meal or when consuming 22 percent of all dietary needs from protein.
More yet to uncover
While these findings offer insight into the potential health consequences of eating too much protein, Razani says this discovery is still preliminary and requires further research. For instance, the tipping point he and his colleagues uncovered shouldn’t be interpreted as a recommendation. Some individuals, based on their age, activity level, and past or current medical history, may have unique protein needs that may alter their risk of getting atherosclerosis.
“We know this [leucine to mTOR] pathway is in the long-term bad for you, but we haven’t shown what level of protein actually causes heart disease and heart attacks in people,” says Razani. “We shouldn’t take away from this conversation that eating protein is bad. Eating protein increases the risk of certain aspects of heart disease that we should be aware of, there’s no doubt about it.”
While plant-based proteins are often considered more heart-friendly and better for overall health, Razani says it would be worth putting plant- and animal-based proteins in a head-to-head comparison to see which fares better in atherosclerosis in terms of activating mTOR in macrophages. He says he hasn’t seen that type of study done yet.
For our own diets, Razani recommends moderation: You don’t have to give up that sizzling beefy steak completely, but less could be more. “As a cardiologist, I would recommend, on a day-in and day-out basis, the Mediterranean or USDA-recommended diet as the way to go until more of this research comes in,” says Razani.