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High-Protein Diet Could Drive Heart Disease

High-protein foods.
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When I get home from my morning gym session, the first thing I reach for is my protein shaker – determined to get ahead of my recovery before I do it all over again tomorrow. According to a survey of the average American diet, I’m not alone in this cycle. Nearly 25% of the American population receive over 22% of all daily calories from protein alone, mostly from animal sources. But what if this ritual isn’t the best thing for our bodies?


A new study published in Nature Metabolism investigated the potentially adverse effects of a high protein diet, which is often promoted as a “healthy lifestyle”.

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Protein is an essential macronutrient

While protein is a vital nutrient for human health, many people in Western societies consume around more protein than the recommended daily allowance on average. Driven by the idea that a high-protein diet is the key to unlocking greater health, we might overlook the potential dangers this could cause, said Dr. Babak Razani, professor of cardiology at the University of Pittsburgh School of Medicine, and corresponding author: “You can read a lot of things on the internet and not only is much of it untrue, it is not based on clinical evidence or efficacy.”


Razani and team previously discovered that excess dietary protein increases the risk of atherosclerosis in mice. The researchers partnered with Dr. Bettina Mittendorfer a metabolism expert at the University of Missouri, Columbia, to further investigate the potential mechanism behind this association, and its relevance in humans.

High-protein diets trigger immune cell activation

The researchers employed a combination of cell, animal and small human studies to explore the pathway underlying the link between a high-protein diet and atherosclerosis shown in mice. Using their previous results, Razani and team investigated the effects of varying protein intake in humans, by comparing the effects of liquid meals, which contained either 10% or 50% of energy as protein, on monocyte mTORC1 activation. They also compared the same outcomes in participants who consumed either a standard-protein mixed meal or a mixed meal with modestly increased protein content (15% kcal versus 22% kcal). Blood samples were collected before and onehour and twohours after consuming the meals to assess plasma amino acid concentrations and monocyte mTORC1 signalling.


The team demonstrated that consuming more than 22% of daily dietary calories through protein negatively impacts human macrophages, which leads to the accumulation of cellular debris inside vessel walls, resulting in the worsening of atherosclerotic plaques.


“When one eats higher amounts of protein, it leads to activation of their macrophages, an immune cell that is a key driver of atherosclerosis, and we identified an important protein in the macrophages called mTOR that mediates this process,” said Razani.


To determine which of the seven amino acids contributed to mTORC1 signalling in monocytes/macrophages, the researchers used cultured human monocyte-derived macrophages (HMDMs) to study the macrophage-specific mTORC1 response to each amino acid. These results were also confirmed in mice.


“We then discovered that only leucine – an amino acid highly enriched in animal-based proteins – is the main activator of the mTOR pathway in macrophages and in turn atherosclerosis risk. Amino acids are the building blocks of proteins, and there are 20 of them that make up any protein we ingest. But it is only leucine that is the bad actor in worsening the heart artery disease,” Razani said.


“We hope that this study starts a conversation about the false notion that dialing up dietary protein consumption is a panacea for improving all aspects of metabolic health. It is much more complex than that,” added Razani.

Finding the protein “sweet spot”

The data also suggest that differences in leucine levels between plant-based and animal diets may explain the differences in their effect on cardiovascular and metabolic health. “We are working on follow-up studies to determine whether consuming mostly plant-based protein (which can lead to lower leucine elevations than animal-based protein) can diminish the risk of cardiovascular disease,” Razani said. “There is a lot of talk about the benefits of plant- vs animal-based proteins and my group has the opportunity to study it mechanistically and with a level of detail that is rarely done.”


Razani outlined several additional questions that need to be addressed in this line of research. First, what happens when someone consumes between the recommended 15% of daily dietary protein to 22% of their daily calories? Could there be a potential number that allows for muscle growth while still avoiding the immune cell cascade that increases atherosclerosis risk?


Further studies are needed to investigate the effects of varying amounts and types of dietary proteins that lead to the increased risk of atherosclerosis, and how these may evolve the current dietary guidelines concerning protein intake.


“We hope that this study raises awareness that increasing dietary protein consumption is not a cure-all for your metabolic health but may put you at a higher risk of heart disease,” said Razani.


Dr. Babak Razani was speaking to Rhianna-lily Smith, Junior Science Editor for Technology Networks.


Reference: Zhang et al. Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk. Nature Metabolism. 2024. doi: 10.1038/s4 2255-024-00984-2