Scientists reveal that consuming over 22% of dietary calories from protein can lead to an increased risk of atherosclerosis — the plaque or buildup of fats, cholesterol and other substances on artery walls — by activating immune cells involved in the process. Recent clinical studies suggest that the amino acid leucine plays a crucial role in driving the formation of arterial plaque, which causes the majority of heart attacks and strokes.

This adverse effect of high protein on heart health is driven by the activation of a signaling pathway (mTORC1) that has been implicated in heart disease development. The researchers conclude that leucine is a key activator of this pathway.

“Leucine is one of the three branched-chain amino acids (BCAA) — leucine, isoleucine and valine. There are 20 amino acids that are building blocks of all proteins, including those we ingest in food,” senior author Babak Razani, MD, Ph.D., professor of cardiology at the University of Pittsburgh School of Medicine, tells Nutrition Insight.

“Ten of the amino acids, including the three BCAAs, are considered ‘essential,’ which means they need to be obtained through the diet and are not synthesized in our body,” he explains.

“Even though many amino acids increase in the bloodstream after protein ingestion, it is predominantly leucine that activates mTORC1 and the deleterious signaling pathways in macrophages, the immune cells which are the key driver of atherosclerosis (or cardiovascular disease).”

Although high-protein diets are often promoted as part of a healthy lifestyle, the researchers recommend considering high protein intake cautiously. However, experts underscore that more studies are needed to verify the results in humans over a more extended period.

Immune cell mechanism
For the study, published in nclick="updateothersitehits('Articlepage','External','OtherSitelink','Rethinking protein: New insights into dietary intake and heart disease risk','Rethinking protein: New insights into dietary intake and heart disease risk','339381','https://www.nature.com/articles/s42255-024-00984-2', 'article','Rethinking protein: New insights into dietary intake and heart disease risk');return no_reload();">Nature metabolism, the team performed experiments on cells, mice and humans. The researchers determined the timeline of immune cell activation after ingesting protein-enriched meals in humans and simulated similar conditions in mice and macrophages.

The study authors compared the effects of liquid meals with either 10% or 50% of energy as protein on the mTORC1 activation in human participants. A second study evaluated these outcomes in participants who consumed either a standard-protein mixed meal or a mixed meal with modestly increased protein content — 15% versus 22% of calories.

The researchers assessed participants’ plasma amino acid concentrations and mTORC1 signaling one to three hours after meal intake.

The team determined the threshold concentration wher leucine promotes adverse mTORC1 signaling at between 100 μM and 300 μM concentration in the blood. They found this concentration after the high protein meal (22% of energy as protein or 25 g) and very high protein meal (50% of energy).

The research team next confirmed protein intake over this threshold drives atherosclerosis in mice with a genetic abnormality that makes them susceptible to the disease. The authors designed diets with graded protein contents to represent the mouse equivalent of average and high protein intakes in the US population.

“Our study shows that dialing up your protein intake for better metabolic health is not a panacea. You could be doing real damage to your arteries,” says Rabak.

“We hope that this research starts a conversation about ways of modifying diets in a precise manner that can influence body function at a molecular level and dampen disease risks.”

“Essential” amino acids
Research released last year suggested that reducing the intake of the nclick="updateothersitehits('Articlepage','External','OtherSitelink','Rethinking protein: New insights into dietary intake and heart disease risk','Rethinking protein: New insights into dietary intake and heart disease risk','339381','https://www.nutritioninsight.com/news/scientists-suggest-restricting-essential-amino-acid-may-be-key-to-extending-lifespan.html', 'article','Rethinking protein: New insights into dietary intake and heart disease risk');return no_reload();">essential amino acid isoleucine — an isomer of leucine — extended the lifespan of mice by 33% for males and 7% for females. The adapted diet made the mice leaner and less frail as they aged and reduced cancer and prostate problems.

Babak comments that in the current study, isoleucine rose to even higher levels than leucine after the human subjects ate a protein-enriched smoothie or meal. However, only leucine was the bad actor.

“The data about isoleucine and its restriction is very interesting. The gist of that data was about protein restriction (particularly isoleucine restriction) in metabolic health and lifespan and did not assess atherosclerosis or cardiovascular disease,” he explains.

“So you have a situation wher one BCAA (isoleucine and not leucine) might cause harm in certain aspects of metabolic disease while another BCAA (leucine and not isoleucine) is problematic in cardiovascular disease.”

“The profound insight here that might not be fully appreciated yet is that not all amino acids, and more precisely, not all branched-chain amino acids, are created equal. They have their unique positives and negatives in our body.”

Additional research needed
At the same time, the study authors and other experts note that more research is needed to study the effects of high-protein diets and leucine intake on humans. Additional clinical trials are crucial to evaluate the impact of different amounts and types of proteins on the identified signaling pathways to ensure correct dietary guidelines on protein intake.

“There are gaps in our knowledge which presents an exciting frontier in nutritional sciences, a sort of precision nutrition renaissance,” stresses Babak. “By understanding the mechanisms of how specific nutrients affect our cells and organs, we can advise on what foods and what composition to take to mitigate disease risk.”

Dr. Duane Mellor, registered dietitian and senior lecturer at Aston University, UK, also calls for careful interpretation of data combining research data from different approaches.

“This study only shows changes in plasma levels and macrophage pathway activation after a single meal in humans. So, the effect of even a day’s food intake in humans is unknown from this study. Although mice are used as a model for human heart disease, they have subtle differences in their normal diet intake and metabolism.”

He also highlights that the study does not show the effects of foods as humans consume them. The protein meals or shakes used are very different from what would be considered a “healthy meal containing protein from meat or fish along with pulses, nuts and seeds as well as cereals like wholegrain bread and pasta.”

Animal vs. plant protein
The researchers also refer to studies indicating that high protein intake from plant sources may not cause adverse health outcomes.

For example, earlier this year, a study revealed that women who consume higher rates of nclick="updateothersitehits('Articlepage','External','OtherSitelink','Rethinking protein: New insights into dietary intake and heart disease risk','Rethinking protein: New insights into dietary intake and heart disease risk','339381','https://www.nutritioninsight.com/news/higher-plant-based-protein-intake-linked-to-healthier-aging-in-women-study-suggests.html', 'article','Rethinking protein: New insights into dietary intake and heart disease risk');return no_reload();">plant-based protein develop fewer chronic diseases and are more likely to be healthier overall as they age.

Tom Sanders, professor emeritus of nutrition and dietetics at King’s College London, UK, comments that high intakes of plant protein and fat do not promote atherogenesis.

“Various amino acids such as methionine and BCAAs (including leucine and isoleucine), which are more abundant animal proteins, have been prime suspects. Leucine concentrations are notably high in whey protein, which is well known to promote muscle growth in pigs.”