February 19, 2024

expert reaction to study looking at high protein intakes and atherosclerosis, some data in mice and some in people

A study published in Nature Metabolism looks at high protein intake and atherosclerosis. 

Prof Robert Storey, Professor of Cardiology, University of Sheffield, said:

“This research provides evidence that a high-protein diet might trigger responses in the body that contribute to the risk of heart attack or stroke as a result of a particular component of protein that is present at higher quantities in animal protein compared with plant proteins.  The researchers performed studies on small groups of volunteers as well as using well-established mouse models of cardiovascular disease, producing convincing results that build on previous work.

“We know that the majority of heart attacks and strokes are caused by the build-up of fat in the blood vessels supplying the heart and brain.  Our white blood cells are a critical part of our immune system but often play a role in diseases, such as the disease that causes this build-up of fat known as atherosclerosis.  Consequently factors that stimulate the white blood cells and cause inflammation may contribute to heart attack risk, alongside other risk factors such as high cholesterol, high blood pressure, smoking and diabetes.

“The researchers show that one of the building blocks of proteins, known as leucine, increases in the bloodstream after a high-protein meal and can stimulate one of the types of white blood cell that is involved in furring of the arteries.  They also show that leucine is the component of protein that increases furring in the arteries when fed to mice.

“This work raises concern about the potential health effects of high-protein diets that are rich in leucine, particularly in people who have other risk factors for heart artery disease such as high cholesterol.  More research is required to replicate these results and look at the impact of leucine-rich foods on cardiovascular health.”

Prof Bryan Williams OBE, Chief Scientific and Medical Officer, the British Heart Foundation, said:

“Despite protein being an important part of our diet there is growing evidence that consuming too much could cause blockages in the walls of blood vessels, leading to heart and circulatory conditions.  This small study adds to this theory identifying Leucine, one of the building blocks of protein, as a substance that can damage the lining of blood vessels.

“Further studies over a longer period of time will help us better understand how protein affects our heart.  A healthy diet, which includes eating protein in moderation, is still one the most important things you can do for your heart health.  For advice on how to eat well visit BHF’s website.”

Dr Duane Mellor, Registered Dietitian and Senior Lecturer, Aston Medical School, Aston University, said:

“This is paper reports a combination of two human research trials, a study looking at white blood cells in the lab and a mouse study.

“Careful interpretation needs to be made when combining research data from different approaches, as one of the human studies involved drinking a single protein shake and the other human trial reported was only half the study (as it was registered) which was meant to investigate the difference between animal and plant protein; in this paper it only seemed to report the effects of animal protein.  Both of these would not be considered healthy meals – they are single milk shakes or meals made to be high in protein specifically for a clinical trial.  Only people who regularly consume protein shakes would consume anything like the ‘meals’ described in this study.  So, what was done here was very different to what would be considered to be a healthy meal containing protein from meat or fish along with pulses, nuts and seeds as well as cereals like wholegrain breads and pasta.

“Also as it is very difficult to do long term feeding studies in people, the researcher switched to mice to look at the effect of protein on arteries.  Again for the mouse studies, they were given a protein supplemented mouse feed, which means that it will not contain the structure or fibre that would normally be found in food.

“So, although this data is interesting, interpretation needs to be done carefully as this study only shows changes in plasma levels and pathway activation in macrophages after a single meal in humans.  So, the effect of even a day’s food intake is not known from this study in humans.  Although mice are used as a model for heart disease in humans, they have subtle differences in both their normal diet intake and metabolism so we need to be careful when using data from studies which gave mice a constant water supply supplemented with protein to predict what might happen in humans.

“Overall, this study shows some of the mechanisms of how proteins and amino acids can potentially increases risk of disease, perhaps stronger evidence for its effect on mice than humans.  However, it does not show the effects of foods as they are typically consumed by most people and their effects on amino acids in blood, let alone if amino acids were bad for human arteries – this paper only provides data on the effect of protein on mice arteries.”

Prof Tom Sanders, Professor emeritus of Nutrition and Dietetics, King’s College London, said:

“This is an interesting study because it focuses on a pathway (mTORQ) involved the promotion of cell proliferation.  There are many previous animal studies showing that the combination of high intakes of animal protein with high intakes of fat promote atherogenesis.  This promotional effect is not seen in high intakes of plant protein with high intakes of fat.  Various amino acids such as methionine and branched chain amino acids (including leucine and isoleucine) have been among prime suspects and these are more abundant animal proteins.  Leucine concentrations are notably high in whey protein, which is well known to promote muscle growth in pigs.

“This study focuses on the possible role of leucine in promoting atherosclerosis via activation by the mTORC signalling pathway in tissue monocytes/macrophages in a strain of mice that has a genetic lipoprotein abnormality that makes it susceptible to developing atherosclerosis.  Activated monocytes/macrophages are known to take up lipoproteins leading to plaque formation.

“The study then attempts to translate some of the biochemical findings to changes brought about by a high protein meal in healthy human participants.  They compared levels of leucine following a high protein/low carbohydrate meal with a meal low in protein/high in carbohydrate.

“They found that plasma leucine levels were elevated 3 hours following the high protein test meal.  They also found some evidence to indicate that isolated blood monocytes were activated after the meal.  The elevation in plasma leucine concentrations following meals was confirmed in two longer term studies where participants consumed high and low protein diets – the high protein diet had 22% energy from protein while the low protein diet had 15% energy from protein (the level of protein eaten in the UK is on average 15%).  The extra protein intake in the high protein group would be equivalent to an extra 35 grams of protein a day (equivalent to one extra medium chicken breast fillet 145g or 40 dried whey protein powder) more protein than the other group.

Limitations of the study

“Animal models of atherosclerosis differ markedly from human atherosclerosis which develops slowly over many decades.  The test meal studies were in a small number of subjects and they only monitored plasma leucine level up to 3 hours following the test meal.  It is well known that plasma amino acids return to baseline values after meal.

Interpretation

“Although observational studies have suggested an association between high intakes of animal protein (especially red and processed meat) and cardiovascular disease, a recent analysis of the Nurses Healthy Study (Am J Clin Nutr, 2024 vol. 119(2) pp. 271-282) found higher protein intakes (both of plant and animal origin) in midlife to be associated with greater longevity and healthy ageing in women.

Conclusion

“This was a proof of principle study that has identified a potential mechanism of relevance to the development of atherosclerosis.  High protein diets are currently fashionable.  It is important, therefore, that further research is done on proteins that are rich in leucine, such whey supplements, to ascertain if they do have adverse effects on cardiovascular health.”

Prof D Joe Millward, Emeritus Professor of Human Nutrition, University of Surrey, said:

“This work relates to how dietary protein controls important cellular processes, which at recommended dietary intakes can be beneficial, e.g. for muscle and bone health, but which we know from previous research can at very high intakes (as might be consumed by some groups) also be damaging for tissues such as the arterial wall resulting in atherosclerosis.  It follows previous work in mice by this group in which they uncovered the link between very high protein intakes and atherosclerotic plaque formation and plaque complexity, and the leucine driven activation of the main controller of cellular function, mTORC1, which became detrimental at high concentrations by increasing atherosclerosis.  The new paper extends that mouse work to human studies with blood immune cells isolated after feeding various protein intakes (from either commercial liquid food supplements, most likely based on milk proteins, or liquidized real foods (potatoes, beans, onions, carrots, corn, bacon, fats, broth and spices) and added animal protein isolates (egg, chicken, beef and whey)), showing these damaging effects occur at protein intakes greater than about 25g per meal (22% of dietary energy), and that in mice, atherosclerosis develops at these intakes.

“The role of leucine in activating mTORC1 is not new, having been shown in other tissues such as muscle after a protein meal, with beneficial effects on muscle protein synthesis.  This has encouraged high protein intakes in athletes and for some to recommend increased protein intakes for the elderly although there is little evidence of any benefit from increased intakes in either case.  Also high protein diets can help with weight loss by reducing appetite.  This work implies that in such groups there is a potential risk of damage to the arteries and atherosclerosis, although it is a complicated issue.

“Firstly the epidemiology of dietary protein intakes and health and disease shows some evidence supporting animal data for an adverse link with cardiovascular disease and mortality although the strongest evidence is for a beneficial protective effect of plant protein intakes.  Whether this is because of lower leucine in plant proteins as the authors suggest or more likely the better provision of protective micronutrients by plant based diets is not known.

“Secondly high protein diets during weight-loss are less likely to induce atherosclerosis because a negative energy balance reduces CVD risk factors and can improve insulin resistance.

“Thirdly there are adaptive mechanisms in humans which increase the capacity for rapid disposal of amino acids after a meal in subjects on habitual high protein intakes, so that the increases in leucine concentrations observed here in the human monocytes may be less marked and less damaging after such adaptation.

“Overall this new paper is a very important contribution to the dietary protein debate, especially given the well known environmental cost of the production of animal source proteins and the need to reduce their excessive consumption in the developed nations.”

‘Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk’ by Xiangyu Zhang et al. was published in Nature Metabolism at 16:00 UK time on Monday 19 February 2024.

DOI: 10.1038/s42255-024-00984-2

Declared interests

Prof Robert Storey: “No relevant disclosures.”

Prof Bryan Williams: “Nothing to declare.”

Dr Duane Mellor: “No conflicts of interest.”

Prof Tom Sanders: “Honorary Nutritional Director HEART UK (pro bono).”

Prof D Joe Millward: “I have no interest to declare.”