Protein Intake and Cardiovascular Health Study Spotlight Take-Away with Chef Dr. Mike

by Michael S. Fenster, MD

Diet, Health, and Contradiction

“But one truth does not displace another. Even apparently contradictory truths do not displace one another. Logic is far too coarse to make the subtle distinctions life demands.”
― D.H. Lawrence, Selected Essays

January 2024: According to a newly published study (Study One), an increased consumption of dietary protein (particularly plant protein) in midlife is associated with an increased likelihood of healthy aging, including a reduction in the risk of cardiovascular morbidity such as myocardial infarction, coronary artery bypass graft surgery (CABG), percutaneous transluminal coronary angioplasty (PCI), and congestive heart failure.[1]

February 2024: According to a newly published study (Study Two), a high-protein diet increases your risk of developing atherosclerosis (the putative mechanism of cardiovascular morbidity) through the effects of the amino acid leucine.[2]

What are we to do?

This contradiction and chaos that seems to follow dietary advice is what continues to erode public confidence and trust, a consequence that is not undeserved — the above example provides ammunition for whatever side of the debate you prefer. How do we reconcile these apparent polar extremes? Let us first examine each study on its merits and its flaws.

The Studies:

  • Study One:
    • An observational study including 48,762 female participants from the Nurses’ Health Study (NHS) cohort.
    • The endpoint of healthy aging was determined as being free from 11 chronic diseases, having good mental health, and being without impairment in cognitive or physical function.
    • A total of 3,721 or 7.6 percent of the cohort met the healthy aging definition.
    • Per the study, “Protein intake was significantly associated with higher odds of healthy aging.”
  • Study Two:
    • A combination of human and mouse in vivo and in vitro nutritional studies.
    • The study focused on the cellular pathway involving the mechanistic target of rapamycin complex 1 (the mTORC1 activation signaling pathway).
    • The mTORC1 pathway plays a crucial role in the regulation of cell growth, metabolism, protein synthesis, and autophagy in response to various environmental and nutritional signals. It also integrates signals from nutrients, growth factors, and cellular energy status to coordinate cellular responses and maintain cellular homeostasis.
    • The study demonstrated “mTORC1 signaling in peripheral blood monocytes was increased in humans consuming protein-enriched meals.”
    • The study also demonstrated that protein-enriched meals, which are high in the essential amino acid leucine, “promote the development of atherosclerotic cardiovascular disease (ASCVD).”

The Take-Aways:

  • Study One:
    • The Nurses’ Health Study is the familiar epidemiological observational study that is so commonly used as a basis for nutritional recommendations. However, it must be remembered that such studies, by their design, can only provide correlation, not causation.
    • Dietary assessment was done by food frequency questionnaires (FFQ) issued every four years from 1984 through 2016.
    • The “deattenuated correlations between protein intake assessed by diet records and FFQs in prior validation studies in the NHS were 0.53 and 0.64,” revealing only a moderate correlation at best (the closer to 1.0, the stronger and more reliable the correlation) between FFQs and actual protein intake.
    • The endpoint, healthy aging, required the absence of these 11 chronic conditions: cancer (except for nonmelanoma skin cancer), type 2 diabetes, myocardial infarction, coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty, congestive heart failure, stroke, kidney failure, chronic obstructive pulmonary disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis.
    • The study concluded that “Each 3%-energy increment of animal or dairy protein intake was associated with 7% and 14% higher odds of healthy aging, whereas the association for each 3%-energy increment of plant protein associated with 38% higher odds of healthy aging, respectively.”
    • The plant-based protein affects were “attenuated when adjusted for intakes of fruits and vegetables; thus, we [the study authors] cannot discount the contributions of other components of those foods that contributed to plant protein intake.”
  • Study Two:
    • A portion of the study protocol involved the use of animal models, the results of which are not always directly transferable or applicable to the human situation.
    • The study was designed to explore mechanistic links between high-protein intake and cardiovascular pathologies.
    • Specifically, the study sought “to evaluate whether high protein intake activates the amino acid–mTORC1–autophagy signaling pathway in people, similar to our [the study researchers’] observation in Apo E-/- mice.”
    • The researchers found that “there is a critical dose above which protein intake activates this deleterious signaling pathway and atherogenesis.”
    • The essential amino acid leucine was found to be the modulator of the response.
    • The results of their study suggest “high dietary protein intake, via increases in plasma leucine, induces dose-dependent activation of a signaling pathway in monocytes/macrophages that is involved in the pathogenesis of atherosclerosis.”

The Caveat:
These current studies represent a common conundrum in navigating current dietary research: conflicting and contrary results from research utilizing differing approaches. Clearly, one of the takeaway points is that the relationship between protein intake and cardiometabolic health is complex.

Protein rich diets are often associated with lower adiposity which, in turn, leads to a lower cardiometabolic risk. Yet, the current mechanistic study suggests a direct pathway involving protein consumption and elevated leucine levels, causing activation of the mTORC1 pathway and leading to an increased risk of cardiovascular morbidity. This implies that, much like the gut microbiome linked TMAO (Trimethylamine-N-oxide) pathway, there are non-lipid pathways and compounds (i.e., pathways not dependent on LDL cholesterol) that can substantially impact cardiovascular disease risk.

An important caveat to the data derived from the mechanistic human and mouse study – which would suggest that achieving a lower body weight through a high-protein diet introduces significant cardiovascular risk through alternative mechanisms – is that the animal model (a critical component of the study) utilized a specific type of genetically unique mice, specifically inbred to express increased vulnerability to developing ASCVD.

The commentary from Professors Rose and Rusu[3] perhaps best summarize the important points regarding both studies — that is, to make one wonder “whether there are certain benefits of particular dietary strategies depending on an individual’s life history and inherent susceptibility [italics mine] (through genetics or otherwise). This is an important consideration, as the effectiveness of certain dietary manipulations depends on background strain and sex in mice and there is different susceptibility to certain cardiometabolic diseases in different people.”  Indeed, we may shape what the world gives us as much as we are shaped by the world.

The Studies:
Korat, Andres V Ardisson; Shea, M Kyla; Jacques, Paul F.; Sebastiani, Paola; Wang, Molin; Eliassen, A Heather; Willett, Walter C.; Sun, Qi. Dietary protein intake in midlife in relation to healthy aging – results from the prospective Nurses’ Health Study cohort. American Journal of Clinical Nutrition. 2024; DOI:

Zhang, X., Kapoor, D., Jeong, SJ. et al. Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk. Nat Metab 6, 359–377 (2024).

Additional Resources:
Rose, Adam J.; Rusu, Patricia M. A leucine–macrophage mTORC1 connection drives increased risk of atherosclerosis with high-protein diets. Nature Metabolism 6, 203-204 (2024).

[1] (Korat, 2024)
[2] (Zhang, 2024)
[3] (Rose, 2024)

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