Is There Really a Such Thing as Too Much Protein?

There’s a lot of noise surrounding what does and doesn’t make for a good diet.

You could go to any one of the multitude of “experts” out there & they’d all give you uniquely different advice! Even the well-researched, pulling from the sea of literature, vary in how they interpret the available evidence & in what studies they find to be the most convincing…

When we consider the three macronutrients: fats, carbohydrates, proteins, we all understand that no diet is sustainable without some combination of each of the nutrients in the trio.

Fats & carbs have gotten their fair share of scrutiny, but up until recently you’d struggle to find many to advise against maximizing your protein intake. Proteins are the building blocks of our tissues; they provide the structural framework of our bodies!

If you’re trying to build more muscle, you’re recommend to eat more protein [1]. If you’re trying to lose weight, eat more protein [2]. For recovery after a tough workout, eat more protein [3]!

We recommend more protein for the young, the old, the men, the women, the active, and the inactive!

So, of course, it raised a few eyebrows when new research coming out of the University of Pittsburgh suggested that ingesting more protein might actually be harmful…

“These results highlight a mechanism, present in both mice and people, whereby 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 [4].”

The western diet is especially high in proteins, more so than others; and with the growing prevalence of Cardiovascular disease, it was only a matter of time before we started to investigate the potential effects of our increased protein intake. We’ve generally accepted the link between a high carbohydrate diet & cardiovascular disease [5,6], we’ve always considered the potential effects of a diet high in fats [7], but until recently most would argue that it’s nearly impossible to see any significant adverse effects from a healthy diet high in proteins.

So, with all that considered, let’s dive a little deeper into the findings coming out of University of Pittsburgh & we’ll see how they fit with what we already know!

The first thing to note about this type of research is that we really never eat the way that the subjects in these studies do!

Zhang et. al’s research consisted of two human studies:

1. A group of fourteen participants, each given two liquid meal tests. Subjects were fed a meal replacement shake made of Boost Plus, Unjury, Sol Carb, dry milk powder, canola oil, & water! Either a “very high protein meal” at 50% proteins, 17% fats, & 33% carbs or a “standard meal” made of 10% protein, 17% fats, & 73% carbs. Blood samples were taken at 1 hour & 3 hours after ingestion.

2. A similarly designed experiment with nine participants. Subjects were fed blended “real food” shakes consisting of: potatoes, beans, carrots, corn, bacon, fats, broth, and spices. The high-protein variant included protein isolates; either whey, chicken, beef, or egg proteins, likely in the form of supplementary powders. The standard “mixed-meal” consisted of 15% protein while the high-protein meal was 22%. Blood samples here were taken at 1 & 2 hours after ingestion.

It’s a little tough to consider either of these experimental meals “real” in any capacity, but it’s fair to give them a pass in the name of science! The “real food” shake, with the inclusion of healthy fats, spices, & vegetables, is at least fairly representative of a typical meal with fiber & a variety of food-sourced micronutrients. The experiment utilizing the Boost-canola oil milkshake should get a little bit more scrutiny, but since our focus lies solely on the protein content & how it may affect our bodies, we’ll disregard that for now!

Zhang’s group found that after ingesting the 50% protein meals, subjects presented with increased mTORC1 activation & thus suppression of autophagy at the 1 and 3 hour mark; similar results were found in the 22% mixed-meal group.

mTORC1 activation has long been known to prevent autophagy [8,9]; possibly most well-known in the body building community! Most people who are locked into the exercise science, muscle building world know mTOR as the primary regulator of skeletal muscle maintenance [8,9]!

Framed in a positive light,

mTORC1 is known as a key regulator in controlling skeletal muscle mass following contraction and mechanical load-induced hypertrophy, synergistic ablation, myotube hypertrophy, and amino acid sensing, in which mTOR interacts with factors of both skeletal muscle hypertrophy and atrophy [9].

Zhang et. al instead point to its potential to induce pathology & to facilitate atherosclerotic plaque formation…

When comparing multiple meals with the same amount of calories, Zhang et. al have found that the higher protein meals lead to significantly more mTORC1 activation! Prior to Zhang’s research, we’d already established a fairly clear relationship between feeding & mTORC1 activation; however, carbs generally got the bulk of the credit [10]! This is why we recommended that you eat plenty of carbs along with your proteins following a strenuous workout [11]! Carbs are known to trigger an insulin response sufficient to activate the mTOR protein synthesizing, muscle mass regulating pathways [10,11]! Seems like the proteins help out as well… or hurt depending on who you ask!

This new research highlights that the high protein meals lead to an increased total circulating amino acid concentration and increased mTORC1 signaling, as well as the reciprocal inhibition of autophagy. The group suggests that high protein meals, specifically those high in leucine, may be leading to increased pathology.

It’s interesting because we similarly view leucine in a very favorable light in the fitness community, as it’s been shown to be a major contributor to muscle growth & preservation [12]!

So; this raises the question:

Should we be concerned about our potential risk of developing atherosclerosis while eating a high-protein diet or is the potential risk overshadowed by our increased ability to grow & maintain muscle mass?

The High Protein Diet & Atherosclerosis

Atherosclerosis, the progressive blockage & hardening of our arteries, has long been a leading cause of mortality throughout the developed world. The process involves fatty plaques building up in the inner layer of arteries. Of course, it’s been closely linked to hyperlipidemia, high cholesterol & hyperglycemia; but, the development of atherosclerosis is also very closely linked to living a sedentary lifestyle [13,14]!

Participants in the human experiments of Zhang’s study were considered if they were between 21 & 70 years old and overweight; they were excluded if they engaged in any structured exercise for more than 90 minutes per week.

That’s important if they’d drawn any direct link to human dietary protein intake & atherosclerosis, but their primary findings were in mice!

Zhang’s group draws their link to atherosclerosis through their research on Apoe−/− mice, which they graciously admit are genetically prone to atherosclerosis, but they highlight that the high protein, high leucine, diets in the humans they studied produced the same physiological effects & activated the same mTORC1 signaling pathway.

The researchers specifically state:

Serum cholesterol concentration [in mice] increased markedly as a result of western diet feeding and was not different between the low-, moderate- and high-protein western diet groups. On the other hand, serum triglyceride concentration was not affected significantly by low-, moderate-, and high-protein western diet feeding… Compared with the low-protein diet, the high-protein, but not the moderate-protein western diet increased plaque burden [4].

This may all be cause for concern, but to what extent?

In layman’s terms, we’ve found that the diet, & thus physiological pathway, most beneficial for muscle production & maintenance is the same as that that leads to the development of atherosclerotic plaques in mice… So, weigh your options wisely!

Is a High Protein Diet for Everyone?

When you’re planning your meals, consider that each of our macronutrients plays a unique & specific role!

Carbohydrates are our abundant, easily-accessible, simple energy source; fats are our complex energy storage, necessary for hormone production & nerve function; proteins are our building blocks & structural support.

If you’re an athlete, tasked to consistently expend energy & produce force, you eat a ton of calories & many of them are from proteins – as they should be!

If you’re a couch potato, sitting all day for work at your desk & then all night at home in front of your TV, and you’re eating a ton of calories (which you shouldn’t), then you should be at least somewhat weary of these latest findings.

There’s no doubt that a link exists between high protein intake & atherosclerosis – the mechanism is plainly laid out in Zhang’s research – but it’s important to highlight that being overweight & sedentary are significantly more concerning risk factors [13].

Figure 8D Zhang et. al, 2024

Highlighting the proposed link between High Protein/Leucine intake & Cardiovascular risk, as well as giving potential “guidelines” for the potential risk for each incremental increase in protein intake.

Zhang’s group don’t provide any clear cut recommendations, but they imply that any level of protein intake over 1.2 grams per kilograms is a significant cardiovascular risk, based on their research.

To offer some pushback, we’ve got a ton of research suggesting that, paired with the appropriate level of physical activity, one could handle a protein intake up to 3 to 4 times Zhang et. al’s recommendations with no adverse effects [15-19]; some reporting no adverse effects at as high as 6.59 grams per kilogram [19]!

So, the moral of the story is: If you work hard, your diet should reflect it; if not, maybe you should dial it back a little!

Eating more protein will not kill you; doing so to supplement your healthy lifestyle has actually been proven to be beneficial time & time again [20]! Make sure your daily protein intake continues to be the major driver in your dietary decisions, your body will thank you!

---

Works Cited & Further Reading

1. Carbone, J. W., & Pasiakos, S. M. (2019). Dietary Protein and Muscle Mass: Translating Science to Application and Health Benefit. Nutrients, 11(5), 1136. https://doi.org/10.3390/nu11051136

2. Moon, J., & Koh, G. (2020). Clinical Evidence and Mechanisms of High-Protein Diet-Induced Weight Loss. Journal of obesity & metabolic syndrome, 29(3), 166–173. https://doi.org/10.7570/jomes20028

3. Macnaughton, L. S., Wardle, S. L., Witard, O. C., McGlory, C., Hamilton, D. L., Jeromson, S., Lawrence, C. E., Wallis, G. A., & Tipton, K. D. (2016). The response of muscle protein synthesis following whole-body resistance exercise is greater following 40 g than 20 g of ingested whey protein. Physiological reports, 4(15), e12893. https://doi.org/10.14814/phy2.12893

4. Zhang, X., Kapoor, D., Jeong, S. J., Fappi, A., Stitham, J., Shabrish, V., Sergin, I., Yousif, E., Rodriguez-Velez, A., Yeh, Y. S., Park, A., Yurdagul, A., Jr, Rom, O., Epelman, S., Schilling, J. D., Sardiello, M., Diwan, A., Cho, J., Stitziel, N. O., Javaheri, A., … Razani, B. (2024). Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk. Nature metabolism, 6(2), 359–377. https://doi.org/10.1038/s42255-024-00984-2

5. Jo, U., & Park, K. (2023). Carbohydrate Intake and Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Prospective Studies. Nutrients, 15(7), 1740. https://doi.org/10.3390/nu15071740

6. Jo, U., & Park, K. (2023). Carbohydrate-based diet may increase the risk of cardiovascular disease: A pooled analysis of two prospective cohort studies. Clinical nutrition (Edinburgh, Scotland), 42(8), 1301–1307. https://doi.org/10.1016/j.clnu.2023.06.013

7. Guasch-Ferré, M., Babio, N., Martínez-González, M. A., Corella, D., Ros, E., Martín-Peláez, S., Estruch, R., Arós, F., Gómez-Gracia, E., Fiol, M., Santos-Lozano, J. M., Serra-Majem, L., Bulló, M., Toledo, E., Barragán, R., Fitó, M., Gea, A., Salas-Salvadó, J., & PREDIMED Study Investigators (2015). Dietary fat intake and risk of cardiovascular disease and all-cause mortality in a population at high risk of cardiovascular disease. The American journal of clinical nutrition, 102(6), 1563–1573. https://doi.org/10.3945/ajcn.115.116046

8. Bodine S.C. (2022). The role of mTORC1 in the regulation of skeletal muscle mass. Faculty reviews, 11, 32. https://doi.org/10.12703/r/11-32

9. Yoon M. S. (2017). mTOR as a Key Regulator in Maintaining Skeletal Muscle Mass. Frontiers in physiology, 8, 788. https://doi.org/10.3389/fphys.2017.00788

10. Wilburn, D. T., Machek, S. B., Cardaci, T. D., & Willoughby, D. S. (2020). Carbohydrate-Induced Insulin Signaling Activates Focal Adhesion Kinase: A Nutrient and Mechanotransduction Crossroads. Nutrients, 12(10), 3145. https://doi.org/10.3390/nu12103145

11. Wang W, Ding Z, Solares GJ, Choi S-M, Wang B, Yoon A, et al. (2017) Co-ingestion of carbohydrate and whey protein increases fasted rates of muscle protein synthesis immediately after resistance exercise in rats. PLoS ONE 12(3): e0173809. https://doi.org/10.1371/journal.pone.0173809

12. Breen, L., & Churchward-Venne, T. A. (2012). Leucine: a nutrient 'trigger' for muscle anabolism, but what more?. The Journal of physiology, 590(9), 2065–2066. https://doi.org/10.1113/jphysiol.2012.230631

13. Lechner, K., von Schacky, C., McKenzie, A. L., Worm, N., Nixdorff, U., Lechner, B., Kränkel, N., Halle, M., Krauss, R. M., & Scherr, J. (2020). Lifestyle factors and high-risk atherosclerosis: Pathways and mechanisms beyond traditional risk factors. European journal of preventive cardiology, 27(4), 394–406. https://doi.org/10.1177/2047487319869400

14. Laufs, U., Wassmann, S., Czech, T., Münzel, T., Eisenhauer, M., Böhm, M., & Nickenig, G. (2005). Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology, 25(4), 809–814. https://doi.org/10.1161/01.ATV.0000158311.24443.af

15. Antonio, J., Ellerbroek, A., Silver, T., Vargas, L., Tamayo, A., Buehn, R., & Peacock, C. A. (2016). A High Protein Diet Has No Harmful Effects: A One-Year Crossover Study in Resistance-Trained Males. Journal of nutrition and metabolism, 2016, 9104792. https://doi.org/10.1155/2016/9104792

16. Antonio, J., Ellerbroek, A., Silver, T., Vargas, L., & Peacock, C. (2016). The effects of a high protein diet on indices of health and body composition--a crossover trial in resistance-trained men. Journal of the International Society of Sports Nutrition, 13, 3. https://doi.org/10.1186/s12970-016-0114-2

17. Antonio, J., Ellerbroek, A., Silver, T., Orris, S., Scheiner, M., Gonzalez, A., & Peacock, C. A. (2015). A high protein diet (3.4 g/kg/d) combined with a heavy resistance training program improves body composition in healthy trained men and women--a follow-up investigation. Journal of the International Society of Sports Nutrition, 12, 39. https://doi.org/10.1186/s12970-015-0100-0

18. Antonio, J., Peacock, C. A., Ellerbroek, A., Fromhoff, B., & Silver, T. (2014). The effects of consuming a high protein diet (4.4 g/kg/d) on body composition in resistance-trained individuals. Journal of the International Society of Sports Nutrition, 11, 19. https://doi.org/10.1186/1550-2783-11-19

19. Antonio, J., Ellerbroek, A., Silver, T., Vargas, L., & Peacock, C. (2016). The effects of a high protein diet on indices of health and body composition--a crossover trial in resistance-trained men. Journal of the International Society of Sports Nutrition, 13, 3. https://doi.org/10.1186/s12970-016-0114-2

20. I. Baum, J., Børsheim, E., R. Allman, B., & Walker, S. (2020). Health Benefits of Dietary Protein throughout the Life Cycle. IntechOpen. doi: 10.5772/intechopen.91404