Protein restriction

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Reduced intake of energy (calorie restriction) has a long history, but for almost as long scientists have been interested in understanding if restriction of specific types of macronutrients would recapitulate the effects of CR. The results of many early studies were mixed, likely due to differences in dietary protein quality and the degree of restriction.[1] However, since the end of the last century, interest in protein restriction (PR) as an intervention has been rekindled by studies which have shown that in flies and mice, total protein restriction or restriction of specific essential amino acids can extend lifespan independently of calorie intake.[2][3]

Human studies

A number of long-term studies suggest that lower protein diets in humans are associated to improved metabolic health and increased lifespan.


A restrospective cohort study based in the National Health And Nutrition Examination Survey (NHANES) III, surveyed 6,381 men and women located in the USA and of 50 years old and over. They found that participants of 50 to 65 years old with high animal-derived protein intake had a 75% increased risk in mortality and a 4-fold increase in risk of age-associated diseases such as cancer.[4] However, the reverse trend was observed in participants aged over 65 years old, in which high animal-derived protein intake was associated to lower cancer risk and mortality. Independently of age, high protein intake was associated to a 5-fold increase in the risk of diabetes, although it is important to note that the particular sample size for diabetes-related deaths was low (n=21). Of note, this study controlled for age, sex, waist circumference and total calories consumption, but did not control for amount of exercise.

Interestingly, the relationships between protein intake and health and lifespan were no longer observed if protein consumed was plant-derived. When controlling for plant-derived protein, no positive nor negative associations were observed with higher mortality risk and incidence of age-related diseases, suggesting that plant-derived protein has added health benefit but rather animal-derived protein has deleterious health effects. This findings are in agreement with previous studies showing consumption of red meat was associated to higher risk of all-cause mortality and cancer.[5]

This study also measured levels of insulin-like growth factor 1 (IGF-1) in a subset of the cohort (n= 2,253 subjects) and found that low protein intake was associated with a significant reduction in IGF-1 and in turn with a lower incidence of cancer. Higher circulating levels of IGF-1 have been extensively associated to an increased risk of cancer  and might promote tumorigenesis.[6][7][8]


A large prospective cohort study based on the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL study, measured dietary protein intake and incidence of diabetes among 38,094 participants in Europe.[9] Similarly to the NHANES III study, they found that higher animal protein intake was associated to increased risk of diabetes. However, in discrepancy to the NHANES III study, the (EPIC)-NL also found an association, although more nuanced, between higher total protein intake and increased incidence of diabetes which was independent of protein source.


A small randomised controlled trial (RCT) showed that moderate protein restriction (PR) improved several health markers in humans and mice.[10] They observed that 7-9% PR led to improved blood glucose levels and blood glucose tolerance, whilst it decreased body mass index (BMI) and fat mass in both humans and mice. However, the human subjects of the study (n=38) were overweight or mildly obese and the control group might have been consuming an excessive amount of protein that consisted of more than 50% of their diet. On the contrary, mice in the control group were fed a diet that consisted of 21% protein.

In the same study, they fed C57BL/6J wild-type mice a diet with reduced branched-chain amino acids (BCAAs) and found it was sufficient to improve metabolic health markers and body composition and had equivalent health effects to those of total PR.

Some of the metabolic effects of PR diets have been proposed to be mediated by FGF21, an insulin-sensitising hormone.[11] Interestingly, there was no increase in the circulating levels of FGF21 in diets with reduced BCAAs, suggesting this form of PR might function via a metabolically distinct pathway.[10]

Animal studies

  1. Green CL, Lamming DW. Regulation of metabolic health by essential dietary amino acids. Mech Ageing Dev. 2019 Jan;177:186-200. doi:10.1016/j.mad.2018.07.004. [Epub 2018 Jul 22]. PMID: 30044947; PMCID: PMC6333505
  2. Mair W, Piper MD, Partridge L. PLoS Biology. 2005 Jul; 3(7):e223. doi: 10.1371/journal.pbio.0030223. Epub 2005 May 31.
  3. Solon-Biet SM, McMahon AC, Ballard JW, Ruohonen K, Wu LE, Cogger VC, Warren A, Huang X, Pichaud N, Melvin RG, Gokarn R, Khalil M, Turner N, Cooney GJ, Sinclair DA, Raubenheimer D, Le Couteur DG, Simpson SJ. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab. 2014 Mar 4; 19(3):418-30. doi: 10.1016/j.cmet.2014.02.009.
  4. Levine, M., Suarez, J., Brandhorst, S., Balasubramanian, P., Cheng, C., & Madia, F. et al. (2014). Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population. Cell Metabolism, 19(3), 407-417. doi: 10.1016/j.cmet.2014.02.006
  5. Sun, Q. (2012). Red Meat Consumption and Mortality. Archives Of Internal Medicine, 172(7), 555. doi: 10.1001/archinternmed.2011.2287
  6. Grimberg, A. (2003). Mechanisms by which IGF-I May Promote Cancer. Cancer Biology &Amp; Therapy, 2(6), 628-633. doi: 10.4161/cbt.2.6.678
  7. Hua, H., Kong, Q., Yin, J., Zhang, J., & Jiang, Y. (2020). Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy. Journal Of Hematology &Amp; Oncology, 13(1). doi: 10.1186/s13045-020-00904-3
  8. Pollak, M., Schernhammer, E., & Hankinson, S. (2004). Insulin-like growth factors and neoplasia. Nature Reviews Cancer, 4(7), 505-518. doi: 10.1038/nrc1387
  9. Sluijs, I., Beulens, J., van der A, D., Spijkerman, A., Grobbee, D., & van der Schouw, Y. (2009). Dietary Intake of Total, Animal, and Vegetable Protein and Risk of Type 2 Diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL Study. Diabetes Care, 33(1), 43-48. doi: 10.2337/dc09-1321
  10. 10.0 10.1 Fontana, L., Cummings, N., Arriola Apelo, S., Neuman, J., Kasza, I., & Schmidt, B. et al. (2016). Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health. Cell Reports, 16(2), 520-530. doi: 10.1016/j.celrep.2016.05.092
  11. Laeger, T., Henagan, T., Albarado, D., Redman, L., Bray, G., & Noland, R. et al. (2014). FGF21 is an endocrine signal of protein restriction. Journal Of Clinical Investigation, 124(9), 3913-3922. doi: 10.1172/jci74915