Dietary intake of total, animal, and plant proteins and risk of all cause, cardiovascular, and cancer mortality: systematic review and dose-response meta-analysis of prospective cohort studiesBMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2412 (Published 22 July 2020) Cite this as: BMJ 2020;370:m2412
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More specific inferences are possible. Re: Dietary intake of total, animal, and plant proteins and risk of all cause, cardiovascular, and cancer mortality: systematic review and dose-response meta-analysis of prospective cohort studies
In their SRMA on protein (animal v. plant v. total) consumption and mortality (all cause, cardiovascular and cancer), Naghshi et al. (1) confirm the known trend of decreased mortality with plant v. animal protein consumption. Even for such a thorough and meticulous study, conclusions are necessarily limited to broad strokes, with such broad categories of nutrients. However, there is the additional problem here of even of classifying protein sources as animal or plant, because animal proteins are often incomplete. That is, meats are almost exclusively muscle meats, with the bones typically tossed in the trash (instead of into the soup, as our forbears did). This single difference in which parts of the animal are consumed makes a profound difference in the amino acid content of the animal protein consumed. Thanks to recent research in nutrition, biochemistry and cellular physiology, this one difference in amino acid consumption—which Naghshi et al. barely touch upon in their Introduction—can now explain these differences in chronic disease prevalence.
Specifically, muscle meats are relatively sulfur amino acid-rich and glycine-poor, whereas collagen is exceedingly glycine-rich (one third mole fraction) and sulfur amino acid-poor (less than 1%). Metabolically, the essential sulfur amino acid methionine and glycine have a reciprocal relationship. When a methionine-rich meal is absorbed (e.g., after a typical meat, fish or poultry meal) hepatic metabolism is switched from methionine salvage mode to methionine clearance mode, by the activation of glycine-N-methyltransferase, the main enzyme of the only clearance pathway for methionine. Each mole of methionine requires two moles of glycine to be cleared (2).
The general dietary shift toward exclusively muscle meat consumption and away from collagen (gelatin) consumption, has therefore resulted in a reduction in plasma glycine levels in the general population. While this may seem paradoxical because a high animal protein diet is rich in all the protein amino acids, the concomitant increase in dietary glycine consumption and decrease in plasma concentration has recently been demonstrated in the Oxford cohort of the EPIC study. Thus, Schmidt et al. (3) observed that while meat-eaters in the UK consumed 20% more glycine each day than vegans (3.12 v 2.61 g/day, respectively), their mean plasma free glycine level was 14% lower (390 v 452 μM, respectively) than that of vegans.
Physiologically, the priming or activation of macrophages of all types, to produce inflammation, is naturally regulated by glycine (4). The glycine receptor is a glycine-gated chloride channel which allows for chloride ion influx, thus stabilizing (by hyperpolarization) the macrophage plasma membrane, and rendering them less susceptible to depolarization by various stimuli (4). The depolarization of the macrophage plasma membrane initiates calcium ion influx and the cascade of inflammatory events. These days, plasma glycine levels are normally in the range of 150 – 350 μM, whereas glycine concentrations optimal for macrophage regulation are in the range of 0.5-1mM (4), well in excess of biochemical requirements for protein synthesis.
There are however, some differences between the findings of Naghshi et al and some previous studies re: meat consumption and other chronic illnesses rooted in inflammation. For example, these authors invoke the 2019 meta-analysis by Han et al (5), which reported increased risk of cancer mortality with higher meat consumption, to explain their not finding increased cancer mortality with higher animal protein consumption. They extended this argument by citing the findings of the 2015 meta-analysis by Zhao et al (6), who reported lower all cause mortality among the higher consumers of fish, and suggesting that differences in fat content of various meat v. fish might be responsible for the differences. They are likely correct, I would argue, in terms of qualitative differences in fat content between meat and fish. Specifically, fish oils are generally rich in omega-3 EPA, an anti-inflammatory dietary component, which may partially offset a glycine deficiency.
In our recent NIA study (7), we observed significantly increased longevity in outbred mice, and this is not the first occasion upon which I have advanced here the hypothesis that glycine deficiency can explain the etiology of all manner of disease rooted in chronic inflammation (8-10). I would even suggest that in Covid pneumonia, wherein acute inflammation (the “cytokine storm”) is what makes this viral infection life-threatening, it is also glycine deficiency that is to blame. Here I would add that the typical comorbidities of diabetes and cardiovascular disease are also expressions of glycine deficiency. Even—and perhaps especially—the Covid risk factor of advanced age can be attributed to the epigenetic shut-down of the main glycine synthetic pathways in senescent cells (11)
To those who might consider the glycine deficiency hypothesis too simple an explanation for such a global spectrum of maladies, I would suggest a consideration of the principle of Ockham’s Razor. Thus, this simplest of hypotheses should be embraced and not rejected, lest there be clear evidence presented against it.
1. Sina Naghshi S, Sadeghi O, Willett WC, et al. Dietary intake of total, animal, and plant proteins and risk of all cause, cardiovascular, and cancer mortality: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ 2020;370:m2412
2. Martinov MV, Vitvitsky VM, Banerjee R, Ataullakhanov FIl. Review: The logic of the hepatic methionine metabolic cycle. Biochim Biophys Acta 2010; 1804: 89–96. doi:10.1016/j.bbapap.2009.10.004
3. Schmidt JA, Rinaldi S, Scalbert A, et al. Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and vegans: a cross-sectional analysis in the EPIC-Oxford cohort. Eur J Clin Nutrition 2016;70:306–12. doi:10.1038/ejcn.2015.144
4. Wheeler MD, Ikejema K, Enomoto N, et al. Glycine: a new anti-inflammatory immunonutrient (Review). Cell Mol Life Sci 1999;56:843–856
5. Han MA, Zeraatkar D, Guyatt GH, et al.. Reduction of red and processed meat intake and cancer mortality and incidence: a systematic review and meta-analysis of cohort studies. Ann Intern Med 2019;171:711-20. doi:10.7326/M19-0699. pmid:31569214
6. Zhao LG, Sun JW, YangY, et al. Fish consumption and all-cause mortality: a meta-analysis of cohort studies.Eur J Clin Nutr 2016;70:155-61. doi:10.1038/ejcn.2015.72. pmid:25969396
7. Miller RA, Harrison DE, Astle CM, Bogue MA, Brind J et al. Glycine supplementation extends lifespan of male and female mice. Aging Cell. 2019 Jun;18(3):e12953. doi: 10.1111/acel.12953. Epub 2019 Mar 27.PMID: 30916479
8. Brind J. Rapid response to: Role of diet in type 2 diabetes incidence: umbrella review of meta-analyses of prospective observational studies. BMJ 2019;366:l2368
9. Brind J. Rapid response to: Autism spectrum disorder: advances in diagnosis and evaluation. BMJ 2018;361:k1674
10. Brind J. Rapid Response to: Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications BMJ 2018;361:k1036
11. Hashizume O, Ohnishi S, Mito T, et al. Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Nature.com/Scientific Reports | 5:10434 | DOI: 10.1038/srep10434
Competing interests: Joel Brind, PhD, is also President and CEO of Natural Food Science, LLC, which makes and markets a glycine supplement product.