Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study
BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j1957 (Published 09 May 2017) Cite this as: BMJ 2017;357:j1957
All rapid responses
Red meat contains N-Glycolylneuraminic acid (Neu5Gc). I am surprised that Drs Potter and Etamadi et al make no mention of it. Neu5Gc occurs in virtually all red mammalian meat – with the exception of humans. In humans, the gene encoding CMP-N-acetylneuraminic acid hydroxylase mutated to an inactive form some three million years ago. It is thought that this conferred protection against an archaic form of malaria1.
When we eat red meat, Neu5Gc is absorbed and gives rise to an innate immune response. In the long term, this creates a chronic a low-grade inflammatory milieu. This will happen even if we eat fresh uncooked raw red meat2.
Such a milieu will promote cancers, insulin-resistance, hyperinsulinaemia and obesity, amongst other diseases.
I suspect that Neu5Gc will prove to be a major driving force of ill health.
01. Chou, H-H, Takematsu, H, Diaz, S et al A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proceedings of the National Academy of Sciences, 1998;95:11751–6.
doi:10.1073/pnas.95.20.11751
02. Samraj, AN, Pearce, OM, Läubli et al A red meat-derived glycan promotes inflammation and cancer progression. Proceedings of the National Academy of Sciences. 2015;112:542–7.
doi: 10.1073/pnas.1417508112
Competing interests: No competing interests
The study by Etemadi and colleagues [1], the comment by John Potter [2] and the editorial by Fiona Godlee [3] all add to the negative publicity heaped on the red meat industry in recent years. This has already forced thousands of traditional livestock producers out of business in the UK [4], to be replaced, ironically, by more intensive ones who cut costs through increased scale and medication, and less natural diets. If the associations the authors find are robust then the criticism is fully justified, but they show signs of siloed thinking, appear to be unaware of differences between feeding systems and could be accused of throwing out the grass-fed ruminant baby with the bath water of intensive, grain-fed, beef. As such, they may inadvertently give yet another twist to the spiral of agricultural intensification.
At first glance, cutting meat consumption, or switching from beef to chicken, look like ways to reduce both greenhouse gas emissions (GHGs) and diet-related diseases. Potter tells us unequivocally that “Overconsumption of meat is bad for health and for the health of our planet”. Few people would deny that overconsumption of anything is bad, yet Etamadi’s study finds increased mortality at every stage from very low to excessively high red meat consumption. Are these perfectly graded associations credible for all nine diseases they cover?
It may be relevant that Etemadi’s study was undertaken in the US where most beef is finished in feedlots on diets based on corn and soya – not natural feeds for ruminants. While a proportion of beef cattle are fed grain-based diets in most parts of the world, many of these receive only modest amounts of grain and others are exclusively fed on grass. But cattle fed some grain are far better able than poultry to utilise arable crop residues, Brewers’ and Distillers’ grains, sugar beet pulp, Miller’s offal and most oilseed bi-products [5] all of which we cannot eat - the exception being soyabean meal, widely included in poultry feed.
There are two key reasons why this could make a difference to the health impact of the meat. First, studies in the UK [6] [7], US [8] and Australia [9] have found that meat from grass-fed cattle has an omega-6 to omega-3 ratio of well under 2:1, while grain-fed beef typically has a ratio of between 8:1 and 11:1 and was found to be 20:1 in one trial. Grass-fed beef was also higher in conjugated linoleic acid and lower in trans fats. Omega-6 breaks down into arachidonic acid which has pro-inflammatory effects which can be counteracted by the long chain omega-3 fatty acids [10]. The consumption of oily fish is recommended for this reason, but there are no longer enough fish in the sea for everyone and for the significant proportion of the population who do not eat oily fish, grass-fed beef or lamb provides an important, if modest, contribution to omega-3 intake in a healthy balance with omega-6.
Second, several studies have noted a pro-oxidant effect from haem iron, which Etemadi and colleagues identify as the key source of higher mortality in red meat consumers. However, some studies [8] have also found higher levels of antioxidants including vitamin E and beta-carotene in grass-fed beef. Zinc is another important antioxidant. While beef is a good source of zinc, liver is much higher still in zinc. There has been a dramatic reduction in ox liver consumption in recent decades. This could mean that some red meat consumers who eat only grain-fed beef and no ox liver do not take in enough antioxidants to counteract the pro-oxidant effect of the haem iron in beef. This would apply particularly to those with below average fruit and vegetable intake, something which characterised the higher red meat consumers in Etemadi and colleagues’ study.
The UN report [11] Potter cites on the environmental side told us that livestock are responsible for 18 per cent of GHS. Almost half (48 per cent) of this related to rainforest clearance for cattle and soya. However, the team only analysed such trends in South America. They did not include regions where grazing land was being converted to forest, or where rainforest was being cleared for palm oil.
In 2013, some of the same authors published a further report [12] with the revised figure of 14.5 per cent. Yet in a third and even less well-known accompanying report [13] they acknowledged that even this was a significant over-estimate, because they based their analysis on rainforest destruction in 2005, which by 2013 had declined significantly.
Grass is the only major crop that restores degraded soil while producing food for humans, albeit indirectly. One major European study [14] has found that up to 1.2 adults cattle grazing per hectare can be carbon neutral – the carbon sequestered and stored by the grass compensates for all their GHGs. Such high levels of sequestration will not continue indefinitely but the importance of not ploughing the grassland to keep this carbon in the ground cannot be over-emphasised.
Grass covers 70 per cent of global farmland, mostly for sound agronomic or environmental reasons. Plough this land for continuous cropping to feed chicken, intensive beef cattle or humans and over a decade or so you release GHGs typically equivalent to 250 tonnes of CO2 per hectare [15], making the land more vulnerable to droughts, floods and soil erosion. Chicken is promoted by many people because the birds convert grain to protein much faster than cattle, but cattle are the most efficient converters of non-human edible feeds to protein.
The evidence suggests to me that the only sustainable way to get human edible food from existing grassland is to graze it with livestock, and where appropriate, grow arable crops in rotation with grass, not in continuous monocultures.
Perhaps the next team of researchers to address the red meat issue could consider the relative impacts of beef and lamb from different production systems?
[1] Etemadi A, Sinha R, Ward MH, Graubard BI, Inoue-Choi M, Dawsey SM, Abnet CC. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study. BMJ 2017; 357.
2] Potter, JD. Red and processed meat, and human and planetary health. BMJ 2017; 357.
[3] Godlee, F. Red meat: another inconvenient truth. BMJ; 357.
[4] Cross J. In the Balance. The Future of the English Beef Industry. EBLEX 2009 pp2-3.
[5] Wilkinson JM. ‘Re-defining efficiency of feed use by livestock’, Animal 2011; 5:1014–1022.
[6] Enser M, Hallett KG, Hewett B, Fursey GAJ, Wood JD and Harrington G. Fatty acid content and composition of UK beef and lamb muscle in relation to production system and implications for human nutrition. Meat Science; 1998, 49:329–341.
[7] Elmore JS, Warren H, Mottram DS, Scollan ND, Enser M, Richardson RI and Wood JD. A comparison of aroma volatile and fatty acid compositions of grilled beef muscle from Aberdeen Angus and Holstein-Friesian steers fed diets based on silage or concentrates. Meat Science; 2004, 68:27–33.
[8] Daley CA, Abbott A, Doyle PS, Nader GA and Larson S. A review of fatty acid profiles and antioxidant content in grass-fed and grain-fed beef. Nutrition Journal; 2010, 9:1–12.
[9] Ponnampalam EN, Mann NJ and Sinclair AJ. Effect of feeding systems on omega-3 fatty acids, conjugated linoleic acid and trans fatty acids in Australian beef cuts: potential impact on human health. Asia Pacific Journal of Clinical Nutrition; 2006, 15:21-29.
[10] Calder PC. n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. Americian Society for Clinical Nutrition; 2006, 83:S1505–S15195.
[11] Steinfeld H, Gerber PJ, Wassenaar T and De Haan C. Livestock’s Long Shadow: Environmental Issues and Options, United Nations Food and Agriculture Organization, 2006, Rome.
[12] Gerber, PJ, Steinfeld, H, Henderson B, Mottet A, Opio C, Dijkman J, Falcucci A and Tempio, G. Tackling Climate Change through Livestock – A Global Assessment of Emissions and Mitigation Opportunities, Food and Agriculture Organization of the United Nations, FAO 2013, Rome.
[13] Opio, C., Gerber, P., Mottet, A., Falcucci, A., Tempio, G., MacLeod, M., Vellinga, T., Henderson, B. and Steinfeld, H. (2013) Greenhouse Gas Emissions from Ruminant Supply Chains – A Global Life Cycle Assessment. Food and Agriculture Organization of the United Nations (FAO), Rome.
[14] Sousanna J.-F, Klumpp K. and Ehrhardt F. (2014) The role of grassland in mitigating climate change, book chapter in EGF at 50 The Future of European Grasslands’, Proceedings of the 25th European Grasslands Federation (ed Hopkins A, Collins RP, Fraser MD, King VR, Lloyd DC, Moorby IM and Robson PRH), Aberystwyth, Wales, 7–11 September, 2014.
[15] Vellinga, T, van den Pol-van Dasselaar, A. & Kuikman, P. Nutrient Cycling in Agroecosystems; 2004, 70:33
Competing interests: In addition to my work for the Sustainable Food Trust, which is a registered charity, I am also a partner in a family organic beef cattle and sheep farm which has its own retail butchers shop.
RE: LOVE Diet
Dear Dr Mann,
Thank YOU for your reply. The topic of the main paper was to determine the association of different types of meat and associated compounds with mortality. The problem of this population based cohort study is the known confusion between association, correlation and causality. The mediation analysis remains unclear. The interdependent interaction between interactions between factors and co-factors doesn’t allow a subgroup analysis. I see the same critical points in your opinion about a possible addiction of Hitler.
I take the problems of addiction very serious. As a psychiatrist I try to treat every day many patients suffering from alcohol and /or drug dependency (DSM-5 criteria). I use the term “substance use disorder”, abuse and addiction are not the same. Until now, I cannot serious assess the personality, personality disorder, possible psychiatric disorders and the drug consumption of Hitler (Goldwater rule, American Psychiatric Association's code of ethics, which states that it's unethical for psychiatrists to make public statements about a public figure they have not evaluated). I have read literature and medical records of excellent, medium and poor quality. It´s evident that his physician, Dr Morell, treated Hitler with an uncommon, heavy polypharmacy, including methamphetamine (crystal methamphetamine is only a form of this drug that looks like glass fragments) and oxycodone, Hitler got local cocaine solution from his otorhinolaryngologist. There are no criteria for a dependency, but maybe an abuse. The book of Norman Ohler is a typical mixture of real facts, legends and incorrect interpretations. It`s well written but unserious with lurid headlines, sorry. I don’t think that Germany lost the war because of any abuse or a dependency of Hitler or the German army.
The problem of alcohol dependency cannot be solved by alcohol prohibition. People with love and peace movement ideas have not beaten Nazi Germany. The points were strong weapons against Krupp Stahl, men like Sir Winston Churchill, who liked Cuban cigars and Whiskey, not men like Chamberlain or the weak, ill President Roosevelt.
I´m afraid of intolerant, dogmatic, idealistic ideologists. Vegetarianism implicates no peace per se. It´s dangerous to believe this.
By the way, beer contains 1.828 mg niacin, 0.164 mg B6, 0.146 mg Pantothenic Acid, 0.018 mg thiamin, 0.07 micrograms B12, 21 micrograms folate /12-oz. glass (United States Department of Agriculture's national nutrient database).
Competing interests: No competing interests
Dear Editor,
We were interested to read Etemadi at al’s paper on mortality from different causes associated with meat, heme iron, nitrates, and nitrites1. It is our view that the hazards attributed to nitrate are due to other factors other than nitrate. The estimate of nitrate consumption is based on the processed meat consumption. Meat consumption is an inappropriate way to estimate nitrate exposure from the diet.
It is estimated that in the average Western diet 1-2 mmol/day of nitrate is consumed, the majority of this from vegetable sources2. Further, human beings synthesise around 1 mmol/day from the oxidation of endogenous nitric oxide synthesis3. In the present study, those in the highest category of meat-derived nitrate consumption were ingesting on average approximately 0.035mmol/day from meat sources. In this context it would seem unlikely that nitrate in itself would be associated with harm.
In contrast to the data presented here there is growing evidence that dietary nitrate may offer significant health benefits. There are observational data4 and randomised control trials5 demonstrating lower blood pressure with exposure to inorganic nitrate far in excess of the quantities described as associated with risk in Etemadi’s paper. This would be expected to be associated with lower risk of mortality from the multiple cardiovascular disease states examined in the study. Multiple other benefits have been demonstrated including in host defence, improvements in exercise efficiency and protection against ischaemia-perfusion injury 6.
It is also perhaps salient to note in a wide ranging review the World Health Organisation came to the conclusion ‘‘Overall, the epidemiological studies showed no consistently increased risk for cancer with increasing consumption of nitrate”.7
1. Etemadi A, Sinha R, Ward MH, Graubard BI, Inoue-Choi M, Dawsey SM, Abnet CC. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study. BMJ 2017; 357.
2. Bonnell A. Nitrate concentrations in vegetables. Epidemiological studies in humans. Proceedings of the International Workshop on Health aspects of nitrate and its metabolites (particularly nitrite). European Commission: Strasbourg, 1995.
3. Forte P, Kneale BJ, Milne E, Chowienczyk PJ, Johnston A, Benjamin N, Ritter JM. Evidence for a Difference in Nitric Oxide Biosynthesis Between Healthy Women and Men. Hypertension 1998; 32(4): 730-734.
4. Smallwood MJ, Ble A, Melzer D, Winyard PG, Benjamin N, Shore AC, Gilchrist M. Relationship Between Urinary Nitrate Excretion and Blood Pressure in the InChianti Cohort. Am J Hypertens 2017.
5. Kapil V, Khambata RS, Robertson A, Caulfield MJ, Ahluwalia A. Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study. Hypertension 2015; 65(2): 320-327.
6. Gilchrist M, Winyard PG, Benjamin N. Dietary nitrate - Good or bad? Nitric Oxide 2010; 22(2): 104-109.
7. Speijers G, Brandt PAvd. Nitrate. Joint FAO/WHO Expert Committee on Food Additives: Geneva, 2003.
Competing interests: MG has previously received financial support from James White Drinks Ltd for the development of a nitrate-depleted form of beetroot juice.
The study population have interesting characteristics. This USA population of half a million people have a BMI 25.8-28.8, an energy intake of 1700-200 cals per day and 15% do vigorous exercise on 5 days of the week. If this is truly accurate, then they may also be accurate recorders of diet.
A 600kg cow will provide just 250kg of lean meat. This contains just 50kg of protein. If I ate an 8 ounce steak every singly day (50g protein) this single carcass would last around 3 years. If I consumed the animal 'nose to tail' it would last half as long again. Of course I would consume it at nothing like that frequency on a typical diet, even the recommended 'healthy' diet currently proposed by national bodies. Indeed the 5 quintile cohorts varied from 3g protein from red meat per day (based on 200cals, 20% of meat consisting of protein), to 26 g per day so the study population seem extremely frugal with red meat. They are a healthy lot indeed.
I am concerned that red meat is produced industrially. Regarding cattle, it can thrive on pasture. By adopting this practice, carbon is sequestered into the soil. It is concerning that much land is set aside for producing food to feed to animals when there is no need to do so.
Competing interests: No competing interests
This study has a fatal flaw in that it does not take into account which participants were taking proton pump inhibitors during the study. Thus the study does not take into account the effect of widely varying amounts of acid used to digest the meats in the stomach and the widely varying digestion products passed on to the intestines. The enormous amounts of proton pump inhibitors being used may be the cause of the red meat results.
Such changed environments have too often been ignored in such studies. The substitution of hydrogenated vegetable oils for butter and lard during WWII, and continuing until this spring, for example.
Competing interests: No competing interests
Dear Dr. Degner,
Thanks for your reply. With all due respect, I disagree with you. Since you’re German, and since you mention Adolf Hitler’s vegetarian diet, as if to suggest that Hitler was a health nut, I wonder if you’re familiar with Norman Ohler’s recent book “High Hitler.” This book alleges that (a) Hitler was a junky and stoned out of his mind on cocaine, meth, and heroin; and (b) every soldier and bureaucrat in the Third Reich was fed a steady diet of crystal meth (Pertivin). Perhaps you should take the issue of addiction more seriously. Here are some links you might find interesting, including one in German:
http://www.torontosun.com/2015/09/11/high-hitler-new-book-alleges-hitler...
http://www.kiwi-verlag.de/buch/der-totale-rausch/978-3-462-04733-2/
Competing interests: No competing interests
Dear Editors/Article Authors,
Kosher and Halal slaughtering increase measurable meat quality parameters. [1][2]
It should be further investigated if observed increased risks of all cause mortality and death due to nine different causes after red meat consumption, are also accounted for Kosher and Halal red meats.
Additional research should also determine if Kosher and Halal white meats further reduce all cause mortality, compared to industrially slaughtered, processed, mixted, stored, transported, shelved white meats.
After all, 24.1% of the global population or 1.8 billion people in 2015 and nearly 3 billion people in 2060 will exclusively consume Halal meat. [3]
References
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093272/
[2] https://www.ncbi.nlm.nih.gov/pubmed/25460116
[3] http://www.pewresearch.org/fact-tank/2017/04/06/why-muslims-are-the-worl...
Competing interests: No competing interests
This paper is very intriguing (1); before generalizing its conclusions to everything and everyone, some points need to be raised.
1. The way meat is eaten in every country is very different both in quantity and quality; so we must be very careful to generalize conclusions
2. In “white meat” the authors place canned tuna and fish; in a way food that is not meat and has a peculiar protective effect on CV death and total mortality; this could maximize the “protective effect” by white meat
3. The quintiles are divided according to “red meat” and “white meat” expressed in gr/1000 kcal; in Italy the data I cloud gather were expressed in gr/day; so assuming a caloric intake of more or less 2000 kcal/day the assumption of the lowest quintile would be 18,6 gr/day for red meat and 74 gr/day for “white meat”, summing 92,6 gr/day non so distant from 106,0 gr/day which is the average consumption in Italy for meat (2) ; it would mean that the Italian population, eating meat as they are eating today would be in lowest quintile, therefore in lowest risk-group
4. In the paper I didn’t find any comment about the way of cooking the meat; in Italy, for example, grilled meat is very seldom cooked (usually in public parties “en plain air”) but not as usual way of cooking, so it could make some difference in the meat content of “cyclic amines” which are supposed to be carcinogenic (3) .
In conclusion the paper has to be taken in consideration cautiously for populations, such as people living in Italy, where the quantity of meat and the way is cooked, is very different from in the USA.
1. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study . BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j1957(Published 09 May 2017)
2. Reduction of meat consumption and greenhouse gas emissions associated with health benefits in Italy. Farchi S, Lapucci E, Michelozzi P. Epidemiol Prev 2015;39(5-6);308-313
3. Carcinogenicity of consumption of red meat and processed meat: A review of scientific news since the IARC decision. José L. Domingo, Martí Nadal. Food and Chemical Toxicology Volume 105, July 2017, Pages 256–261; https://doi.org/10.1016/j.fct.2017.04.028
Competing interests: No competing interests
Re: Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study
Etemadi and colleagues reported that red meat was associated with increased risk of all-cause mortality (1).
I calculated 33 outcomes adjusted with 20 covariates just for red meat in their Figure 1. One can specify around 35 million Cox regression models with the combination of 33 outcomes and 20 covariates (33 x 2^20 = 34603008).
In addition, I calculated, for example, 264 P-values for different linear trends in supplementary tables A-D.
Perhaps significance threshold 0.05 is simply meaningless within this framework.
But let's put these calculations aside.
Recently, Schwingshackl et al reported that high versus low consumption of red meat was associated with an average risk ratio (RR) of 1.10 (95% CI 1.00 to 1.22) for all-cause mortality (supplementary figure 25) (2).
Statistical heterogeneity was evident in their meta-analysis (I^2 93%, tau^2 0.02) and of 12 comparisons, four showed risk ratios below 1 and eight showed risk ratios above 1 (2). One of the included study in their meta-analysis was an earlier publication of the NIH-AARP Diet and Health Study (3).
I replicated their meta-analysis with the use of R software and meta package (4). However, I replaced the aforementioned earlier publication of the NIH-AARP Diet and Health Study (3) by Etemadi et al (1). Furthermore, I calculated prediction interval (PI) which provides expected range for the true association in a new analogous study.
Average RR (95% CI) was 1.10 (1.01 to 1.20) for the association between high versus low consumption of red meat and all-cause mortality in replicated meta-analysis (I^2 92.1%, tau^2 0.0185 with DerSimonian-Laird estimator).
On the other hand, 95% PI was 0.80 to 1.51 so therefore in some future circumstances association between high versus low consumption of red meat and all-cause mortality could be protective.
In sensitivity analysis, average RR was 1.10 (95% CI 0.99 to 1.21, tau^2 0.0255, 95% PI 0.75 to 1.59) with the use of method by Paule and Mandel which has been recommended for estimation of between-study variance (5).
PIs provide more meaningful interpretation of heterogeneous random-effects meta-analyses (6). As Higgins et al stated:
“…appropriate consideration must be given to the whole distribution to avoid misleading generalizations about effects across studies…” (6).
Red meat might be harmful, on average, but less so if one appreciates the distribution of effects depicted by predictive interval.
References
1. Etemadi A, Sinha R, Ward MH, et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study. BMJ 2017;357:j1957.
2. Schwingshackl L, Schwedhelm C, Hoffmann G, et al. Food groups and risk of all-cause mortality: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr 2017 Apr 26 pii: ajcn153148.
3. Sinha R, Cross AJ, Graubard BI, Leitzmann MF, Schatzkin A. Meat intake and mortality: a prospective study of over half a million people. Arch Intern Med 2009;169:562-71.
4. Schwarzer Guido. meta: An R package for meta-analysis. R News 2007;7(3):40-45.
5. Langan D, Higgins JP, Simmonds M. Comparative performance of heterogeneity variance estimators in meta-analysis: a review of simulation studies. Res Synth Methods 2016 Apr 6. doi: 10.1002/jrsm.1198
6. Higgins JP, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. J R Stat Soc Ser A Stat Soc 2009;172:137-159.
Email: jesper.m.kivela@helsinki.fi
Competing interests: I like statistics.