Not long ago a very large study undertaken in China found that eggs consumed as part of the Chinese diet were associated with a reduction in cardiovascular disease risk.
13.1% of participants reported daily consumption (usual amount 0.76 egg/day) and 9.1% reported never or very rare consumption (usual amount 0.29 egg/day). Compared with non-consumers, daily egg consumption was associated with lower risk of CVD [Cardiovascular disease] (HR [Hazard Ratio] 0.89...
Another large study recently published in the Journal of the American Medical Association that found when eggs were consumed in the American diet, they were associated with an increase in cardiovascular risk.
Note use of the words "associated with" rather than "caused" – observational studies do not prove causation. What was the cause for this discrepancy? Some difference between China and the USA must account for these differing results. Genetics is one possibility. However, according to this study:
Cardiovascular disease (CVD) is the leading cause of death in the U.S. and affects Chinese Americans disproportionately compared to other ethnic groups in the American population... Mean systolic and diastolic blood pressure differed significantly by length of residence in the U.S
The cardiovascular health of Chinese living a long time in America is even worse than the typical American, therefore genetics is not responsible. To understand what is at work here we need to take some time out to understand a process known as glycation.
Glycation
The molecule at the top center, just to the left of the arrow, is glyoxal. It contains two carbonyl groups, and is therefore known as a dicarbonyl. Dicarbonyls are sugar breakdown products that form as a result of high temperature cooking (the Maillard reaction). They can also form in the body as result of excessive blood sugar. The NH2 group on the protein is an amine, part of an amino acid, the building blocks of proteins. Carbonyls like to link to amines, expelling a water molecule in the process. A dicarbonyl is therefore prone to attach to a protein or two. The linking of two proteins is shown in the above diagram. However, even linking to a single amino acid is enough to cause trouble. If glyoxal links to lysine, the result is carboxymethyl lysine, abbreviated CML. CML is commonly generated during glycation, and we will be hearing more about it.
These modified proteins are known as "advanced glycation endproducts", or "AGEs" for short. They are not usable as nutrients by the body. What happens when foods containing AGEs and dicarbonyls are consumed? The dicarbonyls are highly reactive and do not make it past the GI tract. Some of the AGEs are absorbed and not all of them excreted — they remain lodged in the body:
Based on a rodent study, Koschinsky et al. have estimated that 10% of the orally-ingested AGEs was absorbed, and only 30% of that was eliminated in the urine [6]. This first study revealed that a significant part of the dietary AGEs is likely to be retained in the body. Our recent studies based on exposures to dietary carboxymethyllysine (CML), one of the best studied AGEs, indicate that its chronic intake leads to an increase of its content in most organs and tissues tested [8,9,10]. Therefore, there is no doubt that exogenous AGEs contribute to the pool of AGEs found in vivo...
The use of a specific isotopologue of CML confirmed unequivocally the causal relationship between the CML supplied via foods and its accumulation in organs and tissues.
Note also that the presence of fat is required to absorb CML.
Clinical studies have shown that high consumption of dietary AGEs is associated with indicators of oxidative stress and inflammation, which may play an important role in causing chronic disease (Uribarri et al., 2007). In animal models, restriction of dietary AGEs (dAGEs) prevents vascular and kidney dysfunction (Zheng et al., 2002), diabetes type 1 or type 2 (Peppa et al., 2003), and improves insulin sensitivity (Sandu et al., 2005). In humans, high vs. low-CML diets have been shown to increase levels of serum AGEs, inflammation markers, endothelial dysfunction, and to impair flow-mediated dilation and insulin sensitivity (Birlouez-Aragon et al., 2010; Luévano-Contreras, Garay-Sevilla, Wrobel, Malacara, & Wrobel, 2013)
When AGEs are absorbed they enter into the bloodstream. While in the bloodstream some of them attach to receptors for AGEs, known as RAGEs. RAGEs were apparently developed by evolution to detect molecules associated with injury, and they are triggered by AGEs. Evolution had no need to contend with the chemical modifications induced by cooking prior to the advent of humanity:
The RAGE–ligand [a ligand is something that binds to and activates a receptor, the RAGE receptor in this case] interactions lead to prolonged inflammation, mainly as a result of RAGE-dependent expression of proinflammatory cytokines and chemokines….
In endothelial [artery lining] cell RAGE–ligand interaction increases leukocyte [white blood cell] adhesion molecules expression and the tissue factor procoagulant activity. AGE–RAGE interaction triggers a vicious cycle of cellular injury, by upregulating the RAGE itself and by attracting polymorphonuclear leukocytes, monocytes, and lymphocytes. S100A12 protein and amphoterin release from such cells triggers a new wave of cell perturbing molecules. It promotes the migration of circulating monocytes into the intima [the innermost layer of the artery] , their conversion to activated macrophages, and their release of cytokines and proteases. Within the intima, activated macrophages increase their lipid uptake – mostly due to an increase of AGE-induced oxidized LDL receptors* – leading to the formation of foam cells. Next, activated SMC [smooth muscle cells] migrates into the intima at sites of vascular lesions, and here proliferates, producing new extracellular matrix.
*Why an overabundance of LDL aggravates atherosclerosis
Let us review what we have found so far:
Glycation results in the creation of AGEs - advanced glycation end products - CML being one. When ingested, AGEs are partially absorbed. They enter the bloodstream and trigger receptors that cause inflammatory cell proliferation and narrowing of the artery, i.e. atherosclerosis. Now we need to know what causes glycation in food, particularly, the production of CML:
(CML) is measured in food, but there is a controversy concerning the most convenient yet reliable method(s) for this task. This work compares three different ELISA assays and HPLC-ESI-ITMS/MS for the analysis of CML in several food items. The four methods showed the same decreasing order of CML concentration:
beef, bacon > chicken>fish > dairy products > grain products > fruits/vegetables
CML in Foods
|
Food |
|
CML (μg/g) |
Boiled |
Egg yolk* |
10 min |
0.6 |
Boiled |
Egg white |
10 min |
1 |
serrano |
pepper |
|
1.1 |
Boiled |
potato |
|
1.15 |
Fried |
potatoes |
|
1.57 |
Flour |
tortilla |
|
2.09 |
Corn |
tortilla |
|
2.51 |
Natural |
yogurt |
|
2.92 |
American |
cheese |
|
3.4 |
Fried |
Egg |
4 min |
4.2 |
pork |
rinds |
|
7.19 |
Poached |
chicken |
|
9.31 |
Poached |
salmon |
|
9.81 |
Grilled |
beef-steak |
4 min |
11.8 |
Grilled |
salmon |
8 min |
12.4 |
Chicken |
nuggets |
|
12.5 |
Grilled |
tuna |
8 min |
15.2 |
Pan-fried |
beef steak |
|
15.7 |
Pan-fried |
chicken breast |
|
16.2 |
Fried |
bacon |
|
17.2 |
Grilled |
beef steak |
8 min |
19.3 |
*Data is from the foregoing study, with the exception of egg data which is from The analysis of advanced glycation endproducts: a mass spectrometry–based approach & its applications, by Scheijen et al., 2016.
As we can see from this data, the temperature at which a protein product is cooked is the crucial variable in the formation of CML - grilled and fried meats are the worst offenders. The only food higher than bacon in CML content is well done steak. However, bacon has more fat which is likely to result in higher absorption of CML. As long as the cooking temperature remains no higher than the boiling point of water the levels of CML are lower. Note also that boiled eggs are among the lowest in CML, and even fried eggs have much less CML than fried meat. Bacon and eggs are an American tradition — Seventy percent of U.S. bacon consumption occurs at breakfast, with eggs. We have a study that shows this correlation in detail:
A Prospective Study of Egg Consumption and Risk of Cardiovascular Disease in Men and Women, published way back in 1999, followed over 100,000 people for 8 to 14 years and considered the consumption of bacon as well as eggs. This study found that US bacon consumption is strongly correlated with with egg consumption:
eggs consumed, weekly
|
<1
|
1
|
2-4
|
5-6
|
>=7
|
Food intakes, serving per 4200 kJ daily energy intake
|
|
|
|
|
|
Bacon, men
|
0.03
|
0.05
|
0.07
|
0.11
|
0.15
|
Bacon, women
|
0.05
|
0.06
|
0.08
|
0.1
|
0.12
|
After adjusting for bacon consumption, and other covariates, they found:
no overall significant association between egg consumption (up to 1 egg per day) and risk of CHD or stroke. We specifically found no evidence for a significant increase in risk with either recent or relatively long-term (over the past decade) egg consumption. Despite somewhat different patterns of egg consumption in men and women, the results from the 2 cohorts were remarkably consistent.
“Confounding” is the term used to denote a spurious association between cause and effect as a result of an additional variable. What did the recent study of US egg consumption, referenced at the outset of this analysis, have to say about confounding?
[R]esidual confounding was a potential reason for inconsistent results. For example, egg consumption was commonly correlated with unhealthy behaviors such as low physical activity, current smoking, and unhealthy dietary patterns [emphasis added]. Failure to consider these factors and others could lead to differential conclusions... In contrast, the current study included comprehensive assessment of these factors.
The study did consider all manner of covariates including overall consumption of meat, but failed to separate out bacon consumption. Given the results of the 1999 study, and what we know about glycation, this is a vital omission — overall meat consumption is not the same as fried meat consumption.
How about bacon consumption in China? Chinese sales of ham & bacon are expected to amount to $573 million in 2019. US sales are expected to amount to $29,806 million. So the combined consumption of Chinese ham and bacon is about 2% of that of the US. This is consistent with what we know of Chinese cuisine - one cannot find bacon at Chinese restaurants. The Chinese have their share of the high AGE foods, such as spare ribs, but, eggs are not traditionally served together with bacon or other fried meat. No doubt the Chinese are consuming pork bellies along with the rest of the pig, but they are not turning those pork bellies into bacon.
To sum up, AGEs trigger the inflammatory process of atherosclerosis. Egg consumption in American cuisine is frequently accompanied by bacon with its high levels of AGEs, and this is not the case in China. This is likely the reason for the differing study results.
Atherosclerosis means cardiovascular disease:
[I]n 2015, cardiovascular disease (CVD), primarily coronary and cerebrovascular atherosclerosis, still caused almost 15 million deaths worldwide (> 25% of all deaths). In the US, > 800,000 people died of CVD in 2014, corresponding to almost 1 in 3 of all deaths
What about cholesterol? High levels of LDL cholesterol aggravate artery inflammation after the AGEs have triggered it.
The moral of the story is enjoy your protein poached, simmered, or stewed. Avoid the high temperatures of frying, grilling, and roasting. If you want to stir fry keep the temperature moderate and avoid browning, which is an indication of chemical change.
Notes:
- This analysis is original work appearing for the first time here.
- This discussion should not be construed to give a free pass to the consumption of sugar. Hyperglycemia due to diabetes or excessive sugar consumption creates AGEs with similar results.
- The study of AGEs and their impact upon health is very active area of current medical research. Most studies referred to here have been published since 2015. Early on it was not recognized that short-term studies of absorption of CML and other AGEs yield unreliable results, likely because the presence of fat is required in order to absorb CML and this was not taken into account. As a result some earlier studies were published that incorrectly showed CML was not absorbed.