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Glycation and Lipoxidation: Part 1

Garbage in, garbage out . . .

While the world obsesses about fats and carbohydrates, there are other issues that muddy the macronutrient waters and have implications for coronary plaque prevention and reversal. Endogenous and exogenous glycation and lipoxidation are two important areas to know about.
Advanced Glycation End-products, or AGEs, is the broad and imprecise name assigned to a diverse group of compounds that result from the reaction of sugars (like glucose and fructose) with the amino groups (NH2) of proteins and fats. These reactions can occur in the body (endogenous) or outside the body in foods that you ingest (exogenous).

Both endogenous and exogenous glycation occur all the time in varied situations and are a part of normal metabolism, but higher levels can accelerate various disease states, including atherosclerosis, hypertension, diabetes, and cancer. AGEs are, in particular, drivers of inflammation and oxidative stress and so are particularly relevant to those of us hoping to gain control over coronary plaque and risk for heart disease.

AGEs accumulate in arteries and atherosclerotic plaque, kidneys, heart muscle, lenses of the eyes, cartilage of the joints, nervous system tissue—essentially any tissue that contains long-lived proteins. The structural proteins of connective tissue, such as that lining arteries, is long-lived and thereby susceptible to AGE accumulation. This leads to increased stiffness over time, as well as increased fibrous and inflammatory proteins (Goh 2008). Feeding experimental animals AGEs leads to weight gain, increased visceral fat accumulation, increase in multiple inflammatory and oxidative stress markers and, if administration continues for 6 or more months, diabetes and atherosclerotic lesions (Unoki 2008; Vlassara 1995).

The two ways AGEs are formed

There are two general ways AGEs are formed: endogenous (within the body) and exogenous (formed outside the body). Over 20 various AGEs have been catalogued to date.

The first, or endogenous, AGEs are the result of experiencing high blood glucose, since glucose results in irreversible glucose modification of proteins, or glycation. The common blood sugar and diabetes measure, hemoglobin A1c (HbA1c), is a measure of glycated hemoglobin, the oxygen-carrying protein in red blood cells. The common HbA1c thereby provides a very useful insight into how rapidly you have been glycating hemoglobin as well as other proteins in the body over the preceding 60 to 90 days.

Exogenous AGEs are the result of reactions in food that occur prior to ingestion, i.e., during preparation or cooking. (And here is where the term “glycation” is especially imprecise, since there are many other reactions that occur that are not strictly glycation, but lipoxidation, or lipid oxidation, and other reactions. Nonetheless, for simplicity we will stick to the conventionally-used term “glycation.”) We cook or heat for safety, taste, and appearance, but the quantity of AGEs created vary with the cooking method. Exogenous AGEs develop faster at higher temperatures and increase with cooking time. Many of the studies, for example, that compare high- versus low-AGE diets used foods cooked by frying or broiling to generate high-AGE content, while using boiling or steaming for low-AGE content, with large differences between the two.

Let’s explore the different forms of glycation in greater depth.

Endogenous Glycation

Diabetes can be viewed as a living model of the long-term consequences of endogenous glycation, since diabetics typically experience high blood sugars every day for many years. AGEs have been shown to accumulate in kidney tissue, structures of the eyes, cartilage, and atherosclerotic plaque in people with diabetes, all of which leads to various complications of diabetes in these organs (Yamagishi 2007). Long-term cardiovascular mortality in people with diabetes is double that compared to non-diabetics (Bo 2006). AGEs likely provide a substantial part of the answer for why the increased cardiovascular risk of diabetes is not fully explained by conventional risk factors.

Higher levels of glucose causes glycation, yielding the AGEs methylglyoxal and glyoxal (Thornalley 1999). Therefore any situation or food that increases blood glucose increases glycation and this starts at a blood glucose of 90 mg/dl.

Fructose is an especially potent agent to provoke glycation, yielding several-fold greater effects than glucose (Sakai 2002). The proliferation of fructose-containing sweeteners in the American diet, such as sweetened soft drinks, high-fructose corn syrup, agave nectar, sucrose, as well as honey and maple syrup, means that we are potentially getting exposed to endogenous glycation-accelerating sugars.

Interestingly, limited observations in experimental models suggests that high levels of triglycerides and total cholesterol increase advanced lipoxidation end-products, the formation of which was blocked with use of the vitamin B6 derivative, pyridoxamine (see part 2 of this discussion) (Alderson 2003).

From Bucala 1992.

Exogenous Glycation

The chemical reactions that occur in food leading to the formation of exogenous AGEs are very temperature-sensitive. Thus, high-temperature processes like deep-frying, broiling, high-temperature baking (>350° F) and barbecuing tend to generate higher levels of AGEs in foods compared to less AGE formation with steaming, poaching, stewing, boiling, and microwaving. In these reactions, foods rich in proteins and fats react to form AGEs like methylglyoxal and carboxymethyllysine.

The highest levels of exogenous AGEs are found in animal products such as meat cooked at high temperature, especially beef and cheese, followed by poultry, pork, and fish. The AGE content of carbohydrate foods, vegetables, fruits, non-cheese dairy, and beverages are low to negligible (though they may pose issues for endogenous glycation). The representative exogenous AGE, carboxymethyllysine, was measured in foods by the Mt. Sinai, New York, group that has performed much of this research; some examples of the carboxymethyllysine content of foods:
Food carboxymethyllysine
Bacon, fried, no added oil 91,577
Bacon, microwaved 9,023
Beef, raw  707
Beef, ground, pan browned 4,928
Beef, steak, pan fried in olive oil 10,058
Beef, steak, broiled  7,479
Beef, steak, microwaved 2,687
Butter, unsalted, whipped 23,340
Margarine, tub 17,520
Cheese, American  8,677
Cheese, cheddar 5,523
Cheese, cottage, 1% fat 1,453
Cheese, feta  8,423
Cheese, parmesan, grated 16,900
Chicken, raw, skinless 769
Chicken, boiled in water 1,210
Chicken, fried in olive oil 7,390
Chicken, grilled 4,848
Chicken, microwaved 1,524
Eggs, fried, 1 large 2,749
Egg, omelet, in olive oil 337
Egg, scrambled, in oil olive 337
Salmon, raw  528
Salmon, microwaved 912
Salmon, broiled  3,347
Salmon, smoked  572
Almonds, roasted  6,650
Sunflower seeds, raw 2,510
Sunflower seeds, roasted and salted  4,693
Walnuts, roasted 7,887

Interestingly, marinating with acidic liquids, such as vinegar and lemon juice, during preparation reduced AGE content by 50% or more. While only 10% of AGEs ingested are absorbed (the rest passing out in the intestinal tract), two-thirds of the absorbed fraction end up deposited in various tissues (Koschinsky 1997). Kidneys are especially vulnerable to exogenous AGEs, as they are responsible for clearing them from the body.

Humans administered a diet high in exogenous AGEs develop high blood levels of AGEs, as well as increased markers of inflammation and oxidative stress (tumor necrosis factor-a, c-reactive protein, vascular adhesion molecule (see table). Conversely, a low-AGE diet reduces these same markers (Vlassara 2002). In addition, AGE-modified LDL was reduced by 33% on a low-AGE diet. 

H-AGE: High-AGE diet   L-AGE: Low-AGE diet
(From Vlassara 2002)

One recent assessment found that healthy adults in New York City ingested 14,700 AGE kU/day (Uribarri 2007). Once ingested, exogenous AGE blood levels peak 4-6 hours after ingestion and then decline to baseline levels within 20 hours; clearance in diabetics is delayed with levels decline to baseline after 48 hours (Koschinsky 1997).

AGEs are so easy to make!
As an illustration of just how easy it is to generate a meal rich in AGEs, here’s what the research group Mount Sinai, New York, did:

For low-AGE meals, steam or boil foods at 212º F for 10 minutes.

For high-AGE meals, fry or broil foods at 450º F for 20 minutes. The AGE content of this meal was five-fold greater than the low-AGE meal (Negrean 2007).

Following consumption of these meals (on separate days), a greater degree of endothelial dysfunction was generated after the high-AGE meal, as well as a significant rise in the serum AGE, methylglyoxal.

Once ingested, AGEs tend to peak in the bloodstream at eight hours after ingestion and were cleared after 24 hours (Koschinsky 1997).


Why AGEs are important for heart health


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