Beware of ‘advanced glycation end’ products (AGEs)

Most chronic diseases incubate over years, not overtly expressing until reaching a critical horizon, often in mid-to-late adulthood. Only after years of incubating do the invading forces unleash their devastation. Whether it’s diabetes, heart disease, Alzheimer’s, sarcopenia, arthritis, or any of the other chronic diseases, we are shocked when we “suddenly” become afflicted. With surprise and fear we cry, “How did this happen to me?”

Guess what? Precursors for most chronic diseases have been there for years, just waiting to erupt.

Inflammation

We now understand that various inflammatory processes – part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, irritants, and toxins – commonly represent the “silent” markers of chronic disease.

The word “inflammation” traces back to the Latin for “set afire.” In some conditions, like rheumatoid arthritis, there are expressions of heat, pain, redness, and swelling. In other cases, like early-onset aging, heart disease, Alzheimer’s, and type 2 diabetes, inflammatory signs are not so obvious. Without sophisticated medical tests, it’s difficult or impossible to know the full extent of inflammatory processes that eventually lead to expressions of a chronic disease.

As these long-term inflammatory processes incubate in the body, waiting to be vented, they may begin to reveal themselves as diabetic-induced shock, signs of early onset Alzheimer’s, or symptoms of inflammatory bowel disease (ulcerative colitis and/or Crohn’s disease). Or, they could manifest as joint pain.

Toxins as inflammatory agents

Toxicity represents the degree to which a substance, usually a chemical or a mixture of substances, can damage an organism (animal, bacterium, or plant), or a substructure of an organism, such as a cell (cytotoxicity) or an organ like the liver (hepatotoxicity).

Effects of a toxin are dose-dependent. Thus, even water can lead to water intoxication (hyponatremia) when taken in too high a dose. Toxicity is species-specific, making cross-species analyses problematic.

There are four types of recognized toxins: chemical, biological, physical, and radiation.

Chemical toxins include nonliving substances such as lead, mercury, and chlorine gas, and such living compounds as methyl alcohol (Methanol — CH₃OH), most medications, and poisons from living species (like snakes).

toxins include nonliving substances such as lead, mercury, and chlorine gas, and such living compounds as methyl alcohol (Methanol — CH₃OH), most medications, and poisons from living species (like snakes). Biological toxins include disease-causing microorganisms and parasites (termed pathogens) that are difficult to measure because their “threshold dose” differs wildly among individuals.

toxins include disease-causing microorganisms and parasites (termed pathogens) that are difficult to measure because their “threshold dose” differs wildly among individuals. Physical toxins include physical substances that interfere with biological processes. These include substances like coal dust, asbestos fibers, or silicon dioxide. Asphyxiant gases, like smog, also are considered physical toxicants.

toxins include physical substances that interfere with biological processes. These include substances like coal dust, asbestos fibers, or silicon dioxide. Asphyxiant gases, like smog, also are considered physical toxicants. Radiation toxins include some weakly radioactive substances, such as uranium. These are classified as chemical toxicants.

Advanced glycation end products (AGEs) are inflammatory toxins

Advanced glycation end products, or AGEs, represent an assorted group of large molecules formed by the process of glycation, which involves bonding of a sugar molecule, such as glucose or fructose, to a protein or fat molecule without help from enzymes. The resulting macromolecules (AGEs) are considered biologic toxins that associate with such issues as diabetes, aging, chronic kidney disease (CKD), anemia, poor skeletal muscle strength and performance, cardiovascular disease, and brain and bone disorders, just to name a few. The figure below shows the many AGEs-induced chronic-disease conditions that reduce longevity.

Humans are exposed to two main sources of AGEs: endogenous AGEs formed within the body, and exogenous AGEs ingested from foods.

Endogenous AGEs

There is not much we can do about endogenous AGEs that generate mainly in the bloodstream from small proportions of the absorbed dietary simple sugars glucose, fructose, and galactose. Since fructose has about 10 times the glycation activity of glucose, it is believed to contribute more than glucose to endogenous AGEs’ inflammatory processes. Some endogenous AGEs are benign, but others are more reactive than the sugars from which they are derived, and thus are implicated in many age-related chronic diseases. For example, elevated endogenous AGEs have been implicated in cardiovascular diseases (where endothelium, fibrinogen, and collagen are damaged); Alzheimer’s disease (where amyloid proteins are side-products of reactions progressing to AGEs); cancer (where acrylamide and other AGE side-products release); peripheral neuropathy (where myelin – a fatty white substance that surrounds the axon of some nerve cells is attacked); and other sensory losses such as deafness (due to demyelination).

Exogenous AGEs

A diet consisting of high levels of animal meats, sugar, and fat represents the major source of exogenous AGEs. Some AGEs are formed when food cooks at elevated temperatures, i.e., during deep-frying, broiling, roasting, or grilling. AGEs also form during high-temperature processing of certain foods such as pasteurized dairy products, cheeses, sausages, and processed meats, as well as commercial breakfast cereals. Glycation processes also may contribute to formation of acrylamide, a potential carcinogen formed during deep-fried cooking of certain foods, particularly potatoes (think french fries).

Until recently, it was thought that exogenous glycation-derived AGEs were negligible contributors to inflammation and disease development. This conclusion was almost entirely based on animal research. Recent research on humans, however, has shown this not to be the case.

Moreover, food manufacturers have added AGEs to foods in the form of flavor enhancers and colorants to improve appearance. Foods with significant browning, caramelization, or directly added preformed AGEs can be high in these compounds. Foods with very high exogenous AGEs include donuts, barbecued meats, cake, and dark-colored soda pop.

Reducing AGEs promotes healthy aging and longevity

Try to reduce or eliminate foods and cooking methods that associate with the highest levels of AGEs. In this respect, a plant-based diet appears optimal.

The number of scientific publications on AGEs has increased astronomically in the past decade. There is now convincing human evidence from in vitro studies, animal models, clinical and pathological studies, epidemiological human cohort studies of aging, and human clinical trials that limiting AGEs promotes reduction in inflammation and oxidative stress, and thus improves health and longevity.

The table below is sourced from an article in the Journal of the American Dietetic Assn. It presents examples of the AGE enzyme activity for different foods. AGE enzyme activity expresses as kilounits (kU) per 100 grams of a food (column 1) or as AGE enzyme activity in kU units per food serving (column 2). The serving size expresses as grams (g) for solids; millileters (mL) for liquids. (A more comprehensive list can be found at the Journal of the American Dietetic Assn.) Not surprisingly, on a comparative basis, animal-based foods contain the most exogenous AGE activity.

FATS AGEs per 100g Serving Size (g) AGEs per serving Almonds, roasted 6,650 30 1,995 Avocado 1,577 30 473 Butter, sweet cream, unsalted (Land O’ Lakes) 23,340 5 1,167 Margarine (tub) 17,520 5 876 Mayonnaise 9,400 5 470 Oil, sesame 21,680 5 1,084 BEEF AGEs per 100g Serving Size AGEs per serving Frankfurter, broiled 450 degrees, 5 min 11,270 90 10,143 Hamburger (McDonald’s) 5,418 90 4,876 Steak, broiled 7,479 90 6,731 Steak, (pan-fried w/olive oil) 10,058 90 9,052 CHICKEN AGEs per 100g Serving Size AGEs per serving Breast with skin, 450 degrees, 45 min. 8,244 90 7,420 Back/thigh w/skin, roasted, BBQ 18,520 90 16,668 Leg w/skin, roasted 10,997 90 9,897 Thigh, w/skin, roasted 11,149 90 10,034 TURKEY AGEs per 100g Serving Size AGEs per serving Burger, pan-fried with cooking spray 7,968 90 7,171 Burger, pan-fried with 5ml Canola oil 8,251 90 7,426 PORK AGEs per 100g Serving Size AGEs per serving Bacon, fried, 5 mins, no added oil 91,577 13 11,905 Bacon, microwaved, 2 slices, 3 min 9,023 13 1,173 Sausage, beef/pork links, pan-fried 5,426 90 4,883 SEAFOOD AGEs per 100g Serving Size AGEs per serving Salmon, filet, broiled 3,347 90 3,012 Salmon, filet, poached 2,292 90 2,063 Shrimp, marinated, raw 1,003 90 903 Shrimp, marinated, grilled on BBQ 2,089 90 1,880 Trout, baked, 25 min 2,138 90 1,924 CHEESE AGEs per 100g Serving Size AGEs per serving American, white, processed 8,677 30 2,603 Feta, Greek, soft 8,423 30 2,527 Parmesan, grated (Kraft) 16,900 15 2,535 Swiss, processed 4,470 30 1,341 SOY AGEs per 100g Serving Size AGEs per serving Burger (Boka burger) microwaved, 1.5 min 67 30 20 Burger (Boka burger) skillet, spray, 5 min 100 30 30 Tofu, broiled 4,107 90 3,696 Tofu, sauteed 5,877 90 5,289 EGGS AGEs per 100g Serving Size AGEs per serving Fried, one large 2,749 45 1,237 Scrambled, one large, pan, high, w/cooking spray, 1 min 117 30 35 Scrambled, pan, high, w/margarine, 1 min 123 30 37 Scrambled, pan, medium-low, w/butter, 2 min 167 30 50 BREADS AGEs per 100g Serving Size AGEs per serving Bagel, toasted 167 30 50 Biscuit (McDonald’s) 1,470 30 441 100% whole wheat 53 30 16 White, Italian 23 30 7 Croissant, w/butter, (Starbucks) 1,113 30 334 Dinner roll 77 30 23 BREAKFAST CEREALS AGEs per 100g Serving Size AGEs per serving Cinnamon Toast Crunch (General Mills) 1,100 30 330 Corn Flakes (Kellogg’s) 233 30 70 Corn Flakes, Honey Nut (Kellogg’s) 320 30 96 Corn Flakes, Sugar Frosted (Kellogg’s) 427 30 128 Cream of Wheat, instant/prepared (Nabisco) 108 175 189 Fiber One (General Mills) 1,403 30 421 Rice Krispies (Kellogg’s) 2,000 30 600 Oatmeal, instant, dry (Quaker Oats) 13 30 4 BREAKFAST FOODS AGEs per 100g Serving Size AGEs per serving French toast, frozen, microwaved (Aunt Jemima) 603 30 181 Hot cakes (McDonald’s) 243 30 73 Pancake from mix 823 30 247 Pancake, frozen, toasted (General Mills) 2,263 30 679 Waffle, frozen, toasted (Kellogg’s) 2,870 30 861 GRAINS & LEGUMES AGEs per 100g Serving Size AGEs per serving Beans, red kidney, raw 116 100 116 Pasta, cooked, 12 min 242 100 242 Pasta, spiral 245 100 245 Rice, white, quick-cooking, 10 min 9 100 9 STARCHY VEGETABLES AGEs per 100g Serving Size AGEs per serving Corn, canned 20 100 20 Potato, sweet, roasted, one hour 72 100 72 Potato, white, boiled, 25 min 17 100 17 Potato, white, roasted 45 min, 5ml oil per svg 218 100 218 Potato, white, french fries (McDonald’s) 1,522 100 1,522 SNACKS AGEs per 100g Serving Size AGEs per serving Corn chips (Dorito’s) 503 30 151 Potato chips, baked (FritoLay) 450 30 135 Nacho cheese pretzel Combos (M&M Mars) 1,680 30 504 Chocolate Teddy Grahams (Nabisco) 1,647 30 494 Goldfish crackers (Pepperidge Farms) 2,177 30 653 Air-popped popcorn w/butter 133 30 40 Microwave popcorn, fat free (PopSecret/General Mills) 33 30 10 COOKIES, CAKES, PASTRIES AGEs per 100g Serving Size AGEs per serving Granola bar, chocolate chunk, soft (Quaker) 507 30 152 Rice Krispies Treat (Kellogg’s) 1,920 30 576 Cookie, biscotti, vanilla almond (Starbuck’s) 3,220 30 966 Cookie, chocolate chip (Nabisco) 1,683 30 505 Cookie, Oreo (Nabisco) 1,770 30 531 Donut, glazed, devil’s food cake (Krispy Kreme) 1,407 30 422 Donut, chocolate-iced, cream-filled (Krispy Kreme) 1,803 30 541 Fruit rollup, “Sizzlin’ red” (General Mills) 980 30 294 Apple pie, individual, baked (McDonald’s) 637 30 191 Pop tart, microwave, 3 secs, high (Kellogg’s) 243 30 73 FRUITS AGEs per 100g Serving Size AGEs per serving Apple, baked 45 100 45 Banana 9 100 9 Cantaloupe 20 100 20 Fig, dried 2,663 30 799 Plums, dried, pitted prunes (Sun-Maid) 167 30 50 Raisin from Post Raisin Brain (Kellogg’s) 120 30 36 VEGETABLES AGEs per 100g Serving Size AGEs per serving Carrots, canned 10 100 10 Celery 43 100 43 Cucumber 31 100 31 Eggplant, grilled, marinated w balsamic vinegar 256 100 256 Eggplant, raw, marinated w balsamic vinegar 116 100 116 Green beans, canned 18 100 18 Portabella mushroom, raw, marinated w balsamic 129 100 129 Onion 36 100 36 Tomato 23 100 23 Tomato sauce (Del Monte Foods) 11 100 11 Grilled broccoli, carrots and celery 226 100 226 Grilled peppers and mushrooms 261 100 261 MILK and MILK PRODUCTS AGEs per 100g Serving Size (mL) AGEs per serving Swiss Miss hot cocoa packet, prepared 262 250 656 Swiss Miss hot cocoa packet, prepared, sugar-free 204 250 511 Milk, fat-free 1 250 2 Milk, whole, 4% fat 5 250 12 Pudding, instant, chocolate, skim milk 1 120 1 Yogurt, cherry (Dannon) 4 250 10 FRUIT JUICES AGEs per 100g Serving Size (mL) AGEs per serving Apple 2 250 5 Orange 6 250 14 Orange, from fresh fruit 0 250 1 Orange, with calcium 3 250 8 Fruit pop, frozen (Dole) 18 60 11 Honey 7 15 1 Sherbet, strawberry (Edy’s) 2 125 3 COMBINATION FOODS AGEs per 100g Serving Size AGEs per serving Bacon/egg/cheese biscuit (McDonald’s) 2,289 100 2,289 Big Mac (McDonald’s) 7,801 100 7,801 Cheeseburger (McDonald’s) 3,402 100 3,402 Chicken McGrill (McDonald’s) 5,171 100 5,171 Double quarter pounder w/cheese (McDonald’s) 6,283 100 6,283 Filet-o-fish (McDonald’s) 6,027 100 6,027 Hummus w/garlic and scallions 884 100 884 Hummus w/vegetables 487 100 487 Veggie burger, 400 degrees F (Amy’s Kitchen) 198 100 198 CHOCOLATE AGEs per 100g Serving Size AGEs per serving Hershey’s Special Dark Chocolate (Hershey Co.) 1,777 30 533 M&Ms, milk chocolate (Mars) 1,500 30 450 Reese’s Peanut Butter Cup (Hershey Co.) 3,440 30 1,032 Snickers (Nestle) 263 30 79 CONDIMENTS AGEs per 100g Serving Size AGEs per serving Pickle, bread and butter 10 30 3 Ketchup 13.33 15 2 Mustard 0 15 0 Soy sauce 60 15 9 BEVERAGES AGEs per 100g Serving Size (mL) AGEs per serving Budweiser beer, (Anheuser Busch) 1.2 250 3 Breast milk, fresh 6.67 30 2 Breast milk, frozen 10 30 3 Coca-Cola Classic 2.8 250 7 Coffee w/milk and sugar 2.4 250 6 Coffee, drip method 1.6 250 4 Pepsi, diet (PepsiCo) 2.8 250 7 Pepsi, diet, caffeine-free (PepsiCo) 2.4 250 6 Pepsi, regular (PepsiCo) 2.4 250 6 Rum, Baccardi Superior (80 proof) 0 250 0 Sprite (Coca-Cola Co.) 1.6 250 4 Tea, teabag (Lipton) 2 250 5 Vodka, Smirnoff (80 proof) 0 250 0 Whiskey, Dewars, white label .4 250 1 Wine, Pinot Grigio 32.8 250 82 Wine, Pinot Noir 11.2 250 28

References

Clarke, R.E., et al. “Dietary advanced glycation end products and risk factors for chronic disease: A systematic review of randomised controlled trials.” Nutrients, 2016; 8(3):125.



DeChristopher, L.R., et al. “Perspective: The paradox in dietary advanced glycation end products research — The source of the serum and urinary advanced glycation end Products is the intestines, not the food.” Advances in Nutrition, 2017 Sept. 15; 8(5):679.



Di Pino, A., et al. “High intake of dietary advanced glycation end products is associated with increased arterial stiffness and inflammation in subjects with type 2 diabetes.” Nutrition, Metabolism, and Cardiovasc Diseases. 2017; Epub; Jul 8.



Uribarri, J., et al. “Dietary advanced glycation end products and their role in health and disease.” Advances in Nutrition. 2015; 15:6(4):461.



Uribarri, J., et al. “Advanced glycation end products in foods and a practical guide to their reduction in the diet.” Journal of the American Dietetic Association. 2010; 110(6):911–16.e12.



Vlassara, H. “Identifying advanced glycation end products as a major source of oxidants in aging: Implications for the management and/or prevention of reduced renal function in elderly persons.” Seminars in Nephrology .2009;29(6):594-603.



www.nutritionfacts.org/video/glycotoxins/



Yacoub, R., et al. “Advanced glycation end products dietary restriction effects on bacterial gut microbiota in peritoneal dialysis patients: A randomized open-label controlled trial.” PLoS One. 2017; 12(9):e0184789.



Yang X. et al. CD36 in chronic kidney disease: novel insights and therapeutic opportunities. Nat Rev Nephrol.2017 Sep 18. doi: 10.1038/nrneph. 2017.126. [Epub ahead of print].

Editor’s Note: This article was edited after publication to clarify the contents of the chart about the ways AGEs present in foods. In addition, the term for ‘water intoxication’ has been corrected.