Advanced Glycation End Products

Think of the look between raw beef and cooked beef, then young skin vs old skin:

In both of these cases the more cooked beef, and the older skin are more damaged then their previous state. One form of damage that may play a large importance in aging is the accumulation of advanced glycation end-products. Advanced glycation end-products (AGEs) are molecules that have been formed because some type of sugar has been attached to it, thus altering both its function and shape. Not only does it end up interfering with the function of the cells but can also end up attaching to receptors (receptors for AGEs, RAGE) and causing inflammation. There are 4 major areas that can form AGEs which are relevant to your health:

1. Intracellular, inside the cell as a result of metabolism
2. Extracellular, mainly in areas that are bathed in blood or blood-related fluids (e.g. blood vessels, lens, neurons)
3. During digestion, due to the mixing and release of nutrients
4. The level of the food, due oxidation, heat, processing, endogenous.

The majority of glycation most likely happens intracellularly thus interventions at this level most likely leads to the largest gains in health. For example one of the ways in which calorie restriction may extend lifespan is due to its ability to decrease the flux through glycolysis leading to both decreased production of short-chain sugars and there removal, short-chain sugars have <5 carbon atoms. While most people think about glucose (which is a 6 chain sugar), the metabolism of glucose and fructose result in short-chain sugars, and the latter are problematic because since they are so short (<5C) it is hard for them to become cyclic. This results in the reactive carbonyl being more available because these short-chain sugars exist mostly in their open form which then allows them to react with their environment inadvertently, e.g. amino acids and nucleic acids. The problem doesn't end with its shortness, but once damaged by free radicals this can allow them to rearrange into α,β-dicarbonyls (01) are more susceptible to oxidation (two double bonds) and thus more likely to propogate oxidative damage:

Compound I is an aldose in the open chain configuration. Tautomerism yields the enediol (II). Subsequent univalent oxidations by O2 or by O2- yield the intermediates III and IV. The diradical IV rapidly collapses to the dicarbonyl (V).

Indeed free radicals may play an important role in short chain sugar toxicity because in SOD-deficient E. coli erthrose, glyceraldehyde, dihydroxyacetone, and glycoaldehyde (the shortest sugar) were more toxic in normal E. coli, which result in a self perpetuating cycle in which detoxifying pathways are then inhibited by the oxidative stress (1).

The degradation of glucose and fructose leads to a variety of short chain sugar intermediates, glucosone, 1-deoxyglucosone, 3-deoxyglucosone, threosone, 1-deoxythreosone, 3-deoxythreosone, 3-deoxypentosone, 1-deoxypentosone, glyoxal, methylglyoxal (MG) (41), with MG also coming from lipid peroxidation systems (from acetone), protein metabolism (aminoacetone) and also nucleic acid degradation (5):

The pathway important for diabetes is most likely the one that starts from glucose. In diabetics the excess of glucose causes an increase flux through the glycolytic pathway (and polyol pathway (6)) which leads to increases in dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P) which are both 3-carbon phosphorylated sugars, which not only lead to the dreaded MG, but are also very reactive themselves (maybe most reactive) (7) and its accumulation in diabetics may be due to oxidative stress inhibiting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (8). G3P may be 2000x more reactive then glucose itself (9).

Calorie restriction interferes with this whole system because the lack of calories decreases the NADH/NAD+ ratio. NAD+ is required for GAPDH to function, thus by increasing availability the removol of both G3P and DHAP is increased and its subsequent production of MG is also decreased (11). In the opposite case of diabetes due to overnutrition NAD+ is not avilable for GAPDH and this whole glycation scenario is exacerbated leading to the many sequelae that diabetics suffer from (and we work so hard to control). Besides the increased triosephosphates, diabetics suffer from another problem and that is the constant hyperglycemia which leads to the extracellular glycation.

Outside of cells glycation doesn't occur due to the production of reactive carbonyls through glycolysis, instead there are other pathways by which the damaging components can be reached, e.g. Namiki pathway, Wolff pathway (figure up top (12)). Below is a more detailed schematic (26):

The Amadori products for the most part are stable (thus the use of HbA1c as a marker), however if the Schiff base proceeds directly through the Namiki pathway can result in the formation of reactive carbonyls such as methylglyoxal and glyoxal, and besides the product the pathway itself likely releases H2O2. Considering the variation possible AGEs are very hetergenous:

Alternative routes for the formation of immunochemically distinct AGEs in vivo.Advanced glycation end-products (AGEs) arise from the decomposition of Amadori products (AGE-1), the glycolysis intermediate product glyceraldehyde (AGE-2), the Schiff base and glucose fragmentation product glycolaldehyde (AGE-3), the triose phosphate and the Amadori product fragmentation product methylglyoxal (AGE-4), the glucose autoxidation product glyoxal (AGE-5), and decomposition product of Amadori products and fructose-3-phosphate to 3-DG (AGE-6). CML, N-(carboxymethyl)lysine; CEL, N-(carboxyethyl)lysine; P-NH2, free amino residue of protein. AR, aldose reductase; SDH, sorbitol dehydrogenase; F-3-PK, fructose-3-phosphokinase. (13).

While in cells there is some semblance of control in terms of the concentration of glucose and detoxifying networks, in the blood the control mechanism and antioxidants are much more diffuse. Thus things like the collagen in your blood vessel can be glycated (14-16) causing atherosclerosis and its removal can result in improvement (17,18). The surface of RBCs (19), your skin causing wrinkles and spots (20), the heart (21), LDL particles (24) and even the lens of the eye (22). The glycation of the extracellular matrix has been implicated in various disease state, Alzheimer's, arthritis, diabetes, retinopathy, and aging (10).

In a prospective study of 1013 adults >65 years, in a 6-year follow up adults with the highest amounts of carboxymethyl-lysine (CML) had the highest risk of overall mortality and CVD mortality (23). In a group of healthy young men higher pentosidine levels were associated with lower values of the Ankle Brachial Index (ABI) a measure of blood flow to the extremities (most common reason for decreased values is atherosclerosis).

Note: AGEs can be classified by ability to fluoresce, form cross-links on proteins, and also toxicity. Things like CML are not fluorescent, do not cross-link, and are non-toxic. The toxic AGEs are usually used to refer to those produced by glyceraldehyde and glycoaldehyde.


In the Diabetes Control and Complications Trial (DCCT) with 216 patients with Type 1 diabetes, 5 years of intensive treatment resulted in "30-32% lower furosine, 9% lower pentosidine, 9-13% lower CML" (32). For most healthy people the excursion of serum glucose levels is due to post-prandial states. During those periods of hyperglycemia, the majority of folks have detoxification systems in place to deal with it. For example in human aortic endothelial cells (33) high glucose lead to AGEs and activation of RAGE, however overexpression of antioxidant systems such as SOD2 resolved this. When glyoxalase 1 (GLO1, detoxifies methylglyoxal, MG) is knocked out (80%) similiar gene expressions are achieved in normal glucose as in cells with high glucose. In high glucose overexpression of GLO1 normalized some pathways, showing that MG may play a large role in the mammalian cells, and indeed is probably true (34). Similiar results are found in rats (35).

To keep fasting sugar low, one should get at least 120g of digestible carbohydrate per day (we want to stay out of ketosis, especially in calorie excess because this may result in increases in MG (39, Atkins Diet), and also consume mixed meals. By snacking to a minimum, glucose excursions are avoided, and by not binging, the post-prandial phase of increased nutrient flux is decreased. See Meal Frequency Post.

Note: Shotgun approach towards plasma and RBC AGEs find that diabetics have higher levels then non-diabetics (38).

Dietary AGEs (dAGEs)

The other source of AGEs is from our diet. Through the process of being exposed to air, heat, and outside its natural protective coverings, various food products can undergo oxidation and the generation of various products, some toxic, some not, but which AGE is a part of. For example, in the picture up at the very top, when applying heat to the beef it becomes brown, as we learned in elementary chemistry color changes are chemical reactions and this browning process is known as the Maillard Reaction. This also accounts for the browning of bread, potatotes, fried onions (the browning of fruit and vegetables is more due to the enzyme polyphenol oxidase, but some Maillard reactions do occur too).

In a study where they calorie restricted mice and fed them either a high AGE diet or low AGE diet, the high AGE diet not only removed the life extending benefits of CR but resulted in EVEN LOWER lifespans then control mice (27).

When looking at healthy adults and chronic kidney disease patients the Low AGE diet resulted in various improvements in markers (28):

Markers of oxidative stress such as 8-iso, TNFa, VCAM1 were down and markers of AGEs such as sCML and sMG (s = serum) were down too. The AGER1 is a protein responsible for detoxification of AGEs and with respect to kidney disease patients, they accumulate AGEs because the kidneys are one major way by which AGEs are removed from the serum (30). It has been found that in these patients AGER1 is depressed despite the increased AGE levels, however in this study, a low AGE diet allowed AGER1 to be increased again, thus maybe offering protection against CKD progression.

In T2DM patients a high AGE diet effected both micro- and macro-vessel endothelial cell function (31). In the post-prandial state the high AGE diet resulted in decreased ability to dilate and impairment of endothelial function as measured by, E-selectin, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1.

Which foods provide the greatest sources of AGEs? Vlassara answered this question in 2010 with a paper title, "Advanced glycation end products in foods and a practical guide to their reduction in the diet," rather then write it out myself I'll just quote it:

The current dAGE database demonstrates that a significantly reduced intake of dAGEs can be achieved by increasing the consumption of fish, legumes, low-fat milk products, vegetables, fruits, and whole grains and by reducing intake of solid fats, fatty meats, full-fat dairy products, and highly processed foods. These guidelines are consistent with recommendations by organizations such as the American Heart Association (42), the American Institute for Cancer Research (43), and the AmericanDiabetes Association (44). It should, therefore, be possible to integrate this new evidence into established guidelines for disease prevention as well as medical nutrition therapy for a wide variety of conditions.
Equally important, consumers can be educated about low-AGE–generating cooking methods such as poaching, steaming, stewing, and boiling. For example, the high AGE content of broiled chicken (5,828 kU/100 g) and broiled beef (5,963 kU/100 g) can be significantly reduced (1,124 kU/100 g and 2,230 kU/100 g, respectively) when the same piece of meat is either boiled or stewed. The use of acidic marinades, such as lemon juice and vinegar, before cooking can also be encouraged to limit dAGE generation. These culinary techniques have long been featured in Mediterranean, Asian, and other cuisines throughout the world to create palatable, easily prepared dishes.

Thus processing of food and high temperatures result in AGE formation.

Beyond just the inflammation and accumulation, it may have immunological implications. When comparing raw foods to their processed versions (36). This may account for the increased number of allergies the western world gets:

Antioxidant Systems

Since antioxidant systems play large roles in removing the toxic AGEs, and oxidative stress plays an important part in the propogation of AGEs, keeping our antioxidant network at its optimum is necessary. Thus things like   vitamins, minerals, and necessary fats are required (this is Triage Theory by Bruce Ames, but he isn't the first to come up with it). It is found that in copper deficiency early and late glycation products are increased (41,42) most likely due to the decrease in copper-dependent enzymes. In diabetics altered metabolism of zinc, magnesium, and copper is associated with increased AGE levels (43).

In a study comparing vegetarians to meat-eaters, the author's hypothesized that vegetarians would have lower AGEs then meat-eaters however this was not found to be the case (44). There were no physical differences between groups, also total carbohydrate intake was the same, however vegetarians did consume more fructose in the form of fruits. However as another paper suggests (45) it could have been a lack of taurine (and in my opinion other nutrients) that resulted in the higher AGE measurements.  Later the author's came out  with another paper (46) and this is what the abstract says:

Advanced glycation end products (AGEs) may play an important adverse role in process of atherosclerosis, diabetes, aging and chronic renal failure. Levels of N(epsilon)-carboxymethyllysine and fluorescent AGE values were estimated in two nutritional population groups--alternative group (vegetarians--plant food, milk products, eggs) and traditional group (omnivorous subjects). Vegetarians have a significantly higher carboxymethyllysine content in plasma and fluorescent AGE values. Intake of proteins, lysine and monosaccharides as well as culinary treatment, consumption of food AGEs (mainly from technologically processed products) and the routes of Maillard reaction in organism are the substantial sources of plasma AGEs. Vegetarians consume less proteins and saccharides. Lysine intake is significantly reduced (low content in plant proteins). Subjects on alternative nutrition do not use high temperature for culinary treatment and consume low amount of technologically processed food. Fructation induced AGE fluorescence is greater as compared with that induced by glucose. It is due to higher participation of a more reactive acyclic form of fructose. Intake of vegetables and fruit with predominance of fructose is significantly higher in vegetarians. Comparison of nutrition and plasma AGEs in vegetarian and omnivorous groups shows that the higher intake of fructose in alternative nutrition of healthy subjects may cause an increase of AGE levels.

Thus besides nutrients, and fructose (which I think plays a smaller role in all this, as its increase in serum is not appreciable), the protein source may play a role. The amino acids lysine and arginine are particularly susceptible to glycation. Arginine makes up 28% of all amino acids in the body (no ref) thus by providing a dietary source, free arginine and lysine in the blood may bind the adducts and result in excretion in the urine, instead of having the reducing sugars react with collagen and plasma proteins. Indeed supplementation (47,48) with these amino acids may result in less glycation. In (48) long-term supplementation with L-arginine resulted in reduction of renal impairment due to AGEs. While the effects are small, over your entire life there are benefits. For these to have effects though, the arginine and lysine must be free in the blood, thus they must be supplemented in low-insulin states, e.g. between meals, else cells will just take them up and they won't be able to scavenge the carbonyls.

Stomach as Bioreactor (49,50)

Atherosclerosis may result partly from processes that occur following food consumption and that involve oxidized lipids in chylomicrons. We investigated reactions that could occur in the acidic pH of the stomach and accelerate the generation of lipid hydroperoxides and co-oxidation of dietary constituents. The ability of dietary polyphenols to invert catalysis from pro-oxidation to antioxidation was examined. The acidic pH of gastric fluid amplified lipid peroxidation catalyzed by metmyoglobin or iron ions. Metmyoglobin catalyzed peroxidation of edible oil, resulting in 8-fold increase of hydroperoxide concentration. The incubation of heated muscle tissue in simulated gastric fluid for 2 h enhanced hydroperoxides accumulation by 6-fold to 1200 microM. In the presence of catechin or red wine polyphenols, metmyoglobin catalyzed the breakdown of hydroperoxides to zero, totally preventing lipid peroxidation and beta-carotene cooxidation. We suggest that human gastric fluid may be an excellent medium for enhancing the oxidation of lipids and other dietary constituents. The results indicate the potentially harmful effects of oxidized fats intake in the presence of endogenous catalysts found in foods, and the major benefit of including in the meal plant dietary antioxidants.

Concluding thoughts

Normal aging can be regarded as a slow cooking process, in that many of the Maillard products accumulate in long-lived proteins in the body, such as those of the skin, arteries, lenses, joints, and cartilage (26)

Related Thoughts
Small amounts of AGEs may have hormetic effect on our protective systems:

Ann N Y Acad Sci. 2008 Apr;1126:257-61.Induction of heat shock proteins and the proteasome system by casein-N epsilon-(carboxymethyl)lysine and N epsilon-(carboxymethyl)lysine in Caco-2 cells.Schmid K, Haslbeck M, Buchner J, Somoza V.

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