Glycation, Diseases and Aging:

Advanced Glycation End Products (AGEs) and Accelerated Aging

Glycation results from the chemical bonding of reducing sugars, such as glucose, to lipids, nucleic acids, and proteins. The advanced glycation end products form and develop as a result of natural chemical processes from the formation of reversible Maillard products (the brown tasty stuff formed in cooking—for example, on the surface of fried foods) to the eventual production of irreversible AGEs. Exposure to AGEs in the body causes inflammation and thus contributes importantly to cardiovascular disease and other chronic inflammatory conditions associated with aging. (1)

“In vitro work has shown that ligation of the advanced glycation end products receptor (RAGE) is part of the complex interactions within oxidative stress and vascular damage, particularly in atherosclerosis and in the accelerated vascular damage that occurs in diabetes.” (1)
Lifespan Boost by Reducing Dietary AGEs

A Study 2 has now reported that putting mice on a low-AGE-containing diet not only reduced systemic AGE accumulation and RAGE levels, but also ameliorated insulin resistance and kidney dysfunction with age, as well as increasing reduced glutathione levels (a good measure of antioxidant status). Moreover, the animals on the low-AGE diet (50% lower than the controls, who received the same amount of food but prepared at a different temperature for a different length of time) also had a significant increase in median (15%) and maximum (6%) lifespan compared to the control animals. “At the median survival for RegAGE, 75% of LowAGE mice were alive, whereas at the maximal survival level for RegAGE, 40% of LowAGE mice were alive.”

The way the researchers produced the low-AGE diet for the mice was by limiting the exposure of the food to high temperatures. “Thus, compared with RegAGE, which is first steam-conditioned and pelleted at 70 to 75ºC for 1 to 2 minutes, and then dried at 55ºC for 30 minutes, LowAGE was only exposed to 80ºC for 1 minute during pelleting.” AGEs in human food can be reduced by boiling, steaming, and stewing food, instead of frying and grilling. Another way would be to microwave the food in the presence of sufficient liquid so that the food is not cooked fully dried. The development of AGEs is delayed in the presence of water.

Increased Pentosidine, an AGE, Is Found in Serum and Synovial Fluid of Patients with Osteoarthritis

An example of an inflammatory process is osteoarthritis (OA), which affects almost 15% of the adult population.3 A recent paper3 reports that pentosidine, an advanced glycation end product (AGE) increasingly accumulates with age in articular cartilage and that the increased pentosidine levels are associated with cartilage destruction.
Glycotoxins and AGEs Increase with Age in Humans

Another very recent paper4 reported that, in a comparison of 172 young (less than 45) and older (over 60) individuals, circulating indicators of AGEs {derivatives of CML [Nε-(carboxymethyl)lysine] or MG (methylglyoxal)} increased with aging and, regardless of age, correlated with indicators of inflammation, such as C-reactive protein, and oxidative stress, such as 8-isoprostane. A similar association was noted between CML and HOMA, an indicator of insulin resistance.

AGEs as a Prognostic Factor in Cardiac Surgery

In a recently published study,4.1 researchers examined levels of CML (carboxymethyllysine), as representative of advanced glycation end products (AGEs), in the pericardial fluid of 75 patients undergoing cardiac surgery and correlated CML to clinical parameters and outcome of these patients, including postoperative cardiac and pulmonary complications, deaths, ventilation time of greater than 24 hours, and intensive care unit stay of greater than 48 hours. Patients in the highest tertile of AGE pericardial fluid concentrations had an increase in all types of investigated adverse events as compared to the group with the lowest AGE concentrations. Only the group of patients in the highest tertile of AGE levels had significantly longer ventilation times and significantly more reduced heart function. Age itself only showed a correlation between increasing age and reduced heart function, but no direct effect on ventilation times. There were three deaths in the highest AGE group as compared to none in the lowest AGE group (not quite significant at P<0.07). Cardiac complications (atrial fibrillation, low cardiac output, postoperative myocardial ischemia) were significantly higher in the highest tertile of AGE concentration. These results are consistent with other evidence for the negative influence of AGEs on cardiovascular function.4.2,4.3

Low-AGE Meal vs. High-AGE Meal on Vasodilation in Type 2 Diabetics

A further new paper5A reports the results of feeding 20 inpatients with type 2 diabetes with a low-AGE meal and a high-AGE meal in a random crossover design. (The meals contained the same ingredients but different amounts of AGEs, which were obtained by varying the cooking temperature and time.)

After the high-AGE meal, the flow-mediated dilation (an indicator of endothelial function) decreased by 36.2%, while after the low-AGE meal, the flow-mediated dilation decreased by 20.9%. “This impairment of macrovascular function after the HAGE [high-AGE] meal was paralleled by an impairment of microvascular function (–67.2%) and increased concentrations of serum AGE and markers of endothelial dysfunction and oxidative stress.” According to the authors, approximately 10% of ingested AGEs are absorbed, and about two-thirds of those are deposited in tissues.

The high-AGE meal resulted in a significant increase in serum methylglyoxal (a highly reactive carbonyl compound) after 4 hours, which was not seen after the low-AGE meal. Moreover, the authors note, “. . . the change in serum methylglyoxal 4 h after the HAGE meal ingestion was negatively correlated with the FMD [flow-mediated dilation] change, suggesting that FMD impairment was at least partly due to the increase in serum methylglyoxal.” The authors conclude, “As a logical consequence, a simple dietetic intervention, which does not necessarily mean deprivation of certain foods, but only the preferred use of low-AGE-producing culinary techniques (boiling, poaching, or stewing) could represent an attractive prevention alternative to pharmacologic approaches.”

Another paper5B published the next year in a different journal by the same group of scientists as paper 5A reports that benfotiamine, a lipid-soluble form of thiamine (vitamin B1) prevents the endothelial dysfunction and oxidative stress in type 2 diabetics following a meal enriched in AGEs.
Thirteen type 2 adult diabetics, aged 56.9 ± 2.8 years and without a history of acute cardiovascular events, were included in the study. (The food was fried/boiled at 230ºC for 20 minutes to ensure a high concentration of AGEs.) Subjects ate the test meal before and after a 3-day therapy with benfotiamine (1050 mg/day) The researchers measured various markers of endothelial dysfunction and oxidative stress.
The HAGE (high-AGE-containing) meal induced a significant impairment in flow-mediated dilation, a measure of endothelial function. This effect was completely prevented by benfotiamine. All the significant markers of endothelial dysfunction examined by the researchers significantly increased after HAGE: E-selectin, ICAM-1, and VCAM-1. These effects were prevented by benfotiamine pretreatment. HAGE significantly increased C-reactive protein, but benfotiamine had no effect on this. The AGE precursor CML significantly increased at 4 hours after the HAGE; this effect was prevented by benfotiamine. Similarly, MG (methylglyoxal) increased 4 hours after the HAGE, and this effect was also prevented by benfotiamine pretreatment.
These are pretty phenomenal results, and, although the number of subjects was small, they were human, and results were consistent. As it is impossible to avoid all AGEs, and eating nothing but boiled and stewed food could be a bummer, we are both now supplementing with benfotiamine.

Quercetin and Catechin May Decrease Proinflammatory Cytokines Released in Response to RAGE

In a cell-culture study,1 the effects of quercetin and catechin were studied as potential inhibitors of proinflammatory cytokines. The researchers studied the results of exposing human THP-1 monocytic cells to S100B, a protein that signals through RAGE to induce the release of proinflammatory cytokines tumor necrosis factor-α and IL-1β. The results showed that the treatment of those cells with 20 and 50 µM of quercetin and catechin resulted in significant inhibitory effects (P<0.05).

AGE Production May Be Reduced in Food Cooked at High Altitudes

It has been suggested that AGEs are produced at a reduced rate when cooked at high altitudes. Support for that hypothesis is provided by the fact that the boiling point of water is reduced to 90–93ºC (as compared to 100ºC at sea level) at 2–3 kilometers above sea level. Hence, wet cooking for a set period of time would produce only about ½ to ¼ of the AGEs in the food at high altitudes as compared to sea level.

Other Natural Products that Reduce Glycation and AGE Formation
1 Benfotiamine, a lipid-soluble form of thiamine, vitamin B16,7
2 Tomato paste8
3 Resveratrol, inositol, and others9
4 Pyridoxamine, a form of vitamin B610,11
5 Carnosine11,12
6 Curcumin13
7 Rosemary14
8 Alpha-lipoic acid15
9 Flavonoids luteolin, rutin, quercetin, kaempferol, and EGCG16
An AGE-Breaking Drug that Has Been Around for Nearly Forever but May Never Get FDA Approval
ALT-71117—this drug actually breaks previously formed “irreversible” AGEs. Might be nice to have, if you could get it. But with a price tag of about $800,000,000 to get FDA approval, it is a wonder that anything gets approved, and the very few large companies that can afford this price want to make sure things remain the same. Hence the recent introduction of a 1300-page Good Manufacturing Practices for dietary supplements rules and regulations from the FDA. “Let’s clean up (Order! We need order!) the dietary supplement industry by getting rid of these small, pesky, innovative companies.” We can anticipate significant price increases in dietary supplements as a result of the increased costs of complying with all these rules and regulations, as well as greatly reduced competition in the industry as thousands of the current 15,000 mostly small businesses go belly-up. But then, getting rid of your competitors with the help of the FDA’s guns by lobbying (and paying them user’s fees) is standard practice of oligopolists.
Advanced Glycation End Products (AGEs) and Accelerated Aging

Glycation results from the chemical bonding of reducing sugars, such as glucose, to lipids, nucleic acids, and proteins. The advanced glycation end products form and develop as a result of natural chemical processes from the formation of reversible Maillard products (the brown tasty stuff formed in cooking—for example, on the surface of fried foods) to the eventual production of irreversible AGEs. Exposure to AGEs in the body causes inflammation and thus contributes importantly to cardiovascular disease and other chronic inflammatory conditions associated with aging. (1)

“In vitro work has shown that ligation of the advanced glycation end products receptor (RAGE) is part of the complex interactions within oxidative stress and vascular damage, particularly in atherosclerosis and in the accelerated vascular damage that occurs in diabetes.” (1)
Lifespan Boost by Reducing Dietary AGEs

A Study 2 has now reported that putting mice on a low-AGE-containing diet not only reduced systemic AGE accumulation and RAGE levels, but also ameliorated insulin resistance and kidney dysfunction with age, as well as increasing reduced glutathione levels (a good measure of antioxidant status). Moreover, the animals on the low-AGE diet (50% lower than the controls, who received the same amount of food but prepared at a different temperature for a different length of time) also had a significant increase in median (15%) and maximum (6%) lifespan compared to the control animals. “At the median survival for RegAGE, 75% of LowAGE mice were alive, whereas at the maximal survival level for RegAGE, 40% of LowAGE mice were alive.”

The way the researchers produced the low-AGE diet for the mice was by limiting the exposure of the food to high temperatures. “Thus, compared with RegAGE, which is first steam-conditioned and pelleted at 70 to 75ºC for 1 to 2 minutes, and then dried at 55ºC for 30 minutes, LowAGE was only exposed to 80ºC for 1 minute during pelleting.” AGEs in human food can be reduced by boiling, steaming, and stewing food, instead of frying and grilling. Another way would be to microwave the food in the presence of sufficient liquid so that the food is not cooked fully dried. The development of AGEs is delayed in the presence of water.

Increased Pentosidine, an AGE, Is Found in Serum and Synovial Fluid of Patients with Osteoarthritis

An example of an inflammatory process is osteoarthritis (OA), which affects almost 15% of the adult population.3 A recent paper3 reports that pentosidine, an advanced glycation end product (AGE) increasingly accumulates with age in articular cartilage and that the increased pentosidine levels are associated with cartilage destruction.
Glycotoxins and AGEs Increase with Age in Humans

Another very recent paper4 reported that, in a comparison of 172 young (less than 45) and older (over 60) individuals, circulating indicators of AGEs {derivatives of CML [Nε-(carboxymethyl)lysine] or MG (methylglyoxal)} increased with aging and, regardless of age, correlated with indicators of inflammation, such as C-reactive protein, and oxidative stress, such as 8-isoprostane. A similar association was noted between CML and HOMA, an indicator of insulin resistance.

AGEs as a Prognostic Factor in Cardiac Surgery

In a recently published study,4.1 researchers examined levels of CML (carboxymethyllysine), as representative of advanced glycation end products (AGEs), in the pericardial fluid of 75 patients undergoing cardiac surgery and correlated CML to clinical parameters and outcome of these patients, including postoperative cardiac and pulmonary complications, deaths, ventilation time of greater than 24 hours, and intensive care unit stay of greater than 48 hours. Patients in the highest tertile of AGE pericardial fluid concentrations had an increase in all types of investigated adverse events as compared to the group with the lowest AGE concentrations. Only the group of patients in the highest tertile of AGE levels had significantly longer ventilation times and significantly more reduced heart function. Age itself only showed a correlation between increasing age and reduced heart function, but no direct effect on ventilation times. There were three deaths in the highest AGE group as compared to none in the lowest AGE group (not quite significant at P<0.07). Cardiac complications (atrial fibrillation, low cardiac output, postoperative myocardial ischemia) were significantly higher in the highest tertile of AGE concentration. These results are consistent with other evidence for the negative influence of AGEs on cardiovascular function.4.2,4.3

Low-AGE Meal vs. High-AGE Meal on Vasodilation in Type 2 Diabetics

A further new paper5A reports the results of feeding 20 inpatients with type 2 diabetes with a low-AGE meal and a high-AGE meal in a random crossover design. (The meals contained the same ingredients but different amounts of AGEs, which were obtained by varying the cooking temperature and time.)

After the high-AGE meal, the flow-mediated dilation (an indicator of endothelial function) decreased by 36.2%, while after the low-AGE meal, the flow-mediated dilation decreased by 20.9%. “This impairment of macrovascular function after the HAGE [high-AGE] meal was paralleled by an impairment of microvascular function (–67.2%) and increased concentrations of serum AGE and markers of endothelial dysfunction and oxidative stress.” According to the authors, approximately 10% of ingested AGEs are absorbed, and about two-thirds of those are deposited in tissues.

The high-AGE meal resulted in a significant increase in serum methylglyoxal (a highly reactive carbonyl compound) after 4 hours, which was not seen after the low-AGE meal. Moreover, the authors note, “. . . the change in serum methylglyoxal 4 h after the HAGE meal ingestion was negatively correlated with the FMD [flow-mediated dilation] change, suggesting that FMD impairment was at least partly due to the increase in serum methylglyoxal.” The authors conclude, “As a logical consequence, a simple dietetic intervention, which does not necessarily mean deprivation of certain foods, but only the preferred use of low-AGE-producing culinary techniques (boiling, poaching, or stewing) could represent an attractive prevention alternative to pharmacologic approaches.”

Another paper5B published the next year in a different journal by the same group of scientists as paper 5A reports that benfotiamine, a lipid-soluble form of thiamine (vitamin B1) prevents the endothelial dysfunction and oxidative stress in type 2 diabetics following a meal enriched in AGEs.
Thirteen type 2 adult diabetics, aged 56.9 ± 2.8 years and without a history of acute cardiovascular events, were included in the study. (The food was fried/boiled at 230ºC for 20 minutes to ensure a high concentration of AGEs.) Subjects ate the test meal before and after a 3-day therapy with benfotiamine (1050 mg/day) The researchers measured various markers of endothelial dysfunction and oxidative stress.
The HAGE (high-AGE-containing) meal induced a significant impairment in flow-mediated dilation, a measure of endothelial function. This effect was completely prevented by benfotiamine. All the significant markers of endothelial dysfunction examined by the researchers significantly increased after HAGE: E-selectin, ICAM-1, and VCAM-1. These effects were prevented by benfotiamine pretreatment. HAGE significantly increased C-reactive protein, but benfotiamine had no effect on this. The AGE precursor CML significantly increased at 4 hours after the HAGE; this effect was prevented by benfotiamine. Similarly, MG (methylglyoxal) increased 4 hours after the HAGE, and this effect was also prevented by benfotiamine pretreatment.
These are pretty phenomenal results, and, although the number of subjects was small, they were human, and results were consistent. As it is impossible to avoid all AGEs, and eating nothing but boiled and stewed food could be a bummer, we are both now supplementing with benfotiamine.

Quercetin and Catechin May Decrease Proinflammatory Cytokines Released in Response to RAGE

In a cell-culture study,1 the effects of quercetin and catechin were studied as potential inhibitors of proinflammatory cytokines. The researchers studied the results of exposing human THP-1 monocytic cells to S100B, a protein that signals through RAGE to induce the release of proinflammatory cytokines tumor necrosis factor-α and IL-1β. The results showed that the treatment of those cells with 20 and 50 µM of quercetin and catechin resulted in significant inhibitory effects (P<0.05).

AGE Production May Be Reduced in Food Cooked at High Altitudes

It has been suggested that AGEs are produced at a reduced rate when cooked at high altitudes. Support for that hypothesis is provided by the fact that the boiling point of water is reduced to 90–93ºC (as compared to 100ºC at sea level) at 2–3 kilometers above sea level. Hence, wet cooking for a set period of time would produce only about ½ to ¼ of the AGEs in the food at high altitudes as compared to sea level.

Other Natural Products that Reduce Glycation and AGE Formation
1 Benfotiamine, a lipid-soluble form of thiamine, vitamin B16,7
2 Tomato paste8
3 Resveratrol, inositol, and others9
4 Pyridoxamine, a form of vitamin B610,11
5 Carnosine11,12
6 Curcumin13
7 Rosemary14
8 Alpha-lipoic acid15
9 Flavonoids luteolin, rutin, quercetin, kaempferol, and EGCG16
An AGE-Breaking Drug that Has Been Around for Nearly Forever but May Never Get FDA Approval
ALT-71117—this drug actually breaks previously formed “irreversible” AGEs. Might be nice to have, if you could get it. But with a price tag of about $800,000,000 to get FDA approval, it is a wonder that anything gets approved, and the very few large companies that can afford this price want to make sure things remain the same. Hence the recent introduction of a 1300-page Good Manufacturing Practices for dietary supplements rules and regulations from the FDA. “Let’s clean up (Order! We need order!) the dietary supplement industry by getting rid of these small, pesky, innovative companies.” We can anticipate significant price increases in dietary supplements as a result of the increased costs of complying with all these rules and regulations, as well as greatly reduced competition in the industry as thousands of the current 15,000 mostly small businesses go belly-up. But then, getting rid of your competitors with the help of the FDA’s guns by lobbying (and paying them user’s fees) is standard practice of oligopolists.

 

 

 

The new database contains more than twice the number of food items than the previously reported database (13) and shows that, based on standard serving sizes, the meat group contained the highest levels of AGEs. Although fats tend to contain more dAGE per gram of weight, meats will likely contribute more to overall dAGE intake because meats are served in larger portions than are fats. When items in the meat category prepared by similar methods were compared, the highest dAGE levels were observed in beef and cheeses followed by poultry, pork, fish, and eggs. Lamb ranked relatively low in dAGEs compared to other meats (Table 1 available online at www.adajournal.org). It is noteworthy that even lean red meats and poultry contain high levels of dAGEs when cooked under dry heat. This is attributable to the fact that among the intracellular components of lean muscle there exist highly reactive amino-lipids, as well as reducing sugars, such as fructose or glucose-6-phosphate, the combination of which in the presence of heat rapidly accelerates new dAGE formation (30,32).

Higher-fat and aged cheeses, such as full-fat American and Parmesan, contained more dAGEs than lower-fat cheeses, such as reduced-fat mozzarella, 2% milk cheddar, and cottage cheese. Whereas cooking is known to drive the generation of new AGEs in foods, it is interesting to note that even uncooked, animal-derived foods such as cheeses can contain large amounts of dAGEs. This is likely due to pasteurization and/or holding times at ambient room temperatures (eg, as in curing or aging processes) (33). Glycation-oxidation reactions, although at a slower rate, continue to occur over time even at cool temperatures, resulting in large accumulation of dAGEs in the long term.

High-fat spreads, including butter, cream cheese, margarine, and mayonnaise, were also among the foods highest in dAGEs, followed by oils and nuts. As with certain cheeses, butter and different types of oils are AGE-rich, even in their uncooked forms. This may be due to various extraction and purification procedures involving heat, in combination with air and dry conditions, however mild they are.

Of note, with heat kept constant, the type of cooking fat used led to different amounts of dAGEs. For instance, scrambled eggs prepared with a cooking spray, margarine, or oil had ~50% to 75% less dAGEs than if cooked with butter (Table 1 available online at www.adajournal.org).

In comparison to the meat and fat groups, the carbohydrate group generally contained lower amounts of AGEs (Table 1 available online at www.adajournal.org). This may be due to the often higher water content or higher level of antioxidants and vitamins in these foods, which may diminish new AGE formation. Furthermore, in this food category, most polysaccharides consist of non-reducing sugars, less likely to give rise to AGEs. The highest dAGE level per gram of food in this category was found in dry-heat processed foods such as crackers, chips, and cookies. This is likely due to the addition of ingredients such as butter, oil, cheese, eggs, and nuts, which during dry-heat processing substantially accelerate dAGE generation. Although AGEs in these snack types of food remain far below those present in meats, they may represent an important health hazard for people who consume multiple snacks during the day or as fast meals (34).

Grains, legumes, breads, vegetables, fruits, and milk were among the lowest items in dAGE, unless prepared with added fats. For instance, biscuits had more than 10 times the amount of dAGEs found in low-fat breads, rolls, or bagels.

Nonfat milk had significantly lower dAGEs than whole milk. Whereas heating increased the dAGE content of milk, the values were modest and remained low relative to those of cheeses (Table 1 available online at www.adajournal.org). Likewise, milk-related products with a high moisture index such as yogurt, pudding, and ice cream were also relatively low in AGEs. However, hot cocoa made from a dehydrated concentrate contained significantly higher amounts of AGEs.

13. Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri J, Vlassara H. Advanced glycoxidation end products in commonly consumed

30. Bucala R, Makita Z, Koschinsky T, Cerami A, Vlassara H. Lipid advanced glycosylation: Pathway for lipid oxidation in vivo. Proc Nat Acad Sci. 1993;90:6434–6438. [PMC free article] [PubMed]

31. Wheeler ML, Daly A, Evert A, Franz MJ, Geil P, Holzmeister LA, Kulkarni K, Loghmani E, Ross TA, Woolf P. Choose Your Foods: Exchange Lists for Diabetes, Sixth Edition, 2008: Description and guidelines for use. J Am Diet Assoc. 2008;108:883–888.

32. Levi B, Werman MJ. Fructose and related phosphate derivatives impose DNA damage and apoptosis in L5178Y mouse lymphoma cells. J Nutr Biochem. 2003;14:49–60. [PubMed]

33. Ahmed N, Mirshekar-Syahkal B, Kennish L, Karachalias N, Babaei-Jadidi R, Thornalley PJ. Assay of advanced glycation endproducts in selected beverages and food by liquid chromatography with tandem mass spectrometric detection. Mol Nutr Food Res. 2005;49:691–699. [PubMed]

34. Story M, Hayes M, Kalina B. Availability of foods in high schools: Is there cause for concern? J Am Diet Assoc. 1996;96:123–126. [PubMed]

 

 

 

 

 

 

unoreactivity from the meal with fructose.[28]
Potential therapy[edit]
Diagram of a resveratrol molecule
AGEs are the subject of ongoing research. There are three therapeutic approaches: preventing the formation of AGEs, breaking crosslinks after they are formed and preventing their negative effects.
Compounds that have been found to inhibit AGE formation in the laboratory include Vitamin C, benfotiamine, pyridoxamine, alpha-lipoic acid,[29] taurine,[30] pimagedine,[31] aspirin,[32][33] carnosine,[34] metformin,[35] pioglitazone,[35] and pentoxifylline.[35]
Studies in rats and mice have found that natural phenols such as resveratrol and curcumin can prevent the negative effects of the AGEs.[36][37]
Compounds that are thought to break some existing AGE crosslinks include Alagebrium (and related ALT-462, ALT-486, and ALT-946)[38] and N-phenacyl thiazolium bromide.[39] One in vitro study shows that rosmarinic acid out performs the AGE breaking potential of ALT-711.[40]
Diagram of a glucosepane molecule
There is, however, no agent known that can break down the most common AGE, glucosepane, which appears 10 to 1,000 times more common in human tissue than any other cross-linking AGE.[41][42]
Some chemicals, on the other hand, like aminoguanidine, might limit the formation of AGEs by reacting with 3-deoxyglucosone.[24]

PMC 21074 . PMID 9177242.
29 Jump up 
^ Abdul, HM; Butterfield, DA (Feb 1, 2007). “Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease”. Free Radical Biology & Medicine. 42 (3): 371–84. doi:10.1016/j.freeradbiomed.2006.11.006. PMC 1808543 . PMID 17210450.
30 Jump up 
^ Nandhini AT, Thirunavukkarasu V, Anuradha CV (August 2005). “Taurine prevents collagen abnormalities in high fructose-fed rats” (PDF). Indian J. Med. Res. 122 (2): 171–7. PMID 16177476.
31 Jump up 
^ A. Gugliucci, “Sour Side of Sugar, A Glycation Web Page Archived July 1, 2007, at the Wayback Machine.
32 Jump up 
^ “Aspirin inhibits the formation of… preview & related info”. Mendeley. doi:10.1016/j.diabres.2006.12.024. Retrieved 2013-11-13.
33 Jump up 
^ Bucala R, Cerami A (1992). “Advanced glycosylation: chemistry, biology, and implications for diabetes and aging”. Adv. Pharmacol. Advances in Pharmacology. 23: 1–34. doi:10.1016/S1054-3589(08)60961-8. ISBN 9780120329236. PMID 1540533.
34 Jump up 
^ Guiotto A, Calderan A, Ruzza P, Borin G (2005). “Carnosine and carnosine-related antioxidants: a review”. Current Medicinal Chemistry. 12 (20): 2293–2315. doi:10.2174/0929867054864796. PMID 16181134.
35 ^ Jump up to: 
a b c Rahbar, S; Figarola, JL (2013-03-25). “Novel inhibitors of advanced glycation endproducts”. Arch. Biochem. Biophys. 419 (1): 63–79. doi:10.1016/j.abb.2003.08.009. PMID 14568010.
36 Jump up 
^ Mizutani, K; Ikeda, K; Yamori, Y (Jul 21, 2000). “Resveratrol inhibits AGEs-induced proliferation and collagen synthesis activity in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats”. Biochemical and Biophysical Research Communications. 274 (1): 61–7. doi:10.1006/bbrc.2000.3097. PMID 10903896.
37 Jump up 
^ Tang Y (May 2014). “Curcumin eliminates the effect of advanced glycation end-products (AGEs) on the divergent regulation of gene expression of receptors of AGEs by interrupting leptin signaling”. Lab Invest. 94 (5): 503–16. doi:10.1038/labinvest.2014.42. PMC 4006284 . PMID 24614199.
38 Jump up 
^ “Advanced glycation end-product cross-link breakersA novel approach to cardiovascular pathologies related to the aging process”. American Journal of Hypertension. 17: S23–S30. doi:10.1016/j.amjhyper.2004.08.022.
39 Jump up 
^ Vasan, S; Zhang, X; Zhang, X; Kapurniotu, A; Bernhagen, J; Teichberg, S; Basgen, J; Wagle, D; Shih, D; Terlecky, I; Bucala, R; Cerami, A; Egan, J; Ulrich, P (Jul 18, 1996). “An agent cleaving glucose-derived protein crosslinks in vitro and in vivo”. Nature. 382 (6588): 275–8. doi:10.1038/382275a0. PMID 8717046.
40 Jump up 
^ Daniel Jean; Maryse Pouligon; Claude Dalle. “Evaluation in vitro of AGE-crosslinks breaking ability of rosmarinic acid” (PDF). Glycative Stress Research.
41 Jump up 
^ Monnier, V. M.; Mustata, G. T.; Biemel, K. L.; Reihl, O.; Lederer, M. O.; Zhenyu, D.; et al. (2005). “Cross-linking of the extracellular matrix by the maillard reaction in aging and diabetes: An update on “a puzzle nearing resolution””. Annals of the New York Academy of Sciences. 1043: 533–544. doi:10.1196/annals.1333.061. PMID 16037276.
42 Jump up 
^ Furber, J.D. (2006). “Extracellular glycation crosslinks: Prospects for removal”. Rejuvenation Research. Elsevier Inc. 9 (2): 274–278. doi:10.1089/rej.2006.9.274. PMID 16706655.
External links[edit]

 

 

 

 

 

 

References
1. Huang et al. Effects of flavonoids on the expression of the pro-inflammatory responses in human monocytes induced by ligation of the receptor for AGEs. Mol Nutr Food Res 50:1129-39 (2006).
2. Cai et al. Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet. Am J Pathol 170:1893-1902 (2007).
3. Senolt et al. Increased pentosidine, an advanced glycation end product in serum and synovial fluid from patients with knee osteoarthritis and its relation with cartilage oligomeric matrix protein. Ann Rheum Dis 64:886-90 (2005).
4. Uribarri et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J Gerontol Ser A: Biol Sci Med Sci 62:427-33 (2007).
4.1. Simm et al. Advanced glycation endproducts: a biomarker for age as an outcome predictor after cardiac surgery? Exp Gerontol 42:668-75 (2007).
4.2. Heine and Dekker. Beyond postprandial hyperglycaemia: metabolic factors associated with cardiovascular disease. Diabetologia 45:461-75 (2002).
4.3 Nerlich and Schleicher. Nε-(carboxymethyl)lysine in atherosclerotic vascular lesions as a marker for local oxidative stress. Atherosclerosis 144:41-7 (1999).
5A. Negrean et al. Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus. Am J Clin Nutr 85:1236-43 (2007).
5B. Stirban et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabet Care 29:2064-71 (2006).
6. Stracke et al. Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats. Exp Clin Endocrinol Diabet 109:330-6 (2001).
7. Hammes et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nature Med 9:294-9 (2003).
8. Kiho et al. Tomato paste fraction inhibiting the formation of advanced glycation end-products. Biosci Biotechnol Biochem 68:200-5 (2004).
9. Rahbar and Figarola. Novel inhibitors of advanced glycation endproducts. Arch Biochem Biophys 419:63-79 (2003).
10. Metz et al. Pyridoxamine, an inhibitor of advanced glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complications. Arch Biochem Biophys 419:41-9 (2003).
11. Monnier. Intervention against the Maillard reaction in vivo. Arch Biochem Biophys 419:1-15 (2003).
12. Brownson and Hipkiss. Carnosine reacts with a glycated protein. Free Rad Biol Med 28:1564-70 (2000).
13. Jain et al. Effect of curcumin on protein glycosylation, lipid peroxidation, and oxygen radical generation in human red blood cells exposed to high glucose levels. Free Rad Biol Med 41:92-6 (2006).
14. Hsieh et al. Low-density lipoprotein, collagen, and thrombin models reveal that Rosemarinus officinalis L. exhibits potent antiglycative effects. J Agric Food Chem 55:2884-91 (2007).
15. Bierhaus et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 46:1481-90 (1997).
16. Wu and Yen. Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts. J Agric Food Chem 53:3167-73 (2005).
17. “Treatment of aged dogs with the cross-link breaker phenyl-4,5-dimethylthazolium [sic] chloride (ALT-711) resulted in a significant reduction of left ventricular stiffness which was accompanied by improvement in cardiac function.” Quoted from Ref. 4.1 above, which cites, as the source of this information, Asif et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 97:2809-13 (2000). A correction to that paper appears in Proc Natl Acad Sci USA 97:5679 (2000), pointing out that the correct name of the compound is 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride

 

 

 

References
1. Huang et al. Effects of flavonoids on the expression of the pro-inflammatory responses in human monocytes induced by ligation of the receptor for AGEs. Mol Nutr Food Res 50:1129-39 (2006).
2. Cai et al. Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet. Am J Pathol 170:1893-1902 (2007).
3. Senolt et al. Increased pentosidine, an advanced glycation end product in serum and synovial fluid from patients with knee osteoarthritis and its relation with cartilage oligomeric matrix protein. Ann Rheum Dis 64:886-90 (2005).
4. Uribarri et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J Gerontol Ser A: Biol Sci Med Sci 62:427-33 (2007).
4.1. Simm et al. Advanced glycation endproducts: a biomarker for age as an outcome predictor after cardiac surgery? Exp Gerontol 42:668-75 (2007).
4.2. Heine and Dekker. Beyond postprandial hyperglycaemia: metabolic factors associated with cardiovascular disease. Diabetologia 45:461-75 (2002).
4.3 Nerlich and Schleicher. Nε-(carboxymethyl)lysine in atherosclerotic vascular lesions as a marker for local oxidative stress. Atherosclerosis 144:41-7 (1999).
5A. Negrean et al. Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus. Am J Clin Nutr 85:1236-43 (2007).
5B. Stirban et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabet Care 29:2064-71 (2006).
6. Stracke et al. Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats. Exp Clin Endocrinol Diabet 109:330-6 (2001).
7. Hammes et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nature Med 9:294-9 (2003).
8. Kiho et al. Tomato paste fraction inhibiting the formation of advanced glycation end-products. Biosci Biotechnol Biochem 68:200-5 (2004).
9. Rahbar and Figarola. Novel inhibitors of advanced glycation endproducts. Arch Biochem Biophys 419:63-79 (2003).
10. Metz et al. Pyridoxamine, an inhibitor of advanced glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complications. Arch Biochem Biophys 419:41-9 (2003).
11. Monnier. Intervention against the Maillard reaction in vivo. Arch Biochem Biophys 419:1-15 (2003).
12. Brownson and Hipkiss. Carnosine reacts with a glycated protein. Free Rad Biol Med 28:1564-70 (2000).
13. Jain et al. Effect of curcumin on protein glycosylation, lipid peroxidation, and oxygen radical generation in human red blood cells exposed to high glucose levels. Free Rad Biol Med 41:92-6 (2006).
14. Hsieh et al. Low-density lipoprotein, collagen, and thrombin models reveal that Rosemarinus officinalis L. exhibits potent antiglycative effects. J Agric Food Chem 55:2884-91 (2007).
15. Bierhaus et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 46:1481-90 (1997).
16. Wu and Yen. Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts. J Agric Food Chem 53:3167-73 (2005).
17. “Treatment of aged dogs with the cross-link breaker phenyl-4,5-dimethylthazolium [sic] chloride (ALT-711) resulted in a significant reduction of left ventricular stiffness which was accompanied by improvement in cardiac function.” Quoted from Ref. 4.1 above, which cites, as the source of this information, Asif et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 97:2809-13 (2000). A correction to that paper appears in Proc Natl Acad Sci USA 97:5679 (2000), pointing out that the correct name of the compound is 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride

Advanced Glycation End Products (AGEs) and Accelerated Aging

Glycation results from the chemical bonding of reducing sugars, such as glucose, to lipids, nucleic acids, and proteins. The advanced glycation end products form and develop as a result of natural chemical processes from the formation of reversible Maillard products (the brown tasty stuff formed in cooking—for example, on the surface of fried foods) to the eventual production of irreversible AGEs. Exposure to AGEs in the body causes inflammation and thus contributes importantly to cardiovascular disease  and other chronic inflammatory conditions associated with aging. (1)

“In vitro work has shown that ligation of the advanced glycation end products receptor (RAGE) is part of the complex interactions within oxidative stress and vascular damage, particularly in atherosclerosis and in the accelerated vascular damage that occurs in diabetes.” (1)

Lifespan Boost by Reducing Dietary AGEs

A Study 2 has now reported that putting mice on a low-AGE-containing diet not only reduced systemic AGE accumulation and RAGE levels, but also ameliorated insulin resistance and kidney dysfunction with age, as well as increasing reduced glutathione levels (a good measure of antioxidant status). Moreover, the animals on the low-AGE diet (50% lower than the controls, who received the same amount of food but prepared at a different temperature for a different length of time) also had a significant increase in median (15%) and maximum (6%) lifespan compared to the control animals. “At the median survival for RegAGE, 75% of LowAGE mice were alive, whereas at the maximal survival level for RegAGE, 40% of LowAGE mice were alive.”

The way the researchers produced the low-AGE diet for the mice was by limiting the exposure of the food to high temperatures. “Thus, compared with RegAGE, which is first steam-conditioned and pelleted at 70 to 75ºC for 1 to 2 minutes, and then dried at 55ºC for 30 minutes, LowAGE was only exposed to 80ºC for 1 minute during pelleting.” AGEs in human food can be reduced by boiling, steaming, and stewing food, instead of frying and grilling. Another way would be to microwave the food in the presence of sufficient liquid so that the food is not cooked fully dried. The development of AGEs is delayed in the presence of water.

Increased Pentosidine, an AGE, Is Found in Serum and Synovial Fluid of Patients with Osteoarthritis

An example of an inflammatory process is osteoarthritis (OA), which affects almost 15% of the adult population.3 A recent paper3 reports that pentosidine, an advanced glycation end product (AGE) increasingly accumulates with age in articular cartilage and that the increased pentosidine levels are associated with cartilage destruction.

Glycotoxins and AGEs Increase with Age in Humans

Another very recent paper4 reported that, in a comparison of 172 young (less than 45) and older (over 60) individuals, circulating indicators of AGEs {derivatives of CML [Nε-(carboxymethyl)lysine] or MG (methylglyoxal)} increased with aging and, regardless of age, correlated with indicators of inflammation, such as C-reactive protein, and oxidative stress, such as 8-isoprostane. A similar association was noted between CML and HOMA, an indicator of insulin resistance.

AGEs as a Prognostic Factor in Cardiac Surgery

In a recently published study,4.1 researchers examined levels of CML (carboxymethyllysine), as representative of advanced glycation end products (AGEs), in the pericardial fluid of 75 patients undergoing cardiac surgery and correlated CML to clinical parameters and outcome of these patients, including postoperative cardiac and pulmonary complications, deaths, ventilation time of greater than 24 hours, and intensive care unit stay of greater than 48 hours. Patients in the highest tertile of AGE pericardial fluid concentrations had an increase in all types of investigated adverse events as compared to the group with the lowest AGE concentrations. Only the group of patients in the highest tertile of AGE levels had significantly longer ventilation times and significantly more reduced heart function. Age itself only showed a correlation between increasing age and reduced heart function, but no direct effect on ventilation times. There were three deaths in the highest AGE group as compared to none in the lowest AGE group (not quite significant at P<0.07). Cardiac complications (atrial fibrillation, low cardiac output, postoperative myocardial ischemia) were significantly higher in the highest tertile of AGE concentration. These results are consistent with other evidence for the negative influence of AGEs on cardiovascular function.4.2,4.3

Low-AGE Meal vs. High-AGE Meal on Vasodilation in Type 2 Diabetics

A further new paper5A reports the results of feeding 20 inpatients with type 2 diabetes with a low-AGE meal and a high-AGE meal in a random crossover design. (The meals contained the same ingredients but different amounts of AGEs, which were obtained by varying the cooking temperature and time.)

After the high-AGE meal, the flow-mediated dilation (an indicator of endothelial function) decreased by 36.2%, while after the low-AGE meal, the flow-mediated dilation decreased by 20.9%. “This impairment of macrovascular function after the HAGE [high-AGE] meal was paralleled by an impairment of microvascular function (–67.2%) and increased concentrations of serum AGE and markers of endothelial dysfunction and oxidative stress.” According to the authors, approximately 10% of ingested AGEs are absorbed, and about two-thirds of those are deposited in tissues.

The high-AGE meal resulted in a significant increase in serum methylglyoxal (a highly reactive carbonyl compound) after 4 hours, which was not seen after the low-AGE meal. Moreover, the authors note, “. . . the change in serum methylglyoxal 4 h after the HAGE meal ingestion was negatively correlated with the FMD [flow-mediated dilation] change, suggesting that FMD impairment was at least partly due to the increase in serum methylglyoxal.” The authors conclude, “As a logical consequence, a simple dietetic intervention, which does not necessarily mean deprivation of certain foods, but only the preferred use of low-AGE-producing culinary techniques (boiling, poaching, or stewing) could represent an attractive prevention alternative to pharmacologic approaches.”

Another paper5B published the next year in a different journal by the same group of scientists as paper 5A reports that benfotiamine, a lipid-soluble form of thiamine (vitamin B1) prevents the endothelial dysfunction and oxidative stress in type 2 diabetics following a meal enriched in AGEs.

Thirteen type 2 adult diabetics, aged 56.9 ± 2.8 years and without a history of acute cardiovascular events, were included in the study. (The food was fried/boiled at 230ºC for 20 minutes to ensure a high concentration of AGEs.) Subjects ate the test meal before and after a 3-day therapy with benfotiamine (1050 mg/day) The researchers measured various markers of endothelial dysfunction and oxidative stress.

The HAGE (high-AGE-containing) meal induced a significant impairment in flow-mediated dilation, a measure of endothelial function. This effect was completely prevented by benfotiamine. All the significant markers of endothelial dysfunction examined by the researchers significantly increased after HAGE: E-selectin, ICAM-1, and VCAM-1. These effects were prevented by benfotiamine pretreatment. HAGE significantly increased C-reactive protein, but benfotiamine had no effect on this. The AGE precursor CML significantly increased at 4 hours after the HAGE; this effect was prevented by benfotiamine. Similarly, MG (methylglyoxal) increased 4 hours after the HAGE, and this effect was also prevented by benfotiamine pretreatment.

These are pretty phenomenal results, and, although the number of subjects was small, they were human, and results were consistent. As it is impossible to avoid all AGEs, and eating nothing but boiled and stewed food could be a bummer, we are both now supplementing with benfotiamine.

Quercetin and Catechin May Decrease Proinflammatory Cytokines Released in Response to RAGE

In a cell-culture study,1 the effects of quercetin and catechin were studied as potential inhibitors of proinflammatory cytokines. The researchers studied the results of exposing human THP-1 monocytic cells to S100B, a protein that signals through RAGE to induce the release of proinflammatory cytokines tumor necrosis factor-α and IL-1β. The results showed that the treatment of those cells with 20 and 50 µM of quercetin and catechin resulted in significant inhibitory effects (P<0.05).

AGE Production May Be Reduced in Food Cooked at High Altitudes

It has been suggested that AGEs are produced at a reduced rate when cooked at high altitudes. Support for that hypothesis is provided by the fact that the boiling point of water is reduced to 90–93ºC (as compared to 100ºC at sea level) at 2–3 kilometers above sea level. Hence, wet cooking for a set period of time would produce only about ½ to ¼ of the AGEs in the food at high altitudes as compared to sea level.

Other Natural Products that Reduce Glycation and AGE Formation

1Benfotiamine, a lipid-soluble form of thiamine, vitamin B16,7

2Tomato paste8

3Resveratrol, inositol, and others9

4Pyridoxamine, a form of vitamin B610,11

5Carnosine11,12

6Curcumin13

7Rosemary14

8Alpha-lipoic acid15

9Flavonoids luteolin, rutin, quercetin, kaempferol, and EGCG16

An AGE-Breaking Drug that Has Been Around for Nearly Forever but May Never Get FDA Approval

ALT-71117—this drug actually breaks previously formed “irreversible” AGEs. Might be nice to have, if you could get it. But with a price tag of about $800,000,000 to get FDA approval, it is a wonder that anything gets approved, and the very few large companies that can afford this price want to make sure things remain the same. Hence the recent introduction of a 1300-page Good Manufacturing Practices for dietary supplements rules and regulations from the FDA. “Let’s clean up (Order! We need order!) the dietary supplement industry by getting rid of these small, pesky, innovative companies.” We can anticipate significant price increases in dietary supplements as a result of the increased costs of complying with all these rules and regulations, as well as greatly reduced competition in the industry as thousands of the current 15,000 mostly small businesses go belly-up. But then, getting rid of your competitors with the help of the FDA’s guns by lobbying (and paying them user’s fees) is standard practice of oligopolists.

References

1. Huang et al. Effects of flavonoids on the expression of the pro-inflammatory responses in human monocytes induced by ligation of the receptor for AGEs. Mol Nutr Food Res 50:1129-39 (2006).

2. Cai et al. Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet. Am J Pathol 170:1893-1902 (2007).

3. Senolt et al. Increased pentosidine, an advanced glycation end product in serum and synovial fluid from patients with knee osteoarthritis and its relation with cartilage oligomeric matrix protein. Ann Rheum Dis 64:886-90 (2005).

4. Uribarri et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J Gerontol Ser A: Biol Sci Med Sci 62:427-33 (2007).

4.1. Simm et al. Advanced glycation endproducts: a biomarker for age as an outcome predictor after cardiac surgery? Exp Gerontol 42:668-75 (2007).

4.2. Heine and Dekker. Beyond postprandial hyperglycaemia: metabolic factors associated with cardiovascular disease. Diabetologia 45:461-75 (2002).

4.3 Nerlich and Schleicher. Nε-(carboxymethyl)lysine in atherosclerotic vascular lesions as a marker for local oxidative stress. Atherosclerosis 144:41-7 (1999).

5A. Negrean et al. Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus. Am J Clin Nutr 85:1236-43 (2007).

5B. Stirban et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabet Care 29:2064-71 (2006).

6. Stracke et al. Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats. Exp Clin Endocrinol Diabet 109:330-6 (2001).

7. Hammes et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nature Med 9:294-9 (2003).

8. Kiho et al. Tomato paste fraction inhibiting the formation of advanced glycation end-products. Biosci Biotechnol Biochem 68:200-5 (2004).

9. Rahbar and Figarola. Novel inhibitors of advanced glycation endproducts. Arch Biochem Biophys 419:63-79 (2003).

10. Metz et al. Pyridoxamine, an inhibitor of advanced glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complications. Arch Biochem Biophys 419:41-9 (2003).

11. Monnier. Intervention against the Maillard reaction in vivo. Arch Biochem Biophys 419:1-15 (2003).

12. Brownson and Hipkiss. Carnosine reacts with a glycated protein. Free Rad Biol Med 28:1564-70 (2000).

13. Jain et al. Effect of curcumin on protein glycosylation, lipid peroxidation, and oxygen radical generation in human red blood cells exposed to high glucose levels. Free Rad Biol Med 41:92-6 (2006).

14. Hsieh et al. Low-density lipoprotein, collagen, and thrombin models reveal that Rosemarinus officinalis L. exhibits potent antiglycative effects. J Agric Food Chem 55:2884-91 (2007).

15. Bierhaus et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 46:1481-90 (1997).

16. Wu and Yen. Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts. J Agric Food Chem 53:3167-73 (2005).

17. “Treatment of aged dogs with the cross-link breaker phenyl-4,5-dimethylthazolium [sic] chloride (ALT-711) resulted in a significant reduction of left ventricular stiffness which was accompanied by improvement in cardiac function.” Quoted from Ref. 4.1 above, which cites, as the source of this information, Asif et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 97:2809-13 (2000). A correction to that paper appears in Proc Natl Acad Sci USA 97:5679 (2000), pointing out that the correct name of the compound is 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride

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