The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 10 No. 2 • June 2007


SPECIAL REPORT
Advanced Glycation End Products (AGEs) and Life Extension

We have discussed many times the important participation of glycation (chemical bonding of reducing sugars, such as glucose, to lipids, nucleic acids, and proteins) in aging. The advanced glycation end products (appropriately called AGEs) 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 disease1 and other chronic inflammatory conditions associated with aging. As noted in paper #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.”

Lifespan Extension by Reducing Dietary AGEs

A new paper2 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. Pentosidine correlated significantly with COMP (cartilage oligomeric matrix protein), a marker of articular cartilage destruction, as well as with matrix metalloproteinase-3, an important degradative enzyme in cartilage breakdown. “Compared with the control group, significantly higher mean (SD) serum pentosidine [132.1 (56.2) vs. 97.7 (24.0) nmol/l, P<0.01] and COMP [4.1 (1.3) vs. 3.3 (1.4) µg/ml, P<0.05] levels were found in the patients with OA (Fig. 1).”

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.

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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