NEW! Durk & Sandy’s Anti-AGE Formulation

Reducing Glycation Reactions for Better Health and Longer Life
By Durk Pearson & Sandy Shaw

First appeared in the February 2008 issue

he Bottom Line: A large variety of age-associated diseases (e.g., joint stiffness, cataracts, Alzheimer’s disease, and cardiovascular disease) and probably aging itself are promoted by the effects of advanced glycation end products (AGEs), an unavoidable byproduct of eating digestible carbohydrates, cooking food, and maintaining tightly regulated (not so well regulated in diabetes) circulating levels of glucose in the bloodstream as a necessary fuel. We developed our Durk & Sandy’s anti-AGE formulation to help prevent these AGE-associated diseases and possibly to extend our lives.

Part I of this report appeared in the June 2007 issue of our Life Extension News, (published in Life Enhancement, September 2007), as a special report entitled “Advanced Glycation End Products (AGEs) and Life Extension.” As we explained in that article, the chemical reaction of glucose (and certain other sugars, such as fructose and ribose) with proteins is a process called glycation, which proceeds via various chemical reactions to produce AGEs, resulting in many of the deleterious effects associated with aging, cancer, and atherosclerosis, including oxidative stress, cross-linking, and chronic inflammatory states. Glycation is particularly severe in diabetes because of hyperglycemia, but it also occurs as an important, ongoing aging process in nondiabetic individuals. Levels of AGEs were found to be increased in older (over 60) as compared to younger (less than 45) humans.

While it is possible to reduce AGEs
created in food preparation, it is not
possible to avoid all AGEs in food.

Increased levels of AGEs have been found in the synovial fluid of patients with osteoarthritis. In one study, the levels of carboxymethyllysine, an AGE, in the pericardial fluid of 75 patients undergoing cardiac surgery correlated with outcome in these patients, including postoperative deaths, pulmonary complications, and intensive-care-unit stays of greater than 48 hours.

A high-AGE-containing meal resulted in a significantly decreased endothelial vasodilation in human type 2 diabetics, while a low-AGE-containing meal decreased vasodilation by much less. The high-AGE meal also resulted in significantly increased methylglyoxal (a highly reactive glycation product), not seen after the low-AGE meal.

Reducing AGEs in the diets of mice resulted in a significantly increased reduced glutathione level (an indicator of improved antioxidant status), and it also, importantly, significantly increased both median (15%) and maximum (6%) lifespan as compared to the mice on the high-AGE diet (same food but prepared at higher temperatures for a longer period of time, which increases glycation reactions). See Part I for the references to all these studies.

Part II. Introducing Durk & Sandy’s
Anti-AGE Formulation

While it is possible to significantly reduce AGEs created in food preparation by reducing temperature and by using boiling, poaching, or stewing rather than frying and grilling, it is not possible to avoid all AGEs in food. Moreover, although you can help keep blood sugar levels down by dietary choices (such as eating a low-glycemic-index diet), glycation still occurs relentlessly throughout life. We have developed a dietary supplement for our own use that, in studies of the individual components, has been shown to be very effective in reducing glycation reactions.

Take one or two capsules with each meal.* Six capsules will provide:

1000 mg


1000 mg


1000 mg


1000 mg

Alpha-lipoic acid

500 mg


50 mg

Thiamine (vitamin B1 as thiamine Hcl)

50 mg

Pyridoxine (vitamin B6 as pyridoxine Hcl)

*We each take two capsules with each meal. Unfortunately, some of these ingredients are expensive. So if you are on a tight budget, you might want to take one capsule with a regular meal and two capsules with a high-AGE-containing or high-glycemic-index meal. For the most limited budgets, take one or two capsules per day only with your highest-AGE-containing or highest-glycemic-index meal of the day. Examples of high-AGE meals include foods that are barbecued, fried, broiled, roasted, or blackened. The more browning you see, the higher the AGE content. Most restaurant meals are both high-glycemic-index and high-AGE, as are fried foods, such as fast-food burgers.


Rutin, a flavonoid found in fruits and vegetables, has been reported to modulate the formation of AGEs.1,2 As explained in Reference 1, “Advanced glycation end products accumulate on long-lived proteins such as collagen, altering structural, biochemical, and physical properties. The concentration of AGE-modified collagen increases in tissues with increasing age and may contribute to the reduction in elasticity of artery, heart, and lung tissues that occurs as organisms age. . . . Additional clinical conditions possibly accelerated by AGEs include neuropathy, nephropathy [kidney dysfunction], retinopathy, joint stiffness, senile cataracts, Alzheimer’s disease, and cardiovascular disease.”

In the first study,1 streptozotocin-induced diabetic rats had increased skin-collagen fluorescence, indicative of glycation. Aminoguanidine (an antiglycation compound) or rutin protected against the formation of these fluorescent adducts. Certain natural metabolites of rutin, including quercetin, also provided protection. The authors calculated that, since the blood glucose concentration of normal humans is about 5 µM, and since the ratio of rutin metabolite to monosaccharide examined in the study was 0.001, only micromolar levels of rutin may be necessary for rutin efficacy in vivo. The amount of active metabolites would need to be about 5 µM, and the authors say that such concentrations could be reached in the human volunteers when 50 mg of rutin were used in their diets.

In Reference 2, rutin was found to have a significant inhibitory effect on glycation of hemoglobin, and it was more effective than aminoguanidine. Testing for glycated hemoglobin is a good way to keep track of long-term glycation.

Carnosine and Histidine

Carnosine is a dipeptide made up of two amino acids, beta-alanine and histidine. Much has been written about the antiglycation and other properties of carnosine—much less about the antiglycation effects of histidine.

Recent papers have reported, for example, that carnosine and its constituents (histidine and beta-alanine) inhibit the glycation of low-density lipoproteins (LDL) that promotes foam-cell formation in vitro3 by stimulating glycated LDL uptake by macrophages, which then migrate into atherosclerotic plaques. One very interesting finding in this study was that carnosine was more effective in preventing glycation of short-lived proteins, a process that takes place rapidly, whereas histidine and beta-alanine provide protection over a longer period of time, as happens in slower glycation reactions, such as those induced by glucose. As the authors explain, “. . . histidine and beta-alanine have been reported to have negligible carbonyl scavenging activity over a 5-hour period. However, over 24 hours, histidine but not beta-alanine afforded significant protection against modifications. Over even longer periods (2–17 days), all three compounds afforded significant protection against aldehyde-mediated protein cross-linking and loss of enzyme activity.”

Another study4 reported that carnosine was highly protective against glycation of human Cu,Zn-superoxide dismutase and thus protects the enzyme from inactivation.

Another recent study5 reported that histidine was even more effective than carnosine in preventing glycation of the enzyme aspartate aminotransferase, a vitamin B6-dependent protein known to be glycated in vivo (the enzyme was incubated with glyceraldehyde, a cross-linking agent, and 20 mM of either carnosine or histidine at 37°C, human body temperature, for 2 days). Histidine at 500 µM (incubated with glyceraldehyde-3-phosphate and the enzyme) was effective at suppressing cross-linking even at a 1:1 ratio, and the effect increased as the ratio of histidine to glycating agent was increased to 10:1. In a previous paper, this same group found that a 10:1 ratio of carnosine to glyceraldehyde-3-phosphate is necessary to prevent protein cross-linking. The authors suggest that “AGE inhibitors such as carnosine may show clinical promise for diseases like Alzheimer’s.”

Histidine and carnosine supplements
effectively protected human
LDL against glucose-induced
oxidation and glycation.

In another study,6 scientists reported that histidine and carnosine delayed diabetic deterioration in mice by significantly decreasing plasma glucose and fibronectin levels, and, as 1 g/l of drinking water, either histidine or carnosine also significantly increased insulin levels. Moreover, histidine and carnosine significantly increased catalase activity and dose-dependently reduced levels of malondialdehyde (a lipid peroxidation product). Glutathione peroxidase activity in mouse kidney and liver was increased in 1-g/l (drinking water) histidine and carnosine treatments, whereas 1-g/l histidine and carnosine significantly reduced elevated levels of tumor necrosis factor-alpha (TNF-alpha), an important inflammatory cytokine. Interestingly, “Histidine supplementation alone effectively increased carnosine content in organs, and supplementing carnosine alone also increased histidine content in organs.”

A separate experiment6 involved 15 healthy human male subjects aged 21–28. Researchers found that histidine and carnosine supplements effectively protected human LDL derived from these subjects against glucose-induced oxidation and glycation. The histidine and carnosine concentrations in the human LDL experiments were 1 and 2 µM, and these concentrations were lower than the concentrations found in the organs of the histidine- and carnosine-supplemented mice. “These results also suggest that these agents might provide effective protection for humans against diabetic development or deterioration.”


Benfotiamine is a lipid-soluble form of thiamine, vitamin B1. While thiamine also has antiglycation effects, it is a water-soluble form of the vitamin that cannot enter fatty tissues. Benfotiamine has been reported to be more bioavailable than thiamine.7

A recent study7 reports that benfotiamine blocks three major pathways of hyperglycemic damage in bovine aortic endothelial cells and prevents diabetic retinopathy in rats. The three pathways blocked by benfotiamine identified in this study are all involved in hyperglycemia- induced vascular damage (which promotes atherosclerosis); they are the hexosamine pathway, the AGE-formation pathway, and the diacylglycerol (DAG)-protein kinase C pathway. Benfotiamine was also found to inhibit hyperglycemia-associated NF-kappaB activation (an important inflammatory signaling molecule). It normalized AGE levels in the retinas of long-term diabetic rats.

Alpha-Lipoic Acid

Among many other beneficial effects, alpha-lipoic acid has been shown to prevent glycation of serum albumin, increase intracellular glutathione levels, quench reactive oxygen species, and chelate heavy metals.8 Interestingly, the reduced form of alpha-lipoic acid, dihydrolipoic acid, participates in the regeneration of ascorbate and vitamin E.8

The authors of this paper8 explain that “Because of their localization and function . . . endothelial cells seem to be a primary target for AGEs and AGE-mediated late diabetic complications. This view is emphasized by the existence of specific receptors for AGEs (e.g., RAGE) on the endothelial surface.” The study reported that alpha-lipoic acid successfully reduced AGE-albumin-dependent activation of NF-kappaB in cultured bovine aortic endothelial cells (BAECs). The BAECs were incubated with AGE albumin for 30 minutes before cellular glutathione was determined. Compared with cells not treated with AGE albumin, there was a 64% reduction of cellular glutathione levels. However, preincubation of the BAECs with alpha-lipoic acid restored glutathione in a dose-dependent manner, from 0.1 mM up to the most effective dose, 2 mM alpha-lipoic acid.

Benfotiamine blocks three major
pathways of hyperglycemic damage in
bovine aortic endothelial cells and
prevents diabetic retinopathy in rats.

The protection of the cells by alpha-lipoic acid against AGE-albumin-dependent activation of NF-kappaB may be very important because “Activation of NF-kappaB has been identified as a central mediator in many life-threatening diseases, such as HIV infection, septicemia, atherosclerosis, and Alzheimer’s disease . . .”

Another paper9 reports on the protective effects of alpha-lipoic acid against AGE products. One of the first steps in atherogenesis is the expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), which increases monocyte (such as macrophage foam cells, which take up glycated LDL) binding to endothelium. NF-kappaB, activated by exposure to AGEs, induces the expression of VCAM-1.

Human umbilical vein endothelial cells (HUVECs) were treated with alpha-lipoic acid at various concentrations and for different periods of time to test whether it could reduce the NF-kappaB-related expression of VCAM-1 after stimulation with AGE albumin. Pretreatment of HUVECs with 10-mM alpha-lipoic acid suppressed VCAM-1 expression to baseline levels no matter how long the treatment lasted, whereas a concentration of 5 mM was required to suppress VCAM-1 when alpha-lipoic acid was administered for 24 hours. The lowest concentration of alpha-lipoic acid (0.05 mM) did not affect VCAM-1, whereas 2 to 24 hours of preincubation with alpha-lipoic acid at 0.5 mM attenuated VCAM-1 response to AGE albumin.


  1. Cervantes-Laurean et al. Inhibition of advanced glycation end product formation on collagen by rutin and its metabolites. J Nutr Biochem 17: 531-40 (2006).
  2. Wu and Yen. Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts. J Agric Food Chem 53: 3167-73 (2005).
  3. Rashid et al. Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro. FEBS Lett 581:1067-70 (2007).
  4. Ukeda et al. Effect of carnosine and related compounds on the inactivation of human Cu,Zn-superoxide dismutase by modification of fructose and glycolaldehyde. Biosci Biotechnol Biochem 66(1):36-43 (2002).
  5. Hobart et al. Anti-crosslinking properties of carnosine: significance of histidine. Life Sci 75:1379-89 (2004).
  6. Lee et al. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol 513:145-50 (2005).
  7. Hammes et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nature Med 9(3):294-9 (2003).
  8. 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).
  9. Kunt et al. Alpha-lipoic acid reduces expression of vascular cell adhesion molecule-1 and endothelial adhesion of human monocytes after stimulation with advanced glycation end products. Clin Sci 96:75-82 (1999).

© Copyright 2008 by Durk Pearson & Sandy Shaw®

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