Age-associated increases in collagen cross-linking and accumulation of advanced glycosylation products are both accelerated by diabetes, suggesting that glucose-derived cross-link formation may contribute to the development of chronic diabetic complications as well as certain physical changes of aging. Aminoguanidine has been found to prevent both the formation of advanced non-enzymatic glycosylation products and the formation of glucose-derived collagen cross-links in vitro. The identification of aminoguanidine as an inhibitor of advanced nonenzymatic glycosylation product formation now makes possible precise experimental definition of the pathogenetic significance of this process and suggests a potential clinical role for aminoguanidine in the future treatment of chronic diabetic complications.1 It has also been found to ameliorate various complications to diabetes and prevent age-related arterial stiffening and cardiac hypertrophy, effects probably dependent on inhibition of AGEs formation. Secondly, aminoguanidine inhibits NO synthase particularly the inducible NO synthase isoform making AMG an important pharmacological tool.2*

Galega officinalis

Galega officinalis (galega, Goat's Rue, French Lilac) is well known for its hypoglycemic action and has been used as part of a plant mixture in the treatment of diabetes mellitus. It has been found to have a novel weight reducing action that, in normal mice, is largely independent of a reduction in food intake. The mechanism of the weight reducing action of galega is unclear but involves loss of body fat.*

Evidence That Serum Levels of the Soluble Receptor for Advanced Glycation End Products Are Inversely Associated with Pancreatic Cancer Risk: A Prospective Study

Li J, Weinstein SJ, Albanes D, et al. Cancer Research. 2011 doi: 10.1158/0008-5472.CAN-10-2573

Cigarette smoking, obesity, type 2 diabetes, and, to a lesser extent, meat cooked at high temperatures are associated with pancreatic cancer. Cigarette smoke and foods cooked at higher temperatures are major environmental sources of advanced glycation end products (AGE). AGEs accumulate during hyperglycemia and elicit oxidative stress and inflammation through interaction with the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) acts as an anti-inflammatory factor to neutralize AGEs and block the effects mediated by RAGE. In this study, we investigated the associations of prediagnostic measures of Nε-(carboxymethyl)-lysine (CML)-AGE and sRAGE with pancreatic cancer in a case–cohort study within a cohort of 29,133 Finnish male smokers. Serum samples and exposure information were collected at baseline (1985–1988). We measured CML-AGE, sRAGE, glucose, and insulin concentrations in fasting serum from 255 incident pancreatic cancer cases that arose through April 2005 and from 485 randomly sampled subcohort participants. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI, adjusted for age, years of smoking, and body mass index. CML-AGE and sRAGE were mutually adjusted. CML-AGE levels were not associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.68 (0.38–1.22), Ptrend = 0.27]. In contrast, sRAGE levels were inversely associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.46 (0.23–0.73), Ptrend = 0.002]. Further adjustment for glucose or insulin levels did not change the observed associations. Our findings suggest that sRAGE is inversely associated with pancreatic cancer risk among Finnish male smokers.*

Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking.

Brownlee M, Vlassara H, Kooney A, Ulrich P, & Cerami, A. Science 27 June 1986. Vol. 232 no. 4758 pp. 1629-1632. DOI: 10.1126/science.3487117

Age-associated increases in collagen cross-linking and accumulation of advanced glycosylation products are both accelerated by diabetes, suggesting that glucose-derived cross-link formation may contribute to the development of chronic diabetic complications as well as certain physical changes of aging. Aminoguanidine, a nucleophilic hydrazine compound, prevented both the formation of fluorescent advanced nonenzymatic glycosylation products and the formation of glucose-derived collagen cross-links in vitro. Aminoguanidine administration to rats was equally effective in preventing diabetes-induced formation of fluorescent advanced nonenzymatic glycosylation products and cross-linking of arterial wall connective tissue protein in vivo. The identification of aminoguanidine as an inhibitor of advanced nonenzymatic glycosylation product formation now makes possible precise experimental definition of the pathogenetic significance of this process and suggests a potential clinical role for aminoguanidine in the future treatment of chronic diabetic complications.*

Biological effects of aminoguanidine

Nilsson BO.Inflammation Research. Volume 48, Number 10, 509-515, DOI: 10.1007/s000110050495

Aminoguanidine (AMG) was prepared more than 100 years ago. During the last 10 years two important effects of AMG have been discovered which have made this molecule attract a lot of interest. Firstly, AMG inhibits, in vitro and in vivo, formation of highly reactive advanced glycosylation end products (AGEs) associated with pathogenesis of secondary complications to diabetes and with cardiovascular changes in aging. AMG ameliorates various complications to diabetes and prevents age related arterial stiffening and cardiac hypertrophy, effects probably dependent on inhibition of AGEs formation. Secondly, AMG inhibits NO synthase particularly the inducible NO synthase isoform making AMG an important pharmacological tool.*

Novel Weight-Reducing Activity of Galega officinalis in Mice

Palit P, Furman BL, Gray AI.. Journal of Pharmacy and Pharmacology. Volume 51, Issue 11, pages 1313–1319, November 1999. DOI: 10.1211/0022357991776895

Galega officinalis (galega, Goat's Rue, French Lilac) is well known for its hypoglycaemic action and has been used as part of a plant mixture in the treatment of diabetes mellitus. During pharmacological investigations of an ethanolic extract of a powdered mixture of equal proportions of G. officinalis, Cressa cretica, Mangifera indica and Syzygium jambolanum, a weight reducing effect of galega was discovered. In this study we have investigated the novel weight reducing effect of galega in mice.*

Galega herb (10% w/w in the diet) caused a significant reduction in body weight in both normal and genetically obese (ob/ob) animals treated for 28 days when compared with respective controls (P < 0.01). In normal mice, the weight loss was reversible and initially associated with a transient reduction in food intake but was then maintained even in the presence of increased eating above the control level. Pair-fed normal mice receiving galega for seven days also showed significant weight loss (P < 0.01, compared with the control) in the presence of increasing food intake. In sharp contrast, weight loss in galega-treated ob/ob mice was accompanied by a persistent reduction in food intake over the 28-day treatment period. Post-mortem examinations of all galega-treated mice revealed a striking absence of body fat. Serum glucose was significantly reduced in both strains of mice receiving galega for 28 days (P < 0.01), whereas serum insulin was significantly reduced only in obese mice (P < 0.01).*

In summary, together with its established hypoglycaemic effects, galega has a novel weight reducing action that, in normal mice, is largely independent of a reduction in food intake. The mechanism of the weight reducing action of galega is unclear but involves loss of body fat.*

Advanced glycation end products (AGEs)

Atherosclerosis is responsible for more than forty percent of the deaths in the US and CVD is the leading cause of death in United States, causing about 38% of all deaths in 2002, and long-term disability for 1.1 million people.4 5 But what’s even more frightening is that one of its primary causes has long been overlooked—and this risk factor resides in your body right now, whether you realise it or not.*

Advanced glycation end products (AGEs) are molecules formed by a process called glycosylation in which excess sugars attach themselves to your body’s proteins and lipids. And once formed, these AGEs are completely irreversible—wreaking havoc on your body, where they damage cells and tissues while prematurely ageing your body.*

Of course, under normal circumstances, this isn’t a problem—a healthy body is well equipped to remove these toxic molecules on a regular basis. But in the all-too-common case of prolonged oxidative stress (caused by high blood sugar, a diet rich in processed food or an environment steeped in toxins), you may not be so lucky. In cases like these, AGEs build up at a faster rate than your body can handle—and studies show that the damage they can do to your tissues… and especially your arteries, kidneys and retinas… is severe.6-9*

Research reveals that AGE accumulation occurs in the small arteries in the heart muscle and arteries that have lost their normal elasticity due to diminished nitric oxide levels, increased plaque formation and inflammation—all of which directly contribute to the risk of serious cardiac events like heart attacks and strokes.10 11 What’s worse, these artery-hardening and clogging effects have been shown to be completely independent of risk factors like age, high blood pressure and hyperglycaemia—which means that when AGEs are involved, even otherwise healthy people may be at risk.12-14*

The only surefire way to protect your heart is to block these toxic, AGE molecules from forming in the first place… and several natural compounds can play a critical role in doing just that.*

For starters, the dipeptide Carnosine is a powerful AGE inhibitor, which protects proteins and lipids from glycation and reduces the damaging effects of oxidative stress. The bad news? Muscle carnosine levels drop by as much as 63 percent from age 10 to age 70, indicating the importance of supplementation with this nutrient.15-19*

Compounds like N-acetyl-cysteine and lipoic acid are also proven to reduce AGE-related cell death.B vitamins are another crucial source of protection. Pyridoxal-5-phosphate—the active form of B6—is converted to pyridoxamine in the liver. Pyridoxamine inhibits AGE formation, which helps to reduce the AGE-initiated aggregation of blood platelets and the formation of clots.20-24 And studies show that alpha-lipoic acid in combination with benfotiamine (a lipid-soluble form of vitamin B1) can block AGE formation by as much as 40 percent.25 As an added benefit, this class of antioxidant vitamins is also known to decrease diabetic complications and inhibit the release of inflammation-causing chemicals like NFkappaB.26*

References

Brownlee M, Vlassara H, Kooney A, Ulrich P, & Cerami, A. Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 27 June 1986. Vol. 232 no. 4758 pp. 1629-1632. DOI: 10.1126/science.3487117

Nilsson BO. Biological effects of aminoguanidine: An update. Inflammation Research. Volume 48, Number 10, 509-515, DOI: 10.1007/s000110050495

Palit P, Furman BL, Gray AI. Novel Weight-Reducing Activity of Galega officinalis in Mice. Journal of Pharmacy and Pharmacology. Volume 51, Issue 11, pages 1313–1319, November 1999. DOI: 10.1211/0022357991776895

Centres for Disease Control and Prevention. Potential Infectious aetiologies of Atherosclerosis: A Multifactorial Perspective. Available at:http://www.cdc.gov/ncidod/eid/vol7no5/oconnor.htm#1. Accessed on: 8-10-09.

United Statesn Institute of Health and Welfare, National Heart Foundation of United States. Heart, stroke and vascular diseases—United Statesn facts 2004. AIHW Cat. No. CVD 27 Cardiovascular Disease Series No. 22. Canberra: AIHW and National Heart Foundation of United States; 2004. Available from:http://www.aihw.gov.au/publications/cvd/hsvd04/hsvd04.pdf

Forbes JM, Soldatos G, Thomas MC. Below the radar: advanced glycation end products that detour “around the side”. Is HbA1c not an accurate enough predictor of long term progression and glycaemic control in diabetes? Clin Biochem Rev. 2005 Nov;26(4):123-34.

Tan D, Wang Y, Lo CY, et al. Methylglyoxal: its presence and potential scavengers. Asia Pac J Clin Nutr. 2008;17 Suppl 1:261-4.

Wendt TM, Tanji N, Guo J, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol. 2003 Apr;162(4):1123-37.

Ahmed N. Advanced glycation endproducts--role in pathology of diabetic complications. Diabetes Res Clin Pract. 2005 Jan;67(1):3-21.

Zieman SJ, Kass DA. Advanced glycation endproduct crosslinking in the cardiovascular system: potential therapeutic target for cardiovascular disease. Drugs. 2004;64(5):459-70.

McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens. 2007 Mar;20(3):242-7.

McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens. 2007 Mar;20(3):242-7.

Semba RD, Najjar SS, Sun K, et al. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens. 2009 Jan;22(1):74-9.

Vlassara H, Fuh H, Donnelly T, et al. Advanced glycation endproducts promote adhesion molecule (VCAM-1, ICAM-1) expression and atheroma formation in normal rabbits. Mol Med. 1995 May;1(4):447-56.

Loske C, Neumann A, Cunningham AM, et al. Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress. J Neural Transm. 1998;105(8-9):1005-15.

Hipkiss AR. Would carnosine or a carnivorous diet help suppress aging and associated pathologies? Ann N Y Acad Sci. 2006 May;1067:369-74.

Reddy VP, Garrett MR, Perry G, et al. Carnosine: a versatile antioxidant and antiglycating agent. Sci Aging Knowledge Environ. 2005 May 4;2005(18):pe12.

Guiotto A, Calderan A, Ruzza P, et al. Carnosine and carnosine-related antioxidants: a review. Curr Med Chem. 2005;12(20):2293-315.

Hipkiss AR, Chana H. Carnosine protects proteins against methylglyoxal-mediated modifications. Biochem Biophys Res Commun. 1998 Jul 9;248(1):28-32.

Hsieh CL, Yang MH, Chyau CC, et al. Kinetic analysis on the sensitivity of glucose- or glyoxal-induced LDL glycation to the inhibitory effect of Psidium guajava extract in a physiomimic system. Biosystems. 2007 Mar;88(1-2):92-100.

Lunceford N, Gugliucci A. Ilex paraguariensis extracts inhibit AGE formation more efficiently than green tea. Fitoterapia. 2005 Jul;76(5):419-27.

Mosimann AL, Wilhelm-Filho D, da Silva EL. Aqueous extract of Ilex paraguariensis attenuates the progression of atherosclerosis in cholesterol-fed rabbits. Biofactors. 2006;26(1):59-70.

Yamagishi S, Matsui T, Takenaka K, Nakamura K, Takeuchi M, Inoue H. Pigment epithelium-derived factor (PEDF) prevents platelet activation and aggregation in diabetic rats by blocking deleterious effects of advanced glycation end products (AGEs). Diabetes Metab Res Rev. 2009 Mar;25(3):266-71.

Suji G, Sivakami S. DNA damage during glycation of lysine by methylglyoxal: assessment of vitamins in preventing damage. Amino Acids. 2007 Nov;33(4):615-21.

Du X, Edelstein D, Brownlee M. Oral benfotiamine plus alpha-lipoic acid normalises complication-causing pathways in type 1 diabetes. Diabetologia. 2008 Oct;51(10):1930-2.

Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 Mar;9(3):294-9.

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.