AGE’s and Curcumin

The title of this may be misleading because, although it’s about AGE, it isn’t actually about age.  The two—the acronym and the word—are related, however.  AGE is the acronym for Advanced Glycation End-products, substances that have something to do with aging, but that are part of a bigger picture. An AGE forms after a chain of chemical reactions that yield glycation, which is the result of a sugar molecule bonding to a protein or lipid molecule without the controlling action of an enzyme. AGE’s may form outside the body by cooking sugars with proteins or inside the body via normal metabolism and aging. In certain circumstances, such as the oxidative stress that occasionally accompanies the hyperglycemia of diabetes, AGE formation can exceed normal levels.

What Do AGE’s Mean For Me? In diabetes-related AGE formation, high glucose levels ultimately cause reactive oxygen species (ROS) that have the potential to attack DNA and to become prime factors in aging and in age-related chronic diseases. From this come the vascular complications of diabetes, where a cascade of events leads to inhibition of vascular dilation (contributing to elevated blood pressure), to the oxidation of low-density lipoprotein (LDL), and to the secretion of pro-inflammatory chemicals that increase oxidative stress.  In the long run, atherosclerosis, arthritis, myocardial infarction (heart attack), retinopathy, or any of several other conditions may develop.

AGE’s may be more reactive than the sugars from which they are made, two of which are fructose and glucose. Glycation is a haphazard process, and is not the same thing as glycosylation, which is controlled by enzymes. Glycation occurs in the Maillard reaction, the phenomenon that makes food taste exceptional when it gets browned.  Remember that this entails an amino acid and a sugar in an event that is enhanced in an alkaline environment. Toasted bread, fried onions, roasted coffee, maple syrup, biscuits, dark-colored sodas, donuts, barbecued meats and tater tots are examples.  Although the results are similar to the naked eye, caramelization is quite a different process. Yes, both involve heat, but caramelization excuses amino acids from the party and relies solely on some kinds of sugars. Once in a while Maillard and caramelization occur at the same time. High temperature, low moisture and alkaline conditions promote the Maillard reaction. Browning doesn’t happen until water is vaporized at a temperature exceeding the boiling point.

What Happens Inside The Body? Maillard-type reactions occur inside the body, albeit at much lower temperatures. There are slow, complex reactions that cause the formation of AGE’s, some of which are believed to be responsible for the amyloid proteins that lead to Alzheimer’s disease.  Degenerative eye disease and diabetes have received the most attention, however, followed by recent interest in an association of glucose to neurodegeneration. Recent study has associated type 2 diabetes with cerebral atrophy, cognitive impairment and dementia at glucose levels deemed to be within normal range (Herbuin, 2012).

Some animals, notably rats and mice, either already have, or can be bred to have, physiological traits that parallel those of human body systems and mechanisms. Animal models can develop diabetes, for example, either spontaneously via breeding or by chemical or surgical means. Of course, for each advantage there may be a limitation, but it is recognized that without such laboratory partners there would be little progress in medical research (Chatzigeorgiou, 2009). Oxidative stress has been studied as a factor in degenerative diseases for years. Its inhibition has been the goal, and appears to have been realized in experiments with diabetic rats performed in India in the late 1990’s, where AGE’s and the cross-linking of collagen were addressed by the use of curcumin, the active ingredient of the turmeric spice. Doses as high as 200 mg/kg of body weight, for a period of two months, attenuated not only degradative processes, but also the accumulation of lipid peroxidation by-products (Sajithlal, 1998).

Malondialdehyde is an organic compound used as a marker for the specific oxidative stress resulting from the corruption of polyunsaturated fats (PUFA’s). As a reactive aldehyde, malondialdehyde is analogous to AGE’s. One of the wear-and-tear pigments remaining after this assault on PUFA’s is called lipofuscin, whose presence is viewed as a symptom of membrane damage or of damage to the mitochondria. Accumulation of lipofuscin is implicated in Alzheimer’s disease, Parkinson’s disease, ALS, COPD, and macular degeneration, among other disorders. Calorie restriction and increased glutathione are but two approaches to control this symbol of aging and its sequelae.   The anti-oxidant and anti-aging characteristics of curcumin were found to wield considerable influence in the prevention of malondialdehyde and lipofuscin formation, even at comparatively low doses of 30 mg/kg (Sarvalkar, 2011).

Those suffering the diabetes complications that corrupt vision, renal function, nerves, blood vessels, and the skin have found hope in the interruption of protein glycation by curcumin, where it was seen to be one of several natural substances to interfere with the reaction of glycated materials and their respective receptors. The therapeutic potential in delaying or preventing diabetic complications using curcumin is viewed as a safe and simple complement to conventional therapies (Elosta, 2012) (Ahmed, 2005).

Besides the diminution of AGE potency, curcumin inhibits the unfavorable activities tied to enzymes such as the pro-inflammatory COX2, the peroxide-forming lipoxygenase and the unfriendly nuclear factor kappa beta. Remarkably, curcumin also was discovered to have probiotic characteristics and to enhance treatment routes for such refractory conditions as Crohn’s, certain cancers, cirrhosis of the liver, and COPD (Chronic Obstructive Pulmonay Disease) (Bengmark, 2009).

It has become clear that some natural substances can replace drugs, without side effects. Anti-AGE strategies, addressing more than one body system and using curcumin in the arsenal, are here right now.

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

Bengmark S, Mesa MD, Gil A. Plant-derived health: the effects of turmeric and curcuminoids. Nutr Hosp. 2009 May-Jun;24(3):273-81.

Ishita Chattopadhyay, Kaushik Biswas, Uday Bandyopadhyay, and Ranajit K. Banerjee Turmeric and curcumin : Biological actions and medicinal applications Current Science. 2004, 10 July; 87 (1): 44-53

Chatzigeorgiou A, Halapas A, Kalafatakis K, Kamper E. The use of animal models in the study of diabetes mellitus. In Vivo. 2009 Mar-Apr;23(2):245-58.

Cherbuin, Nicolas, Sachdev, Perminder, MD, PhD, Anstey, Kaarin. Higher normal fasting plasma glucose is associated with hippocampal atrophy: the path study. Neurology Journal. September 2012 Volume 79 Issue 10: Pages: 1019-1026

Elosta A, Ghous T, Ahmed N. Natural products as anti-glycation agents: possible therapeutic potential for diabetic complications. Curr Diabetes Rev. 2012 Mar;8(2):92-108.

Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri J, Vlassara H. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc. 2004 Aug;104(8):1287-91.

Alison Goldin, BA; Joshua A. Beckman, MD; Ann Marie Schmidt, MD; Mark A. Creager, MD Basic Science for Clinicians: Advanced Glycation End Products—Sparking the Development of Diabetic Vascular Injury Circulation. 2006; 114: 597-605

Jakus V, Rietbrock N. Advanced glycation end-products and the progress of diabetic vascular complications. Physiol Res. 2004;53(2):131-42.

Krajcovicová-Kudlácková M, Sebeková K, Schinzel R, Klvanová J. Advanced glycation end products and nutrition. Physiol Res. 2002;51(3):313-6.

Manmei Li, Zhong Liu, Zhulin Zhang and Lin Ma Inhibitory effects of curcumin derivatives on nonenzymatic glucosylation in vitro Frontiers of Chemistry in China . Volume 1, Number 2 (2006), 227-231

Lin J, Tang Y, Kang Q, Chen A. Curcumin eliminates the inhibitory effect of advanced glycation end-products (AGEs) on gene expression of AGE receptor-1 in hepatic stellate cells in vitro. Lab Invest. 2012 Jun;92(6):827-41.

Lin J, Tang Y, Kang Q, Feng Y, Chen A. Curcumin inhibits gene expression of receptor for advanced glycation end-products (RAGE) in hepatic stellate cells in vitro by elevating PPARγ activity and attenuating oxidative stress. Br J Pharmacol. 2012 Aug;166(8):2212-27. doi: 10.1111/j.1476-5381.2012.01910.x.

Ji-ping Liu, Liang Feng, Mao-mao Zhu, Ru-Shang Wang, Ming-hua Zhang, Shao-ying Hu, Xiao-bin Jia, Jin-Jie Wu The In Vitro Protective Effects of Curcumin and Demethoxycurcumin in Curcuma longa Extract on Advanced Glycation End Products-Induced Mesangial Cell Apoptosis and Oxidative Stress Planta Med. 2012; 12: 1311-1398 DOI: 10.1055/s-0032-1315257

Okamoto T, Yamagishi S, Inagaki Y, Amano S, Koga K, Abe R, Takeuchi M, Ohno S, Yoshimura A, Makita Z. Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin. FASEB J. 2002 Dec;16(14):1928-30. Epub 2002 Oct 4.

Rees DA, Alcolado JC. Animal models of diabetes mellitus. Diabet Med. 2005 Apr;22(4):359-70.

Sajithlal GB, Chithra P, Chandrakasan G. Effect of curcumin on the advanced glycation and cross-linking of collagen in diabetic rats. Biochem Pharmacol. 1998 Dec 15;56(12):1607-14.

P. P. Sarvalkar, M. V. Walvekar and L. P. Bhopale Antioxidative effect of curcumin (Curcuma longa) on lipid peroxidation and lipofuscinogenesis in submandibular gland of D-galactose- induced aging male mice Journal of Medicinal Plants Research. 30 September, 2011 Vol. 5(20): 5191-5193