AGEs

Advanced Gylcation End Products

Advanced Gylcation End Products, AGEs, refer to a group of compounds produced following a series of glycation reactions. These reactions take place between proteins, lipids and nucleic acids when in the presence of sugar and can occur within nearly all cells of the body. AGE products are associated with the normal process of ageing, as the mechanisms involved in removing and reducing them becoming less efficient, thus leading to their accumulation. AGEs can be produced endogenously through an organisms normal metabolic processes as well as exogenously through environmental factors such as diet and smoking. More recently genetics has also been recognised to play an influential role.

The reaction involved in the production of AGE products is known overall as glycation. This is a non-enzymatic, multi-step reaction between the carbonly group of reducing sugars and the amino group or N terminal group pf proteins. The reaction is characterised by the production of a Schiff base which are produced quickly and reversibly making them chemically unstable. Over a period of weeks these Schiff bases may slowly rearrange resulting in the formation of a much more stable Amadori product. Subsequent oxidative reactions may take place producing the final AGE product alongside reactive oxygen species, (ROS).

Following glycation CML is recognised to be one of the most prevalent AGE compounds found within an organism, as both a protein and lipid adduct. Other AGE compounds include Pentosidine, Dicarbonyl compounds: 3-deoxyglucosome, methylglyoxal and glyoxal. Glucosepane, carboxyethyl-lysine and pyrraline. However due to their heterogeneous, complex and unstable nature it is difficult to determine all AGE compounds formed and their role.

AGEs may also form cross links between proteins following glycation. This characteristic enables cross links to be formed between key molecules in the extracellular and intracellular structure of a cell, ultimately disrupting cellular function. Collagen is understood to be one of the main targets for crosslinks due to its low turnover and high presence. With over 30% of the bodies protein collagen. The most prevalent cross link to form is between the amino acid group Lysine and Arginine. The AGE product formed following these cross links is Glucosepane, these cross links can form within key domains of collagen such as the binding sites for intergrin, proteoglycans and collogenase. As well as altering the physical properties of collagen which can cause fibril stiffness. The Glucosapene crosslink is found 10-1000 times higher than any other AGE product, this is thought to be due to the greater presence of these pairs and the ease at which the reaction can take place. Similarly another crosslink pair that commonly forms is between Lysine and Lysine is known as MOLD. The bond between these two is favoured due to the close positioning of the residues.

AGEs cause harm to the body not only through the formation of cross links but alsodue to their ability to interact with cell surface receptors. AGEs are recognised to bind to receptors identified as RAGE, once bound they can activate a number of signalling pathways including mitogen activated protein kinases (MAPK), extracellular signal related kinases (ERK) andphopphatidyl-inositol 3 kinase (p21Ras). Activation of the RAGE receptor leads to stimulation of the NFkB (nuclear factor kappa-B) transcription factor leading to the activation and transcription of pro-inflammatory genes. The increase in inflammatory signals is further intensified by NFkB up regulating the expression of RAGE.

In addition RAGE has been recognised to indirectly elevate the level of oxidative species, whilst also decreasing the activity of antioxidant defences.

The concentration of AGE within an organism depends on the how quickly the compounds are being formed but also how quickly they are being removed. Several AGE related detoxifying pathways have been identified within the body, aimed at defending against glycation. One of these pathways is the glutathione dependent glyoxalase system. With reduced glutathione (GSH) catalysing the conversion of glyoxal and other compounds to D-lactate, and other less toxic forms.

Similarly a group of receptors known as AGER1-3 are thought to counteract the effects of RAGE by regulating the degradation and endocytosis of AGE products. In some cases inhibiting the signalling pathway of RAGE.

The accumulation of AGEs have been associated with a number of neurological, renal and cardiovascular diseases. With Alzheimers, Diabetes, atherosclerosis and Rheumatoid arthritis to name a few. Activation of RAGE signalling and downstream pathways are understood to be elevated in patients with these inflammatory related diseases, with increased activation of harmful cytokines, adhesion factors and growth factors. In addition, immune cells such as T lymphocytes, B lymphocytes and macrophages have all been found to express high levels of the RAGE receptor. And due to the multi-ligand nature of RAGE, interaction with a wide range of inflammatory stimuli can be induced, further amplifying the inflammatory response. Taking this into account RAGE can be considered one of the major pharmacological targets within humans, to prevent the onset and progression of these sometimes debilitating diseases.