Advanced Glycation End Products
Advanced Glycation End Products (AGEs) are a group of compounds produced from a series of glycation reactions. Such reactions occur when proteins, lipids and nucleic acids are exposed to sugars, and this process takes place within the majority of cells. AGEs are produced both endogenously, through 'normal' metabolic processes, and exogenously, as a result of environmental factors such as diet and smoking. Recent studies suggest AGEs to be implicated in numerous degenerative diseases. The mechanisms responsible for their removal and reduction become less efficient with age, resulting in their accumulation.
How are AGEs Formed?
AGEs are formed as a result of sequential glycation reactions. Glycation is a non-enzymatic, multi-step reaction that occurs between the carbonyl group of reducing sugars and the amino group, or N-terminal group, of proteins. The reaction is characterised by the production of a Schiff bases which, due to their quick and reversible production, are chemically unstable. Over a time period of a few weeks, Schiff bases may slowly rearrange to form a more stable Amordi product. Subsequent oxidative reactions result in the final production of AGEs, as well as reactive oxygen species (ROS).
CML is recognised as one of the most prevalent AGE compound within an organism, as both a protein and lipid adduct. Other noteable AGEs include: Pentosidine, Glucosepane, Carboxyethyl-lysine, Pyrraline and several dicarbonyl compounds (3-deoxyglucosome, methylglyoxal and glyoxal, for example). Due to the heterogenous, complex and unstable nature of AGEs, it remains difficult to determine all compounds formed and their subsequent roles.
AGEs Role in Disease
Following glycation, AGEs are capable of forming cross-links between proteins. It is this characteristic which potentiates the disruption of cellular function; for example, it enables the formation of cross-links between crucial molecules involved in both extra- and intra-cellular cell structure. Collagen is understood to be one of the main targets in this process, due to its low turnover and high presence. Glucosepane, an advanced AGE with observed lysine-arginine protein cross-linking, binds collagen at the binding sites for integrin proteoglycans and collogenase. It also alters collagen physical properties, which can cause fibril stiffness. Lysine-lysine protein cross-links, known as MOLD, commonly form, and are favoured due to the close position of the residues.
AGEs also cause harm through their ability to interact with cell surface receptors. For example, AGEs bind RAGE receptors (also referred to as AGERs), which activates numerous signalling pathways, including mitogen activated protein kinases (MAPK), extracellular signal related kinases (ERK) and phosphatidyl-inositol 3 kinase (p21Ras). This results in the stimulation of the NFkB (nuclear factor kappa-B) transcription factor, which subsequently activates the transcription of pro-inflammatory genes. The increase in inflammatory signals is further intensified by NFkB up regulating the expression of RAGE, and due to the multi-ligand nature of the receptor (T lymphocytes, B lymphocytes and macrophages express high levels of the RAGE receptor). RAGE has also been recognised to indirectly elevate the level of oxidative species, whilst simultaneously decreasing the activity of antioxidant defences. This ultimately presents RAGE receptors as a major pharmaceutical target.
Several AGE-related detoxifying pathways, which primarily defend against glycation, have been identified within the body. One of these pathways is the glutathione dependent glyoxalase system. In this process, reduced glutathione (GSH) catalyses 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, the signalling pathway of RAGE is inhibited.
The accumulation of AGEs has been associated with a number of neurological, renal and cardiovascular diseases; such as Alzheimers, Diabetes, atherosclerosis and Rheumatoid arthritis. Abbexa offers unique products to support studies into both potential treatments, and the role that AGEs play in the above diseases (published here). The AGE ELISA Kit has been shown to effectively measure AGE concentration in serum.