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this damage is true, AGEs also affect the dermal glycoproteins and glycosaminoglycans. This in turn negatively effects the dermal extracellular matrix (ECM) in terms of growth, differentiation, motility of the fibroblasts, the cytokine response, enzymatic activity, increased action of metalloproteinase production (MMP1, 2 and 9) and vascular haemostasis. This obviously is not good, however, it gets worse.
Schiff bases are common enzymatic intermediates and are reversible. This is happening throughout the body and indeed is a natural reaction process. This is not an instant reaction, taking a few hours. Essentially a Schiff base is where a double bond forms between the carbon atom of the glucose and the nitrogen atom of the lysine.
On a systemic level Simm et al (2007) conclusively showed the oxidative conditions that arise from the formation of AGEs can lead to cardiovascular disease, and a few years later Srikanth et al’s (2011) decisive paper showed how AGEs is instrumental in the development of Alzheimer's. This has built on the knowledge of AGEs directly responsible as a causative factor in cataracts, macular degeneration, diabetic neuropathy, coronary artery disease and lower-extremity skin ulcers. Quite a damage list for a bit of sugar. The short story of Glycation is that it involves non-enzymatic reactions between a sugar and a free amine group of Lysine and Arginine amino acids in proteins.
If, however there is continued exposure to the sugar [glucose], the Schiff base [glucose + protein complex] undergoes rearrangement, which is a non-enzymatic glycosylation, resulting in a more stable but much less reversible compound known as an Amadori product, which takes a few weeks to complete the reaction. At this point the reaction is not reversible. Amadori products are named after Mario Amadori, an Italian chemist (1886-1941). Chemically speaking, an Amadori product is where the hydrogen atom from the hydroxyl group adjacent to the carbon-nitrogen double bond moves to bond to the nitrogen, leaving a ketone. Amadori products undergo further change to irreversible Advanced Glycation End products [AGEs].
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HOW DOES GLYCATION AFFECT COLLAGEN AND ELASTIN? When fructose as a sugar joins up with the amino acid lysine we get something called fructoselysine, which in turn can be oxidatively cleaved to form smaller reactive compounds, such as carboxymethyl lysine (CML) and pentosidine. This is the way glycation affects collagen, as collagen fibres with Lysine and Arginine being part of the triple helix structure are easily glycated, thus reducing the elasticity and structural resilience of the collagen and elastin structure. What you may not know is that collagen can have a half-life of 15 or more years in the skin, so easily can become cross-linked, stiff and non-functioning as it cannot in this state be catabolised. This build-up of effectively 'dead' collagen is the real problem. While above is the short story, it is a massive oversimplification of a series of very complicated chemical processes. Glucose is a reactive compound because it has an aldehyde group as part of its structure. This is just a carbon atom with a double-bond oxygen and one hydrogen molecule linked to the rest of the glucose molecule. This diagram is termed a linear structure, just for ease of understanding, however glucose is generally found in a cyclic form and cannot react easily with proteins.
In this diagram you can see the same structure as in the linear format with one major difference – the aldehyde group is no longer available.
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It is still there, yet 'locked up' in the circle and not freely available. This makes a big difference. When you have lots of glucose in your system, post that wonderful super Sunday with fudge and chocolate sauce, glucose does attract and attach itself to molecules of proteins. This reaction is termed a Schiff base, named after the German Hugo Schiff (1834-1915).
(Lopez 2009)
THE ULTRAVIOLET (UVA) FACTOR We know that ultraviolet light causes damage to the dermal extra cellular matrix and structural alterations take place. Masaki et al (1999) showed decreased dermal fibroblast cell viability due to the UVA generation of reactive oxygen species (ROS), which was accelerated in the presence of AGEs that amplified the degenerative phenomena of the skin associated with the ageing process. In addition to this damage, UVA is responsible for the up regulation of MMPs 1, 3 and 9; all enzymes that degrade collagen and elastin, not to mention the inflammatory cytokines interleukin (IL) 1 alpha and IL 6. Thus we get a double whammy of UV and glycation damage to increase the deleterious effects on the skin and other organs of the body. A recent study by Crisan et al (2013), using histological and immuno-histochemical imaging, revealed implicitly the role of UV in the modulation and accumulation of glyco-oxidation products at the dermal level, in particular the CML distribution at epidermal level, especially in the germinative layers, suggesting the impact of cytokines on glycation mechanisms. N- (carboxymethyl) lysine (CML), a known biomarker of oxidative stress, is caused by cleavage of the previously mentioned Fructoselysine (FL) and pentosidine. Simple sugars like fructose and galactose undergo glycation at about 10 times a higher rate than glucose; most sweeteners today are approximately 50% fructose or a fructose derivative. This results in glycation and free radical oxidation, which has
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APJ 19