Aging- Glycation, AGE's and more

It is now well established that the process of glycation, (cross-linking) is one of the most important causes of aging, perhaps equally as important as the process of oxidation, (free radical damage).

During everyday metabolism, sugar molecules (such as glucose and fructose), and reactive aldehydes and/or ketones may attach to free amino groups on proteins, a process called non-enzymatic glycosylation (glycation). This reaction is also sometimes called the Maillard reaction. It results in a glycated protein, i.e. a protein carrying sugar (or similar) molecules on it. This glycated protein, (also called an Amadori product) may then react with any other proteins resulting in irreversible bonding between the two. This bonding process is named 'cross-linking.'

Affected molecules can be anything from collagen and elastin, to enzymes and immunoproteins. Facilitators during cross-linking are the carbonyl groups (+ C=O -) which act like glue, fixing the two proteins together. Carbonyls are chemical groups which are formed as a result of a sugar (or an aldehyde or a ketone or a free radical) reacting with aminoacids on a protein. In addition, carbonyls can be formed in other situations involving lipids or DNA so they are not necessarily restricted to proteins. So, carbonyls may cause not only protein-to-protein cross-linking, but also protein-to-DNA, or protein-to-lipid cross-linking, which is equally damaging to the organism. Recently, a condition called 'carbonyl stress' has been described. It involves increased levels of reactive carbonyl compounds which make cross-linking much more likely.

Cross-linking results in formation of large insoluble aggregates of damaged proteins in the tissues. These aggregates have been named AGEs (Advanced Glycosylation End products) (or 'post-Amadori products', or 'glycotoxins') and may then go on to interact with free radicals and cause further tissue injury, through chronic oxidation. Although a steady rate of AGE formation happens as a result of normal ageing (starting after the age of 20), formation of AGEs is accelerated during hyperglycaemic states such as diabetes. Copper, iron and other metals may hasten AGE formation.

Once formed, AGEs inhibit cellular transport processes, stimulate cells to produce more free radicals (such as superoxide and nitric oxide), and activate pro-inflammatory cytokines such as Tumour Necrosis Factor alpha (TNF-a) and interleukin 6. In addition, some AGEs are immunogenic (causing age-related auto-immunity) or mutagenic (increasing the risk of cancer), whereas others increase the activity of adhesion molecules, reduce protein degradation rate and reduce cell proliferation, all of which ensure that the risk of degenerative disease is increased. Also, AGEs stimulate apoptosis, resulting in excessive loss of cells and contributing further to the risk of degeneration. Some AGEs up-regulate genes which are involved in chronic inflammation reactions.

At the clinical level, cross-linking contributes significantly to diabetic complications, lower immunity and increased risk of cancer, atherosclerosis and hypertension, Alzheimer's disease (through the formation of amyloid, which is a type of AGE), cataract, kidney damage, skin ageing, and other age-related diseases.

The process of cross-linking through glycation was hitherto thought to be irreversible, and this was one typical example of the immutability of ageing. There are hundreds of compounds aimed at preventing cross-linking, but during the past few years, new products have also been developed directed specifically at breaking the abnormal bonds between already cross-linked proteins, practically reversing protein ageing. Both classes of drugs, the cross-link inhibitors and the cross-link breakers, have been found to offer remarkable benefits at the clinical level.

Cross-link Inhibitors:There are several commercially available inhibitors of cross-linking. Examples of these include:

Nutritional:Carnosine, and Alpha Lipoic Acid
Drugs:Aminoguanidine, Metformin, Acarbose,

Some of these, (like acarbose and metformin) are already in use as anti-diabetic drugs, but new research coming to light is now emphasizing their additional anti-cross-linking effects.

Other not yet widely available inhibitors are, OPB9195 (2,3-diaminophenazone), Phenazinediamine, Pyridoxamine, Tenilsetam and several hundred others still in development. The Alteon Corporation alone has identified over 850 separate cross-link inhibitors, including ALT711.

Many cross-link inhibitors are nucleophilic traps, (scavengers) for reactive carbonyl intermediates. They are also copper chelators, and so they minimise the risk of both cross-linking and consequent AGE-related damage. In addition, they block soluble receptors (sRAGEs) or specific receptors (RAGEs) which recognize AGEs. Some soluble receptors circulate freely, whereas specific ones can be found on macrophages, fibroblasts and endothelial cells. When an AGE molecule interacts with a RAGE it forms an adduct which is then prone to create more damage through oxidation and increased metal toxicity.

To read all of this article, with full clinical references, please see:
<http://www.antiaging-systems.com/extract/crosslinking.htm>