Advanced Glycation End Products

ADVANCED GLYCATION END PRODUCTS

Proteins or lipids become glycated as a result of exposure to

sugars. This is commonly seen in the matrix of the cells.

Advanced Glycation End Products (AGEs) act as biomarkers. AGEs are implicated

in chronic degenerative diseases like diabetes mellitus, atherosclerosis, chronic

kidney disease and Alzheimer’s disease.

Formation

The protein (Lysine residues usually) reacts with the reducing sugar to give a N-

substituted glycosylamine and water. This is a spontaneous, non-enzymatic

reaction called Maillard Reaction. It is a reversible reaction.

The N-substituted glycosylamine then undergoes Amadori rearrangement to

give Ketosamines. The formation of Ketosamines are irreversible.

Mechanism of action

1. AGEs affect nearly every cell in the body and are believed to play an

important role in aging. AGEs can link to any type of proteins and form

stable and irreversible bonds. Their bioavailability depends on the half-

life time of those proteins.

2. Cross-linking of collagen proteins contributes to the rigidity and loss of

elasticity of tissues and increased resistance to proteolysis, inhibition of

tissue remodeling and thickening of capillary basement membrane

leading to widespread alterations. This also affects vessel wall elasticity.

3. AGEs exert their effects via receptors, with a proven pathogenic

significance, as they mediate cellular responses through the generation

of oxygen-free radicals. This leads to induction of Oxygen Stress, which is

believed to mediate the chronic complications of Diabetes Mellitus and

Chronic Kidney disease.

Effects

1. Ageing

Skin collagen and lens have a very long half-life so these places are the most likely

sites for AGEs accumulation. Bonds to other types of proteins with shorter

half-lives are unstable.So these bonds lead to AGEs degradation followed by renal

excretion of AGEs-moieties. The accumulation of AGEs in skin collagen and

lens bring about the degenerative changes with aging, i.e, wrinkling of skin

and progressive worsening of eyesight.

2. Heart failure

AGEs affect the heart by two different pathways:

Interference with matrix proteins of coronary arteries causing

atherosclerosis and Interaction with RAGE (AGE specific receptors) to bring

about metabolic alterations in the myocardium and inflammatory

responses in the vascular endothelium on top of oxidative stress, leading to

heart failure.

3. Diabetes Mellitus

Increased AGEs mediate the long term complications of diabetes mellitus

such as atherosclerosis and cataract formation. Atherosclerosis occurs due

to deposition of AGEs in the vessel wall which leads to deposition of plasma

proteins and LDL particles in the vessel wall, progressing to atherosclerosis.

The rate of formation of AGEs in diabetes is said to be proportional to the

square of glucose concentration.

4. AGEs also are implicated in other conditions like Alzheimer’s disease and

Stroke.