Glucosepane is a lysine-arginine protein cross-linking product and advanced glycation end product (AGE) derived from D-glucose. It is an irreversible, covalent cross-link product that has been found to make intermolecular and intramolecular cross-links in the collagen of the extracellular matrix (ECM) and crystallin of the eyes. Covalent protein cross-links irreversibly link proteins together in the ECM of tissues. Glucosepane is present in human tissues at levels 10 to 1000 times higher than any other cross-linking AGE, and is currently considered to be the most important cross-linking AGE. Role in aging Aging leads to progressive loss of elasticity and stiffening of tissues rich in the ECM such as joints, cartilage, arteries, lungs and skin. It has been shown that these effects are brought about by the accumulation of cross-links in the ECM on long-lived proteins. Studies done on glucosepane by the Monnier group have shown that the level of glucosepane cross-links in human collagen in the ECM increases progressively with age and at a more rapid pace in people with diabetes, thus suggesting the role of glucosepane in the long-term effects associated with diabetes and aging such as arteriosclerosis, joint stiffening and skin wrinkling. In fact, they report that in the ECM of the skin of a non-diabetic 90-year-old, glucosepane accounts for about 50 times the protein cross-linking as all other forms of protein cross-linking. Further, the build up of cross-links such as glucosepane within and between proteins is shown to reduce proteolytic degradation in the ECM. This leads to increased cross-link accumulation and is thought to be linked to the thickening of basement membranes in capillaries, glomeruli, lens, and lungs. Atomic-force microscopy experiments identified nanoscale morphologic differences in collagen fibril structures as a function of ageing in skin. A decrease in Young's modulus of the transverse fibril was observed. These changes are thought to be due to the accumulation of glucosepane in tissue. It is proposed that this is due to a change in the fibril density caused by age-related differences in water retention. Computational studies using all-atom simulations revealed that glucosepane results in less tightly held helical structure in the collagen molecule and increase porosity to water. This was confirmed with water content measurement that showed higher content in Achilles and anterior tibias tendon tissue from older individuals compared to young people. Formation As an AGE, the reaction pathway that leads to glucosepane formation is known as the Maillard