Mechanisms of maturation and ageing of collagen.

The deleterious age-related changes in collagen that manifest in the stiffening of the joints, the vascular system and the renal and retinal capillaries are primarily due to the intermolecular cross-linking of the collagen molecules within the tissues. The formation of cross-links was elegantly demonstrated by Verzar over 40 years ago but the nature and mechanisms are only now being unravelled. Cross-linking involves two different mechanisms, one a precise enzymically controlled cross-linking during development and maturation and the other an adventitious non-enzymic mechanism following maturation of the tissue. It is this additional non-enzymic cross-linking, known as glycation, involving reaction with glucose and subsequent oxidation products of the complex, that is the major cause of dysfunction of collagenous tissues in old age. The process is accelerated in diabetic subjects due to the higher levels of glucose. The effect of glycation on cell-matrix interactions is now being studied and may be shown to be an equally important aspect of ageing of collagen. An understanding of these mechanisms is now leading to the development of inhibitors of glycation and compounds capable of cleaving the cross-links, thus alleviating the devastating effects of ageing.