Overview The Discovery of a New Biochemical Pathway In the early 1900's Maillard and later Amadori described the formation of complexes between sugars and the amino acids of proteins that were believed to cause the toughening and discoloration of food during the cooking process and after prolonged storage. Subsequent studies led to the hypothesis that formation of these amino-sugar structures was an important step along a new biochemical pathway in which permanent glucose structures, called "Advanced Glycosylation Endproducts" (A.G.E.s), were formed on the surface of proteins. These A.G.E.s were able to further interact with adjacent proteins to form pathological links between proteins, called A.G.E. Crosslinks. The harmful consequences of A.G.E. formation in man was proposed in 1986 by Brownlee et al as an outgrowth of a research effort focused on diabetes. A.G.E.s and A.G.E. Crosslinks are now considered to be likely causative factors in the development of many age-related and diabetic disorders, particularly those associated with the cardiovascular and renal systems, by causing biochemical and structural alterations on proteins. The A.G.E. Crosslink has been found to be unique in biology and is prevalent in animal models of diabetes and aging. Figure I. The A.G.E. Pathway (click on graphic to enlarge) The A.G.E. Pathway represents one of several pathological processes believed to be responsible for aging, including caloric intake, regulation of telomere length, DNA turnover and build-up of senescent products, among others. Figure I shows the A.G.E. Pathway leading to the formation of pathological A.G.E. Crosslinks. For a complete review of the historical literature on the formation of A.G.E.s, see Ledl and Schleicher 1990. How Diabetes and Aging are Related The A.G.E. Pathway may provide the scientific explanation for how and why many of the medical complications of the aging process occur with higher frequency and earlier in life in diabetic patients. Diabetic individuals form excessive amounts of A.G.E.s earlier in life than do non-diabetic individuals, due primarily to chronic hyperglycemia. For this reason, diabetes may be viewed as an accelerated form of aging. Why many aging individuals develop diabetes-like complications such as retinopathy, nephropathy and vascular disorders may be related to the mechanism by which A.G.E.s are removed from the human body. A.G.E. removal likely occurs via a specialized subset of cellular receptors. Immuno-compromised individuals or perhaps the aging process itself may result in loss over time of this important means of A.G.E. removal. The formation of A.G.E.s and A.G.E. Crosslinks is a key explanation for why caloric intake has been implicated as a major mechanism for the aging process. Whether A.G.E.s form via the A.G.E. Pathway or accumulate through ingestion of foods, the resulting damage to tissues and to DNA significantly contributes to the aging process. Next