Collagen-rich tissues like arteries, skin, lung and tendons become progressively stiffer with age. These changes occur more rapidly in diabetes suggesting that the diabetic state accelerates the aging process. In spite of intense research efforts the molecular mechanism responsible for the age-related crosslinking of postmature collagen remains largely unelucidated. We hypothesized that the Maillard or nonenzymatic browning reaction which occurs between glucose and amino groups could explain in part the age- and diabetes-related modifications of collagen. Progress achieved in the past 2 1/2 years led to the isolation of two novel fluorescent peptides (""""""""P"""""""" and """"""""M"""""""") from aged human collagen and the observation that the amount of collagen-linked fluorescence in diabetic subjects correlates overall with severity of long-term complications. Progress on the Maillard reaction chemistry led to the detection of glucose-derived pyrroles in a model system for nonenzymatic browning of proteins, and the development of an animal model of accelerated browning and crosslinking. In the coming five years we propose 1) to elucidate the structure of the fluorophores """"""""P"""""""" and """"""""M"""""""" using a combination of proton-, 13C-NMR, 3-dimensional fluorescence and FAB-mass spectroscopy. 2) to investigate the effects of age and diabetes on the accumulation of """"""""P"""""""" and """"""""M"""""""" in various tissues obtained at autopsy, 3) to correlate the amount of """"""""P"""""""" and """"""""M"""""""" in aortic tissue with degree of arterial stiffness and antemortem blood pressure. 4) to purify and elucidate the structure of the major compounds of the Maillard reaction formed under physiological conditions in model systems. and 5) to establish the presence of the characterized compounds of the Maillard reaction in aging and diabetic human collagen and their relationship to fluorophores """"""""P"""""""" and """"""""M"""""""".
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