The main objective of aging research is to determine the fundamental processes which explains maximal longevity and to understand the underlying mechanisms of age-related disease processes in hope of preventing debilities which affect the quality of life in old age. Because of this objective, interest has been in the development of biomarkers expedited by a pragmatic interest in establishing reproducible scientific criteria for assessing the effectiveness of interventions that affect aging especially in animal species that have life spans significantly less than that of human. Although many interventions have been proposed, the only one which is currently scientifically valid in altering aging is dietary restriction. Pentosidine is a fluorescent protein cross-link isolated from senescent human extracellular matrix. It is formed through the nonenzymatic reaction of pentose sugars such as ribose with lysine and arginine residues. A more recent study showed that hexoses (i.e., glucose) can form this cross-link. Pentosidine levels are responsive to metabolic conditions which affect life span of humans and animals: a) it is increased in hyperglycemia induced by diabetes, b) it is increased in uremia which kills many rodent species, and c) it is decreased by dietary restriction. We propose to investigate the validity of pentosidine as a biomarker of aging by testing the hypothesis that the rate of accumulation of pentosidine is related to maximum life span of rodent species, and that the genetic susceptibility to uremia will significantly increase, while food restriction will decrease the accumulation rate, respectively. A long-term longitudinal study is proposed by measuring individual rates of accumulation of pentosidine in skin and tail tendons of C57BL/6NNIA mice and Fischer 344 rats fed ad libitum vs. food restricted from early life (3 months) to spontaneous death of each animal. Pentosidine will be measured in tissue biopsies taken every 6 months and correlated with maximum longevity of individual animals. In a further study, pentosidine will be measured cross-sectionally and longitudinally in skin and tail tendons of Fischer 344 and F344/Brown-Norway F1 hydrid representing rat species which are susceptible and resistant to renal disease, respectively. The further objective of this study is to determine the relationship of pentosidine to another biomarker of aging, fluorophore """"""""M"""""""", and to investigate the molecular origin of pentosidine in vivo as reflected by potential precursor sugars in the plasma of food restricted vs. ad libitum fed rodents.
