COLLAGEN CROSSLINKS: BIOMARKERS OF AGING

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The purpose of this study is to screen a panel of biochemical assays as potential markers of aging in connective tissue in rats and mice. These assays will include both enzymatically and nonenzymatically mediated changes in collagen crosslinking: that is, the assays will encompass both programmed events (under enzymatic control, such as the synthesis of lysyl oxidase-derived crosslinks) and age-related "random" events (the mechanisms of which do not appear to be under cellular control, as typified by synthesis of such compounds as nonenzymatically glycosylated lysine and hydroxylysine and advanced Maillard products). Age- associated changes in these crosslinks will be measured in collagen derived from skin, tail tendon, heart, lungs and aorta of rats and mice. The relationship between tissue content of specific crosslinks and chronological age will be examined throughout the lifetime of the animals, with emphasis on the second half of the lifespan. Sampling at multiple intervals should provide sufficient data for determining what mathematical function best describes the rate of change of the specific parameters evaluated. To determine if the rate of change of any of the parameters can be correlated with longevity, tissues from rats and mice fed diets that extend their lifespan will also be analyzed. Finally, the study will determine if there are any correlations between age-related collagen crosslink content of tissues and advanced Maillard product content of hydrolysates of blood proteins such as hemoglobin and albumin. Rats and mice ranging in age from 3 to 30 months are to be provided by NIA. In addition to performing cross-sectional studies on these animals, it is proposed to perform a longitudinal study on one cohort from each group, in which nonlethal assays will be performed on the same animals every 6 months throughout their lifespans. Finally, in order to obtain data from time points near the end of the lifespan, it is proposed to obtain mice and rats aged 30 months and 24 months, respectively; animals from these groups will be sacrificed at 3 month intervals. HPLC methodologies are now available for rapid, quantitative analysis of collagen crosslinks. Previous studies have documented that the crosslinks to be analyzed change with age (increase or decrease) throughout the lifespan not only of short-lived species such as rats, but also of long-lived species such as monkeys and humans. The specific goals of this study are determining the precise relationship between age-associated changes and chronological age, and determining if the rate of change of these parameters can be used to predict longevity.