Project 5 will provide measurements of age-sensitive markers of collagen aging, metabolic status and oxidative stress int he group of 600 genotyped female UM-HET3 mice for studies of genetic linkage and biomarker validation. The test battery will also be performed on the 180 mice in Population 2, to see if mice selected for alleles that covey extended lifespan also show diminished level of protein glycation and oxidation. The set of tests includes measures of collagen glycation (furosine) and the glycoxidation products pentosidine and N/epsilon- carboxymethyl-lysine, whose rate of age-dependent increase is known from prior work to vary among inbred strains and to be sensitive to the age- retarding effects of calorie restriction. Data derived from Project 5 will confirm and extend pilot work suggesting that protein glycation and glycoxidation are under genetic control in the UM-HET3 mouse stock, and will show whether the genetic and non-genetic factors that influence these post-translational modifications also influence protein conformation (Project 4), affect the immune cells, muscle, and bone tissue (Projects 1, 2 and 3), and might be associated with individual differences in DNA sequence stability (Project 6). In addition, the data derived from Project 5 will permit a comprehensive evaluation of several indices of protein modification, including formation of methionine sulfoxide and the thermal stability of tail tendon collagen, a sensitive marker of collagen crosslinking. The relationships of these adducts to the other markers of metabolic state (pentosidine, furosine and CML), and their possible links to age- sensitive measures of immune, muscle, and bone function, will emerge from the combination of correlational and genetic analyses possible only within the context of a multi-component program.
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