The central goal of this research program is to count and map polymorphic loci in the mouse that alter longevity via an effect on the aging process. The work will focus on a population of UM-HET3 mice, bred as the progeny of CB6F1 mothers mated to C3D2F1 fathers. This four-way cross breeding scheme will produce a group of 600 mice (400 females and 200 males) that are effectively full sibs. Each mouse will be genotyped using SSLP markers at each of 150 polymorphic loci, and allowed to live until natural death or severe morbidity, to search for quantitative trait locus (QTL) alleles that are preferentially associated with exceptional longevity. Each mouse in the main population will also be tested for a number of age-sensitive traits: T cell subset levels, antibody responses, a variety of collagen cross- links, and eye lens opacity, as well as body weight trajectories. Each of these traits is known to vary with genotype in mice, and each has been shown in at least one strain or species to predict subsequent longevity. QTL found to be associated both with unusually long life span and also with relatively """"""""youthful"""""""" levels of one or more of the age-dependent traits will be taken as plausible candidates for loci that alter the aging rate. Each mouse will also receive a complete histopathological necropsy, both to search for QTL that modify the risk of specific late-life illnesses, and also to determine which longevity- associated QTL reduce risks of multiple terminal illnesses. An initial genome scan at an average resolution of 15 - 20 cM will be followed by higher resolution analyses (3 - 5 cM) of regions found in the initial scan to be of particular interest. The proposal includes two ancillary studies in addition to the main gene mapping program. One study involves the longitudinal characterization of mice selected for optimal combinations of longevity-related alleles, to see if inheritance of these combinations leads both to exceptional longevity and to decelerated aging in multiple phenotypic domains. The second ancillary study is designed to produce a series of additional four-way cross populations, using esoteric grandparental stocks likely to contain alleles rarely found in laboratory adapted mice. The goal of this part of the program is to produce mouse populations with exceptional longevity and/or very low spontaneous tumor risk because with these characteristics would be excellent tools for further genetic analysis in future work.
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