This Program Project on Genetics of Age-Sensitive Traits in Mice takes an integrated, multi-system in mice takes an integrated, multi-system approach to two related, fundamental questions in basic gerontology: (1) whether major aspects of the aging process are coordinately regulated at rates that differ among individuals; and (2) whether the pace of age- related change is under the control of polymorphic genetic loci. Each of the six projects is devoted mainly to assessing a set of age-sensitive traits in a specific physiological or biochemical domain-immunity, muscle, bone, protein structure, collagen modification, and somatic mutation-in a population of 600 female mice bred using a four-way cross procedure. Each of these 600 mice will also be genotyped at approximately 150 polymorphic loci. The combination of genetic and phenotypic data will allow the Analysis Core to map genes that influence age-sensitive traits in each domain and to see if some of these polymorphisms influence multiple traits in different domains. The data will also help to identify sets of traits that covary among mice-a key test of their usefulness as biomarkers of aging- and make it possible to determine the extent to which this co-variation is attributable to genetic and non-genetic factors. A second population of 180 test mice will be produced by genotypic selection, so that 50% of the mice bear allele combination shown to be associated with extended longevity influence age-dependent traits in a range of physiological and biochemical areas. Dr. Richard A. Miller will direct the Administrative Core and serve as overall Program Director. The Genotyping, Animal, and Analysis cores will be directed respectively by David Burke, Richard Miller, and Andrzej Galecki. The six research projects focus on Immunity (Miller), Muscles (Susan Brooks), Bones (Steven Goldstein), Proteins (Ari Gafni), Collagen Adducts (Vincent Monnier, Case Western Reserve) and Somatic Mutations (Eric Radany). This Program represents a collaboration among a set of biogerontologists who will collaborate towards the solution of problems that no one of the laboratories can address by itself. At worst, the Program should help to map genes that influence traits relevant to age-associated changes in tissue structure and function, and will test the idea that changes with age in protein and DNA structure may influence muscles, bones, and immune cells. At best, the program may permit the localization of loci that influence multiple age-sensitive domains and are thus plausible candidates for genes that regulate the rate of aging per se.
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