This proposal aims to develop mouse models with extended lifespans and delayed pathologies to help learn how such pathologies can either be retarded, prevented, or cured. The proposal's Specific Aims are to: 1) Verify that the Legl(a) and the Leg2(a) alleles from the MOLD and CAST inbred mouse strains respectively each increase murine lifespans by at least 10%, and determine whether the effects of these alleles are additive or synergistic. Mice from three genetically diverse inbred strains will be made singly and doubly congenic for Leg1(a) and Leg2(a). To decrease the chance that homozygosity for early lethal alleles from the backgrounds of these strains will reduce life spans, the effects of Leg1(a) and Leg2(a) will be determined on F1 hybrids between pairs of unrelated congenics. 2) Accelerate selective breeding to increase life spans in mice. Cryopreserved sperm are already collected from the longest-lived males (30-50% longer than the mean life span) of initial four-way crosses. These males will fertilize unrelated females using ICSI. Female offspring will be fertilized with sperm from an unrelated long-lived male. This breeding cycle will be repeated three times, and, at each cycle, the life spans and pathologies of the offspring will be compared to controls. To avoid inadvertent inbreeding depression, controls will be selected from the initial four-way crosses. Sperm from all males living more than 40 months will be preserved. 3) Determine if genetic loci that retard basic aging mechanisms are found in 10 other wild-derived inbred mouse strains of independent origin besides MOLD and CAST. Polymorphic DNA markers will be used to scan the genomes of offspring from six four-way crosses involving 12 unrelated wild-derived strains. As already shown for Leg1(a) and Leg2(a), alleles that extend maximum life spans by 10% or more can be detected.
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