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.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Resource-Related Research Projects (R24)
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National Center for Research Resources Initial Review Group (RIRG)
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Rall, William F
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Jackson Laboratory
Bar Harbor
United States
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Guo, Youming; Li, Pengfei; Bledsoe, Grant et al. (2015) Kallistatin inhibits TGF-?-induced endothelial-mesenchymal transition by differential regulation of microRNA-21 and eNOS expression. Exp Cell Res 337:103-10
Flurkey, Kevin; Brandvain, Yaniv; Klebanov, Simon et al. (2007) PohnB6F1: a cross of wild and domestic mice that is a new model of extended female reproductive life span. J Gerontol A Biol Sci Med Sci 62:1187-98
Yuan, Rong; Flurkey, Kevin; Van Aelst-Bouma, Renee et al. (2006) Altered growth characteristics of skin fibroblasts from wild-derived mice, and genetic loci regulating fibroblast clone size. Aging Cell 5:203-12
Klebanov, Simon; Astle, Clinton M; DeSimone, Olga et al. (2005) Adipose tissue transplantation protects ob/ob mice from obesity, normalizes insulin sensitivity and restores fertility. J Endocrinol 186:203-11
Klebanov, S; Astle, C M; Roderick, T H et al. (2001) Maximum life spans in mice are extended by wild strain alleles. Exp Biol Med (Maywood) 226:854-9