The long term objectives of this proposal are to study the interaction of the effect of several genes and environmental factors on life span and to demonstrate that the interactions between these genes are as important in conferring longer life span as the presence of individual genes. We will (a) study the role of one genetic region (Hb-2) in life span using congenic strains of mice. Three strains will be used: B10 (H-2b); B10.D2/nSn (H-2d) and B10.BR (H-2k) and hybrids among them to rank higher survival with heterozygosity of H-2. The study will also test whether subregions of H-2 located near the K end or the D end are important. For the effect of the K end we will compare (B10.A x B10.D2/nSn)F1. We will (b) study the role of several genetic regions in life span using hybrids and recombinant lines, especially a segment of Chromosome 17 carrying H-2, a segment of Chromosome 4 carrying b and sex. These segments will be investigated using backcross mice (C57BL/6xDBA/2)F1 x DBA/2, recombinant lines; and F2 hybrids produced by mating (C57BL/6 x DBA/2)F1 mice. Using backcross mice we will attempt to confirm the role of the segment of Chromosome 4 carrying b interacting with sex in life span and finding that the more heterozygosity, the longer the life span. Also, the role of these interactions and the b locus in immune vigor and in development of non-lymphoma solid tumors will be studied. The genetic interaction between heterozygosity at one or more loci and homozygosity at a second or more loci affecting life span will be investigated using the F2d hybrid mice. For example, the interaction between H-2b/H-2b, H-2b/H-2d, H-2d/H-2d will be studied with respect to MUP-1a/MUP-1a, MUP-1a/MUP-1b and MUP-1b/MUP-1b and sex because the MUP-1 is a genetic marker of the segment of Chromosome 4 carrying b. We will also determine if other genetic systems (homozygous or heterozygous) in addition to H-2, MUP-1 or sex influence life span (Idh-1, Gpd-1, Gpi-1, Hbb,Mod-1, esterase D and C8). On the other hand, the recombinant lines between C57BL/6 and DBA/2 will compare the number of dominant alleles derived from such chromosomes which will produce an effect on life span. Our studies will attempt to relate genotypes to disease patterns associated with aging and immune disturbances. Immune deficiencies and diseases associated with some genotypes in mice may help future attempts to identify similar relationships in man.
