MARKER LOCI ASSOCIATED WITH LIFE-SPAN IN GENETICALLY HETEROGENEOUS MICE

Background, Little is known about the number or chromosomal location o f genetic loci that might identify individuals destined to have a long life span. Analysis of gene/life span associations in mice, which are short-lived compared to humans, might provide guidance for an analysi s of the genetic basis of life span in humans. Methods. A group of 144 genetically heterogeneous mice, produced by a four-way cross between two F-1 hybrid mouse stocks, was genotyped at 82 loci, and the mice we re allowed to live either until their natural deaths or until they bec ame extremely ill. Each mouse was also necropsied to determine the pro bable cause of death. An analysis of variance was used to seek relatio nships between life span (dependent variable) and the independent vari ables sex and allele for each marker locus. Results. Five markers on d ifferent chromosomes were associated with differential longevity in ma le mice, and two other markers were associated with longevity in femal e mice. Post hoc probabilities were suggestive but not definitive, rea ching p <.003 for the four strongest effects. Associations between mar ker loci and life span were sex-specific in almost all cases, affectin g either males or females but not both. The strongest effects led to d ifferences in mean survival of about 20% in the affected sex. The surv ival curves are consistent with the idea that the markers are linked t o loci that influence the mortality risks of the longest-lived animals in the cohort. Associations between markers and life span did not app ear to reflect associations of these markers to specific diseases in t hese mice. Conclusions. Associations between genetic markers and life span in mice bred by using a four-way cross are strong enough to deser ve further analysis and seem to be sex-specific in their effects.