Marker loci associated with life span in genetically heterogeneous mice.

BACKGROUND Little is known about the number or chromosomal location of 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 analysis 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 F1 hybrid mouse stocks, was genotyped at 82 loci, and the mice were allowed to live either until their natural deaths or until they became extremely ill. Each mouse was also necropsied to determine the probable cause of death. An analysis of variance was used to seek relationships between life span (dependent variable) and the independent variables sex and allele for each marker locus. RESULTS Five markers on different chromosomes were associated with differential longevity in male mice, and two other markers were associated with longevity in female mice. Post hoc probabilities were suggestive but not definitive, reaching p < .003 for the four strongest effects. Associations between marker loci and life span were sex-specific in almost all cases, affecting either males or females but not both. The strongest effects led to differences in mean survival of about 20% in the affected sex. The survival curves are consistent with the idea that the markers are linked to loci that influence the mortality risks of the longest-lived animals in the cohort. Associations between markers and life span did not appear to reflect associations of these markers to specific diseases in these mice. CONCLUSIONS Associations between genetic markers and life span in mice bred by using a four-way cross are strong enough to deserve further analysis and seem to be sex-specific in their effects.