Fig. 1. QTL mapping of longevity identifies sex- and age-specific loci.

(A) General scheme of the UM-HET3 four-way intercross and the end points examined in this study. The UM-HET3 mice come from a cross of a female (BALB/cByJ × C57BL/6J) F₁ and a male (C3H/HeJ × DBA/2J) F₁. The 3276 mice in this study are either controls (n = 2356) or were treated with 20 drugs that had no population-level effect on longevity (n = 920, data S1), from the NIA ITP conducted at two different sites (UT and UM) and spanning years 2004 to 2011. Natural life span, body weight, and DNA were collected from these mice. A separate UM-HET3 cohort (Glenn Center, UM) was used to obtain livers from young and old males and females for RNA sequencing to study sex- and age-related gene expression changes and haplotype-specific expression. (B) (Left) Distribution of female and male life spans. (Right) QTL mapping results for longevity in four analyses. The “Both, no sex int” includes all mice with sex as a fixed effect and site as a random effect and cohort year as a nested random effect within site. The “Both, sex int” tests for sex-by-haplotype interactions. The Male and Female models are restricted to one sex. Solid and dashed horizontal lines indicate permutation-based significance thresholds for α = 0.05 and 0.2, respectively. (C) QTL scans for life span performed after excluding different percentiles of mice that die early. (Left) Distribution of lifespan values after exclusion of mice. The labels indicate the minimal life span in days and the number of mice. (Right) Overlaid QTL scans, colored by truncation level for females and males. Solid and dashed horizontal lines indicate permutation-based significance thresholds as in (B). (D) Median longevity ofmice stratified by haplotype at male loci on chromosomes 2 and 10, female loci on chromosomes 3, and male and females at the chromosome 12 locus, after exclusion of different proportions of early deaths. Alleles B, C, H, and D correspond to CBy, B6, C3, and D2 strains, respectively.