Prepubertal castration eliminates sex differences in lifespan and growth trajectories in genetically heterogeneous mice

Abstract

Sex differences in aging and longevity have been widely observed, with females consistently outliving males across human populations. However, the mechanisms driving these disparities remain poorly understood. In this study, we explored the influence of post-pubertal testicular effects on sex differences in aging by prepubertally castrating genetically heterogeneous (UM-HET3) mice, a unique mouse model that emulates human sex differences in age-related mortality. Prepubertal castration eliminated the longevity disparity between sexes by reducing the elevated early- to mid-life mortality rate observed in males and extending their median lifespan to match that of females. Additionally, castration extended the duration of body weight growth and attenuated the inverse correlation between early-age body weight and lifespan in males, aligning their growth trajectories with those of females. Our findings suggest that post-pubertal testicular actions in genetically diverse mice are primarily responsible for sex differences in longevity as well as growth trajectories. These findings offer a foundation for further investigation into the fundamental mechanisms driving sex-specific aging patterns and the development of potential pro-longevity interventions.

Keywords: age-specific mortality; aging; body composition; body weight; castration; growth; lifespan; sex differences.

FIGURE 1

Prepubertal castration prolonged lifespan and eliminated sex differences in the age‐specific mortality hazard. (a) Survival curves (SHAM, n = 231; ORX, n = 221; median lifespan SHAM vs. ORX, 771 vs. 850 days; Log‐rank test, p = 0.0123) and (b) age‐specific mortality hazard rate for ORX or SHAM males. (c) Survival curves (Male, n = 1281; Female, n = 1017; median lifespan Male vs. Female, 760 vs. 874 days; Log‐rank test, p < 0.0001) and (d) age‐specific mortality hazard rate for historical ITP control males and females. (e) Combined survival curves (Log‐rank test, Males vs. SHAM, p = 0.2877; Female vs. ORX, p = 0.1117). (f) Age‐specific mortality hazard rate for all groups.

FIGURE 2

Prepubertal castration shifted growth pattern and correlation between bodyweight and lifespan to female levels. (a) Body weights at wean and 6 months (Wean SAHM, n = 222; Wean ORX, n = 207; 6 months SHAM, n = 172; 6 months ORX, n = 158; t‐test, wean, p = 0.2713; 6 months, p < 0.0001). (b) Body composition at 4 months (SHAM, n = 42; ORX, n = 45; t‐test, Lean mass, p < 0.0001; Fat mass, p = 0.2975). (c) Plasma IGF‐1 levels at 4 months (SHAM, n = 21; ORX, n = 18; t‐test, p = 0.2941). (d) Bodyweight changes in historical ITP control mice, (e) castrated and sham‐operated male mice, and (f) combined historical ITP female and castrated male groups. (g) The correlation between bodyweight at 6 months to lifespan in historical ITP control mice months (Male, n = 1094; Female, n = 887), (h) castrated and sham‐operated male mice, (SHAM, n = 172; ORX, n = 158), and (i) combined groups. All bars and error bars represent mean ± SEM.