Aging
Testosterone in relation to lifespan and fertility in men and women C Mary Schooling* C Mary Schooling Zhu Liduzi Jiesisibieke
Background: Testosterone use is controversial, with little evidence from trials. Recent genetic evidence in humans of antagonist pleiotropy between fertility and survival suggests that testosterone could reduce survival while promoting fertility. We used mendelian randomization (MR) to assess sex-specific testosterone on lifespan (maternal and paternal attained age) and fertility adjusted for relevant confounders, such as body mass index (BMI).
Methods: We identified independent (r2<0.001) genetic variants strongly (p<5e-8) associated with testosterone and un-associated with sex hormone binding globulin, i.e., bio-testosterone (men) and total testosterone (women) from the largest most densely genotyped genome wide association studies (GWAS) and applied them to the largest GWAS of maternal and paternal attained age and sex-specific participant fertility adjusted, where relevant, for sex-specific BMI from the largest suitable GWAS
Results: Using UK Biobank GWAS, testosterone in men (n=178782), was unrelated to paternal lifespan (n=415311) (-0.29 years per effect size, 95% confidence interval (CI) -0.69 to 0.12) but was associated with fertility (n=209872) (0.03 children, 95% CI 0.01 to 0.06); testosterone in women (n=230454) was unrelated to maternal lifespan (n=412937) (years -0.11, 95% CI -0.49 to 0.27) and to fertility (n=250782) (0.01, -0.01 to 0.03). BMI from GIANT (men=152893, women=171977) strongly decreased testosterone in men but not women. Testosterone in men was associated with shorter lifespan -1.78 years (95% CI -0.82 to -2.77) after adjusting for BMI and remained associated with fertility.
Conclusions: This study illustrates the importance of considering negative confounding in MR studies. Consistent with antagonist pleiotropy, testosterone in men was associated with shorter lifespan but more children. Whether targeting dietary and environmental drivers of testosterone could address disparities in lifespan between men and women might bear consideration.