Testosterone and longevity in men and women: A Mendelian randomization study in the UK Biobank

Background After decades of rising life expectancy, life expectancy in the developed West is currently stagnated and remains shorter in men than women. Very well-established evolutionary biology theory suggests that lifespan trades off against reproductive success, possibly sex-specifically. We examined whether a key driver of reproductive success, testosterone, affected lifespan using a Mendelian randomization study of longevity in the UK Biobank to obtain unbiased estimates, along with control exposures. Methods We applied published genetic instruments for testosterone to obtain inverse variance weighted estimates of associations with longevity, proxied by survival to (i.e., age at) recruitment, in 167020 men and 194174 women. We similarly obtained estimates for smoking initiation, and absorbate, a marker of vitamin C metabolism, because. We also conducted sensitivity analysis. Results Overall testosterone was associated with poorer survival (0.10 years younger at recruitment per effect size of testosterone, 95% confidence interval (CI) 0.004 to 0.20). As expected, smoking initiation was also associated with poorer survival (0.37 years younger, 95% CI 0.25 to 0.50), but not absorbate (0.01 years younger, 95% CI −0.09 to 0.11). Sensitivity analysis generally gave a similar interpretation Conclusions Consistent, with well-established theory, testosterone reduced longevity. Several aspects of a healthy lifestyle (such as a low animal fat diet) and several widely used medications (such as statins, metformin, dexamethasone and possibly aspirin) happen to modulate testosterone. Explicitly designing interventions sex-specifically based on these insights might be a means of addressing stagnating life expectancy and sexual disparities in life expectancy.