Investigating the association of testosterone with survival in men and women using a Mendelian randomization study in the UK Biobank

Abstract

Life expectancy in the developed West is currently stagnated and remains shorter in men than women. Well-established evolutionary biology theory suggests lifespan trades-off against reproductive success, possibly sex-specifically. We examined whether a key driver of reproductive success, testosterone, affected survival using a Mendelian randomization longevity study in the UK Biobank to obtain unbiased estimates, along with control exposures. We applied published genetic instruments for testosterone to obtain inverse variance weighted estimates of associations with survival to (i.e., age at) recruitment, in 167,020 men and 194,174 women. We similarly obtained estimates for a positive control (smoking initiation), and a negative control (absorbate), a marker of vitamin C metabolism. 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). Several aspects of a healthy lifestyle (low animal fat diet) and several widely used medications (statins, metformin, dexamethasone and possibly aspirin) may modulate testosterone. Explicitly designing interventions sex-specifically based on these insights might help address stagnating life expectancy and sexual disparities.

Sex and gender differences in health and disease. Part I. Evolutionary

“…Негативная роль тестостерона в отношении отдельных иммунных функций может быть связана с его ролью в обеспечении перераспределения пластических и энергетических ресурсов между иммунной и генеративной системами. Таким образом опосредуется дорогостоящий эволюционный компромисс выживание/репродукция [24][25][26].…”

“…Возможное объяснение этого противоречия состоит в том, что наличие факторов риска ССЗ (ожирение, метаболический синдром, курение и т.д.) само по себе может снижать уровень тестостерона [25,29,30].…”

Testosterone and lifespan in males: At the right time and the right level

“…Although it seems a reasonable approach to extend the lifespan by reducing the level of testosterone, the studies produced mixed results (Dunn et al, 2021;Hughes & Kumari, 2019;Paternostro, 1994). In spite of the extensive research on the effect of reduction of testosterone level in the past several decades, there are still hug gaps in understanding its role in the lifespan in males (Morley et al, 2005;Schooling & Zhao, 2021). With the emerge a new concept of principal law of lifespan (PLOSP) (Gu, 2022a(Gu, , 2022b, the role of testosterone in the lifespan of males may be examined in a different angle.…”