Dehydroepiandrosterone sulfate on lifespan in men and women using Mendelian randomization.

Background and aim: Dehydroepiandrosterone (DHEA) and DHEA-sulfate (-s) fall with age and are implicated in aging. Observational studies suggest DHEA/DHEA-s could lengthen life in specifically older men. No trial has established the role of DHEA/DHEA-s in aging or lifespan. We assessed the role of DHEA-s in lifespan and key biological determinants, (blood pressure, Apolipoprotein B (ApoB), and haemoglobin A1C (HbA1c)), for men and women in a two-sample mendelian randomization (MR) study using naturally occurring genetic randomization to obviate confounding.

Methods and results: We assessed associations of sex-specific DHEA-s from Life-Adult/Life-Heart (men = 4327, women = 3501) with lifespan, based on paternal (n = 415311) and maternal (n = 412937) attained age, and with blood pressure, ApoB and Hba1c (men = 167020, women = 194,174) from the UK Biobank. We used inverse variance weighted (IVW) estimates with sensitivity analysis. DHEA-s was unrelated to lifespan in women using IVW, 0.04 years per logged μmol/L DHEA-s, 95 % confidence interval (CI) -0.50 to 0.58, DHEA-s was associated with shorter lifespan in men (-1.15 years, 95 % CI -1.72 to -0.58) with a difference by sex (p = 0.0017), sensitivity analysis gave similar estimates. DHEA-s was unrelated to blood pressure in women and positively associated with systolic and diastolic blood pressure in men with a difference by sex for diastolic blood pressure. DHEA-s was possibly associated with lower ApoB in men.

Conclusions: DHEA-s has different associations with lifespan and blood pressure in men and women. In settings where DHEA is an unregulated supplement, such as the United States, whether public health benefits might accrue from more regulation could be considered.