Higher DHEA-S Levels Linked to Shorter Lifespan in Men, Not Women
A Mendelian randomization study finds genetically elevated DHEA-S is associated with shorter lifespan in men—raising questions about unregulated DHEA supplementation.
Summary
DHEA is a popular supplement often marketed for anti-aging benefits, but this large genetic study challenges that narrative—at least for men. Researchers used Mendelian randomization, a method that uses genetic variants as proxies to test cause-and-effect, to examine whether higher DHEA-sulfate levels affect lifespan. Using data from over 400,000 individuals in the UK Biobank, they found that genetically higher DHEA-S was associated with roughly 1.15 fewer years of life in men, while showing no significant effect in women. Men with higher DHEA-S also tended to have elevated blood pressure, which may partly explain the lifespan finding. The authors suggest that in countries like the United States where DHEA is sold freely as a supplement, regulators may want to reconsider its status.
Detailed Summary
DHEA (dehydroepiandrosterone) and its sulfated form DHEA-S are steroid hormones that decline naturally with age, leading many to theorize they could be protective against aging. This assumption has fueled widespread use of DHEA as an over-the-counter supplement, particularly in the United States. But observational data are easily confounded, and no clinical trial has definitively established a lifespan benefit.
To cut through the confounding, researchers Schooling and Zhao employed two-sample Mendelian randomization (MR), which uses genetic variants naturally associated with DHEA-S levels as instruments to estimate causal effects—essentially mimicking a randomized trial using nature's own variation. Sex-specific genetic instruments for DHEA-S were drawn from the Life-Adult/Life-Heart cohorts, and outcomes including lifespan (via parental attained age), blood pressure, ApoB, and HbA1c were sourced from the UK Biobank.
The headline result was striking: genetically higher DHEA-S was associated with approximately 1.15 fewer years of lifespan in men (95% CI: -1.72 to -0.58), while women showed no significant effect. This sex difference was statistically robust (p = 0.0017). In men, DHEA-S was also linked to higher systolic and diastolic blood pressure, a potential mechanism for the shortened lifespan. A possible association with lower ApoB in men was also noted, a partial offset that warrants further investigation.
These findings carry real public health weight. DHEA supplements are widely available without a prescription in the U.S. and are frequently promoted for anti-aging, energy, and hormonal balance. This study's genetic design strengthens the case that the relationship may not be benign in men.
Important caveats apply. The MR approach assumes genetic instruments only affect outcomes through DHEA-S, which cannot be fully verified. Additionally, lifespan was estimated via parental attained age—a proxy measure with inherent imprecision. This summary is based on the abstract only, and full methodology and supplementary analyses were not reviewable.
Key Findings
- Genetically higher DHEA-S was linked to ~1.15 fewer years of lifespan in men but had no effect in women.
- Men with higher DHEA-S showed elevated systolic and diastolic blood pressure, a potential lifespan mechanism.
- DHEA-S may be associated with modestly lower ApoB in men, a partial cardiovascular counterpoint.
- No lifespan or blood pressure effects were detected in women, highlighting a clear sex-specific divergence.
- Authors suggest regulatory consideration of DHEA supplements in the U.S., where they are sold freely.
Methodology
Two-sample Mendelian randomization using sex-specific genetic instruments for DHEA-S from Life-Adult/Life-Heart cohorts (men n=4,327; women n=3,501). Outcomes assessed in UK Biobank: lifespan via parental attained age (n>400,000) and cardiometabolic markers (n>160,000 per sex). Inverse variance weighted estimates with sensitivity analyses were employed.
Study Limitations
Lifespan was estimated using parental attained age as a proxy, introducing measurement imprecision. The Mendelian randomization framework assumes genetic instruments affect lifespan only through DHEA-S, an assumption that cannot be fully verified. This summary is based on the abstract only, as the full text was not accessible.
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