The manuscript's claim that DHEA-S shortens male lifespan relies on a fundamentally flawed Mendelian randomization (MR) analysis. The core problem is extremely weak genetic instruments: Only 3 variants per sex, explaining just 1% of DHEA-S variance (!), likely inflated by a small discovery cohort. These variants are also pleiotropic (affecting multiple steroid/metabolic pathways), and thus violate a key MR assumption. With only 3 variants, standard pleiotropy tests (MR-Egger, weighted median) are useless. Under the circumstances, claims of "no pleiotropy" are completely untenable.
Critical biases compound this: Adjusting the exposure GWAS for BMI introduces collider bias. Using noisy parental lifespan as a proxy outcome injects measurement error, socio-economic confounding, and sex-discordant genetic issues. Statistical power is overstated, and multiple testing (10+ primary tests) is ignored -- the key lifespan finding wouldn't survive correction.
Also LOL(!!!) at using this junk to push policy recommendations against DHEA supplements. Is this a hatchet job funded by a private interest group?! Even if we take the most generous interpretation of their findings, MR assesses lifelong genetic exposure, not short-term supplementation in relevant populations.
And basically it's a textbook case of why so much of the scientific literature is junk. Maybe I'll seriously write the editors a letter regarding this paper.
Or put a comment on PubPeer! https://pubpeer.com/publications/ABEC366688EE00BCD774A32A7CC...
I trust this comment without a nugget of doubt.
rs45446698 (CYP3A7) is also associated with testosterone, height, BMI, bone density, C‑reactive protein, estrogen, and urate. It's also heavily involved in the metabolism of drugs and exogenous chemicals in infants and neonates; it's not as widely expressed in adults: https://en.wikipedia.org/wiki/CYP3A7
rs615567 (FGF9) is associated with bone development, vision traits, blood pressure, and cardiovascular disease. Also lots of other stuff: https://en.wikipedia.org/wiki/FGF9
rs36155566 (MCM9) is a member of the mini-chromosome maintenance (MCM) protein family, and it's involved in various processes related to cell division. Reviewed here: https://www.sciencedirect.com/science/article/pii/S258900422...
These are ultra-pleiotropic genes. They do a lot. You'd be hard-pressed to pick worse genes as yardsticks. (Maybe CYP3A4, lol.)
So you simply can't look at those three -- which together explain just ~1% of DHEA-S variance -- and pin anything on DHEA-S! They didn't even attempt to measure DHEA-S in their larger cohort to bolster their findings. It's really shoddy.
I guess there will always be study variability in results, but I've grown kind of jaded by MR analyses at this point.
It's also one of those dubious bullshit upsell add-ons you'll see in men's clinics that exist to give people who don't need it prescriptions for TRT.
Lifelong supplementation that would be equivalent to a genetic predisposition to making more of it naturally has to be exceedingly rare, though, probably to the point that zero people ever have done it.
cj•7mo ago
The bottom of the article seems to try to draw a link between high DHEA and testosterone and blood preassure.
Might be a bit of a leap, but higher DHEA -> higher testosterone -> higher blood pressure seems to be the takeaway?
This study [0] also links DHEA to higher IGF-1, and IIRC high IGF-1 is also linked to higher rates of cancer.
IGF-1, testosterone, estrogen, etc... they all seem to have optimal health benefits when in an "ideal range". Too low is bad. Too high is also bad. No free lunch it seems.
[0] https://pubmed.ncbi.nlm.nih.gov/9876338/