3 ms·

Junk study. Literally everything about it is garbage. I know that I shouldn't be, but I'm astounded that this passed peer review. The manuscript's claim that

Junk study. Literally everything about it is garbage. I know that I shouldn't be, but I'm astounded that this passed peer review. 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.

flobosg 1y ago
> Maybe I'll seriously write the editors a letter regarding this paper. Or put a comment on PubPeer! https://pubpeer.com/publications/ABEC366688EE00BCD774A32A7CC97A https://pubpeer.com/publications/ABEC366688EE00BCD774A32A7CC...
aDyslecticCrow 1y ago
I have no idea what half of these words mean, but my phone screen is slightly warm from the rage and disappointment in the words... it can only come from a truly disappointed researcher. I trust this comment without a nugget of doubt.
- A_D_E_P_T 1y ago
  There are a lot of flaws but here's the most glaring: They looked at three genes to determine whether DHEA-S affects longevity in men. But the problem is that the genes they tracked as markers for DHEA-S are also involved in lots of other stuff! 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 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 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/S2589004223008143 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.
derbOac 1y ago
Just to add to this, I was surprised to see this because my impression of the literature is that lower DHEA-S and greater declines in DHEA-S are usually associated with greater mortality rates and shorter lifespan, not the other way around. I guess there will always be study variability in results, but I've grown kind of jaded by MR analyses at this point.

flobosg 1y ago

> Maybe I'll seriously write the editors a letter regarding this paper. Or put a comment on PubPeer! https://pubpeer.com/publications/ABEC366688EE00BCD774A32A7CC97A https://pubpeer.com/publications/ABEC366688EE00BCD774A32A7CC...

aDyslecticCrow 1y ago

I have no idea what half of these words mean, but my phone screen is slightly warm from the rage and disappointment in the words... it can only come from a truly disappointed researcher. I trust this comment without a nugget of doubt.

A_D_E_P_T 1y ago
There are a lot of flaws but here's the most glaring: They looked at three genes to determine whether DHEA-S affects longevity in men. But the problem is that the genes they tracked as markers for DHEA-S are also involved in lots of other stuff! 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 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 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/S2589004223008143 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.

derbOac 1y ago

Just to add to this, I was surprised to see this because my impression of the literature is that lower DHEA-S and greater declines in DHEA-S are usually associated with greater mortality rates and shorter lifespan, not the other way around. I guess there will always be study variability in results, but I've grown kind of jaded by MR analyses at this point.