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Comment by Alex3917 | Hacker News Reader

> metformin blocks a specific part of the cell's energy-making machinery called mitochondrial complex

Keep in mind that any mitochondrial complex I inhibitor that is sufficiently strong is going to cause PSP if you take it for long enough, which is basically a fatal and untreatable version of Parkinson's disease. I haven't seen much research on this being a risk specifically for metformin, but I'd be careful about trying to use it prophylactically for longevity purposes rather than for a specific medical condition.

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This comment may unnecessarily discourage people from using metformin.

- There is no evidence linking metformin to PSP, let alone a causal relationship. - PSP is also very rare, prevalence ~ 7 per 100,000 [1]. - Metformin is used by 100+ million people [2]. - It has been safely prescribed for type 2 diabetes since the late 1950s [2].

Metformin is a highly effective and widely used medication. It would be unfortunate for people to avoid it based on speculative claims. If there’s specific evidence suggesting metformin as a risk factor for PSP, I’d be interested, but the leap from "mitochondrial complex I inhibition is associated with PSP" to "metformin causes PSP" is unwarranted.

As for the prophylactic use comment: we are all going to decay and die, trying to mitigate those risks with metformin is not unreasonable. There is evidence supporting its potential benefits, though some of these may reflect its established role in managing diabetes. (talk to your doctor, etc.)

[1] https://link.springer.com/article/10.1007/s00415-023-11791-2 [2] https://www.metabolismjournal.com/article/S0026-0495%2822%29...

> the leap from "mitochondrial complex I inhibition is associated with PSP" to "metformin causes PSP" is unwarranted

The mechanism of action is relatively straightforward: the inhibition is caused by a building up oxides within the mitochondria, which makes them less efficient at producing energy. And if the mitochondria go long enough without a mitochondrial antioxidant clearing out the oxides, they eventually die. And if enough of the mitochondria within your brain die, you get PSP.

My best guess as to the reason we haven't seen an association between PSP and metformin is that metformin is actually a mitochondrial type I adaptogen rather than a mitochondrial type I inhibitor. I'm definitely not telling people not to take it, but if you are then I think setting a couple Google scholar alerts would be prudent.

This seems unlikely but possible. Metformin is widely prescribed worldwide and as far as I know, no correlation has been shown. Granted, what its prescribed for - diabetes and prediabetes - are themselves risk factors for neurodegenerative diseases.

Source?

Metformin is one of the most widely studied drugs on the market. I can't find any study that links it to PSP (Progressive Supranuclear Palsy).

There aren't any papers that I know of on metformin and PSP, but there are lots of papers on rotenone/acetogenins and PSP.

Very interesting. I wonder if there is any study/evidence indicating PSP can happen to somebody taking metformin that does _not_ have T2D.

The hypothesis of developing something like PSP after consumption of a mitochondrial inhibitor is plausible, but in reality metformin is not strong enough to cause such damages.

Before something like that even starts to develop, a person who consumed the substance would feel a pronounced air hunger. Which does not happen with metformin, indicating that it is too mild to lead to negative consequences like that.

Cyanide, on the other hand, is a strong mitochondrial inhibitor and it causes serious consequences (neurological, metabolical) including death.

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