41–50 of 65 posts
Re: longevity, ITP didn't find any significant impact from metformin. Afaik they're the most rigorous testers of this sort of thing, so that's pretty significant to me. https://pubmed.ncbi.nlm.nih.gov/27312235/
Interventions Testing Program (by The National Institute on Aging) for the unfamiliar, like me.
I don’t get it. Why would decreasing the function of mitochondria be a good thing? Can anyone explain?
Obviously, if you restrict too much, you starve. Animals in a state of nature seem to automatically find the right balance and eat roughly exactly what they need. Animals placed into situations in which food is nearly costless, effectively infinite, and you don't need to be active except to the extent you do it freely for recreation, seem to struggle. Humans suffering from diseases of civilization are one such example, but human pets and livestock seem to have the same problems. Presumably, lab rats are basically like that, too. Life in a plastic cage with no predators and food given to you directly by gods is not very similar to life in the wild.
FTA: "But until now, scientists have been unable to determine how, exactly, the drug works." Try that next time you submit a PR: Yeah... it works, but "I am unable to determine how exactly". I find this concept absolutely mind blowing. We take drugs that the creators of the drugs don't understand how they work. I realize that biology is hard to understand, but this sounds crazy.
I've submitted just such PRs before, usually with a comment along the line of "this hack is dumb and I do not yet understand why it is necessary, but it works now, tests prove it works, and I have more urgent things to do." Sometimes this is unacceptable but often it is just what the doctor ordered. Of course, unlike with biology, it is usually not beyond my skills to eventually understand the whole system, but it ma…
FTA: "But until now, scientists have been unable to determine how, exactly, the drug works." Try that next time you submit a PR: Yeah... it works, but "I am unable to determine how exactly". I find this concept absolutely mind blowing. We take drugs that the creators of the drugs don't understand how they work. I realize that biology is hard to understand, but this sounds crazy.
Evolution just pushes straight to master.
Earlier quoted context omitted.
That's very common actually! The mechanism of action for many drugs is unknown. And then it gets even weirder with psychoactive drugs: eventually the answer is "this drug effects this neurotransmitter which gives you this subjective first person experience, and we don't really know why". It brings up a lot of philosophical and existential questions!
How do people come to find these drugs then? If you don't have a theory about how something works, what would make you test whether it works?
It's actually the other way around. They didn't have very serious theories about the etiology of depression back then, the only clue they had was from the pharmacology of these drugs, which led to the situation where for many years the leading theory on depression was that it was caused by low levels of monoamine neurotransmitters(serotonin, norepinephrine and dopamine). The main evidence for this initially was the fact that these drugs seemed to work, and that they increased the levels or effects of monoamines. This theory has since become discredited as we've learned more, although the connection between monoamines and depression is still strong. It's just not the whole picture.
I don’t get it. Why would decreasing the function of mitochondria be a good thing? Can anyone explain?
I also did not understand why it would lower blood glucose, but that is due to my lack of understanding cells. I asked some help from ChatGPT and got this info: "Inhibiting a mitochondrial complex (e.g. one of the electron transport chain complexes) would decrease a cell’s ability to generate ATP through oxidative phosphorylation. As a result, cells would rely more heavily on glycolysis to meet their energy needs, wh…
This is a dubious statement. While glycolysis indeed consumes glucose, the amount of that consumption is expected to be significantly lower than through oxidative phosphorylation.
For example, if you deprive cells from oxygen, oxidative phosphorylation gets inhibited and glycolysis kicks in as an alternative metabolic pathway. As a result, blood glucose level goes through the roof. This is what can be seen in patients with acute respiratory distress syndrome.
But it is more complicated than that - when oxygen level drops, the nervous system starts gluconeogenesis as an attempt to compensate for the lack of oxygen by increasing the levels of glucose in the bloodstream. So we have multiple parallel effects going on: lower glucose consumption by oxidative phosphorylation due to the lack of oxygen + higher glucose consumption by glycolysis + higher glucose injection via gluconeogenesis. The net result of that formula is that blood glucose level goes up for almost all patients with hypoxemia.
Still, glycolysis alone cannot explain the effect of metformin. If it was really a glycolysis with such an amplitude caused by metformin intake, people would start to develop lactic acidosis, air hunger, cellular damages, neuropathy, dementia, cancer.
Honestly speaking, the only viable explanation so far is that metformin may cause mitochondria training by mildly and temporary putting a strain on ETC. Like a mild physical activity would do. Anything more impactful than "mild" would lead to an excessive oxidative stress, cellular damages, air hunger, suffocation, and tons of dangerous consequences.
Some papers also claim that metformin inhibits gluconeogenesis thus lowering glucose levels, which is another argument in favor of the "biochemical training by metformin" theory. Mitochondria seem to become more robust after a mild stress environment created by metformin, as if you visited a gym.
> 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 tr…
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…
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.
> 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 tr…
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).
FTA: "But until now, scientists have been unable to determine how, exactly, the drug works." Try that next time you submit a PR: Yeah... it works, but "I am unable to determine how exactly". I find this concept absolutely mind blowing. We take drugs that the creators of the drugs don't understand how they work. I realize that biology is hard to understand, but this sounds crazy.
They've been in use since at least the early 19th century. We have had a bunch of them (though in humans, at least, we pretty much only use 4 or 5 in developed countries these days). We do this every day in surgical suites around the world. People expect to be unconscious during surgery. But we don't really know how they do it.
Or take antipsychotics: the companies were looking for antihistamines and noticed psychotic patients got better on some of them. If it works... you keep using it until something better shows up.
The thing that gets me about all this, though, is how long it took for them to find a doctor that recognized what they needed in order to lose weight was treatment for the insulin sensitivity, rather than admonishments to "eat less." There must be so many other people with a treatable condition being written off in the same way.