Thanks for the source! I fear he may be “mis-using” toxicity as “inhibition” again, rather than any real assay of damage.
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Is not the inbihition the result of something. If it’s not toxicity what would it be instead?
Caloric restriction inhibits too - it “slows everything down”
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@AlexKChen
As I have understanded it the biological pathways for how CR and metformin inhibit mitochondria differs. So there exists different ways to achieve the inhibition. It’s the same with other processes also such as AMPK activation. For example metformin has a direct upregulation of AMPK but rapamycin has an indirect upregulation of AMPK etc.
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There is another group of medications for diabetes was found to reduce risk of all causes of dementia compare to other groups.
MedPage Today
From: MedPage Today | Endocrinology Update daily.headlines@broadcaster3.medpagetoday.com
Date: October 18, 2022 at 1:04:18 PM PDT
Glitazones & Dementia*
A study of U.S. veterans with type 2 diabetes found that those treated with thiazolidinedione had a 22% reduced risk of all-cause dementia versus metformin, while those treated with a sulfonylurea saw a 12% higher risk. (BMJ Open Diabetes Research & Care)
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Here is todays digging work in the mine 
“These clinical findings are in accordance with recent studies showing that metformin (a well-known mitochondrial poison) actually prevents the onset of nearly every type of cancer studied in diabetic patients.”
Source: Mitochondrial dysfunction in breast cancer cells prevents tumor growth: understanding chemoprevention with metformin - PubMed
One little bit strange thing is that in two places in the article above they use quote marks around the word poison. I don’t know if the meaning of that is the same as in my country Sweden. If we put quote marks around a word like that it does mean it’s not a 100% true statement. Is it the same in english?
This goes quite good in what this person is commenting in a forum:
“metformin acts like very weak cyanide. This means it disrupts slightly (not totally, like cyanide does) the process by which we break down nutrients with oxygen for energy. With this, there’s less Reactive Oxygen Species being released, less inflammation, and less DNA damage.”
Source: World’s first anti-aging trial is happening! Using metformin to “TAME” aging - NAD+ Forums
This was also very interesting reading regarding complex IV instead of complex I inhibition. In this text they also say that guanides/biguanides (such as Metformin) has cyanide replicated effects:
“Although inhibition of mitochondrial complex I is frequently invoked as metformin’s primary mechanism of action, the metabolic effects of complex I inhibition have not been thoroughly evaluated in vivo. Here, we show that acute portal infusion of piericidin A, a potent and specific complex I inhibitor, does not reduce hepatic gluconeogenesis in vivo. In contrast, we show that metformin, phenformin, and galegine selectively inhibit hepatic gluconeogenesis from glycerol. Specifically, we show that guanides/biguanides interact with complex IV to reduce its enzymatic activity, leading to indirect inhibition of glycerol-3-phosphate (G3P) dehydrogenase (GPD2), increased cytosolic redox, and reduced glycerol-derived gluconeogenesis. We report that inhibition of complex IV with potassium cyanide replicates the effects of the guanides/biguanides in vitro”
Source: Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis - PubMed
This makes me remember little bit more about the Peter Attia and Nir Barzilai interview. Nir mentioned the word cyanide connect to metformin. If I find that part I will add the quote here.
But to connect metformin to cyanide is very interesting because this is a really heavy poison.
“Cyanide is one of the most rapidly lethal poisons known to man. Cyanide can lead to death in a few minutes to a few hours; therefore, rapid treatment is needed in these patients”
Source: Cyanide Toxicity - StatPearls - NCBI Bookshelf
After some more digging in the mine I found this article:
“Summaries of these studies are provided in Table 3 and in Fig. 2 where metformin is depicted to act as a weak mitochondrial poison that inhibits complex 1 thereby reducing the ATP/AMP ratio with the activation of AMPK resulting from the elevated levels of AMP”
Source: Metformin: Is it a drug for all reasons and diseases? - PubMed
Here is also Peter Attia in another podcast:
“I started it pretty early. I started in 2010 but I stoped it as well in 2018. [Why did you stop?] It was actually impairing zone 2 significantly. Metformin is a mitocondrial toxin, which is a good thing if your mitocondria are really defective. Taking a little bit a toxicity hit to the mitocondria produces a lot of other benefits that is why metformin is such a great drug for people with diabetes type 2. But I began to question sort of how valuable it was in people that could otherwise be healthy, and I don’t think I know the answer yet.”
Source: https://podbay.fm/p/the-goop-podcast/e/1588143660
This image was also very interesting summary about the hormetic effect of metformin and the importance of dosing right. Hormesis as I mentioned earlier is about making the body stronger by exposing it to stress for example by poison, damage or something else that causes a stress response.
Source: The Hormetic Effect of Metformin: "Less Is More"? - PubMed
If you find some kind of science article that contradicts that metformin has toxic effects please let me know. But it feels like things point in that direction?
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Interesting sources.
https://www.nature.com/articles/4400782
Does cyanide even irreversibly damage the mitochondria or release cytochrome c at very tiny doses? Like, with cyanide you KNOW its toxic when you feel it, but I’m more scared of air pollution or aldehydes or alkylating agents than I am even of cyanide (at subthreshold doses)
Now we are going into deep waters when we start talking about cytochrome c. I have never heard of that before so sorry I can not give a good answer to your question. But it feels like we can agree that metformin most likely has toxic effects (even if you see these effects as small)?
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Still not convinced - like I said - need molecular assays
Ok, curious question, what would you say is happening instead? I mean what is causing the inhibition? Do you know if there exists any science studies supporting that view or studies which question the mitochondrial toxic effect? Would be super interesting to read more about that 
I have started to try to find the quote with Nir Barzilai so some time this week I will probably find it. Will be interesting to see what he really said and not just what I recall he said. I could be totally wrong on what he said. Let’s see what I find
@AlexKChen & @desertshores I found the interview clip plus an seperate article with Nir Barzilai. He is the worlds leading researcher when it comes to metformin for longevity. He is also the leader of the big TAME trial (Target Aging with MEtformin). Here is what he says:
“Other side of metformin is what happens to the mitochondria because in a way and I hope I won’t regret saying it here but metformin is a weak cyanide. [I thought cyanide acted at complex 4. Oh, you just mean more broadly speaking it’s inhibiting ETC] Right, it inhibits. There is less ROS production and there is less inflammation and there is other things that’s going on just because the mitochondria is less oxidative pathway going down.”
“metformin acts like very weak cyanide. This means it disrupts slightly (not totally, like cyanide does) the process by which we break down nutrients with oxygen for energy. With this, there’s less Reactive Oxygen Species being released, less inflammation, and less DNA damage.”
If you find some study or other source that contradicts that metformin does not have toxic effects on mitochondria please let me know. But until then I would say things lean quite much towards that metformin has these toxic effects. I want also to point out again that it’s not neccessary unhealthy to take something that has toxic effects. The important thing is that the dose has hormetic effect which means that the body gets stronger and healthier and not the opposite.
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I’m actually WAY less scared of cyanide than I am off pesticides or pollution… there’s no evidence cyanide acts on multiple targets or causes any real damage of subthreshold… It may even be hormetic. Carbon monoxide is too
There is no minimum safe dose of pollution or lead. There is one for CN and CO
Yes, I’m not scared of things that are toxic either if the dose is right and it has a hormetic effect. It would be great if you could find any paper or something that support your view that metformin does not have any mitochondrial toxic effect. It would be very interesting to see how well that contradicts to what people like Nir Barzilai and Peter Attia and the other papers are saying. Let me know if you find something. I’m open for changing my mind but I would like to have more substance to a statement
Since many human studies have used metformin in various doses, you would think that any adverse effects of the minuscule amount of cyanide contained in metformin would have raised a huge red flag before now.
Can you cite any studies in humans that even mentions cyanide?
You have cited Petri dish and microscope slide studies so far.
I can’t find any human studies that test the effect of the cyanide contained in metformin.
Have you found any studies on the effect of cyanide in metformin on humans?
Other than the minor negative effect of metformin on resistance training.
The vast majority of metformin studies using thousand of humans has been positive.
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Nir Barzilai does not mean that metformin is cyanide. He means that it has similiar weak toxic effects as cyanide on mitochondria. I don’t understand why this view of toxicity creates such of big emotions in the topic. Let’s take some steps back from emotions and own opinions and try to seek other studies or other research experts who claim the opposite. It should not be so hard to find. If you find something let me know. I will see if I can find something also and get back.
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No emotions other than you seem to be stuck on this. Why?
Calling metformin a “mitotoxin” makes some people not take it when they could benefit from taking it (esp if they’re taking rapamycin), on the margin. I took an unnecessarily long break from metformin because of these people. It’s really not the right word
for that matter, every TCA metabolite could be a mitotoxin too. Especially succinate
The reason why I like deep dive in topics is because I like to understand how things works like the biological pathways for different longevity compounds etc. I’m not so interested in just opinions. I want to find support in science and/or experts. It’s not easy and a very time consuming process but the result from all this usually gives a much deeper understanding and learning. I made a deep dive in the compound metformin couple of years ago which gave me a lot. This thread has also deepen my understanding little bit extra which I really appreciate and is good content to my book. I appreciate also that you have questioned me and forced me to find better support for the view of toxicity. I just want to give the ball back now to you or someone else who has a different view and really try to find support for that metformin is none toxic. If someone can find better support than the things I have presented above I will gladly change my view in the topic. That would deeper my knowledge even more. So the reason I’m stuck is because I have a big passion in deep learning
@AlexKChen
I understand your concern but I don’t think it’s good either in the long term to avoid how the reality most likely looks like. It can hurt the reputation if different claims are not good supported. And as I said before it’s nothing wrong with that something is toxic. It’s just to get the dose right and from that you get a nice hormetic effect and the body gets healthier. This is good aligned with many other compounds and interventions in the longevity area. I think we need to change our perception of viewing that toxicity and/or damage always is something bad for us.
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Read Antifragile: Things That Gain from Disorder. Book by Nassim Nicholas Taleb.
Examples of how stressing the body makes it stronger.
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Thanks for the book recommendation Siim Lands book Stronger by stress is also a great book on the topic.