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
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.
Read Antifragile: Things That Gain from Disorder. Book by Nassim Nicholas Taleb.
Examples of how stressing the body makes it stronger.
Thanks for the book recommendation Siim Lands book Stronger by stress is also a great book on the topic.
Its a decent AMPK activator, not a toxin by any meaningful usage of the word. Its a fact that some things that increase lifespan may be in the short term not ideal towards fitness/health. Such a easy concept its just crazy how many people seem to not get it or maybe just not want to accept it.
This is an interesting paper
Several studies provide evidence that metformin partially inhibits complex I of the electron transport chain (ETC) with subsequent alteration of the mitochondrial performance, but the molecular mechanisms underlying this process have not been characterized in detail21,22,23. Thus, metformin may compromise ATP production in mitochondria leading to an increase of the AMP/ATP ratio. As a consequence of energy depletion, glycolysis is induced to maintain cellular metabolism. Even though mitochondrial poisons increase oxidative cellular damage by mechanisms involving increased reactive oxygen species24,25, there is no evidence that metformin induces the generation of reactive oxygen species and/or accumulation of oxidative damage26,27. In fact, the transcription factor SKN-1/Nrf2 is activated upon metformin treatment, resulting in increased expression of antioxidant genes in cells and animal models10. Reduced accumulation of oxidative damage may contribute to the inhibitory effects of metformin treatment in carcinogenesis models3,28,29.
mice fed metformin ate more, were lighter, and produced more heat
…for all the time I spent in longevity, this is the FIRST time I really deep-dove into this paper…
This shows in a good way that the dose is important and that the optimal longevity dose probably is some where between too little and too much.
the lifespan-shortening dose was 10x the lifespan-increasing one. But we need more gradations.
Furthermore, the inhibition of mitochondrial respiration by metformin is reported to be concentration-dependent, with no effect at concentrations lower than 1 mM42. Serum level of metformin was 0.45±0.09 mM (mean±s.e.m.) in 0.1% metformin-treated mice, which is considerably higher than seen in the serum of diabetic patients treated with metformin43, but lower than those used in most in vitro models that demonstrate inhibition of mitochondrial respiration by this compound21,22,42
40 micromolar with 1g/day metformin (https://academic.oup.com/edrv/article/42/1/77/5902802?login=true ). This is 1/10th the lifespan increasing concentration seen above.
So what would those two doses be in humans? 500 mg vs 5 g?
I stumbled upon this old podcast and here Peter Attia explains little bit more his view on metformin and mitochondrial toxicity. (Again I’m not against metformin I curious of the mechanism behind and also again toxicity is not something bad if it’s taken in the right dose)
“I was kind of suprised at how high my lactate levels were even at baseline. You know I was walking around at a lactate level of 1.6 millimole. Now it would dip a little bit when I would start exercising. But I was realizing that I just had you know higher lactate levels than I wanted to. And when I thought about it and I was like wait this is obvious I’m taking a mitochondrial toxin of course my lactate levels arge going to be higher. So then I did the experiment, and I did all this sort of talking with a friend of mine Iñigo San-Millán who’s also been on the podcast, of stopping metformin and starting it again just to see if we could reproduce the effect and sure enough it was clearly the metformin that was allowing my lactate levels and this you do this at a fixed power level right so you on an ergometer you would just say look at this many watts or this many miles per hour on a threadmill you could watch your lactate level go up and down as a function of metformin.”
Source: #123–Joan Mannick & Nir Barzilai: Rapamycin and metformin—longevity, immune enhancement, & COVID-19 - YouTube
In that episode Nir Barzilai also points out two times that metformin has toxic properties.
TAME trials have metformin at 1500-1700mg/day
I think I heard recently that now the TAME trial has been funded but do someone know when it will be started?
Metformin slows down DNA aging.
Researchers at the Chinese PLA General Hospital in Beijing took blood samples from 32 men with type 2 diabetes. The mean age of the men was 73 years.
Half of the men had been taking 500 milligrams of metformin a day for at least five years to control their diabetes, the other half were taking other medications.
The researchers extracted the DNA from the men’s blood cells and determined how many methyl groups were attached to important genes in that DNA. As organisms age, more methyl groups become attached to genes. As a result, the genes sometimes function less well.
The number of methylated genes in your DNA therefore says something about the rate at which you age. The more methylated genes, the faster your biological clock ticks at the DNA level.
Study cited by ergo-log.com is below.
Came late to the party. So there is talk above about Metformin as a poison. That is true, with respect to Goat’s rue, or French Lilac, from which Metformin was derived. Study below is downloadable for free.
The discovery of metformin is derived from galegine, a natural product isolated from
the medicinal plant Galega officinalis (Goat’s rue), which has been traditionally used in
Europe . Galegine, a guanidine alkaloid containing an isoamylene, is known to enhance
glucose uptake and inhibition of acetyl-CoA carboxylase and is thus expected to contribute
to the weight-reducing effect . However, G. officinalis is toxic to animals, shown through
accidental livestock poisoning in the field as well as laboratory studies. Additionally,
galegine is believed to be the major toxin of G. officinalis and causes blood pressure lowering,
paralysis, and death in sheep . Metformin is structurally modified from galegine
containing a biguanide moiety (Figure 1). Interestingly, this small modification decreased
the toxicity, but still keeps the glucose lowering effect . Pharmacokinetically, metformin
does not undergo hepatic metabolism, so it is considered safe from a hepatic standpoint,
and metformin-induced hepatotoxicity is very rare, with less than 20 cases having been
described over several decades . Various clinical studies also supported the safety and
tolerability of metformin treatment [8–10]. Thus, metformin has been used for almost
70 years to treat T2DM patients with its safety and clinical usefulness.
Acarbose may reduce bioavailability of Metformin.
An update on Metformin: have been taking it inconsistently, lower dose between 250 and 500 mg. hA1c improved a little from 5.9 to 5.6. All blood markers, besides lipids, continue to be normal. Lipids decreases (started taking a statin), but still higher than normal.
Ive discontinued Metformin after starting Acarbose and reaching my weight goal with Tirzepatide/GLP-1 agonist.
A1C went from 7.8 to 4.8
Have you attempted using Acarbose? A1C shouldnt be the only standard in measuring glucose as BG spikes can still occur in those with low A1C and spikes are often just as damaging as a continuously high BG.