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.
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.
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…
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
Many, if not most, in vitro ([Table 1](javascript:;)) and in vivo ([Table 2](javascript:;)) studies that have examined the cellular and molecular mechanisms by which metformin reduces HGP have utilized supra-pharmacological (>1 mM) metformin doses that may not be clinically relevant ([57-61](javascript:;)). Furthermore, few in vivo studies report plasma and tissue metformin concentrations ([Table 2](javascript:;)). This should be a common practice, as pharmacokinetic properties differ between species, as well as treatment regimens. One of the most widely studied mechanisms of metformin action, complex I inhibition leading to altered hepatic energy charge, is only observed at millimolar concentrations. Approximately 2 mM metformin is required to alter adenine nucleotides, and significant complex I inhibition has consistently been reported to occur only with metformin concentrations of at least 1 mM to 5 mM ([57-59](javascript:;), [62](javascript:;), [63](javascript:;)).
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.
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.
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 [3]. 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 [4]. 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 [5]. 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 [6]. 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 [7]. 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.
In our youthful matreotype-associated drugs, we have identified phenformin (Figure 4b, Figure S9, Table S2), an analog of metformin. Both phenformin and metformin have been shown to increase C. elegans lifespan (Pryor & Cabreiro, 2015). Here, we found that treating late L4 C. elegans with metformin, prolonged collagen expression in a dose-dependent manner (Figure 5e; Figure S10, Table S6). This is consistent with a study showing metformin slows extracellular matrix morphological decline of the cuticle (Haes et al., 2014). This suggests that one unexplored aspect of the metformin’s mechanism of action might be via improved collagen homeostasis. Given this exciting finding, we decided to prioritize our investigations into drugs that will enhance collagen homeostasis in mammals but have not shown any pro-longevity phenotypes in any organisms. We, therefore, chose to test the retinoic acid receptor agonist tretinoin since tretinoin treatment prevents MMP upregulation and stimulates collagen synthesis in photo-aged skin (Griffiths et al., 1993; Mukherjee et al., 2006). Our analysis showed that tretinoin had an enriched differential expression of matrisome genes (Figure S9). Furthermore, tretinoin has been predicted to associate with a youthful expression pattern by the in-silico analysis of Janssens and colleagues but did not increase C. elegans lifespan at 50 μM (Janssens et al., 2019). With our reporter system, we found that treatment with 10 μM of tretinoin prolonged collagen expression and increased lifespan (Figure 5f–i; Figure S10, Tables S6, S7), confirming that tretinoin indeed promotes healthy aging.
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.
