#50

Maybe I’m reading too much into it, but by using the word “claim” are you implying you think the results are wrong?

#51

Is it 50-50 to start with, with the possibility of modificators? Or does anyone know the exact statistic how often mice research translates to humans?

#52

How do we jump from a in vitro and in vivo tests cell study = into elderly patients? How is late life defined? over 50? over 60?

Highlights

  • Late life metformin treatment limits cell survival and shortens lifespan.
  • Metformin exacerbates aging-associated mitochondrial dysfunction causing fatal ATP exhaustion.
  • Old cells fail to upregulate glycolysis as a compensatory response to metformin.
  • The dietary restriction (DR) mimetic response to metformin is abrogated in old animals.
  • PKA and not AMPK pathway instigates the early life DR response to metformin.
  • Stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo.
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#53

It has been said that metformin was a dirty drug meaning it affected many bits of physiology. Here is a study on an aspect of metformin intolerance that has nothing to do with exercise/ lactate

“Our results indicate that metformin inhibits transporters and enzymes in the gut that are associated with the disposition of serotonin and histamine and suggest that clinically, metformin concentrations in the gut may be sufficient to inhibit these proteins.”

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#54

Joseph, I interpret that study as an explanation for why some people experience negative gastrointestinal side effects.

Metformin, a biguanide, is used worldwide as first-line therapy for the treatment of type 2 diabetes, and acts primarily in the liver to reduce gluconeogenesis [1, 2]. However, 30–50 % of patients on metformin report gastrointestinal (GI) side effects, such as diarrhea and bloating [3–6]. These GI side effects are generally dose-dependent, and for the majority of patients, subside after several doses. However, in approximately 5 % of patients, these side effects are severe enough to warrant discontinuation of the drug, and these patients switch to other anti-diabetic drugs. Several hypotheses as to the cause of these metformin-induced GI side effects have been proposed, including mal-absorption of bile salts in the ileum [7], increased serotonin release from human gut mucosa [8], increased gastrointestinal hormone levels and increased gastric acid secretion.

Given the important roles that histamine plays in the gastrointestinal tract, it is not surprising that when histamine levels increase due to impaired histamine degradation or ingestion, GI effects such as nausea, vomiting and diarrhea can occur.

The studies described in this manuscript focus on potential mechanisms by which metformin produces gastrointestinal side effects.

So, it applies to the very small percentage of people that have side effects that don’t resolve.

.

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#55

I’ve looked more in depth about this and this is much more complex than I thought.

It seems that this is not going to work because even though the plasma half-life is short (approximately 4–9 hours) the tissue half-life is much longer due to tissue accumulation.
The mitochondrial concentration of metformin is estimated to be several times higher than plasma concentrations and the effective tissue half-life may extend up to 17–31 hours so daily dosing is going to accumulate over several days.

OK but… not so according to this more recent paper: Metformin and Systemic Metabolism (2020)

In it they say that very high concentration of Metformin reduces Mitochondria respiration by 30% but normal lower concentration increases it instead and that there is no accumulation in mitochondria:

This paper along the original one in that thread also makes a compelling case for (normal/low dose) Metformin.

Those papers seem compelling enough for me to at least give it a try. It seems that Attia is a little bit lagging with respect to the literature on the topic. If he only looked at lactate it seems that there is more of it but from the gut not the skeletal muscles.
As I’m running 50~80km/week I should notice any adverse effects on mitochondria respiration.

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#56

@cl-user thanks. this is good info. Please report back on your experience. In my experience, I didn’t feel anything at low or moderate intensity exercise…only at higher intensities…beyond conversational effort (zone 2). If I had been measuring lactate, I might have seen something at lower intensities.

That said, I don’t know that higher lactate is a bad thing. It is an obstacle to higher performance (ie, going faster in a race), but might be a good thing for positive physiological changes in the body. I’ve heard Mike T Nelson PhD talk at length about the probable benefits of exogenous lactate.

In addition, Metformin has more potential issues than ATP production. I’m not confident i know why i didn’t feel well on a low-dose, extended release metformin all the time. Perhaps it built up in my body, whereas when I take it for 3-4 days every 2 weeks, I feel nothing from it (as far as I can tell).

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#57

@ng0rge I agree. I posted the study to make the point that metformin has many effects beyond lowering liver production of glucose. Some of those effects can be good and some can be bad, depending on the person. I’ll bet its a small percentage of people prescribed metformin for high blood sugar also engage in high intensity exercise often enough to feel a difference with metformin.

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#58

There was a non-significant 7% “increase” in median lifespan in males, relative to short-lived controls (median LS 780 days), and a nonsignificant 2% reduction in maximum lifespan. In females, there was zero effect on either metric. This is noise, folks.
https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12496

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#59

Maybe looking at human studies is better for Metformin, particularly the effect it has on prostate. Anyway, if you use Rapamycin more likely than not your blood sugar will rise, it could be smart to counter that with Metformin or other blood sugar lowering drug.
Just my 2 cents.

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#60

Yes, but that ‘something’ could simply be “rapa causes glucose intolerance, and metformin ameliorates that.” And the mice don’t get any exercise.

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#61

I would think that Metformin helps if you have diabetes, but does not fix diabetes. Its benefits for non-diabetics are not clear.

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#62

It might help preventing diabetes. As we get older more and more likely you would get it. Metformin would likely delay this.

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#63

Turmeric and Curcumin supposedly are excellent in preventing someone who is prediabetic from getting full blown diabetes.

#64

The primary active ingredient in Turmeric is thought to be Curcumin which is an HDAC inhibitor. There are others of those as well such as pterostilbene, quercetin and berberine.

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#65

My spontaneous question is: what is the relevance of HDAC inhibitors with respect to glycemic control? Do they express or inhibit specific genes involved in glucose homeostasis?

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#66

Linking a post

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#67

FWIW review

Article

“Metformin: historical overview”

Published: 03 August 2017

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#68

HDAC inhibitors affect gene expression. Gene expression is the key pathway through which cells operate. Hence if gene expression is suboptimal other things will go wrong.

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#69

I was curious as well. Here’s a chart showing the anti-inflammatory effect of HDAC inhibitors. The question to glycemic control is whether inflammation is a cause or an effect of dysregulated glycemic control.

In any case, chronic inflammation underlies much of the chronic diseases of aging. It’s a hallmark of aging. This (HDAC inhibitors) seems like a good lever to pull periodically.

IMG_7449
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