What's the Deal with Renewed Interest in Metformin?

[Melih]

I had tried that too, but got another hypo. I had taken it in the morning and then the hypo would begin at night.

[alorac]

Here is a link to a paper claiming that metformin shortens lifespan in the elderly.

863357v1.full.pdf

Specifically, it claims “By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life.” “In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients.”

[mccoy]

@DrT

As far as effects on muscle strength goes, I can only state my own experience. I’m a 67 y-o male. I exercise on alternate days. 500mg SR metformin before breakfast. I don’t do much in the summer; just some jogging and pull-ups on a high bar. I can do 18 pull-ups (maybe more if I really tried) which, according to an athletic performance comparison website I found, puts me in the top 1% for my age.
That’s good enough for me.

Apparently, Metformin may prevent muscle hypertrophy but not muscle strength (in the words of Nir Barzilai). But I’m afraid all of us (or nearly so) sin in vanity and desire hypertrophy.

[DrT]

At 67 I’m kinda past the “bigger is better” meme. I’ve read about too many bodybuilders dying prematurely to ever be convinced that that is a sensible path. Hyperplasia is a cornerstone of the “Antagonistic Pleiotropy” theory.
I just try to keep what I’ve got.

[DrT]

You could make that assumption.

But have you had your insulin level checked?

I’ve had mine measured both fasting and random (2 hours after a meal) and both readings were < 2 IU/L. The machine doesn’t measure below 2.
I take 500 mg metformin just before breakfast and don’t have problems BUT I have to make sure I eat exactly on time and LOTS. If I’m 15 minutes late I risk a headache, hypo etc.
I think if you haven’t tried the Slow Release or Extended Release metformin you might try it.
I have taken the Immediate Release stuff but it was a bit gnarly for me.

Let us know what you do.

[mccoy]

@DrT

At 67 I’m kinda past the “bigger is better” meme. I’ve read about too many bodybuilders dying prematurely to ever be convinced that that is a sensible path. Hyperplasia is a cornerstone of the “Antagonistic Pleiotropy” theory.
I just try to keep what I’ve got.

DrT, it’s not so easy to get bigger though. And bodybuilders often do their best to die prematurely, sometimes being successful.

[Melih]

I have not had a recent blood panel, but my panel (fasted state) from before starting rapamycin.

Glucose 4.28 mmol/l (<5.56)
Insulin 1.7 mU/l (2.6-24.9)
HOMA 0.3

Planning to do a full panel w/ DEXA in 6-12 months. Might try slow release after this.

[约瑟夫]

FWIW…

The proposed TAME Study plan is to use conventional metformin, Not “extended release /slow release”.

From the “Metformin Master”, Nir Barzilai.

[KarlT]

@Joseph

If you wait until you are ready, it is almost certainly too late.

I like that.
But then there’s “haste makes waste”?

[KarlT]

@alorac

Here is a link to a paper claiming that metformin shortens lifespan in the elderly.

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

[AnUser]

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?

[Jonas]

@alorac

By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life.” “In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients

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.

[Joseph_Lavelle]

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.”

Prediction and validation of enzyme and transporter off-targets for metformin

[ng0rge]

@Joseph_Lavelle

It has been said that metformin was a dirty drug meaning it affected many bits of physiology.

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.

.

[cl-user]

@Joseph_Lavelle

Attia was probably using a lot. That would be like him to maximize something he believed in.

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:

Hollinger used supra-pharmacological metformin (20 mM) and found that it could reduce oxygen
uptake in mitochondria by 30% [76]. In 2000, two studies showed that metformin inhibited the activity
of mitochondrial complex I, leading to a decrease in ATP production [47, 48]. It was thus
proposed that the principal mechanism of metformin action is through inhibition of
mitochondrial complex 1 activity [42, 44], however, metformin is a weak inhibitor of
mitochondrial complex 1 with an IC50 of 19–66 mM [78, 79]. To support metformin
inhibition of mitochondrial complex 1, it was proposed that mitochondrial membrane
potential could drive the accumulation of positively charged metformin in the mitochondrial
matrix [48]. However, metformin concentrations remained the same in mitochondria isolated
from mouse livers between 30 min and 4 h after oral administration [46], which does not
support metformin accumulation in hepatocyte mitochondria.

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

@abstract

Metformin can improve patients’ hyperglycemia through significant suppression of hepatic
glucose production. However, up to 300 times higher concentrations of metformin accumulate in
the intestine than in the circulation, where it alters nutrient metabolism in intestinal epithelial cells
and microbiome, leading to increased lactate production. Hepatocytes use lactate to make glucose
at the cost of energy expenditure, creating a futile intestine-liver cycle. Furthermore, metformin
reduces blood lipopolysaccharides and its initiated low-grade of inflammation and increased
oxidative phosphorylation in liver and adipose tissues. These metformin effects result in the
improvement of insulin sensitivity and glucose utilization in extrahepatic tissues. This review
discusses the current understanding of metformin’s impact on systemic metabolism and its
molecular mechanisms of action in various tissues.

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.

[Joseph_Lavelle]

@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).

[Joseph_Lavelle]

@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.

[RapamycinCurious]

@Sebastian

the result in the ITP was actually that the metformin treated mice lived about 7% longer than the control group. 7% isn’t nothing. The difference wasn’t statistically significant, but that doesn’t mean it isn’t real, since the ITP is only statistically powered to detect larger differences.

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

[Goran]

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.

[RapamycinCurious]

@Neo

you can also look at the effect in ITP when Met was combined with rapa which increases the signal that something is happening with Met

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