Evidence that Metformin Does Not Interfere in the Beneficial Response to Exercise

There have been suggested that metformin, a at best weak calorie restriction mimetic, can suppress some of the beneficial metabolic response to exercise. Metformin is in general a poor choice in comparison to mTOR inhibitors when it comes to animal evidence for an ability to modestly slow the progression of aging. The primary human evidence for metformin to be useful, and why it attracted interest in the first place, comes from a large study of diabetic patients, and the gain in life expectancy was not large. Researchers here provide evidence against any suppression by metformin of beneficial mechanisms resulting from exercise, but I can't say that this does much to make metformin an attractive option. At the end of the day, small effect sizes are just not worth chasing, given the many other lines of research and development that offer greater promise.

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise with or without metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed.

Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress, and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g. the gut.

Link: https://doi.org/10.1139/apnm-2021-0194


Here a recent and imo very interesting paper about Metformin

- [ Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes ] -

Metformin, the most commonly prescribed anti-diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti-aging drug-the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose-dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations.

Source: https://onlinelibrary.wiley.com/doi/10.1111/acel.13488

Posted by: Dysmorphic at November 28th, 2021 11:23 AM

In animals purposely put on shitty diets or genetically crippled metformin reduces mortality. This is not anti-aging.
In unhealthy (diabetic) humans metformin reduces mortality. This is not anti-aging.
In healthy humans not on shitty diets it does next to nothing. No anti-aging here either.

Posted by: Jones at November 30th, 2021 2:13 PM

Anyways... the mentioned study looked at acute effects of exercise. Too bad the abstract doesn't mention what kind of exercise. I guess endurance training. Muscle does adapt differently to endurance and weight training. So what about mTor dependend muscular hypertrophy?

Posted by: Jones at November 30th, 2021 2:38 PM

there was a study which found a statistically significant increase of lifespan (a couple to few months) in people prescribed metformin to compared to healthier peers on the same cohort which din't have the need for MF. It is not anti-aging per se but the effect is real, albeit small.

Posted by: Cuberat at November 30th, 2021 2:47 PM

This is also a gem:
Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism

The diabetes drug metformin is to be clinically tested in aged humans to achieve health span extension, but little is known about responses of old non-diabetic individuals to this drug. By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life, contrary to its positive early life effects. Mechanistically, metformin exacerbates aging-associated mitochondrial dysfunction towards respiratory failure, aggravated by the inability of old cells to upregulate glycolysis in response to metformin, leading to ATP exhaustion. The beneficial dietary restriction effect of metformin on lipid reserves is abrogated in old animals, contributing to metabolic failure, while ectopic stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. The toxicity is also suspended in nematodes carrying diabetes-like insulin receptor insufficiency and showing prolonged resilience to metabolic stress induced by metformin. In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients. Novel regulators of life extension by metformin are also presented.

- 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.

Posted by: Jones at November 30th, 2021 3:11 PM

When reading on how exactly metformin works it makes no sense since it messes with mitochondria. It might have a bit hormetic effect to increase mitophagy and repair. I guess half its benefits come from disruption of intestinal absorption, though :)

What i have learnt recently is that MF dose above 2000 mg/day doesn't have any additional effect.

I would say for everybody who's overweight it is of more benefit than not if the side effects can be tolerated. I have seen some notes that it depletes vitamin B and D, so it might cause damage and some of the diabetic neuro degradation could be a associated with MF. This one i don't have a peer-reviewed publication, though.

Posted by: Cuberat at November 30th, 2021 4:46 PM

'Peer reviewed' doesn't mean shit nowadays...

When I need a laugh I go here sometimes:

This one I liked a lot:
The publisher IOS Press retracted a total of 79 papers last month from two journals, some for citing work unrelated to the subject of the articles and some for, well, everything.

and this:
Anatomy journal retracts 13 papers

ohh... this:
Springer Nature geosciences journal retracts 44 articles filled with gibberish

All peer reviewed studies some even in very respected journals... and for every retracted study there're dozens (hundreds?) flagged on pubpeer.com as 'problematic' often utterly fake which won't be retracted.
In a couple of years there is more bullshit in peer reviewed journals than real science.

Posted by: Jones at November 30th, 2021 4:59 PM

At least it some albeit low standard . Internet forums are even less reliable. I can tell my pesonal observations, but they are all flowed methodologically and quite inexact.

Posted by: Cuberat at November 30th, 2021 9:20 PM
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