Late Life Metformin Treatment Limits Cell Survival And Shortens Lifespan

[Mito]

Abstract
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 by triggering an aging-associated failure of energy metabolism.

 

[ecstatichamster]

this is a fantastic find @Mito thank you!

 

[Sativa]

I've seen Metaformin mentioned a few times on this forum; my approach would be to simply mimic it's 'desirable' pharmacological properties (all well studied etc) using other more sustainable substances etc; this would allow you to bypass Metaformin's mitochondrial impairment 'vibe'...
This study lists some of the possible reasons drugs like Metformin are to be avoided and why Peat has cautioned against it even without explicitly saying what he has against it.

"...One of the first biguanides, phenformin, was withdrawn from the US market in 1976 because of the common occurrence of elevated lactate. Today, metformin is the only biguanide used clinically for the management of diabetes mellitus. Metformin is thought to increase the risk of elevated lactate, but the correlation remains controversial. The proposed mechanism includes inhibition of gluconeogenesis and mitochondrial impairment.[104]".
Etiology and therapeutic approach to elevated lactate

Ask any ER doctor about metformin and he/she will tell you this is one of the first things to rule out when somebody presents with ketoacidosis or lactic acidosis. Chronic alcoholism is the other big factor...
Metformin also lowers the NAD/NADH ratio and this alone should tell you how "good" metformin is for your metabolism. Its main mechanism is to simulate starvation, so definitely not something you want to take chronically.

personally, i reckon most patented pharma drugs are poor substandard mimic's of what natural substances are capable of doing - in a much more respectful & 'responsible' manner, ie how they engage with the biological organism... sustainability factor also seems relevant.
But there is always a special place in my heart for the synthetic pharma drug Memantine lol

 

[RNR]

Sativa - what would some of those other substances be that mimic mets benefits? Berberine is an obvious one, but what about others?

 

[Hans]

Peter Attia changed his mind a bit on metformin lately (finally lol).
He think the main benefit of metformin for extending lifespan is that it inhibits complex I of the ETC, which upregulates certain pathways which mimics fasting.
Aspirin also inhibits complex I to a degree and would be much safer and beneficial while providing the same benefits.

The study above is a really good find. The side effects of metformin is much more than just creating lactate though, as it also completes with vitamin B1 and B12 for entry into the cell for one, which creates a host of other side effects.

 

[SB4]

@Mito @haidut I am not sure if I am reading this write but isn't the problem with these studies they are using massive doses of metformin? According to Peter @ Hyperlipid the dose that puts you in ICU is 200umol. Hyperlipid: Metformin (02) The dose makes the poison

Yet the study is using 10 - 50 mM. So if I am reading this right, the study is using concentrations of metformin 50 - 250 times that of a dose that would put you in the ICU?

To address the outcomes of metformin treatment at different age, we treated young adult (3 days old, day 1 of adulthood), adult at the age of reproduction decline (day 4 of adulthood), middle aged (day 8 of adulthood) and old (day 10 of adulthood) wild type C. elegans worms with different doses of metformin – 10mM, 25mM and 50mM. 50mM metformin is the common dose used to induce lifespan extension in C. elegans while 10mM is the lowest dose linked to reproducible life extension in this model in previous reports (Cabreiro et al., 2013; Onken and Driscoll, 2010; Pryor et al., 2019). We found that metformin treatment started at young age (days 1 and 4 of adulthood) extended lifespan of nematodes at all doses used (Figure 1A and Figure S1A). Within treatment initiated on day 8 of adulthood, the doses of 50mM and 25mM metformin reduced median lifespan but extended maximal lifespan consistent with previous observations (Cabreiro et al., 2013) while 10mM dose was longevity-extending with no detrimental effects

I have gone on to read some further posts by Peter and he seems to be saying that the Complex 1 inhibition only happens at massive doses where as the mtG3PDH / complex 2 happens at the lower dose.

This interests me because my symptoms regularly get significantly worse after carbs. Yet at night time when I should be insulin resistant, the carbs have a much less effect on my symptoms. I speculate that the reason the carbs worsen my symptoms is that insulin reduces the amount of fat my cells are seeing after a glucose meal and for some mysterious reason my cells are very poor at metabolising carbs (there is research to show CFS metabolism is running flat out, suggesting that the mito is using full fat for energy, and cytosol is generating lots of lactate for extra atp, kinda like cancer metabolism). Yet when I am insulin resistant at night, the randle cycle isn't really at play so my cells are still running mostly on fat resulting on minimizing symptoms.

 

[rob]

Metformin looks like it's an inhibitor of thiamine transport (Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). - PubMed - NCBI). Given that diabetics are already thought to be thiamine deficient, no wonder the addition of metformin could be problematic in the long run.