Metformin Shortens Lifespan in the Elderly?

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

A brief summary can be found here

Specifically, the research report 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.”

Two items to note: (1) The article is a preprint which, as far as I know, has not been published in a peer-reviewed journal. (2) It states that “ATP exhaustion and late life metformin toxicity are alleviated by in vivo rapamycin co-treatment,” a statement I don’t find comforting because I take rapamycin weekly and metformin daily.

I am not sufficiently knowledgeable to evaluate the validity of this paper and would appreciate the comments of others

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I would definitely like to know more about this.

Is anyone knowledgeable on this subject?

Thank you very much.

Sincerely

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Discussion.

16 This study, performed in nematodes and human cells, …

That says it all for me.

It is not a study on humans, but on human cells. It may be interesting if it were a study on mice, like the ITP studies.

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Considering that metformin is prescribed to treat a metabolic syndrome, I find it hard to believe that a patient with untreated diabetes would live longer than one taking Metformin.

The mice from the ITP would also tend to agree.

The argument against this paper is basically all the data provided in the TAME trial… see this website: TAME - Targeting Aging with Metformin - American Federation for Aging Research , and see this presentation:

MP-Justice.pdf (2.9 MB)

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I don’t see how any of the TAME data argue against this paper. For example, the TAME presentation refers to Metformin in mice “started at midlife.” This paper argues specifically for harm in ELDERLY populations. I am concerned that by continuing to take metformin at age 83, I may not live long enough to see the results of the TAME trial.

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Thanks for posting this @alorac. It is definitely an interesting study and raises questions deserving of follow up, especially in deriving protocols for getting at its main take-aways in human clinical settings. I take 850 mg. in the evening primarily as a longevity intervention. I will continue to do so until we see evidence more likely to be applicable to older humans but will keep my eye on this topic to see if anything develops.

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You can’t even imagine how many times I have flip-flopped on taking metformin.
As I don’t have diabetes I would think that the benefits are probably minimal or even detrimental for someone my age (~83).

The authors of the “paper claiming that metformin shortens lifespan in the elderly” seem to have enough academic credentials to make this paper alarming to me. So once again I will flip-flop and stop taking metformin. Also since metformin has a limiting effect on muscle gain, this may be another benefit of stopping it for the elderly who do resistance training.

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The issue is not whether taking Metformin extends elderly lifespan but taking Rapamycin and Metformin together as they are synergistic.

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We must start with the premise: There is no proof that rapamycin extends lifespan in humans.
We hope it does based on mouse results.
There is no proof that metformin and rapamycin are synergistic in humans.
The biggest drawback to metformin, IMO, is that it impedes resistance training muscle growth.
This is of course a problem for those of us who are old and trying to stave off sarcopenia.
There is also no proof, that I am aware of, that rapamycin aids in muscle growth. In fact one would think quite the opposite because of the suppression of mTORC1.

“Activation of mTORC1 leads to increased muscle protein synthesis, which contributes to muscle hypertrophy over time with resistance training.”

“At the molecular level, the mammalian target of rapamycin complex 1 (mTORC1) is a critical signaling complex that regulates muscle mass”

Currently, I am betting the farm on rapamycin+acarbose not rapamycin and metformin.

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I think the opposite.

I think we start with the premise that Rapamycin extends the lifespan and healthspan of all mammals.

Since Rapamycin and Metformin are very synergistic in mice and mildly proven to be synergistic in humans, we should assume that more synergies in humans haven’t been fully proven due to a lack of funding.

Metformin can impede resistance training muscle growth. However, it does not seem to affect muscle strength.

My father is 77 and takes Metformin, Creatine, and protein powder and has been able to build muscle. I don’t think taking Metformin means you won’t build muscle. It may make it a bit harder though. Whatever blunting effect metformin may have is completely overcome and then some by the creatine and protein.

That’s the tradeoff here. How much does each factor matter to you? For me, I’ll be taking Rapamycin + Metformin + Acarbose. (plus a whole bunch of other supplements that probably interplay with everything else.)

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Why is your father taking metformin, dose, and how long?

He’s taking 500 mg of Metformin a day.

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I asked ChatGPT to summarize the findings…

I received this reply back:

The document you’ve provided is a comprehensive study on the effects of metformin treatment in late life, conducted through various experiments on C. elegans and human cells. Here’s a summary based on the first 16 pages out of 76, covering key points and findings:

### Overview
- Objective: Investigate the effects of metformin, a diabetes drug, on aging, especially focusing on old non-diabetic individuals.
- Key Findings: Metformin shortens lifespan and limits cell survival when provided in late life, exacerbating aging-associated mitochondrial dysfunction leading to ATP exhaustion. Contrary to its beneficial effects in early life, late-life metformin treatment fails to induce a dietary restriction mimetic response and instead triggers metabolic failure.
- Mechanisms: The study explores metformin’s exacerbation of mitochondrial dysfunction, its failure to induce compensatory glycolysis in older cells, and its adverse impact on lipid metabolism in late life. It contrasts with the drug’s early-life benefits, including lifespan extension and stress resistance adaptations.

### Detailed Insights
- Mitochondrial Dysfunction and ATP Exhaustion: Metformin worsens aging-related mitochondrial issues, causing severe ATP depletion. This effect is more pronounced in older organisms, where metformin fails to upregulate glycolysis as a compensatory mechanism, leading to energy crisis and cell viability loss.
- Lipid Metabolism: In early life, metformin mimics dietary restriction effects, beneficially altering lipid metabolism. However, this response is absent in late life; instead, metformin exacerbates pre-existing lipid imbalances, contributing to metabolic deterioration.
- Genetic and Environmental Modifiers: The study identifies specific genetic and environmental factors that modify metformin’s effects. For instance, AMPK (a key energy sensor) and PKA pathways play roles in metformin’s impact on lipid metabolism, with age-specific differences in their engagement.
- Implications for Non-Diabetic Elderly: The findings caution against the unexamined use of metformin for healthspan extension in non-diabetic elderly individuals. Metformin’s late-life effects include alarming metabolic decay and reduced cell survival, challenging its prospective benefits for this population.

### Conclusion
The study presents a nuanced view of metformin’s age-dependent effects, highlighting potential risks of late-life treatment in non-diabetic elderly. It suggests a need for careful consideration and further research into metformin’s use as an anti-aging intervention in this group.

This summary covers significant aspects of the research findings up to page 16. The document contains extensive details on the experiments conducted, their outcomes, and implications, which would require a full review for comprehensive understanding.

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I don’t think we should be looking at a C. Elegans and human cell culture study for Metformin. There are so many in vivo studies on Metformin that provide better results.

This summary also focuses on Metformin’s lipid effects? I didn’t even realize Metformin has a great effect on lipids. Again, we can’t trust ChatGPT for everything as it hallucinates frequently.

Here’s a human meta-analysis to counter ChatGPT.

A meta-analysis published in 2017 that included 53 different studies concluded that metformin reduces all-cause mortality and diseases of aging, independent of its effect on diabetes. The analysis found that the use of metformin lowers the risk of cancer, cardiovascular disease, stroke, and death, says Justice.

And another meta-analysis that shows positive, neutral and negative studies of Metformin.

I’d trust both of these over a one study ChatGPT summary.

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