#61

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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#62

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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#63

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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#64

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

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#65

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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#66

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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#67

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

#68

He’s taking 500 mg of Metformin a day.

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#69

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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#70

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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#71

Appreciated your candor about the flip-flop. I am age 74 and am right there with you in this uncertainty. Started metformin as A1C is 5.8, entry point to pre-diabetes. Then read that this level of A1C is not something to be alarmed about in a person my age and is not likely to progress to diabetes. But, the downsides of metformin – “mitochondrial posion”? --are more stressful in an older person. So I stopped taking it. But lipids, Alzheimiers, osteoporosis are concerning too, so maybe restart metformin on swimming days, which are non-lifting days?

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#72

This is my question and response to Gemini.

Metformin has demonstrated research-based life or healthspan benefits via its role in AMPK and other functions. More recent evidence suggests that these benefits may decline or even reverse in the elderly. Review that evidence and assess its soundness based on the type of research.

It’s true that there’s a growing body of research exploring the potential age-related changes in the effectiveness and safety of metformin. Here’s a breakdown of that evidence and the considerations for interpreting it:

Potential Decline in Benefits

  • Mitochondrial Function: Some studies have suggested that metformin might negatively impact mitochondrial function in older adults. Mitochondria are the “powerhouses” of our cells, and their decline is connected to aging. Impairment in their function could offset some of the potential lifespan extending effects of metformin.
  • Frailty: There is a concern that while metformin might reduce the risk of specific age-related diseases, it could potentially increase the risk of frailty in older adults. This is important, as frailty significantly impacts overall healthspan.
  • Nutrient Absorption: Metformin can sometimes interfere with the absorption of nutrients like vitamin B12, which is crucial for healthy aging, especially in maintaining cognitive function.

Soundness of the Evidence

It’s important to note that much of the evidence around metformin’s declining benefits in the elderly is still emerging and comes from diverse research types:

  • Animal Studies: Many insights come from studies in mice and other animal models. While valuable, these findings might not fully translate to humans.
  • Observational Studies: Some human studies are observational, meaning they track metformin use and health outcomes in large populations. These studies can suggest associations, but don’t directly establish cause-and-effect.
  • Clinical Trials: More targeted clinical trials with older populations are needed to get a definitive answer on long-term effects. There are initiatives like the TAME (Targeting Aging with Metformin) trial specifically examining this.

Key Considerations

  • Individual Variability: Responses to medications can vary significantly among older adults due to changes in metabolism, kidney function, and other physiological factors.
  • Dose and Duration: The dosage and length of metformin treatment in the elderly may need adjustments compared to younger populations.
  • Co-Existing Conditions: Older adults often have multiple health conditions, and the interplay of metformin with other medications needs careful consideration.

What This Means

The current evidence does not suggest a blanket discontinuation of metformin in the elderly. Instead, it highlights the importance of:

  • Careful Monitoring: Regular checkups to assess kidney function, vitamin levels, and overall health status are important for older patients on metformin.
  • Personalized Medicine: Clinicians should tailor the use of metformin based on the individual patient’s characteristics and potential risk factors.
  • Ongoing Research: The results of trials such as TAME will provide much clearer guidance on the long-term use of metformin in promoting healthy aging.
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#73

When will the TAME study produce its first results?

It’s a bit tricky to give a precise date for the first results of the TAME study. Here’s why:

  • Study Design: TAME is designed to track the development of multiple age-related diseases (heart disease, cancer, dementia, etc.). This means researchers need enough time for a significant number of participants to develop these conditions to determine if metformin makes a difference.
  • Statistical Power: The study is designed to detect moderate effects. This requires a longer follow-up period to gather enough data to be statistically significant.
  • Potential Early Stopping: If metformin demonstrates clear benefits or risks for any specific condition earlier in the trial, the FDA has the power to recommend stopping the trial early for ethical reasons. This could lead to results coming sooner than initially planned.

Current Estimates:

  • Initial Timeline: The original estimated timeline for the trial was about six years. Since delays are common in research, it’s likely to take longer.
  • Ongoing: The TAME trial is actively recruiting and the study continues. There’s a chance we might see some preliminary findings or interim analysis within the next few years, but definitive results will likely take longer.

Where to find updates:

  • ClinicalTrials.gov: The official TAME trial listing ([invalid URL removed]) might provide updates on the study’s progress.
  • Nir Barzilai’s Presentations: Dr. Nir Barzilai, the principal investigator of the TAME trial, often shares updates in scientific conferences and presentations. Keep an eye on websites for gerontology organizations.
  • News Articles: Major developments in the TAME trial would likely be covered by science and health news outlets.

Please note: It’s best to rely on official study channels or reputable science sources for the most accurate updates on the TAME trial timeline.

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#74

The metformin issue presents a bit of a quandary. I have reviewed the scant evidence behind the claim that metformin accelerates aging in the elderly and find it unconvincing. Based on what we know today, such potential harm might be vitiated by careful attention to diet and exercise. On the other hand, it looks like the results of the TAME study might be several years out.

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#75

hate to see a negative about metformin/elderly especially since my endo just prescribed it and I’m 66
What are symptoms of problems with being
“elderly” and taking it?
BTW, I don’t consider myself elderly yet, even through the numbers don’t look good, lol.
maybe it’s time to add some galantamine

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#76

To the best of my knowledge the TAME trial has still not been funded, and therefore not started. They have been trying to nail down funding for over 6 years. I don’t think it’s going to happen.

If it’s anything like the tech startup works the longer the fundraising goes on, the lower the success.

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#77

Based on the weak evidence to date, for which several alternate explanations seem possible, my opinion is for those in the 70’s (possibly earlier if warranted by personal circumstances) should be mindful of diet and fitness if taking metformin. Much has been written on the dietary issues. @RapAdmin’s information on likely TAME funding suggests that it is not practical to wait for guidance from sound research. If you are 75, taking metformin will be a highly personal decision based in part on how you react to it and the details of your diet and fitness

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#78

All medications have side effects especially when taking higher doses.
For the elderly metformin should not be higher than 1500 mg/day
There is zero evidence that metformin shortens lifespan in the elderly.

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#79

On February 12, a link was posted to an article, “Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism.” It is stated:

“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.”

In my opinion, the evidentiary value of this article exceeds zero.

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#80

Thank you for posting this article title @alorac. I found and gave it a brief (but not a careful) read.

First, the article I located was a preprint. I was unable to find a published version of the 2019 article.

The article is based mostly on tests performed on C. elegans with a reference to human fibroblasts emerging later on in the article and not addressed in the abstract. There are also vague references to the work of papers written by other scientists, such as a study of elderly diabetic patients taking metformin where the implications were not immediately clear. Overall, I read quite a few scientific papers daily and I have to say that this paper is one of the most poorly organized and in many places vague I can recall reading in many years.

While the findings of this study are definitely interesting, its value for human action is only to suggest a path for research more directly relevant to older humans taking metformin as a life extension supplement. Before that, it could be worth replicating the study.

One thing in particular disturbed me about the article. Neither the title nor the entire somewhat detailed abstract mentioned C. elegans. To the contrary, it left the impression that it might be relevant to human clinical practice. As a scientific publication, I would consider this omission dishonest. A more charitable interpretation is that it was a poor translation from German, perhaps corrected before publication.

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