Metformin - yet another u-turn?

[TomBAvoider]

Metformin's claimed effects in healthy (i.e. non-diabetic) humans have certainly been full of twists, turns and reversals. Extends life, cuts down on cancer; no it doesn't and not in non-diabetics. Blunts or eliminates the benefits of exercise, poor effects on vo2max and muscle training.

Latest plot twist: attenuates muscle atrophy (in the immobilized), generally slows the senescence of muscle tissues and keeps those cells young in older people:

https://onlinelibrary.wiley.com/doi/10.1111/acel.13936

Stay tuned, I'm sure another 180 is just around the corner.

Edited September 18, 2023 by TomBAvoider

[Ron Put]

Very short-term. I am not sure how significant the differences are. Or, what other confounding factors there were. I am not sure if it's relevant, but it likely is, that some of the participants had A1C 5.9 which is rather high, and most were stage A obese. Importantly, I didn't notice insulin data mentioned.

[Alex K Chen]

 

Quote

 

Alessandro CellerinoAlessandro Cellerino • 1st • 1stProfessor and Research Group Leader (Aging and Longevity)| Book writer | Co-founder of QuantaBrainProfessor and Research Group Leader (Aging and Longevity)| Book writer | Co-founder of QuantaBrain26m • Edited • 26 minutes ago

 

This is my take on this very recent and potentially game-changing paper

hashtag#metformin decelerates hashtag#agingclocks in hashtag#male hashtag#monkeys

https://lnkd.in/dmmwqMRW

This paper reports that a 40 week treatment with metformin in old monkeys prevents hashtag#atrophy of the frontal hashtag#cortex, improves working hashtag#memory (a cognitive function very sensitive to aging) and prevents/retards a whole host of different hashtag#aginghallmarks at the cellular and molecular levels. The sheer magnitude of the effects reported is stunning, as metformin-treated monkeys in many respects show phenotypes typical of young or middle-aged monkeys, as if metformin halted aging completely. The data on cortical atrophy are particularly impressive from my point of view.

I see three fundamental issues with this paper

#1 The study is based on five treated and five control monkeys. It is an inescapable law of statistics that underpowered studies tend to overestimate effect sizes. This is simply because, when the numerosity of the sample is small, on one hand only very large effect sizes reach significance and on the other hand the error on the effect size is large and in half of the cases it will be overestimated. See

Power failure: why small sample size undermines the reliability of neuroscience. Button KS, et al. Nat Rev Neurosci. 2013;14(5):365–376

This means that potentially a replication of this study with a larger sample sizes will find smaller effects, or none at all.

#2 There is no assessment of the monkeys before onset of the treatment. It is entirely possible that -due to chance- the treated monkeys differed significantly from control monkeys in key clinical aspects before starting the treatment. This phenomenon is well-known to longevity aficionados, as it is clearly visible -and was reported by the authors- in the first rapamycin study in mice

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Harrison DE et. Nature. 2009 Jul 16;460(7253):392-5

Where animals were randomly assigned to groups at the start of the study but were treated much later. The male controls had lower survivorship than the treated group before the treatment started, overestimating the effects of metformin in male mice.

#3 as correctly pointed out by Matt Kaeberlein in his podcast, it is unclear what diet the control monkeys were following. Monkeys on ad libitum processed chow develop dysfunctions in glucose homeostasis not seen when rations are controlled. See Fig. 5 of

Caloric restriction improves health and survival of rhesus monkeys. Mattison JA et al. Nat Commun. 2017 Jan 17;8:14063

So, if the monkeys had impaired glucose homeostasis at the start of the treatment, then the effect of metformin was that of rectifying a disease condition and not to retard aging.

 

 

[this was globally shared btw]

[Alex K Chen]

Quote

 

We also saw that explainable or Gen X DNAm biomarkers provided deeper mechanistic insights into the effects of specific interventions. By examining system-specific scores, we identified targeted effects on different physiological systems. For instance, smoking cessation primarily decreased lung-specific system score, whereas metformin exhibited extensive effects across inflammatory, brain, and metabolic systems. These findings suggest that Gen X biomarkers can uncover nuanced responses to interventions that whole-body clocks might overlook. Understanding the specific systems affected by various interventions can inform the development of targeted therapies that address the underlying causes of aging in specific organs or tissues. For example, interventions that target inflammation and oxidative stress in the vascular system can help reduce cardiovascular aging, while those that enhance neuroplasticity and reduce neuroinflammation can support healthy brain agin

 

https://www.biorxiv.org/content/10.1101/2024.10.22.619522v1.full

Edited November 2 by Alex K Chen

[IgorF]

(a bit ironically) - metformin of 2024 is semaglutid %)

but seriously - I personally hope both these tools could help move forward in research (in addition to do some good work as drugs for those who could benefit of them

[Alex K Chen]

Quote

This is my take on this very recent and potentially game-changing paper

hashtag#metformin decelerates hashtag#agingclocks in hashtag#male hashtag#monkeys

https://lnkd.in/dmmwqMRW

This paper reports that a 40 months treatment with metformin in old monkeys prevents hashtag#atrophy of the frontal hashtag#cortex, improves working hashtag#memory (a cognitive function very sensitive to aging) and prevents/retards a whole host of different hashtag#aginghallmarks at the cellular and molecular levels. The sheer magnitude of the effects reported is stunning, as metformin-treated monkeys in many respects show phenotypes typical of young or middle-aged monkeys, as if metformin halted aging completely. The data on cortical atrophy are particularly impressive from my point of view.

I see three fundamental issues with this paper

#1 The study is based on five treated and five control monkeys. It is an inescapable law of statistics that underpowered studies tend to overestimate effect sizes. This is simply because, when the numerosity of the sample is small, on one hand only very large effect sizes reach significance and on the other hand the error on the effect size is large and in half of the cases it will be overestimated. See

Power failure: why small sample size undermines the reliability of neuroscience. Button KS, et al. Nat Rev Neurosci. 2013;14(5):365–376

This means that potentially a replication of this study with a larger sample size will find smaller effects, or none at all.

#2 There is no assessment of the monkeys before onset of the treatment. It is entirely possible that -due to chance- the treated monkeys differed significantly from control monkeys in key clinical aspects before starting the treatment. This phenomenon is well-known to longevity aficionados, as it is clearly visible -and was reported by the authors- in the first rapamycin study in mice

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Harrison DE et. Nature. 2009 Jul 16;460(7253):392-5

where animals were randomly assigned to groups at the start of the study but were treated much later. The male controls had lower survivorship than the treated group before the treatment started, overestimating the life-extending effects of rapamycin in male mice.

#3 as correctly pointed out by Matt Kaeberlein in his podcast, it is unclear what diet the control monkeys were following. Monkeys on ad libitum processed chow develop dysfunctions in glucose homeostasis not seen when rations are controlled. See Fig. 5 of

Caloric restriction improves health and survival of rhesus monkeys. Mattison JA et al. Nat Commun. 2017 Jan 17;8:14063

So, if the monkeys had impaired glucose homeostasis at the start of the treatment, then the effect of metformin was that of rectifying a disease condition and not of retarding aging.