I agree with your enthusiasm for treatments and drugs that inhibit mTORC1 selectively. Low dose rapamycin is our best practical pro-longevity treatment today. I only wish we had a large randomized clinical trial for stronger direct support.
In contrast, the evidence of any direct in vivo action of metformin on mTORC1 is dubious. In vitro studies may be of little relevance in this context.
Even indirect effects of metformin via AMPK activation are controversial.
A careful study by Keys and colleagues of a large Danish cohort of twins (2022)found no reduction in all-cause mortality by metformin treatment.
They point out that the highly influential Bannister et al. study (2014, pushed by a high profile TED presentation) has not been replicated despite a 10-year period in which to do so. Here is the link to the Keys paper that makes me highly skeptical about use of metformin to modulate aging rates.
Could you highlight any strong in vivo studies on metformin targeting mTORC1 selectively or otherwise?
I am not quite sure what to make of this Cell paper yet.
In the NIA Interventions Testing Program (systematic studies of the impact of drugs on longevity) metformin has inly weak effects in males (p ~0.3) and no effect in females:
found no reduction in all-cause mortality by metformin treatment.
Right, but that's not what they were looking for and, even if that's what they wanted, the data they had wouldn't have allowed them to assess this claim.
Roughly speaking, they compared:
- people with diabetes that was treated with Metformin
- their twins who didn't have diabetes and were not taking Metformin
As far as I can tell, they didn't isolate the impact of metformin alone (vs the combined impact of having diabetes and taking metformin).
The context of the Keys et al 2022 study is the earlier claim by Bannister et al. (2014) that
“individuals with Type 2 diabetes who initiated metformin monotherapy as their first-line treatment exhibit lower mortality over follow-up compared to the general population WITHOUT diabetes.” (emphasis added)
That is an exceedingly strong and apparent wrong claim. Mortality rates are worse among metformin treated subjects.
Of course there is no perfect control of the type we might want in principle (metaformin-treated non-diabetics or non-treated Type 2 diabetics).
However the first type of these case-controls studies has been done in genetically diverse mice by the NIA ITP team and the results are reasonable strong and negative.
Yes, I understand the context, and the Keys study suggests that Bannister et al. (2014) is wrong.
My point is that you seem to be saying that the Keys study shows that metformin doesn't increase life expectancy. I am basing this understanding on two things you wrote:
"found no reduction in all-cause mortality by metformin treatment"
"Mortality rates are worse among metformin treated subjects."
But the Keys study does not show that Metformin doesn't increase life expectancy (or reduce all-cause mortality). It shows that Metformin isn't enough to counteract the impact (on lifespan) of diabetes. But it seems to say nothing about whether people (whether diabetic or not) would live longer with metformin or without.
I realize the Keys study isn't the only piece of research in this area. But the topic of my original comment (and this one) are simply that particular study, and what you say it shows.
If I have misunderstood anything I am happy to be corrected/educated.
I think you summarize this well. Banninster’s claim was that even the T2 diabetics lived longer on metformin than even healthy controls. That is clearly debunked. I do not know of any heslth controls being put on metformin at say 70 years of age to find out if is lowers all-cause mortality. Mouse data is a strong No. The cell paper is a study of about 12 monkeys and a lot of bioinformatic hocus-pocus of the type I do. But I prefer much larger numbers and much stronger effects.
In contrast, the evidence of any direct in vivo action of metformin on mTORC1 is dubious. In vitro studies may be of little relevance in this context.
Even indirect effects of metformin via AMPK activation are controversial.
A careful study by Keys and colleagues of a large Danish cohort of twins (2022)found no reduction in all-cause mortality by metformin treatment.
They point out that the highly influential Bannister et al. study (2014, pushed by a high profile TED presentation) has not been replicated despite a 10-year period in which to do so. Here is the link to the Keys paper that makes me highly skeptical about use of metformin to modulate aging rates.
https://pubmed.ncbi.nlm.nih.gov/36287641/
Could you highlight any strong in vivo studies on metformin targeting mTORC1 selectively or otherwise?
I am not quite sure what to make of this Cell paper yet.
In the NIA Interventions Testing Program (systematic studies of the impact of drugs on longevity) metformin has inly weak effects in males (p ~0.3) and no effect in females:
https://phenome.jax.org/itp/surv/Met/C2012
In contrast adding rapamycin work wonders (in mice).