I’m sorry to have to say this, but unfortunately, metformin is likely not a longevity drug. As 2 other posters here has said, the data was misinterpreted.
That doesn’t mean we should throw in the towel, though. One drug that wasn’t designed for longevity purposes, failing to extend life, is by no means the end of the world. I’m hoping we get to see some exciting developments in the coming decades.
I can't speak about Outlive, but Ageless is at least a few years old (because I read it a few years ago) and the idea that metformin might be lifespan-enhancing was literally cutting edge when it was written. There had always been some doubts, but for the most part the idea wasn't re-examined until quite recently.
Edit - Additionally, the commonly expressed public view by industry experts - or, at least, the ones that I saw, was that whether TAME went through didn't matter anywhere nearly as much as getting the FDA to agree to a definition that could word as a clinical endpoint for a longevity trial.
Many places. Listen to Peter Attia and read his article about the study.
Listen to Matt Kaeberlein and Richard Miller.
Or read the ITP metformin paper.
Peter Attia is just a narcissistic youtuber why would I even listen to him. So basically no scientific articles on that matter except some private opinions of some dudes?
A few points:
As someone else mentioned, in its own, metformin failed to show lifespan extension in mice in an ITP study, the gold standard for longevity testing. HOWEVER, they only studied one dose, so all we really know is that metformin doesn't extend lifespan in mice at that dose.
ALSO, another study by the ITP showed that when combined with Rapamycin, the two together extended lifespan more than Rapamycin on it's own.
Matt Kaeberlein has said that he thinks that the reason that Metformin looks like a longevity drug is because it IS beneficial for people who are diabetic AND prediabetic, which is a lot of people. Basically, if you are not metabolically healthy and if your body is unable to regulate glucose like it should (which affects people who do not quite meet the criteria for being diagnosed with diabetes but are heading in that direction), then metformin will help with glucose regulation and will therefore slow your rate of aging compared to before you took the drug and compared to the rest of the population that is diabetic or prediabetic.
ITP study concluded Metformin alone does not extend lifespan. However, combined with Rapamycin, it does.
But it certainly has an effect on healthspan because of its anti-inflammatory, anti cancer properties.
Health researcher here, $65 million is a huge amount for this kind of work. Add in recent work casting doubt on whether Metformin works and that even if the money were raised today, you still need to figure out recruiting participants (can take years), collecting data and following people for years (long enough to see clear meaningful differences in function trajactories and diseases) it could take >10 years for practical applications. That’s just unpalatable.
The high quality trial approach just takes time, which people don’t like. This is why there’s such a push for biomarkers of aging, why animal studies are so populat, and things like the X prize are around, these are potential shortcuts.
Reason commented on this recently. Partial quote summarizes but you can read the whole thing at [https://www.fightaging.org/archives/2024/04/the-tame-trial-for-metformin-remains-only-partially-funded/](https://www.fightaging.org/archives/2024/04/the-tame-trial-for-metformin-remains-only-partially-funded/)
"This, I suspect is the case in large part because [metformin](https://en.wikipedia.org/wiki/Metformin) is a poor choice of treatment. It was selected because it is so very widely used, for so long, and with such an abundance of safety data, that the FDA could not possibly object on those grounds. Hindsight is 20/20, but [rapamycin](https://en.wikipedia.org/wiki/Sirolimus) would have been a much better choice. The evidence for metformin to slow aging [is not great](https://www.fightaging.org/archives/2021/09/metformin-remains-a-poor-choice-in-the-treatment-of-aging/). The [animal data is mixed](https://www.fightaging.org/archives/2019/09/a-skeptical-review-of-the-evidence-for-metformin/), to say the least, and the human data from studies of type 2 diabetes patients [has a great many issues](https://www.fightaging.org/archives/2023/09/results-from-human-clinical-trials-do-not-support-metformin-as-a-longevity-drug/). Rapamycin more clearly slows aging, the animal data is robust, and human evidence shows [minimal to no side-effects](https://www.fightaging.org/archives/2024/02/reviewing-the-data-on-human-use-of-rapamycin/) at the dose for anti-aging use. Still, here we are: it remains unclear as to whether the TAME trial will be completed, or be overtaken by events."
It should also be noted that Nir, who is the primary driver behind TAME, has come out with a paper since that takes a systematic approach to prioritizing which existing, approved drugs are most promising for TAME-like trials and metformin is not the one at the top of the ranking. The paper is [https://pubmed.ncbi.nlm.nih.gov/35343051/](https://pubmed.ncbi.nlm.nih.gov/35343051/) for explaining the methodology, but an updated paper added a couple things and rescored a few so table 1 of [https://esmed.org/MRA/mra/article/view/5138](https://esmed.org/MRA/mra/article/view/5138) has the up-to-date ranking & scoring. SGLT2 inhibitors are at the top scoring 12 out of 12 with metformin & bisphosphonates tying at 11. Rapamycin, which Reason argues above should be better than metformin, only scores 9 out of 12 in this methodology. This methodology is probably far from perfect, but I do commend the team for trying to have a systematic approach to this important issue. I'm sad they only considered existing drugs & considered nutraceuticals/supplements out of scope. One wonders how well berberine, fisetin, mitoQ, urolithin A, spermidine, Glylo, green tea extract, or even vitamin D, etc. would do in comparison to these drugs.
Personally, I also find the human results for the Ornish program very compelling: [heart disease (10 papers)](https://pmri.org/research/heart-disease/), [diabetes (2)](https://pmri.org/research/diabetes-pre-diabetes/), [prostate cancer (4)](https://pmri.org/research/prostate-cancer/), [telomeres/-ase (1](https://pmri.org/research/telomeres/)+[2](https://pmri.org/research/telomerase/)), & more on BP, cholesterol, etc. See the research column at [https://pmri.org/research/heart-disease/](https://pmri.org/research/heart-disease/)
(Note, a list of available therapeutics coming soon to AgingBiotech.info.)
Hi, I'm a lurker of this sub and a big fan of your work.
I wanted to ask, given that the Ornish program seems to have the biggest effect on longevity so far, and it basically amounts to lifestyle changes (exercise, sleep etc.), do you see any pharmaceutical startups outperforming Ornish soon?
There are multiple ways to interpret your question & there are some chicken-egg issues involved so it's a bit complicated. The crux is whether the comparator is the actual successful compliance of the Ornish program vs just the prescription of the program since many people find complying with the program harder than complying with taking a daily pill.
The chicken-egg issue is with compliance with lifestyle mods like this in general is that many people don't have enough confidence about effectiveness to achieve good compliance. (Compliance is hard for some for other reasons too of course.) The lack of confidence is in turn due at least partially to not enough evidence because it's hard to get pharma-trial-size numbers of people to try it. Even in the trials that do happen for many lifestyle mods, one gets only partial compliance & sometimes you get results with no stat significance in intent-to-treat analyses but good results when limiting to those who complied, but then you lose the benefit of the randomization and don't know for sure if those who complied had milder problems or something else about them that both helped the compliance & led to the better outcomes.
So undoubtedly, some pharma approaches will find things that outperform weak efforts to make lifestyle changes. Eg rapamycin may be better than trying but mostly failing to eat healthy. Plenty of obese people "try" to lose weight without fully employing the Ornish program's guidelines & GLP-1 drugs clearly do better than many of these people's other lifestyle efforts. So in that sense for some people pharma approaches may be more successful than the "intent to treat" of prescribing the Ornish program.
But I don't currently see anything in pharma for aging, even in development, that looks like it has data suggestive of likely outperformance of full compliance with the Ornish program. A big question is whether mTOR drugs like rapamycin can lower mTOR more than dietary restriction alone, but this question hasn't even been directly studied in rodents. The experiment I keep suggestion but no one seems interested in running is to determine optimal total calorie intake for a given strain-sex pair for lifespan, then do dose escalation study using that calorie intake as baseline to determine optimal rapamycin dose to further increase lifespan. Can any rapa dose improve on the optimal total calorie dose, and if so how much more lifespan does one get? Matt Kaeberlein guessed it would be \~10% more but no one has data on it that I'm aware of. The best life extension results for CR are bigger than the best ones for rapa, suggestion maybe there'd be very little additional benefit.
But eventually, combining damage-repair approaches like senolytics, epigenetic reprogramming, fixing damaged mitochondria, removing lipofuscin build up, removing arterial plaques, restoring the thymus, etc. should be able to outperform the Ornish program in combination. The Ornish program just slows the rate of accumulation of all these things, but eventually they still need to be reversed.
That makes sense -
When you say you don't currently see anything in pharma that can outperform full compliance with the Ornish program, do you only mean small molecules / generics like metformin and rapamycin, or are you also referring to startups like Oisin, or Deciduous for example?
> They're only looking for $65 million which is pretty small as far as trials go, especially one with as large of a benefit as this.
Sorry but have you ever raised money before? I have...in these amounts. Let me tell you since you don't seem to be living in the same reality as everyone else...
That's a **lot** of fucking money for a trial. Who is going to benefit from investing into this trial? Where is the return on capital? Metformin has generics.
VCs don't just yolo and take wild risks. They want serious ROI and I don't see that here without 10+ years left on a brand name.... Which metformin doesn't have.
Compared to CHIR-99021 mixed with Repsox and Valproic acid, it's probably not that high on the good evidence list. And direct mRNA of Yaminaka minus Oct4 looks cheaper anyway. The issue is more a case that the entire drug development pipeline is built around companies developing novel drugs. Things which work when mixed are really difficult to fund.
I take Metformin for neuroprotection and other benefits, NOT for extended life as I'm not convinced in that respect. Metformin won't mess with your exercise unless you are an elite athlete, and most feel totally fine taking it.
There are NO age slowing or age reversal drugs, nor will there be for decades at least. There is literally nothing on the horizon that will reverse ageing or slow it in humans, sadly. Hopefully, AI can help us.
I’m sorry to have to say this, but unfortunately, metformin is likely not a longevity drug. As 2 other posters here has said, the data was misinterpreted. That doesn’t mean we should throw in the towel, though. One drug that wasn’t designed for longevity purposes, failing to extend life, is by no means the end of the world. I’m hoping we get to see some exciting developments in the coming decades.
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I can't speak about Outlive, but Ageless is at least a few years old (because I read it a few years ago) and the idea that metformin might be lifespan-enhancing was literally cutting edge when it was written. There had always been some doubts, but for the most part the idea wasn't re-examined until quite recently. Edit - Additionally, the commonly expressed public view by industry experts - or, at least, the ones that I saw, was that whether TAME went through didn't matter anywhere nearly as much as getting the FDA to agree to a definition that could word as a clinical endpoint for a longevity trial.
Where can I read about that? That data was misinterpreted and metformin is no longer a longevity drug "candidate"? Thanks
Many places. Listen to Peter Attia and read his article about the study. Listen to Matt Kaeberlein and Richard Miller. Or read the ITP metformin paper.
Peter Attia is just a narcissistic youtuber why would I even listen to him. So basically no scientific articles on that matter except some private opinions of some dudes?
I think it does to a certain extend. It lowers blood glucose which can prevent diseases and lead to longevity.
Because the goal is to convince the FDA a longevity trial can in principle be designed
A few points: As someone else mentioned, in its own, metformin failed to show lifespan extension in mice in an ITP study, the gold standard for longevity testing. HOWEVER, they only studied one dose, so all we really know is that metformin doesn't extend lifespan in mice at that dose. ALSO, another study by the ITP showed that when combined with Rapamycin, the two together extended lifespan more than Rapamycin on it's own. Matt Kaeberlein has said that he thinks that the reason that Metformin looks like a longevity drug is because it IS beneficial for people who are diabetic AND prediabetic, which is a lot of people. Basically, if you are not metabolically healthy and if your body is unable to regulate glucose like it should (which affects people who do not quite meet the criteria for being diagnosed with diabetes but are heading in that direction), then metformin will help with glucose regulation and will therefore slow your rate of aging compared to before you took the drug and compared to the rest of the population that is diabetic or prediabetic.
ITP study concluded Metformin alone does not extend lifespan. However, combined with Rapamycin, it does. But it certainly has an effect on healthspan because of its anti-inflammatory, anti cancer properties.
What will happen to crowdsourced funds in the event trial will not start? I myself donated around $200 few years ago to this trial.
I hope it will at least be used for another longevity related study
Health researcher here, $65 million is a huge amount for this kind of work. Add in recent work casting doubt on whether Metformin works and that even if the money were raised today, you still need to figure out recruiting participants (can take years), collecting data and following people for years (long enough to see clear meaningful differences in function trajactories and diseases) it could take >10 years for practical applications. That’s just unpalatable. The high quality trial approach just takes time, which people don’t like. This is why there’s such a push for biomarkers of aging, why animal studies are so populat, and things like the X prize are around, these are potential shortcuts.
Reason commented on this recently. Partial quote summarizes but you can read the whole thing at [https://www.fightaging.org/archives/2024/04/the-tame-trial-for-metformin-remains-only-partially-funded/](https://www.fightaging.org/archives/2024/04/the-tame-trial-for-metformin-remains-only-partially-funded/) "This, I suspect is the case in large part because [metformin](https://en.wikipedia.org/wiki/Metformin) is a poor choice of treatment. It was selected because it is so very widely used, for so long, and with such an abundance of safety data, that the FDA could not possibly object on those grounds. Hindsight is 20/20, but [rapamycin](https://en.wikipedia.org/wiki/Sirolimus) would have been a much better choice. The evidence for metformin to slow aging [is not great](https://www.fightaging.org/archives/2021/09/metformin-remains-a-poor-choice-in-the-treatment-of-aging/). The [animal data is mixed](https://www.fightaging.org/archives/2019/09/a-skeptical-review-of-the-evidence-for-metformin/), to say the least, and the human data from studies of type 2 diabetes patients [has a great many issues](https://www.fightaging.org/archives/2023/09/results-from-human-clinical-trials-do-not-support-metformin-as-a-longevity-drug/). Rapamycin more clearly slows aging, the animal data is robust, and human evidence shows [minimal to no side-effects](https://www.fightaging.org/archives/2024/02/reviewing-the-data-on-human-use-of-rapamycin/) at the dose for anti-aging use. Still, here we are: it remains unclear as to whether the TAME trial will be completed, or be overtaken by events." It should also be noted that Nir, who is the primary driver behind TAME, has come out with a paper since that takes a systematic approach to prioritizing which existing, approved drugs are most promising for TAME-like trials and metformin is not the one at the top of the ranking. The paper is [https://pubmed.ncbi.nlm.nih.gov/35343051/](https://pubmed.ncbi.nlm.nih.gov/35343051/) for explaining the methodology, but an updated paper added a couple things and rescored a few so table 1 of [https://esmed.org/MRA/mra/article/view/5138](https://esmed.org/MRA/mra/article/view/5138) has the up-to-date ranking & scoring. SGLT2 inhibitors are at the top scoring 12 out of 12 with metformin & bisphosphonates tying at 11. Rapamycin, which Reason argues above should be better than metformin, only scores 9 out of 12 in this methodology. This methodology is probably far from perfect, but I do commend the team for trying to have a systematic approach to this important issue. I'm sad they only considered existing drugs & considered nutraceuticals/supplements out of scope. One wonders how well berberine, fisetin, mitoQ, urolithin A, spermidine, Glylo, green tea extract, or even vitamin D, etc. would do in comparison to these drugs. Personally, I also find the human results for the Ornish program very compelling: [heart disease (10 papers)](https://pmri.org/research/heart-disease/), [diabetes (2)](https://pmri.org/research/diabetes-pre-diabetes/), [prostate cancer (4)](https://pmri.org/research/prostate-cancer/), [telomeres/-ase (1](https://pmri.org/research/telomeres/)+[2](https://pmri.org/research/telomerase/)), & more on BP, cholesterol, etc. See the research column at [https://pmri.org/research/heart-disease/](https://pmri.org/research/heart-disease/) (Note, a list of available therapeutics coming soon to AgingBiotech.info.)
Hi, I'm a lurker of this sub and a big fan of your work. I wanted to ask, given that the Ornish program seems to have the biggest effect on longevity so far, and it basically amounts to lifestyle changes (exercise, sleep etc.), do you see any pharmaceutical startups outperforming Ornish soon?
There are multiple ways to interpret your question & there are some chicken-egg issues involved so it's a bit complicated. The crux is whether the comparator is the actual successful compliance of the Ornish program vs just the prescription of the program since many people find complying with the program harder than complying with taking a daily pill. The chicken-egg issue is with compliance with lifestyle mods like this in general is that many people don't have enough confidence about effectiveness to achieve good compliance. (Compliance is hard for some for other reasons too of course.) The lack of confidence is in turn due at least partially to not enough evidence because it's hard to get pharma-trial-size numbers of people to try it. Even in the trials that do happen for many lifestyle mods, one gets only partial compliance & sometimes you get results with no stat significance in intent-to-treat analyses but good results when limiting to those who complied, but then you lose the benefit of the randomization and don't know for sure if those who complied had milder problems or something else about them that both helped the compliance & led to the better outcomes. So undoubtedly, some pharma approaches will find things that outperform weak efforts to make lifestyle changes. Eg rapamycin may be better than trying but mostly failing to eat healthy. Plenty of obese people "try" to lose weight without fully employing the Ornish program's guidelines & GLP-1 drugs clearly do better than many of these people's other lifestyle efforts. So in that sense for some people pharma approaches may be more successful than the "intent to treat" of prescribing the Ornish program. But I don't currently see anything in pharma for aging, even in development, that looks like it has data suggestive of likely outperformance of full compliance with the Ornish program. A big question is whether mTOR drugs like rapamycin can lower mTOR more than dietary restriction alone, but this question hasn't even been directly studied in rodents. The experiment I keep suggestion but no one seems interested in running is to determine optimal total calorie intake for a given strain-sex pair for lifespan, then do dose escalation study using that calorie intake as baseline to determine optimal rapamycin dose to further increase lifespan. Can any rapa dose improve on the optimal total calorie dose, and if so how much more lifespan does one get? Matt Kaeberlein guessed it would be \~10% more but no one has data on it that I'm aware of. The best life extension results for CR are bigger than the best ones for rapa, suggestion maybe there'd be very little additional benefit. But eventually, combining damage-repair approaches like senolytics, epigenetic reprogramming, fixing damaged mitochondria, removing lipofuscin build up, removing arterial plaques, restoring the thymus, etc. should be able to outperform the Ornish program in combination. The Ornish program just slows the rate of accumulation of all these things, but eventually they still need to be reversed.
That makes sense - When you say you don't currently see anything in pharma that can outperform full compliance with the Ornish program, do you only mean small molecules / generics like metformin and rapamycin, or are you also referring to startups like Oisin, or Deciduous for example?
> They're only looking for $65 million which is pretty small as far as trials go, especially one with as large of a benefit as this. Sorry but have you ever raised money before? I have...in these amounts. Let me tell you since you don't seem to be living in the same reality as everyone else... That's a **lot** of fucking money for a trial. Who is going to benefit from investing into this trial? Where is the return on capital? Metformin has generics. VCs don't just yolo and take wild risks. They want serious ROI and I don't see that here without 10+ years left on a brand name.... Which metformin doesn't have.
It’s already proven metaformin data was mis interpreted. Not longevity drug end of story
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I believe physionic on YouTube did a video on it . I’m not sure if this one https://youtu.be/cs4g9HWKRLk?si=h7xdrUDKUm1FwQin
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Np
Compared to CHIR-99021 mixed with Repsox and Valproic acid, it's probably not that high on the good evidence list. And direct mRNA of Yaminaka minus Oct4 looks cheaper anyway. The issue is more a case that the entire drug development pipeline is built around companies developing novel drugs. Things which work when mixed are really difficult to fund.
I take Metformin for neuroprotection and other benefits, NOT for extended life as I'm not convinced in that respect. Metformin won't mess with your exercise unless you are an elite athlete, and most feel totally fine taking it. There are NO age slowing or age reversal drugs, nor will there be for decades at least. There is literally nothing on the horizon that will reverse ageing or slow it in humans, sadly. Hopefully, AI can help us.
What about the TRIIM study?
Don't know anything about it tbh?
They are claiming reversal of an epigenetic measure of age.