> It works by decreasing glucose production in the liver, increasing the insulin sensitivity of body tissues, and increasing GDF15 secretion, which reduces appetite and caloric intake.
Emphasis mine. So, looks like the actual aging deceleration is just the cliche, that it's healthy to not be overweight?
A principal mechanism of action of metformin is AMPK-dependenent inhibition of mTORC1 in the liver. [1] mTORC1 inhibition also occurs when fasted and when taking Rapamycin. Rapamycin has been floated many times as a life extension drug. [2]
mTOR is one of the major nutrient sensing pathways in the body, particularly sensitive to amino acids (especially methionine and leucine) but also to energy levels in general via AMPK. Inhibition of mTOR slows down cell division and induces autophagic flux -- further mTOR dysregulation is implicated in about 70% of cancers. It is an incredibly highly conserved pathway in everything from yeast to humans, and [m]TOR inhibition has been shown to dramatically extend life in basically everything that moves. I believe there's a life extension trial in humans under way around Rapamycin but I could be mistaken.
It acts as a very targeted partial starvation mimetic.
[edit] > that it's healthy to not be overweight?
This is separately also true. But what's neat about metformin is that generally diabetics on metformin are less likely to develop cancer than non-diabetics. [3] So it stands to reason that non-diabetics taking metformin would have even lower incidence of cancer no?
[edit] I find this stuff very cool, and I personally expect mTOR to be the next golden child after everyone gets on GLP-1s.
This guy gives a pretty good explanation of (Insulin's effects on the body), from the point of view of adapting it into a lifestyle diet. He also built a pretty amazing DIY cottage in Costa Rica.
https://www.youtube.com/watch?v=hDxXprgv3kk&t=2s
This video actually helped to motivate me to get into meal prepping, and significant weight loss.
It usually gets attributed to oxidative stress, but I think it’s also more exposure to toxins and inflammation sources.
Your mercury load is higher if you eat twice as much fish, meanwhile the benefits of eating some fish are proportionally higher than eating a lot of fish. You want small portions of a lot of things, not large portions nor narrow selection.
Interesting work. There are also clinical trials, recent and ongoing, looking at the effects of metformin on aging in humans, too, including the TAME trial[0].
For those who can't access the article, the dosage they used was 20mg/kg per day. The pills I've seen are 500mg, so for me that works out to 3-4 pills per day. I know some people who already take doses like that for high blood sugar with no ill effects, but some also do have ill effects. Also I am not a monkey, so no idea if this would be a great idea to try.
I couldn't find the exact doses TAME is using, but some writeups point out that there's no effect on glucose levels beyond about 1,600mg per day.
Here's more info [1] on the TAM trial, courtesy of Dr Michael Greger.
Apparently, the TAME trial has gotten FDA approval since 2015, but has yet to be launched as a full fledged clinical trial, apparently because "there is no way in hell to make money on it. So how would we fund a clinical trial? Well, yes, the only way is philanthropic" [2]
If I am diagnosed with type II diabetes is it worth choosing metformin over other options (other considerations being the same for the different choices)?
Metformin is almost always the first medication that you primary physician will prescribe, along with dietary restrictions. There's a reason it's first on almost every single list of diabetes medications. The side-effects are super low and rare, and maximum dosage of it is rather high.
Three months later they check your A1C, and if you aren't responding to Metformin well enough then they'll slap on a second medication from one of the other categories. I think Sulfonylureas combine pretty well with it.
If you're still not responding well your primary will give up and send you to an endocrinologist, who should have enough knowledge of the alternatives to discuss which one is best for you. It's completely fair to say "I'd like to try XYZ because the side effect of <side effect> appeals to me".
In addition to following your doctor’s directions, It can’t hurt to also check your diet is including enough vitamins and minerals - magnesium for example is a common deficiency and effects insulin. Although also make sure you doctor is aware of the supplements !
Something to be aware of is that it can cause genital physical deformities in male offspring.
> Boys were more likely to be born with genital birth defects if their fathers took the commonly prescribed diabetes drug metformin in the three months before conception, according to a new study by Stanford Medicine investigators and their collaborators in Denmark.
It does often cause significant gastrointestinal problems. Same as weight loss drugs. A lot of people think these drugs are free lunch but they are not.
It's so frustrating to get seemingly contradictory results across species with the same treatment. The Interventions Testing Program found no increase in median or maximum lifespan in mice, male or female, treated with metformin (though it did in combination with rapamycin) [0].
I realize "decelarating the aging clock" might be subtly different than increasing lifespan, but it's a reasonable enough comparison, imho. Hopefully we can soon capitalize on improvements in AI to faithfully model human biology in silico, and conduct experiments that way.
I am pessimistic about purely in silico or even in vitro methodd to tackle a problem as complex as aging rates. Improving mouse models to incorporate a high level of genetic diversity is a better first step. This is what our group of resesrchers is doing now. Results are promising and results are also highly dependent in genetics and sex.
Perhaps we should be looking at function levels at 70, 80, 90% of lifespan rather than looking for quantity of life.
Logistically speaking, humans tend to have a lot of disposable income at 60-70% of life expectancy. From the Enlightened Self Interest perspective, extending that zone before functional decline would not only improve society but also be profitable.
This study shows the combination of Metformin and Everolimus( Rapymyacin) is more effective at cancer than either alone. More research is needed.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464161/
I have NET cancer and am taking Everoliumus. I am thinking about recruiting other NET cancer patients to do an informal test of Metformin and Everolimus( Rapymyacin). Is there any structure or web site or other tools to help us with this?
Interesting, Metformin is mostly commonly used to help treat high sugar levels in diabetics. I'm curious if this is the same mechanism or if its a novel mechanism.
There's data to suggest that too much sugar can cause all kinds of problems to the brain, increasing oxidative stress is one of them.
Maybe the answer we're all looking for is to cut sugar from our diets.
I haven't read the CELL paper yet (would love to, if somebody has a PDF to share).
But I'm surprised I yet haven't seen a mention of Dr. Michael Greger's book [1] How Not to Die, which does an excellent job of elaborating how various diseases -- including cardiovascular diseases, diabetes, etc -- result in death.
I found it immensely helpful in plugging a lot of holes in my understanding of my own health (FWIW: 40s, no chronic diseases, but tendency towards high(er) A1C, cholesterol)
He has subsequently released other books -- How Not To Age, How Not to Diet, etc -- which one might call as capitalizing on the trend, not to put too fine a point on it. [However, I do find his books, videos and discussions quite informative, and not too technical, without going into the hyper-masculine, pseudo-science-y word salad territory waded into by, say, Huberman.]
There's a brief video [2] on side effects of metformin as a life extension drug, which seems relevant to the CELL paper above.
My wife did geriatric care when she was a student doctor. When I told her about this article she said and I quote: "I've met loads of old people on metformin, its not done anything for them"
(Genuine Q): Why are people - or even just HN readers - really so interested in living longer?
Both my father and my father-in-law have dementia.
My father's dementia is fairly advanced (he doesn't know who I am and hasn't for a while, there are times where he doesn't know who my mother is) although he's still living at home.
My father-in-law's dementia is less advanced although he's much more frail as he was diagnosed with bladder cancer, had it removed, so has ended up with the whole tubes+bags "solution".
My OH and I were discussing this for the Nth time last week.
Apologies for being blunt, but our current perspective is this: try make your life count, and hope for it to end cleanly. Via Dignitas, if necessary.
There is no way I want to see out my final years in the way that my father or my father-in-law are doing now :(
The people in this space talk a lot about not just life span, but health span. I don't know anyone who wants to suffer for a long time, of course we'd want to live well.
I know for myself, I'd love to be around to watch my kids grow up. Even better if I can do that while being old-man jacked and physically capable enough to still enjoy life. I don't think this has to mean that you're putting off enjoying life in the current moment though.
It seems like a funny question to ask who's "interested in living longer"? Taken to an extreme that's a pretty depression question.
"decelerates aging clock" implies slowing down processes of decreasing health, not just living longer in a frail state at the end. In particular if you click the link, the first thing it says is:
• Metformin prevents brain atrophy, elevating cognitive function in aged male primates
• Metformin slows the pace of aging across diverse male primate tissues
• Metformin counterparts neuronal aging, delivering geroprotection via Nrf2 in male primates
It doesn't even say you'd live longer. If I could get something that doesn't extend my life at all, just keeps my brain fresher into my old age, I would jump on that as well.
Nobody expects to live longer and have dementia. People are betting that they will escape that and there's a good probability that they will do. Not to mention that if you are around your 30s or 40s it would be terrible to not care about your general health just to find out in the next 10 or 20 years that science found a cure to dementia but now your body is too much fucked to take advantage of that.
I find life awesome. I truly fucking enjoy it. I am not rich, I can't retire and probably will never be able to do so, but I also enjoy my work even if not all the time. I think the world is moving towards a terrible inflexion point, I think we are in a fucking crisis right now, and still, fuck that. I don't want to leave this boat.
Now that said, I completely accept that not everyone shares my point of view, and I also accept that probably I wouldn't understand their reasons for doing so.
Maybe you should stop worrying about it. Some people would eagerly take any opportunity to live a few more years, it makes no sense to you, but it makes to them. It is not like they are forcing you to also live more than what you want.
I care more about being healthier longer. And I’d like that to last as long as I can and not a lot longer necessarily. It’s because I love life because it’s life, and wouldn’t mind if it went on for a long time. I could learn so many things.
But, even if it’s 60 years I want them to be healthy. So I do the things I am supposed to to age more slowly because aging is causative to ill health. My things I do is eat reasonable amounts of healthy food and exercise regularly. I supplement a few things like magnesium and taurine, that I specifically do better taking than not.
But if they came out with a “never age until you die” pill I would take it immediately.
But I think you’re confusing long life with long health span. I don’t think anyone dreams of living a long full life is hellish degenerative ill health.
Your Father and Father-in-laws conditions are due to the process of aging, not the number of years they have lived. It is the process of aging which anti-aging advocates want to delay or eliminate. Living longer doesn't mean tacking on years at the end, continuing the aging process for longer; it means adding years to the middle before aging begins, as well as lessening the effects of aging when that time eventually comes.
I want the entire system to have longer maintenance and repair: skin smooth, head of hair, muscles not atrophied, bones not brittle, oxygenated blood circulating and keeping a brain well functioning without its own independent deterioration, risk of cancer mitigated, but also easily repairable if its occurring
I look at the London borough checklist of what people died from in the 1600s, and it makes me optimistic that the things people currently die of will be solved
I just don't want to be felled by those things. Its nice that solving for them includes a high probability of centenarian lifespans, I’m fine crossing that bridge when we get there.
To flip your question around, why are you living right now?
I developed a severe intestinal disorder in my 20s. Some people can get it or ones like it in their teens, others their 30s, 40s, 50s, etc. and many won't ever develop such issues, although they're reasonably common to a less severe extreme than my case.
Knowing this, and that I could explain my disorder for years being debilitating and putting me in agonizing pain and suffering, why would you want to live any longer when it could happen to you too?
Not everyone is going to develop such cognitive disorders as you discuss, and often they're a result of complex genetic and lifestyle factors, as well as likely having to do with aspects of aging like reduced function of organs. So it's quite possible these diseases and disorders aren't inevitable simply as a consequence of living long enough, or could be treated and reversed as medical science advances.
If I sound bitter by the way, I am slightly, but do mean for this to still be conveyed productively.
To hear someone asking "why are people interested in living longer?" makes me genuinely want to know why you're interested in living longer. You could die right now and free up resources for the rest of us, or donate resources to younger people than you who are in need, or simply give it to me since I'm neither senile nor old (not even 30) nor have a family history of such disorders as you mentioned, nor would I put it to poor use.
I suspect you want to live. The simple fact is, it's that same desire to live and to continue enjoying life to the fullest that makes those of us with foresight interested in prolonging our healthy lives.
Not going to lie, I really hate all the recent coverage on Metformin becoming a “miracle pill” - as I’ve been on Metformin for almost 10 years now without issue.
I really hope my prescription costs and access to Metformin is not ruined by everyone’s quest to out live their children
[+] [-] generalizations|1 year ago|reply
> It works by decreasing glucose production in the liver, increasing the insulin sensitivity of body tissues, and increasing GDF15 secretion, which reduces appetite and caloric intake.
Emphasis mine. So, looks like the actual aging deceleration is just the cliche, that it's healthy to not be overweight?
[+] [-] arcticbull|1 year ago|reply
A principal mechanism of action of metformin is AMPK-dependenent inhibition of mTORC1 in the liver. [1] mTORC1 inhibition also occurs when fasted and when taking Rapamycin. Rapamycin has been floated many times as a life extension drug. [2]
mTOR is one of the major nutrient sensing pathways in the body, particularly sensitive to amino acids (especially methionine and leucine) but also to energy levels in general via AMPK. Inhibition of mTOR slows down cell division and induces autophagic flux -- further mTOR dysregulation is implicated in about 70% of cancers. It is an incredibly highly conserved pathway in everything from yeast to humans, and [m]TOR inhibition has been shown to dramatically extend life in basically everything that moves. I believe there's a life extension trial in humans under way around Rapamycin but I could be mistaken.
It acts as a very targeted partial starvation mimetic.
[edit] > that it's healthy to not be overweight?
This is separately also true. But what's neat about metformin is that generally diabetics on metformin are less likely to develop cancer than non-diabetics. [3] So it stands to reason that non-diabetics taking metformin would have even lower incidence of cancer no?
[edit] I find this stuff very cool, and I personally expect mTOR to be the next golden child after everyone gets on GLP-1s.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299044/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841986/
[+] [-] dukeofdoom|1 year ago|reply
This video actually helped to motivate me to get into meal prepping, and significant weight loss.
[+] [-] unknown|1 year ago|reply
[deleted]
[+] [-] hinkley|1 year ago|reply
Your mercury load is higher if you eat twice as much fish, meanwhile the benefits of eating some fish are proportionally higher than eating a lot of fish. You want small portions of a lot of things, not large portions nor narrow selection.
[+] [-] aaron695|1 year ago|reply
[deleted]
[+] [-] onlyrealcuzzo|1 year ago|reply
Are typical monkeys obese like typical Americans?
[+] [-] huqedato|1 year ago|reply
[+] [-] dewarrn1|1 year ago|reply
[0]: https://www.afar.org/tame-trial
[+] [-] matthewdgreen|1 year ago|reply
I couldn't find the exact doses TAME is using, but some writeups point out that there's no effect on glucose levels beyond about 1,600mg per day.
[+] [-] aanet|1 year ago|reply
Apparently, the TAME trial has gotten FDA approval since 2015, but has yet to be launched as a full fledged clinical trial, apparently because "there is no way in hell to make money on it. So how would we fund a clinical trial? Well, yes, the only way is philanthropic" [2]
[1] https://nutritionfacts.org/video/the-tame-trial-targeting-ag... [2] https://youtu.be/_9I0R8I16XQ?feature=shared&t=105
[+] [-] robwwilliams|1 year ago|reply
[+] [-] tocs3|1 year ago|reply
[+] [-] shaftway|1 year ago|reply
Three months later they check your A1C, and if you aren't responding to Metformin well enough then they'll slap on a second medication from one of the other categories. I think Sulfonylureas combine pretty well with it.
If you're still not responding well your primary will give up and send you to an endocrinologist, who should have enough knowledge of the alternatives to discuss which one is best for you. It's completely fair to say "I'd like to try XYZ because the side effect of <side effect> appeals to me".
[+] [-] bityard|1 year ago|reply
[+] [-] mint2|1 year ago|reply
[+] [-] _qua|1 year ago|reply
[+] [-] lambdaba|1 year ago|reply
[+] [-] unknown|1 year ago|reply
[deleted]
[+] [-] fnord77|1 year ago|reply
[+] [-] toomuchtodo|1 year ago|reply
> Boys were more likely to be born with genital birth defects if their fathers took the commonly prescribed diabetes drug metformin in the three months before conception, according to a new study by Stanford Medicine investigators and their collaborators in Denmark.
https://med.stanford.edu/news/all-news/2022/03/birth-defects...
https://www.acpjournals.org/doi/10.7326/M21-4389
[+] [-] caseyy|1 year ago|reply
[+] [-] birriel|1 year ago|reply
I realize "decelarating the aging clock" might be subtly different than increasing lifespan, but it's a reasonable enough comparison, imho. Hopefully we can soon capitalize on improvements in AI to faithfully model human biology in silico, and conduct experiments that way.
[0] https://www.nia.nih.gov/research/dab/interventions-testing-p...
[+] [-] robwwilliams|1 year ago|reply
https://pubmed.ncbi.nlm.nih.gov/36173858/
https://pubmed.ncbi.nlm.nih.gov/34666007/
https://pubmed.ncbi.nlm.nih.gov/34552269/
[+] [-] hinkley|1 year ago|reply
Logistically speaking, humans tend to have a lot of disposable income at 60-70% of life expectancy. From the Enlightened Self Interest perspective, extending that zone before functional decline would not only improve society but also be profitable.
[+] [-] tines|1 year ago|reply
[+] [-] Randypea|1 year ago|reply
[+] [-] bognition|1 year ago|reply
There's data to suggest that too much sugar can cause all kinds of problems to the brain, increasing oxidative stress is one of them.
Maybe the answer we're all looking for is to cut sugar from our diets.
[+] [-] ninetyninenine|1 year ago|reply
Data is controversial. It's not "not enough" data or anything like that either.
[+] [-] kamaal|1 year ago|reply
Ideally it should cause the same effect?
[+] [-] aanet|1 year ago|reply
But I'm surprised I yet haven't seen a mention of Dr. Michael Greger's book [1] How Not to Die, which does an excellent job of elaborating how various diseases -- including cardiovascular diseases, diabetes, etc -- result in death.
I found it immensely helpful in plugging a lot of holes in my understanding of my own health (FWIW: 40s, no chronic diseases, but tendency towards high(er) A1C, cholesterol)
He has subsequently released other books -- How Not To Age, How Not to Diet, etc -- which one might call as capitalizing on the trend, not to put too fine a point on it. [However, I do find his books, videos and discussions quite informative, and not too technical, without going into the hyper-masculine, pseudo-science-y word salad territory waded into by, say, Huberman.]
There's a brief video [2] on side effects of metformin as a life extension drug, which seems relevant to the CELL paper above.
[1] https://nutritionfacts.org/book/how-not-to-die/ [2] https://nutritionfacts.org/video/side-effects-of-metformin-a...
[+] [-] KaiserPro|1 year ago|reply
[+] [-] unsupp0rted|1 year ago|reply
[+] [-] 7e|1 year ago|reply
[+] [-] non-|1 year ago|reply
Can't see the full paper to see if they compared the results of metformin vs a low-sugar diet.
EDIT: Already brought up and discussed here https://news.ycombinator.com/item?id=41522931#41523725
[+] [-] unknown|1 year ago|reply
[deleted]
[+] [-] logifail|1 year ago|reply
Both my father and my father-in-law have dementia.
My father's dementia is fairly advanced (he doesn't know who I am and hasn't for a while, there are times where he doesn't know who my mother is) although he's still living at home.
My father-in-law's dementia is less advanced although he's much more frail as he was diagnosed with bladder cancer, had it removed, so has ended up with the whole tubes+bags "solution".
My OH and I were discussing this for the Nth time last week.
Apologies for being blunt, but our current perspective is this: try make your life count, and hope for it to end cleanly. Via Dignitas, if necessary.
There is no way I want to see out my final years in the way that my father or my father-in-law are doing now :(
[+] [-] switchbak|1 year ago|reply
I know for myself, I'd love to be around to watch my kids grow up. Even better if I can do that while being old-man jacked and physically capable enough to still enjoy life. I don't think this has to mean that you're putting off enjoying life in the current moment though.
It seems like a funny question to ask who's "interested in living longer"? Taken to an extreme that's a pretty depression question.
[+] [-] eqvinox|1 year ago|reply
• Metformin prevents brain atrophy, elevating cognitive function in aged male primates • Metformin slows the pace of aging across diverse male primate tissues • Metformin counterparts neuronal aging, delivering geroprotection via Nrf2 in male primates
It doesn't even say you'd live longer. If I could get something that doesn't extend my life at all, just keeps my brain fresher into my old age, I would jump on that as well.
[+] [-] barrucadu|1 year ago|reply
There's no point in living longer if your faculties are too degraded to enjoy it, you may as well just be dead.
[+] [-] elzbardico|1 year ago|reply
[+] [-] elzbardico|1 year ago|reply
Now that said, I completely accept that not everyone shares my point of view, and I also accept that probably I wouldn't understand their reasons for doing so.
Maybe you should stop worrying about it. Some people would eagerly take any opportunity to live a few more years, it makes no sense to you, but it makes to them. It is not like they are forcing you to also live more than what you want.
[+] [-] fnordpiglet|1 year ago|reply
But, even if it’s 60 years I want them to be healthy. So I do the things I am supposed to to age more slowly because aging is causative to ill health. My things I do is eat reasonable amounts of healthy food and exercise regularly. I supplement a few things like magnesium and taurine, that I specifically do better taking than not.
But if they came out with a “never age until you die” pill I would take it immediately.
But I think you’re confusing long life with long health span. I don’t think anyone dreams of living a long full life is hellish degenerative ill health.
[+] [-] jjk166|1 year ago|reply
[+] [-] yieldcrv|1 year ago|reply
I want the entire system to have longer maintenance and repair: skin smooth, head of hair, muscles not atrophied, bones not brittle, oxygenated blood circulating and keeping a brain well functioning without its own independent deterioration, risk of cancer mitigated, but also easily repairable if its occurring
I look at the London borough checklist of what people died from in the 1600s, and it makes me optimistic that the things people currently die of will be solved
I just don't want to be felled by those things. Its nice that solving for them includes a high probability of centenarian lifespans, I’m fine crossing that bridge when we get there.
[+] [-] monkeyfun|1 year ago|reply
I developed a severe intestinal disorder in my 20s. Some people can get it or ones like it in their teens, others their 30s, 40s, 50s, etc. and many won't ever develop such issues, although they're reasonably common to a less severe extreme than my case.
Knowing this, and that I could explain my disorder for years being debilitating and putting me in agonizing pain and suffering, why would you want to live any longer when it could happen to you too?
Not everyone is going to develop such cognitive disorders as you discuss, and often they're a result of complex genetic and lifestyle factors, as well as likely having to do with aspects of aging like reduced function of organs. So it's quite possible these diseases and disorders aren't inevitable simply as a consequence of living long enough, or could be treated and reversed as medical science advances.
If I sound bitter by the way, I am slightly, but do mean for this to still be conveyed productively.
To hear someone asking "why are people interested in living longer?" makes me genuinely want to know why you're interested in living longer. You could die right now and free up resources for the rest of us, or donate resources to younger people than you who are in need, or simply give it to me since I'm neither senile nor old (not even 30) nor have a family history of such disorders as you mentioned, nor would I put it to poor use.
I suspect you want to live. The simple fact is, it's that same desire to live and to continue enjoying life to the fullest that makes those of us with foresight interested in prolonging our healthy lives.
[+] [-] rileymat2|1 year ago|reply
> The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging.
And some people call Alzheimer's type 3 diabetes. So there could be something protective?
[+] [-] tempestn|1 year ago|reply
[+] [-] Gelob|1 year ago|reply
[deleted]
[+] [-] testfrequency|1 year ago|reply
I really hope my prescription costs and access to Metformin is not ruined by everyone’s quest to out live their children