> 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.
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.
Interesting how this is the opposed of fitness recommendations where it’s all about mTOR activation to build muscle with protein or even pure leucine supplements. That would imply a strong inverse correlation between muscle mass and longevity, but I’m not aware of research showing this, even maybe the opposite. How do you explain this apparent paradox? Maybe the problem is mTOR over activation, not an intermittent one, kind of like insulin? In that case phases of muscle building with autophagy in between (ie intermittent fasting) could be the best of both.
I believe you're on the right track. To me, it only seems paradoxical when viewed in isolation. mTOR activation is conducive to growth, but unchecked growth is called cancer.
A person (and the processes in their body) goes through cycles on a daily and long-term basis. One is not constantly eating, exercising, and growing.
Muscle mass and strength are not the same thing, though they are highly correlated. I believe most studies on the elderly use measures like grip strength, which is a proxy for frailty.
The elderly don't have the same capacity for growth or energy. However, they can avoid wasting away by remaining active. They certainly benefit from autophagy as it clears senescent cells. Perhaps this shift is the body's way of reducing the risk of cancer.
As an aside, a curious data point is that men have shorter lifespans than women on average. There are likely several reasons for this, but I wonder if this has to do with the hormonal effect on mTOR. Perhaps our ability to grow is finite, and excessive activation of mTOR "runs out the clock" faster.
Rapamycin and related rapalogs will be far better than metformin at inhibiting mTORC1, and at a low and intermittent dose of 4-6 mg ONCE per week are quite safe. Best paper I know of now is Kaeberlein et al 2023:
What about stuff like Berberine? Is that all smoke and mirror? It's always hard to tell if the research around "traditional" compounds is actually legit or just other countries engaging in what is effectively marketing.
Everyone on GLP-1s? Is that a future most people actually want?
I believe that these things work. But I for one don't want more years as a wage slave, particularly when coupled with anhedonia. Sure, I'll extract more value for my corporate overlords, but what's in it for me? For some definition a long life without any pleasure is an optimization, but I'd argue the validity of this definition.
> Everyone on GLP-1s? Is that a future most people actually want?
I want a future where people aren't dying of cancer, cardiovascular disease, losing limbs and eyes to diabetes, getting strokes and where they're living long and healthy lives. I don't really care so much about the means. GLP-1s are the only proven non-surgical intervention that allows people to lose a clinically significant (>5%) amount of weight and keep it off long-term (>5 years).
So instead of natural selection making it so that people who live longer aren't affected by these issues - you'll have a populace that is dependent on a drug. Perfect recipe for powerful centralized control I suppose.
The drug is a shim until gene therapy is proven safe and effective. We are patching a bug in the human wrt the peptide hormone mechanism in scope. It is, very broadly speaking, a reward center defect. Morally speaking, we should show the human grace and attempt to assist humans with this buggy reward center at scale via bioengineering.
Declaring broad swaths of people "defective" because they don't subscribe to the same value is you seems quite dystopian to me. You say messiah, I say Nazi.
Having a medical condition isn't a moral failing; observing said medical conditions and advocating for providing help with potentially malfunctioning reward centers leading to lower agency and desired individual outcome doesn't strike me as "being a Nazi.". If a human doesn't want the help, they don't have to take it. If they do, make it widely and affordably available. Strange take. Context below.
> The consistency that I'm hearing from all across patient groups is gain of control, whereas previously, there was a loss of control… All of a sudden they're able to step back and say, 'oh, well I had this shopping phenomenon that was going on, gambling, addiction, or alcoholism, and all of a sudden, it just stopped,' -- Dr. Gitanjali Srivastava, Vanderbilt Medical Center
> 1. GLP-1 drugs appear to dramatically reduce addictive drive across substances. 2. GLP-1 drugs can reach vastly more patients than existing medications and they have positive mental health benefits for anxiety and depression. 3. This is our first ever opportunity to make a big dent in the addiction crisis, which kills 770,000 people a year between opioids, cigarettes, and alcohol.
Prior to Iodized salt, Switzerland was suffering from a rash of people with Goiter, which is disfiguring and decreases your quality of life, and also a large population with cretinism which causes stunted growth and mental retardation.
Then, they introduced iodized salt, and those issues which used to be somewhat prevalent only 100 years ago are practically nonexistent now.
We have destroyed natural selection in humans a long time ago when by creating effective healthcare, so don't worry about it.
There are many companies making different versions of this drug, I don't see why you think its some kind of conspiracy intended to control the masses, literally if the benefit is greater than the costs what is your issue with it?
The "benefit greater than the cost" is very much unproven. It's a psychoactive drug first and foremost, and one that deeply affects the reward mechanisms. What the sibling post calls "defects" I call variety, uniqueness, and not being a robot.
> Everyone on GLP-1s? Is that a future most people actually want?
If it's a net positive to my life what is the problem?
You have a very dismal view of the world, it is possible to enjoy one's work, or at least tolerate it, or work for yourself in the current economic system. Personally I appreciate the improved standard of living I have thanks to the efficiency of our profit driven system.
Exactly. It's like, yeah, lots of things suck about life and this life could easily be better for billions if we mildly reduced the quality of life for the richest 1,000 humans on the planet, but compared to the 1300's this shit is a cakewalk.
I describe it as "appetite calming." Not sure how else to put it. I used to have a low grade constant craving for food. I wasn't obese but the weight had crept up. Losing weight was impossible. I had high blood sugar, blood pressure, and cholesterol. (Now on meds for all those things and they are under control.)
Immediately after going on metformin my appetite calmed. Slowly, over the next year, I lost 25 pounds. I did not try to diet. My BMI is now 23.7.
After a few months I started weight training. I changed my diet to lower carbs. I haven't lowered my HbA1c into a totally comfortable level (it is 5.6 and 5.7 and above is prediabetic). But I am better.
But before any of those changes, just the Metformin alone calmed my appetite.
I can go hours without thinking about food. I am just less concerned. I feel normal.
Just as a data point, the last time I got Covid, it was quite mild. It's at least possible that the better metabolic health and weight loss had an impact.
I can't say what MetFORMin did for me on its own since I also changed my diet and lifestyle significantly when I started it. But since starting it I lost 50 pounds, and got my blood sugar from a diabetic range into a normal range, along with many positive side effects such as increased energy, no more sleep apnea, blood pressure in normal range (was over 170/90). Again MET didn't do these things itself, but I do think it helped to achieve the weight loss and blood sugar control that would have been harder without it. I was on a low dose and never had any negative side effects, and am now off of it after 6 months and maintaining.
Absolutely not unless you are fighting serious obesity. In contrast, I can imagine low dose intermittent mTORC1 inhibition as generally advantageous over a much wider population of individuals 50 years and older.
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.
Despite the unnecessarily picturesque location and overt shirtlessness, this was actually an accurate overview of nutritional metabolism for how short it is.
I've been researching this topic (in the context of keto) on my own for the last 10 years or so and can say that nothing he said is wrong. I don't know why all of this isn't common knowledge at this point, other than the signal just gets lost in the noise between dry research papers and fad-pushing articles and products.
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.
From the lens of the mTOR model -- if you just eat a lot of food all the time, mTOR is constantly agonized and your body consistently operates in anabolic mode. Periods of fasting (either explicit through hours/days without eating, or implicit through low calorie diets, or synthetic via metformin or rapamycin) allow your body to enter catabolic mode and tear down aggregated and misfolded proteins. Recent Noble Prize winner Yoshinori Otsumi discovered autophagy does that specifically. [1, 2]
As a SWE/EE I tend to look at things through that lens, and it seems like most processes in the body are AC coupled. DC signals tend to get filtered out and not recognized properly. Lower calorie diets and fasting convert mTOR agonism from a DC signal to an AC signal and it's the periodic alternation of modes that keeps you healthy. Periods where you can tear down the broken and periods where you can rebuild.
Another example, people look at stress hormone cortisol as leading to central adiposity in the context of insulin resistance. This is fundamentally backwards - cortisol is a potent insulin antagonist, it's a catabolic hormone that prevents insulin secretion, disrupts insulin signaling and mobilizes stored fat. The problem is when it's constantly elevated (DC signal) it stops working, and the opposite happens.
mTOR inhibition also modulates the immune system and suppresses hyperimmunity. This reduces inflammation (via Hypoxia-indidible factor 1-alpha / HIF1A and several downstream processes). Which explains why metformin reduces inflammation too. Even more interesting is that inhibition of mTOR in the AMPK-mTOR-HIF1A pathway makes vaccines significantly less effective.
I walk first thing in the morning before eating. So that’s fasting exercise. It’s definitely pulled down my pain levels enough that I’m putting off medical intervention for now. I do need to go in anyway because I want to see where my A1Cs are. I was flirting with the lower edge of the danger zone a few years ago.
My first quibble is: honestly an 8 hour window for eating is pretty large, that's like, late breakfast, lunch and dinner. Is that fasting? It seems like kind of a normal eating schedule.
My first thought when I read something like this is "why would it be severely detrimental" and the first response is "the kind of people who are overweight are the ones who are going to be trying new diets to lose weight, and being overweight in the first place is severely detrimental to lifespan." Controlling for that, there may be something further confounding, for instance.
People skip breakfast all the time, and skipping breakfast leads to a 60% increase cancer risk. Peter Attia has a writeup on this [1]. Turns out, the people who skip breakfast are far less health conscious. People who skipped breakfast were 3X as likely to smoke. As he says, 'health and lifestyle characteristics between groups can either mask or exaggerate the association between frequency of breakfast consumption and mortality.'
I'd be very surprised if a kinda normal ish eating schedule led to a materially worse outcome when properly controlled. But proper control is damn near impossible in nutrition studies.
>My first quibble is: honestly an 8 hour window for eating is pretty large, that's like, late breakfast, lunch and dinner. Is that fasting? It seems like kind of a normal eating schedule.
Even worse, they define, "time-restricted eating" as being up to 12 hours!
>Time-restricted eating, a type of intermittent fasting, involves limiting the hours for eating to a specific number of hours each day, which may range from a 4- to 12-hour time window in 24 hours.
Thanks for the insight - especially that bit about skipping breakfast. I've seen that kind of silly conclusion from poorly controlled data in studies in my field, apparently I am blind to it in other fields.
Fasting increases nitric oxide levels. Maybe that's bad for people with existing cardiovascular issues? Probably the same people who would try intermittent fasting- it's a relatively bigger population. Of course you have to balance that against complications from being overweight.
Nitric oxide actually dilates your blood vessels, reduces blood pressure and improves cardiovascular outcomes. [1] Water fasting for a couple of days brings your systolic and diastolic numbers waaaaay down over 10 days.
> The average reduction in blood pressure was 37/13 mm Hg, with the greatest decrease being observed for subjects with the most severe hypertension. [2]
It's probably just a poor job of controlling variables in the study.
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.
I've been taking 2000mg of metformin every day for years, no ill effects. I guess I'm one of the lucky ones? Also, I'm a type of monkey more commonly referred to as "human".
Same here, 2kmg every day split between 1 in the morning and one in the evening. I did have Diarrhea at the beginning but that went away in a few days.
I am more forgetful now and a little bit more irritated at times, and I've heard this could be related to Metformin.
1k pills here, but I can only take one once a day. They're really hard on the stomach, and even when taken with food. A second pill (which my doctor would like to see) just always makes me puke.
More like "the asshole! They're not called "Metfartmin" for nothing! If you want to live a long smelly life with no friends and certainly with no bed partner then Metformin may be the pill for you.
I told a friend about this drug's life-extension possibilities. We set out to meet at Starbucks but, prior to leaving, he took 2 x 500-mg Metformin (he's a diabetic and so has a prescription). An hour later he arrived and confessed that his tardiness was incurred when a fart was revealed to contain a lump. He had to return home to change his pants.
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.
Hmm, that is a very long time to suffer the side effects. The information leaflets often say to discontinue much sooner.
Well, if your doctor was okay with it, then who are internet strangers to judge? If you had the usual non-tolerance GI problems (more frequent than in 1 in 10 patients), I can only admire the perseverance. It takes a lot of self-care from keeping close to a toilet to hydration.
My wife had this problem when she started metformin. After 2 weeks of diarrhea she tried a different approach, she purposely skipped her medication every other day for a week. The she gradually started taking it every day. The problems went away over night. Her doctor was baffled which is…funny.
I think some drugs are more easily tolerated by the body if they are gradually introduced.
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.
Improving the genetic diversity of mouse models doesn't help you when a humans are far more complex, anyway. You may find a universal effect for a mouse, it's still a mouse. You're trying to fix the space shuttle by testing changes on automobiles.
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.
Yep, optimize healthspan not necessary lifespan. Best to do both and “rectangularize” survival functions (falling off a cliff). Lots of effort on this now.
yep, mice are burning calories much more actively than larger mammals, and if anything i'd not be surprised for the opposite result - ie. if mice on metformin die earlier from exhaustion and starvation.
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.
The “sugar” in “high blood sugar” is glucose. Your body converts starches (say rice or bread) into glucose quite quickly which elevates your “blood sugar” in the short term. If you are healthy your body can quickly turn glucose into glycogen or fats or utilize it as an energy source but if you have Type I or Type II diabetes that process is impaired.
If you cut back radically on carbohydrate consumption, see
you certainly will lower your blood sugar, your body will now use proteins and fat for energy as much as it can and produce both ketone bodies and glucose from those other macronutrients as well as stored fat and muscle tissues.
Table sugar and ‘high fructose corn syrup’ are roughly equivalent to 50% fructose and 50% glucose so far as your metabolism are concerned. Certainly fruit (rich in fructose and sometimes sugar alcohols) is good for you in moderation but probably not in excess. Your metabolism is certainly capable of converting fructose and some sugar alcohols into glucose. The story of what fructose does to you is much less studied than glucose. Certainly excessive amounts of sucrose and HFCS contribute empty calories that raise your blood sugar.
Plus one in this, I reverted my Type II diabetes in 3-ish months by radically cutting out carbs (including sugars) and adding more protein to my diet. My lab results have been consistently in the "OK" range since.
1) Not clear how lit review published in 2021 casts doubt on a study published in 2024
2) The lit review does not say the data is controversial, only that the claim of life extension is, and then goes on to say "However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health" which is entirely consistent with the monkey study under discussion here
That article discusses the earlier experiments on nematodes and mice and doubts the applicability to humans of some results.
This new study provides data about positive results in primates, so it removes some of the earlier objections.
Nevertheless, it is not clear yet whether the risks of harmful effects of long-term treatment with high doses of metformin do not outweigh its beneficial effects.
Where I agree with the article linked by you is that metformin is not the actual cause of lifespan extension, but it mimics the effects of some other primary cause, perhaps calorie restriction.
Therefore, the studies on the metformin effects should concentrate on establishing which is the mechanism of its action, even if that is much more difficult than just establishing a correlation between metformin intake and ageing. When the mechanism of metformin action will be understood, it is likely that the same effects will be achievable in safer ways.
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"
While yes, I agree, what I'm trying to point out is there is a large population of people who regularly take metformin for a number of reasons in the UK. If there was a strong correlation in cognitive improvement we should be able to detect it now.
(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.
Survival instinct is deeply hard wired into all animals, including humans. It's natural to want to continue living.
Anti-aging is picking up now because there's a growing belief that significantly extending the healthy human lifespan is within scientific/technological reach.
> I personally would prefer to survive longer. If you don't, that's your business.
Ideally I'd die in my sleep 75-80 +/- a few years having seen some grandkids. Doing daft stuff now to push that number further out just seems pointless.
The next generations will have enough problems to deal with without having one more cranky 90+ year-old constantly popping pills claiming he can live forever.
I don't know that we have evidence that survival instinct goes away after reproduction. It's still valuable to our species to survive after reproduction in order to protect and nurture offspring, for example.
There's no evolutionary reason that survival instinct would turn off after a certain age.
> There's no evolutionary reason that survival instinct would turn off after a certain age
Umm, without wishing to get too clinical or morbid, it's clear that once your offspring have reached adulthood there will always come a point beyond which you rely on them more than they rely on you, right?
I'd trade length of lifespan for quality in a heartbeat. Getting old is not very pleasant. I'm already starting to feel the creaks and decline merely in my mid 40. I'd love to have more time now but do have to work and when/if I will be able to retire I will be too worn out and lacking the desire to do the things I'd do know with that time. I'd be content to live healthily till say 65-70. My mom who is at that age is saying that she used to say the same thing when she was young but she no longer things like that. I guess we all do have some survival instinct kicking in no matter what we rationalize prior.
Why does quality and lifespan have to be a dichotomy? In fact the more I think about it, living a quality lifestyle often leads to longer life (eating healthy, keeping fit, having meaningful friendships).
Both my wife and I have signed the papers to decline extended life in a vegetative state and have confirmed our desires with our kids.
The aging process will have the final word, but it’s a process. Nobody is healthy one day and in vegetative state the next.
It’s a good idea to live a healthy life, but you are merely shifting the odds. Many a health nut has hit 60 and found themselves with new problems every year, and each one is a small thing, but it adds up.
"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.
I guess it's not so obvious if GP is the top comment. It seems broader messaging around anti-aging needs to be even better (nothing against the paper). Sometimes I like the jargon of negligible senescence and longevity escape velocity, because I don't think it's possible to know the meaning of those phrases and also think the goal is eking out as much substandard life as possible, so if you can't have a two-way conversation at least you can put in a semantic roadblock that invites a curious reader to look up the meaning and then not have the GP's question.
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.
Living is risky, yeah, I know it. A lot of it is a fucking gamble, your profession, the place you decide to live, the people you enter relationships with.
Nothing is assured.
Yeah, maybe we will be all unemployable and miserable due to LLMs taking our jobs and failing to create others. Maybe we shouldn't have reproduced as our kids will never get to become adults due to a nuclear war or a fucking serious pandemic with a virus that will make SARS-COV-2 look like nothing.
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 totally get where you're coming from. I voluntarily left the workforce and now we live off my wife's income as a public school teacher. She’s got about 15 years until retirement, and while we’re not rich, we’re definitely comfortable. Surprisingly, we’ve managed to do better financially on a single income than we did with two.
Leaving the traditional workforce was an easy decision for me. COVID had me working from home, and my startup didn’t make it through the pandemic—raising capital was tough. Once I experienced working from home, I knew I couldn’t go back to the office or work for anyone else.
I feel the same way about retirement. While my wife supports us financially, I support her by managing the household. I take care of the pets, make her lunch, clean, help with her lessons and emails, and handle groceries and errands. I really enjoy this role. It frees me up to work on personal projects like novel-writing and developing a SaaS product I’m passionate about.
I get a lot of satisfaction from making my wife’s life easier, especially since being an elementary school teacher is no walk in the park. Thanks to my support, she’s been able to raise over $60k for a unique program at her school in just two years. She’s sharing her success stories at conferences worldwide, and seeing her thrive makes me happy too.
I’m not spending my time golfing or vacationing. I keep my mind sharp and enjoy the work I do. Yes, I worry about the future—like the fear of being so sick that I become a burden, and no, I don’t have enough saved up for that possibility.
I feel like my generation (X) is in a tricky spot, but for now, I’m content.
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.
So who will pay for your long healthy life? The default answer is: you will, by working longer. Any other answer has this problem: why is this magic source of funds not currently available to cover even our current shorter lifespans?
OK, so we've established that you have to continue working. Are you sure that you as a geriatric man on artificial life extension will be competitive with a younger guy who can go crazy and use the same tech to, say, never sleep - never mind that he'll die at 40? And even if we aren't talking extremes: you as a pill-supported walking corpse have to be ever vigilant of your own mortality. Someone younger can afford to take more risks.
Your argument is easily applied to all medical advancements, do you think we should stop using antibiotics? Vaccines? Maybe you should let the individuals determine what's best for themselves instead to trying to prescribe your strange anti capitalism ideology for them.
Anyway medical research is focused on giving us on better quality of life as we age, which is what people objectively value, not whatever you think they are trying to do.
> Anyway medical research is focused on giving us on better quality of life as we age
Polite correction: medical research is focussed on returns for those funding said research.
Treating Americans is definitely a cash-cow for Big Pharma, indeed if a potential new drug can't/won't make it past the FDA then it will likely be killed off regardless of what the rest of the world might want/need/approve.
Check out US healthcare spend per capita compared with everywhere else on the planet.
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.
The greatest challenge of chronic pain isn't necessarily the pain, but how it warps and taints parts of you beyond your control.
People who haven't experienced their failure are completely unaware of the incredible mechanisms of our evolution that keep us from suicide. They're also unaware of what choosing to live means in the face of the eventual erosion of those failsafes by pain.
It's like hurtling down the interstate at 70mph in heavy traffic and having the power steering go out. There's no sense of freedom and accomplishment in having to fight just to keep to your lane, only terror from all the parts of you that know how easily you'd crash if you stopped trying for even a few seconds. It's exhausting in every sense.
Diabetes causes rupturing of small blood vessels, which has been seen in eyes and feet.
It would follow that the same is happening in the brain and an anti-diabetic medicine would directly improve brain longevity in affected individuals.
*I am not a doctor, but also I can correlate data without bias.
People are interested in slowing aging, which means living longer in good health.
The ultimate goal would be negligible senescence.
Dementia and other chronic diseases that plague our end days now are consequences of aging. They don't just come randomly, they are a result of the aging process, which is nothing but slow deterioration, possibly a programmed one.
I'm old enough to see some the advances in medical care different family members were able to receive when they became very ill over the decades. I'm young enough to be optimistic that when it's my turn the treatments available will be even more significant.
There's a certain quality of life I wouldn't want to spend a prolonged time in. I understand your point about not wanting to be in bad health. Most of the activities I do that will likely prolong my life (diet, exercise, manage stress, build social bonds, supplements, pharmacology, screenings) will also increase my likelihood of prolonging the amount of time I have in good health.
Why am I interested in living longer? I think it's better than the alternative.
This is personal and depends on your perspectives. Obviously the people who want to live longer don't share the same point of view as you. And it is ok, as long as you are not forced to adopt their point of view and vice-versa.
There's miseries in all stages of life. I've known people that still enjoyed life into their 80s and even 90s. I'm not very afraid of being physical uncomfortable, and I enjoy being here enough to want to fight for more time.
Why are you conflating long lifespan with miserable last 10-20 years of the life?
I aspire to be like that French gym trainer who was in near-perfect health and an optimal presence of mind at 96 years old when he died suddenly (I think of heart attack).
I certainly wouldn't want to live forever one way or the other, but most people who talk about living longer mean slowing or halting the aging process, not simply surviving more years as a decaying husk.
...but that doesn't really answer why, does it? To "do more stuff"? To "see more things"? To "earn more money"? To "learn more"? Why?
A friend wasn't enjoying her job a year or two ago and said she felt seriously underpaid for the stuff she was being asked to handle. I asked her if she would feel any happier if they doubled or tripled her salary. After thinking about it she realised the amount of money wouldn't fix the problem, the issue was with the work environment, not the monetary package tagged on to her employment.
Life is finite.
So at least for all of us who don't have some desperately unkind medical issue that specifically shortens it, maybe we need to take a deep breath and learn to deal with that.
> To "do more stuff"? To "see more things"? To "earn more money"? To "learn more"? Why?
Yes, to all of it.
Life will still be finite with a longer life, but more is more. If offered the opportunity to have your lifespan shortened for no gain would you take it? Obviously not, and likewise if you have the opportunity to increase your lifespan for no cost, it's exactly the same decision.
Even if that were possible, and theoretically we could take the entirety of a person's brain and emulate every synapse into digital storage, along with enough compute to run everything (which is a massive hurdle to overcome), would it really still be you?
I kind of think about it a bit like the transporter deck from Star Trek. Are those people really travelling somewhere else or are they getting cloned and then done like Hugh Jackman at the end of The Prestige?
How would anyone even know? A computer simulated you would seem like you to everyone else, but you'd already be gone.
The correct answer is that there is no "you". Continuity in consciousness is an illusion that can be deconstructed through deep enough meditation, or more accessibly through psychedelics. It certainly feels like there is as "you" at the center, but what you call "you" is sort of a narrative that your brain is stitching together at each moment, and it can be subject to distortion, revision, reinvention.
You are not the same "you" from moment to moment--you are just reassembled by your brain every second in a way that feels conscious. So I would say there is a false dichotomy in the center here. If "you" are already an illusion, digital emulation just manipulates that illusion in different ways. Whether or not "you" survive in a literal sense is not the right question, there was not a fixed "you" to keep or lose in the first place
Worse, still, unless the current me blinks out of existence, "old me" will still be around - unless we can replace neurons in-place with computational analogs, the original me is destined to die, almost no matter what, even if a copy/download is made. From the download's perspective, it continues, but the original, if not ended then and there, still faces a grim end and will know it.
I’m in the middle of a sci-fi book that explores this. The answer is that you won’t be the same person. Your mind will meld with the computer’s AI and you will go insane and try to exterminate the human race. I wouldn’t risk it.
...but why? Dying is natural. Dying is normal. It's what's supposed to happen.
> I wanna know what happens
I've reproduced three times so I've ticked that particular biological box.
My OH is away this week. Our eldest cooked lunch on Tuesday when a meeting I was in ran over by an hour. I stumbled into the kitchen an hour later than planned to find the three of them eating what he'd prepared from what he'd found in the fridge and he'd made enough for me, too. They're pretty well set.
> I want to download my brain into a computer and see what humanity does over the next couple million years
I'm absolutely, completely OK with not doing that :)
I'm confident the next generation will figure it out, just like ours did, and the one before us, and so on...
It's also natural and normal to die in infancy, but we've solved that and I don't hear many complaints
Edit: looked it up, 49% is the estimated rate for hunter-gatherer societies and 48% until ~200 years ago (depending on the country, may also be ~60% or as "low" as ~40%). In 1950 it was still more than a quarter; only within living memory has it truly become abnormal to die soon after birth. https://ourworldindata.org/child-mortality
This argument of what's "natural" holds so little water to me, I don't understand in what state of belief anyone even brings this up. Is this a religious thing? Why say "it's natural to die and therefore we should always continue to do so"? Arguments of overpopulation, psychological issues (and unknown unknowns), and other real problems, I can certainly understand, but "it's natural"? Please explain
The people who want to extend their lives are the ones whose lives tend to be pretty good. The CEO plotting world domination kind of archetype. The rest of us are expected to be expendable biorobots who serve them. Unfortunately, this won't play out the way their fantasies tell them. The rich and powerful will be trapped by the need to always maintain their fragile lives. This in turn will slow down progress and open up the gates to a younger and more daring group to come to power.
This is true. Shifting a populations life expectancy up to suspend biological aging would be a panic moment for most governments that are tied to huge benefit systems based on age. Good luck changing the retirement age, again.
The bigger problem with extending lifespans beyond what evolution has optimized for is that you end up competing against your offspring for resources, and you give pathogens a non-moving genetic target to attack (which defeats the whole point of sexual reproduction).
"you end up competing against your offspring for resources"
This was relevant in the pre-agriculture era. We already live in densities several orders of magnitude higher than evolution optimized us for.
I am more concerned about the somewhat artificial societal resources, such as top jobs. We might get a very ossified elite. We almost saw a presidential election with two ancient guys competing. With longevity widespread, this may become a pattern.
"you give pathogens a non-moving genetic target to attack"
True, but we generally try to manage new infectious diseases by scientific means, not by "0.6 per cent of population is resistant to this, let the rest croak". See: AIDS, Covid.
> This was relevant in the pre-agriculture era. We already live in densities several orders of magnitude higher than evolution optimized us for.
I mean, keep in mind that we're living in a snapshot of time that's very much not stable or sustainable. It's like we're all embers born in a massive forest fire that started a few days ago. Everything seems normal and stable for us in this situation because our frame of reference is effectively a few seconds. However, this forest fire will eventually consume all the available fuel and things will return to baseline, no matter how hard we fantasize that we're going to somehow spread the forest fire to other planets.
Any temporary victories we've made over evolution are just that. We've already seen how absolutely vicious pathogens can be toward monoculture biomasses. Just ask the Gros Michel banana.
Yeah, of course tomorrow a global plague may eradicate us all, or "all except Sentinelese people".
Nevertheless, looking at our prehistory, the worst bottleneck of the human race was probably some 900 thousand years ago, way, way before we had anything resembling civilization.
So, at least for me, the question of whether we are more resilient as civilization vs. as primitive people in their pristine state, is very much open. Too many people seem to be sure that going with the natural flow is long-term better. But it feels a bit like the Noble Savage myth reiterated for current sensibilities.
I think this comment generalizes too much. I do not think Europeans are all the same on this (and probably Asians too).
As an example I have the impression that what you wrote is true for Dutch people (I don't know if it's true but I've heard/read they are more on the side of making elderly people comfortable in their last moments rather than trying to treat them with expensive procedures).
While here in Greece we do try to prolong the life of even the most hopeless situations (that might be changing). It's not rare to have our elderly parents/grandparents bedridden at home for years.
Partly, I think that the culture is more affected by the lack of history than most people realize. If you've lived in Europe, and I'm sure elsewhere, you understand your mortality implicitly from the centuries-old buildings and streets. At least that's what I got out of it.
Doubt it, besides there aren't a lot of reasons for us all to not just casually choose death had it been for humans' innate fear of death, which I think is kind of good thing.
Yes, I went back to a country with socialized medicine where patients as well as doctors are still relatively courteous to each other. It was a huge relief to leave the US, professionally speaking. BTW, I don't really get why you're so riled up.
It's natural to be afraid. I'm afraid too, at times. But people are only willing to suffer so much. In this regard, US people offer an interesting contrast: they tend to view as normal not to suffer at all in routine care (minor surgery, for example), but are willing to accept an incredibly bad quality of life in desperate situations. In Europe for example, it tends towards the opposite. Again, I'm just one guy. YMMV.
I'm not paying my doctor to be a therapist or a rabbi. I am paying for the best medical care I can get - and if I want to prolong my life (in whatever condition), that's my choice.
When I hear "don't be afraid of death", that's not medical advice. Medical advice is "there's nothing I can do for you", which is fine, but I'm going to shop for a second opinion. Maybe a third.
For the record, I'm not afraid of death, I just want to postpone it for as long as possible. If medical technology allowed, I'd be very happy with "indefinitely".
> I'm not paying my doctor to be a therapist or a rabbi. I am paying for the best medical care I can get - and if I want to prolong my life (in whatever condition), that's my choice.
Not saying anything else.
> When I hear "don't be afraid of death"
Didn't say that either!?
You're assuming opinions, here. Also, 'healthy' life prolongation was not my point. There's a personal threshold for everyone where people just prefer dying. It can be lower or higher, and my observation is that it's heavily influenced by local culture.
I don't really have a comparative opinion about that. What I mean is that I've seen countless examples of US patients and docs willing to go to extremes of treatment that would be considered unreasonable elsewhere. But I was just a bloke in one big university hospital, so YMMV I guess. Still, the culture gap was pretty surprising.
Probably not that common, as my anecdotal ass has been on Metformin for many years and there's been zero side effects. I'm quite regular. In the past I had plenty of stomach/stool issues, but I've found that more fiber in my diet fixed that up nicely.
I don't know about shitting your pants levels bad but gastrointestinal side effects are very common with Metformin, on the order of ~30% taking it will have... quite a time at the start (I was definitely one). My doctor said something like 10%-15% of diabetics end up having to move to something else because while it generally gets better for most after taking it a while, it doesn't for all. On the flipside, many take it and would never even guess that could be a side effect. Just luck of the draw.
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
I'm on Metformin and not worried about it given the likely reason you ended up on Metformin 10 years ago is it was already generic and cheap to make, especially compared to many of the alternatives. Where you get screwed is needing a pill that's under heavy patents or still complicated/expensive to make even when it isn't.
That is true in a lot of areas. Unfortunately, that's not how the pharma industry works. If a medication is patented, the company who owns it sets the price (or licensing price) according to demand. As an example, there was a scandal or two in the past few years where private equity firms were buying pharma companies and jacking up the price of medications to the point where the users of those medications got to choose between bankruptcy and living.
(Disclaimer 1: I don't know if metformin is patented.)
(Disclaimer 2: This is not an anti-capitlaist rant. Capitalism works fine with adequate governmental regulation. However, practically nothing about the US healthcare system is adequately regulated.)
I'd also mention that most of the insulin these days is not extracted from animals as it once was. One can make arguments for/against this, but for safety reasons almost all of it is now made with biopharmaceutical (bacterial recombinant) processes.
It is my understanding that the expensive insulin is actually more complicated than the insulin that we had a couple of decades ago and that makes it easier to dose correctly so that therapeutic outcomes are improved.
That was due to cartel behavior (and now should be limited by the recent drug capping initiative) - elsewhere in the world insulin is extremely affordable.
Insulin is an interesting case because the insulin you get today is manufactured in a different process than the original batches which has let manufacturers skirt around both generic alternatives and the original patent.
> 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?