> 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.
> 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?