13 ms·

https://en.wikipedia.org/wiki/Metformin https://en.wikipedia.org/wiki/Metformin: > It works by decreasing glucose production in the liver, increasing the insul

https://en.wikipedia.org/wiki/Metformin https://en.wikipedia.org/wiki/Metformin: > 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?

deleted 2y ago
[deleted]
arcticbull 2y ago
Likely not. 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/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299044/ [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ [3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841986/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841986/
- riehwvfbk 2y ago
  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.
  - arcticbull 2y ago
    > 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).
    - riehwvfbk 2y ago
      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.
      - deleted 2y ago
        [deleted]
      - mahin 2y ago
        So just like all the life saving drugs being prescribed now?
        Teever 2y ago
        Or the vitamins that we fortify our bread and milk with.
onlyrealcuzzo 2y ago
> Emphasis mine. So, looks like the actual aging deceleration is just the cliche, that it's healthy to not be overweight? Are typical monkeys obese like typical Americans?
- bee_rider 2y ago
  I wonder how they control for that in lab monkeys. They aren’t typical, right? I guess they probably get less exercise than wild monkeys.
  - ugh123 2y ago
    This article describes some of what they do with lab primates for obesity: https://www.nytimes.com/2011/02/20/health/20monkey.html https://www.nytimes.com/2011/02/20/health/20monkey.html Essentially: put them in small cages for years, give them a nearly unlimited supply of food, and give them nothing to do. Terrible.
dukeofdoom 2y ago
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 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.
- bityard 2y ago
  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.
hinkley 2y ago
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.
- arcticbull 2y ago
  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. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329718/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329718/ [2] https://www.nobelprize.org/prizes/medicine/2016/press-release/ https://www.nobelprize.org/prizes/medicine/2016/press-releas...
  - hinkley 2y ago
    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.
aaron695 2y ago
[dead]

deleted 2y ago

[deleted]

arcticbull 2y ago

Likely not. 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/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299044/ [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ [3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841986/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841986/

riehwvfbk 2y ago
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.
- arcticbull 2y ago
  > 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).
  - riehwvfbk 2y ago
    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.
    - deleted 2y ago
      [deleted]
    - mahin 2y ago
      So just like all the life saving drugs being prescribed now?
      - Teever 2y ago
        Or the vitamins that we fortify our bread and milk with.

onlyrealcuzzo 2y ago

> Emphasis mine. So, looks like the actual aging deceleration is just the cliche, that it's healthy to not be overweight? Are typical monkeys obese like typical Americans?

bee_rider 2y ago
I wonder how they control for that in lab monkeys. They aren’t typical, right? I guess they probably get less exercise than wild monkeys.
- ugh123 2y ago
  This article describes some of what they do with lab primates for obesity: https://www.nytimes.com/2011/02/20/health/20monkey.html https://www.nytimes.com/2011/02/20/health/20monkey.html Essentially: put them in small cages for years, give them a nearly unlimited supply of food, and give them nothing to do. Terrible.

dukeofdoom 2y ago

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 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.

bityard 2y ago
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.

hinkley 2y ago

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.

arcticbull 2y ago
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. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329718/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329718/ [2] https://www.nobelprize.org/prizes/medicine/2016/press-release/ https://www.nobelprize.org/prizes/medicine/2016/press-releas...
- hinkley 2y ago
  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.

aaron695 2y ago

[dead]