35 replies to this topic

[nickthird]

Heart disease rate about only 76% of that of non-diabetics, overall cancer rate 94% etc. And this is a review of all quality trials combined (free full text).

 

Why aren't everyone who wants to combat aging on this?

 

What age should you start on this?

 

Market price / mo, china sourced price?

[Rorororo]

Because it's a prescription used to treat diabetes. Not many doctors will prescribe this for longevity.

[Rorororo]

Now tell me what you know about astaxanthin. I would highly appreciate any feedback.
https://www.longecit...in/#entry877156

[Kevnzworld]

I’m a non diabetic and I’ve been taking metformin for 6-7 years. Life Extension recommended that all middle aged adults should consider taking it years ago.
One should review their research before taking it.

[Michael]

Unfortunately, there are a series of related flaws in the underlying studies in this report — notably, various time-related biases of the kind embedded in this widely-cited study, and other similar ones ("immortal time bias," "time-lagging bias," and "time-window bias" (notable in this study and most of those in the meta-analysis)), as well as prevalent user bias.

[nickthird]

Things are not as black and white as you present...

 

I've given a peek to some of these stuff... of course presenting the honored critiquing professor that we must emphasise has such a high social status...

[WillNitschke]

An elephant in the room question: If the primary action of metaformin is to reduce high glucose sugar levels and your blood sugar levels are normal, exactly what do you expect metformin to achieve?

If metaformin is having some other effect, what is it?

[Andey]

An elephant in the room question: If the primary action of metaformin is to reduce high glucose sugar levels and your blood sugar levels are normal, exactly what do you expect metformin to achieve?

If metaformin is having some other effect, what is it?

Complex I inhibitor, AMPK activator, but nobody knows for sure. You could look at Attia’s podcast with Nir Barzilai for more information

[sedentary]

here this is recent; https://www.ncbi.nlm...les/PMC6339796/

 

and another recent very interesting study of combination DHEA and metformin; https://onlinelibrar...1111/acel.13028

 

merely entertaining silicon valley jumping on it; https://www.cnbc.com...con-valley.html

 

another proposition on how it might work; https://www.asiansci...ng-human-cells/

 

anyway, if you google it, there isnt a single article that claims it DOESNT extend lifespan :o

Edited by sedentary, 21 September 2019 - 09:56 PM.

[Guest]

I'm sorry, but this has been discussed extensively before. Michael Rae did some good analysis on the merits of Metformin. You can read it up here:

 

https://www.longecit...-mean-lifespan/

 

http://www.longecity...d-nondiabetics/

 

 

In short:

 

1. mice-studies show mixed results. Some studies show no statistically significant effect on lifespan (notably the best effects are seen on mice models of obesity; the neutral results occured in non-obese mice).

 

2. Studies comparing the disease outcome of diabetic metformin users to non-diabetic people are few and far between (most studies used in the review, that OP cites, did NOT do that!).

 

 

There was one famous epidemiological study in 2014, which claimed, that diaebtic metformin users perform better than non-diabetics. This study turned out to be seriously flawed because of monitoring and censoring problems:

 

- diabetics got frequent medical check-ups, thus any kind of disease was caught early on and treated (even those unrelated to diabetes); the non-diabetic controls got far less frequent medical check-ups

 

- if diabetic patients had a progression in their diabetic status, and had to take an additional drug (so in addition to metformin), they were excluded from the study from that point on. In other words: only the best performing metformin-users were used for the statistical analysis (and those, whose disease progressed - i.e. higher mortality - were left out)

 

 

Similar, in a current meta-analysis, that actually looked at NON-DIABETIC PEOPLE USING METFORMIN:

 

"Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis." (July 2019)

https://cardiab.biom...2933-019-0900-7

 

Metformin only improved mortality for diabetic-people. But it did nothing for people without well established metabolic disease (as in the mice studies).

 

 

If you're a sedentary and heavily overweigth or sugar-consuming type of person, Metformin might be a good idea. If you don't got metabolic disease, you only get the side effects.

 

 

 

Edit:

 

here you can read up about some of the rodent studies in metformin and lifespan (they are even missing 2 of the neutral studies done by NIA):

https://www.ncbi.nlm...les/PMC3906334/

 

it's a very mixed situation between life-extension, neutral (= no effect), and shortening the life span (yes, that happened more than once).

Edited by Guest, 22 September 2019 - 02:43 PM.

[Andey]

 

"Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis." (July 2019)

https://cardiab.biom...2933-019-0900-7

 

Metformin only improved mortality for diabetic-people. But it did nothing for people without well established metabolic disease (as in the mice studies).

 

 

  I think you read this study incorrect, its not what they claimed as a result

"Metformin reduces cardiovascular mortality, all-cause mortality and CV events in CAD patients. For MI patients and CAD patients without T2DM, metformin has no significant effect of reducing the incidence of CV events."

They dont claim metformin has no benefits for patients without T2DM, only that it doesnt have benefits for reducing CV enents.

 

If you look how authors get to that conclusion ... I would say its a messed up big time. They get a conclusion "For MI patients and CAD patients without T2DM, metformin has no significant effect of reducing the incidence of CV events." from 4  studies (figure 5.b)

3 out of 4 are severely underpowered studies with CI of 0.5 to 5.  (even worse 2 of them was 4 month studies on a small number of people)You simply cannot get any conclusion from CI-s like that, its undetermined.

One study that was powered enough (Retwiński 2018) they stated it showed benefit from metformin with HR 0.18 CI (0.05 - 0.65) for for CV events but... in reality it doesnt have non T2D group treated with metformin. 

You could check it here https://www.mp.pl/ka.../node/14685/pdf

Its a mess.

 

Our best bet is probably to wait until the TAME study results and we will finally know definitive answer. 

My gut feeling is that its slightly beneficial esp with XR version, though I dont sure if they would test different drug forms

[Kevnzworld]

This is why the TAME trial is so important.
https://www.fightagi...ceed-this-year/

[sedentary]

yeah every time i go to a metformin thread the argument against it is well there are no studies on healthy people without diabetes. but whats major concern when it comes to diabetes? AGEs! and guess what, they are as much present in non diabetics as in diabetics. difference is, diabetics cannot clear them properly and need help in form of medication. that doesnt mean healthy people clear them perfectly either though, they just do not get as much bad reaction from build up as diabetics do. so basically you might build up as much AGEs as a diabetic and they might feel really sick, you wont feel a thing but overtime it will make you sick anyway slowly but surely. AGEs are serious problem. and guess what, metformin clears them! so how would that not benefit a healthy being then?? over time, metformin might be useless, but with 50 years of use, you might finally get a benefit even without diabetis. considering, all AGEs kept at bay. https://www.ncbi.nlm...les/PMC5059570/

 

again, people misunderstand that healthy people also develop AGEs. so if you are not diabetic and still get AGEs, why isnt metformin considered a good add on therapy for good health regardless?

if im wrong, please someone show me proof that healthy people do not develop AGEs. as far as i have been reading, we all do. now, im not sure of the complication where it comes down to clearance when you are diabetic versus not. still, it affects us all. unless proven otherwise!?

Edited by sedentary, 22 September 2019 - 10:37 PM.

[Guest]

It doesn't matter if there is an in-vitro study for some mechanistic plausibility narrative (AGEs cleared in cell cultures).

 

It doesn't matter, if there is some parallel/improvement on some aging bio-markers.

 

It doesn't matter, if people with serious disease states benefit (unless you are one of them).

 

 

The only measure is, if it there is life-extension in "normal" human beings. Nothing else.

 

 

As studies on human lifespan are very hard to do, we often have to do with animal models. But again: try to get close to human beings, i.e.: yeast cells < nematodes < flies < mice < dogs < monkeys < humans. Only because it works in an inbred-strain of short lived mice, it doesn't mean it necessarily translates to humans. In mice models Metformin has a very mixed performance. It appears to work particularly well in certain disease models of mice or rodents enduring bad animal-husbandry. In other studies it doesn't work at all or even decreases lifespan.

 

 

Second are prospective cohort studies. In those you have to be particularly keen on avoiding statistical fallacies. Besides the problems of under-powered studies in terms of participants and follow up. Again: Metformin studies have very serious flaws so far and therefore do not give an indication, that it's a good idea for people without metabolic disease.

 

 

 

Arguing along the line, that there is some mechanism that a drug might target (AGEs), and that bio-markers and in-vitro studies "prove" your theory of benefits for non-diseased people is not helpful. One good example:

 

2-deoxyglucose suppresses glucose energy-metabolism almost completely. It's a pure keto-diet mimetic. It activates AMPK. It supresses mTOR. It heavily activates autophagy. It reduces inflammation better than Aspirin. It extends lifespan of nematodes. But long term use - despite short term improvements - kills rats due to some completely unexpected/unexplained side effect:

https://www.ncbi.nlm...pubmed/21167272

https://www.ncbi.nlm...les/PMC2830378/

Edited by Guest, 22 September 2019 - 11:42 PM.

[sedentary]

"The only measure is, if it there is life-extension in "normal" human beings"

 

who do you consider normal human beings? disease free, perfect human beings? we are all diseased, imperfect genetically in some way or another. not sure i get your "normal" reference

[joesixpack]

An elephant in the room question: If the primary action of metaformin is to reduce high glucose sugar levels and your blood sugar levels are normal, exactly what do you expect metformin to achieve?

If metaformin is having some other effect, what is it?

Just an uneducated thought, Keto? If it drops sugar levels for normal sugar levels might it trigger some kind of keto response?

[WillNitschke]

My deep suspicion is that the human body's internal design is already optimised as far as it can go, as that's an inevitable consequence of evolutionary selection. At least optimised up to and just passed child rearing, anyway. So any compound that is going to be effective for lifespan extension is going to have to address the breaking down of the system over time. Hence, why I am wondering aloud why some people who are essentially still 'optimised' think they will benefit from metformin...?

This seems to be something David Sinclair has publicly promoted (although other researchers appear to be in agreement with him.) BUT... does anyone have David Sinclair's blood work information? Is he already pre-diabetic perhaps?

Edited by WillNitschke, 23 September 2019 - 03:27 AM.

[joesixpack]

My deep suspicion is that the human body's internal design is already optimised as far as it can go, as that's an inevitable consequence of evolutionary selection. At least optimised up to and just passed child rearing, anyway. So any compound that is going to be effective for lifespan extension is going to have to address the breaking down of the system over time. Hence, why I am wondering aloud why some people who are essentially still 'optimised' think they will benefit from metformin...?

This seems to be something David Sinclair has publicly promoted (although other researchers appear to be in agreement with him.) BUT... does anyone have David Sinclair's blood work information? Is he already pre-diabetic perhaps?

Maybe, since we are past the age of reproducing?

[WillNitschke]

Stumbled across another new interview with David SInclair here:



His claim is that Metformin is useful because it smooths out blood sugar spikes. And that it stimulates AMPK... but since the argument is that this causes the creation of new mitochondria... this should surely improve energy levels, hence translate (perhaps) into better athletic performance. Or at least not hurt it. Which got me wondering about that recent study that shows the opposite. To his credit, Sinclair does bring this up and now his new argument is that one shouldn't take Metformin on training/recovery days... only intermittently.

I'm not really happy about that answer. Sinclair says Metformin does X. Study comes up showing it produces opposite results from what's anticipated. So the solution is to keep taking it, just not so regularly... (!)

Hard to know what to make of this.


 

Edited by WillNitschke, 23 September 2019 - 05:54 AM.

[sedentary]

im still waiting for someone to post scientific proof that "normal" or otherwise healthy people do not also develop AGEs just like diabetics do.

and that metformin can be detrimental to anyone who is not diabetic. so far, none. obviously diabetics cannot clear AGEs as well as otherwise normal people and it builds up. but im pretty sure so do non diabetics and just never know it.

 

by the way im not using metformin, or planning to ever use it. i just have relative using it at really old age without any disease. and im curious if it is major cause of her lifespan. considering its quite unusual since all her relatives died relatively young. its a reason why i have been involved with those metformin threads lately.

Edited by sedentary, 23 September 2019 - 11:35 PM.

[WillNitschke]

Metformin has known side effects. The risks are relatively low but not zero. When you wrote that you want proof that "metformin can be detrimental to anyone who is not diabetic" I don't understand the question. You seem to be denying medical science by asserting that it's perfectly safe? Or what are you saying? No drug with significant metabolic effects is likely to be "safe" for everyone at all times. The question appears to be, do the benefits outweigh the risks? I don't think that question is answerable yet.

[pamojja]

AGEs! and guess what, they are as much present in non diabetics as in diabetics. difference is, diabetics cannot clear them properly and need help in form of medication. that doesnt mean healthy people clear them perfectly either though, they just do not get as much bad reaction from build up as diabetics do. so basically you might build up as much AGEs as a diabetic and they might feel really sick, you wont feel a thing but overtime it will make you sick anyway slowly but surely. AGEs are serious problem. and guess what, metformin clears them! so how would that not benefit a healthy being then?? over time, metformin might be useless, but with 50 years of use, you might finally get a benefit even without diabetis. considering, all AGEs kept at bay. https://www.ncbi.nlm...les/PMC5059570/

 

Metformin doesn't 'clears' AGEs at all. At least the most commonly tested lab-marker for glycated hemoglobin (HbA1c). It might reduce it a bit in non-diabetics, but don't you think it is a huge difference if in a non-diabetic in average from 5.1% to 5%, but in a diabetic from maybe 7.4 to 6.9%? (these are made-up numbers, I didn't check for papers). A diabetic on metformin still will always have more AGEs than a non-diabetic. So there must be an other mechanism at play.
 

As a prediabetic myself having it under control with diet, I always used Metformin during my 6 weeks vacation to South-India, where it is too difficult for real low-carb. However checking my records of HbA1c for the last 7 years I did so, the difference for me is 5 vs. 5.3% HbA1c (which means 0.3 less glycated hemoglobin on metformin).

 

You might wonder why I consider myself a pre-diabetic with such a low average HbA1c? The reason is that I take above 20g of ascorbic acid a day, and that amount has been shown in a study to reduce HbA1c even a whooping 1% in non-diabetics!

 

http://www.longecity...156#entry797721

 

We have observed a significant "false" lowering of GHb in animals and humans supplementing ascorbic acid (AA) at multigram levels. Mice receiving ~7.5 mg/d (equivalent to > 10 g/day in a 70 kg human) exhibited no decrease in plasma glucose, but a 23% reduction in GHb.2 In humans, supplementation of AA for several months did not lower fasting plasma glucose.3,4 We studied 139 consecutive consenting non-diabetic patients in an oncology clinic. The patients had been encouraged as part of their treatment to supplement AA. Self-reported daily intake varied from 0 to 20 g/day. The plasma AA levels ranged from 11.4 to 517 µmol/L and correlated well with the reported intake. Regression analysis of their GHb and plasma AA values showed a statistically significant inverse association (eg, each 30 µmol/L increase in plasma AA concentration resulted in a decrease of 0.1 in GHb).

A 1 g oral dose of AA can raise plasma AA to 130 µmol/L within an hour and such doses at intervals of about two hours throughout the day can maintain ~230 µmol AA/L.5 Similar levels could also be achieved by use of sustained-release AA tablets. This AA concentration would induce an approximate 0.7 depression in GHb. The GHb assay used in our study, affinity chromatography, is not affected by the presence of AA.3 Thus, unlike the case with Hb D Punjab, our results were not caused by analytical method artifact. More likely, the decreased GHb associated with AA supplementation appears related to an in vivo inhibition of glycation by the elevated plasma AA levels, and not a decrease in average plasma glucose.3 If this is true, the effect has implications not only for interpretation of GHb but also for human ageing, in which glycation of proteins plays a prominent role in age-related degenerative changes.

 

My average fasting blood glucose despite all my intervention has still been 103 mg/dl.

Edited by pamojja, 24 September 2019 - 09:18 AM.

[sedentary]

20g of ascorbic acid wow. that cannot be without side effects

[pamojja]

20g of ascorbic acid wow. that cannot be without side effects

 

Yea, too many are the side benefits. But if you mean bad effects, only by crossing above 50 g per day do I get a liquid bowel movement, immetiately ceased by lowering the next dose again. During the rhinitis season it helps me like any antihistamine (without their side-effects) - by taking a teaspoon in water any sneezing-fit ceases within minutes. However, with really bad rhinitis days it has to be repeated, and above 30 g (4 doses) flatulence starts for me. No bad effect below that dose at all. But bowel-tolerance is indeed very individual, some might only tolerate 10g a day, some few even much less.
 

[sedentary]

hmm i see. i usually avoid synthetic vitamin c sold in stores because of a report that says 90% of ascorbic acid is made in china. i try to get natural vitamin c from food, but it will be quite difficult to do that at such dose heh

[sedentary]

i kept this article which is now old but very interesting; https://www.scienced...51202142210.htm intestinal bacteria are affected by metformin a lot. and in a positive way. i figured this might be related when a relative i have given metformin recently expressed gratefulness because i helped them fix their intestinal problems with the medication. i was confused... metformin is for diabetics and thats why i recommended you take it. why would that have anything to do with your stomach discomfort?? then i went home and found this old article. i guess it make sense now that metformin does a lot of positive ACTUALLY through influencing beneficial bacteria. im still not sure how the exact mechanism through which it works, but let me tell you, me and the person using it being clueless to this reporting huge benefit, then i guess this article is to be taken serious.

Edited by sedentary, 23 October 2019 - 03:44 AM.

[WillNitschke]

i kept this article which is now old but very interesting; https://www.scienced...51202142210.htm intestinal bacteria are affected by metformin a lot. and in a positive way. i figured this might be related when a relative i have given metformin recently expressed gratefulness because i helped them fix their intestinal problems with the medication. i was confused... metformin is for diabetics and thats why i recommended you take it. why would that have anything to do with your stomach discomfort?? then i went home and found this old article. i guess it make sense now that metformin does a lot of positive ACTUALLY through influencing beneficial bacteria. im still not sure how the exact mechanism through which it works, but let me tell you, me and the person using it being clueless to this reporting huge benefit, then i guess this article is to be taken serious.

 

You hardly have to resort to metformin to achieve such a result. I suspect you'd get optimal results by simply eating a healthy diet, which most diabetics refuse to do, hence why (many) are diabetic.

Consider this interesting study:

https://www.ncbi.nlm...les/PMC4401881/

Fasting blood sugar dropped from 8.99 mmol to 7.7 mmol. And A1c down from 7.61, to 6.4, by drinking kafir on a daily basis. I've seen other studies showing more significant benefits, so this may be highly dependent on your existing gut bacteria and the type of probiotic composition.

I suspect, however, if you already eat healthy (hence maintaining a good body weight) all of these types of interventions are going to do "f*ck all" as scientists say... ;-)




 

[pamojja]

As a prediabetic myself having it under control with diet, I always used Metformin during my 6 weeks vacation to South-India, where it is too difficult for real low-carb. However checking my records of HbA1c for the last 7 years I did so, the difference for me is 5 vs. 5.3% HbA1c (which means 0.3 less glycated hemoglobin on metformin)...

 

My average fasting blood glucose despite all my interventions has still been 103 mg/dl.

 

You hardly have to resort to metformin to achieve such a result. I suspect you'd get optimal results by simply eating a healthy diet, which most diabetics refuse to do, hence why (many) are diabetic.

 

Not so fast. I've been on a healthy diet since 10 years (vegetables, nuts, fish, eggs, probiotic food everyday), and because end of last year my prediabetic numbers have gone up 10 mg/dl, I decided to continue with a 500 mg/d dose of metformin this year after my vacation to high-carbing India.

 

However, since it showed no improvement with blood-glucose I dropped it again. Retesting months later without, my blood-glucose (fasting and postprandial) has gone up an other 20 mg/dl. Only once in that testing period I had a small bowl of rice: 217 mg/dl postprandial. Which is diabetic - with only a tiny slip in an otherwise very healthy diet.

 

We are all different with different bio-chemical individuality. And I better go back to a at least small dose of metformin for the time being. Without any rice.

Edited by pamojja, 23 October 2019 - 07:48 AM.

[WillNitschke]

Not so fast. I've been on a healthy diet since 10 years (vegetables, nuts, fish, eggs, probiotic food everyday), and because end of last year my prediabetic numbers have gone up 10 mg/dl, I decided to continue with a 500 mg/d dose of metformin this year after my vacation to high-carbing India.

 

However, since it showed no improvement with blood-glucose I dropped it again. Retesting months later without, my blood-glucose (fasting and postprandial) has gone up an other 20 mg/dl. Only once in that testing period I had a small bowl of rice: 217 mg/dl postprandial. Which is diabetic - with only a tiny slip in an otherwise very healthy diet.

 

We are all different with different bio-chemical individuality. And I better go back to a at least small dose of metformin for the time being. Without any rice.

 

Please re-read my statements before objecting to something I didn't claim. Thin people can also be diabetic because of some genetic or other metabolic disorder. However, the majority of diabetics are obese. Likewise, obese people may not be diabetic -- or at least -- more genetically resistant to it, using the conventional markers for the disease.

The point I'm making here is that posting studies on benefits provided to sick people is no evidence whatsoever that the intervention is going to work on healthy people. If I post a study showing the Vitamin D supplements help treat rickets, how is that evidence of any kind that vitamin D supplementation is a net benefit if your levels are optimal already?

[pamojja]

The point I'm making here is that posting studies on benefits provided to sick people is no evidence whatsoever that the intervention is going to work on healthy people.

 

Now you're more reasonable. It simply isn't just the lack of a healthy diet making (many) diabetic.

 

 

Please re-read my statements before objecting to something I didn't claim.

 

I suspect you'd get optimal results by simply eating a healthy diet, which most diabetics refuse to do, hence why (many) are diabetic.

I suspect, however, if you already eat healthy (hence maintaining a good body weight) all of these types of interventions are going to do "f*ck all" as scientists say... ;-)

 

I've a BMI of 20, eat healthy, and obviously need metformin to stay out of the diabetic range.