Metformin and longevity

[mccoy]

I'm in the process to listen (for teh secodn time) to Peter Attia podcast latest episode, with Nir Barzilai. That's an exceptional discussion on the effects o metformin on longevity, plus details on GH and IGF-1, insulin resistance and more...

Nir Barzilai, M.D.: How to tame aging (EP.35)

[mccoy]

In the initial diagram, we see how Metformin acts thru AMPK -dependent pathways but also through AMPK independent pathways. And speaking about the former, there are so many more pathways than than the known mTOR inhibition.

 

[mccoy]

The apparent paradox of insuline resistance (benefitting C-elegans, detrimental to mammals).

 

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The apparent paradox: The Science paper showed that nematodes [worms] with the insulin-resistant, visceral fat live longer. But Nir showed that mammalians live longer if you surgically remove the visceral fat and make them insulin sensitive.

How Nir made sense of this paradox:

• • Only so much glucose can be stored in the muscle so the muscle becomes IR as a protective mechanism, and so the excess glucose goes to the liver (because it at least has the capacity to turn glucose into fat) and to the fat cells
• “So what am I telling you? I’m saying that insulin resistance is a protective mechanism. It’s a modulator, it’s a stress response. . .So now, I understand why a stress response mechanism in one animal causes them to live longer and in another animal, it’s a pain in the butt.”

 

[mccoy]

Paradox of insuline sensitivity as  a possible CV hazard (which I didn't grasp very well):

 

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• Peter’s hypothesis in this hypothetical is that the one who needed 90 units of insulin to dispose of glucose with the same efficacy as the person who needed 30, is sooner, rather than later, going to have a harder time disposing of glucose
• Nir says that there’s another possibility:
  • It’s possible that the people who are more insulin sensitive will be first to get other macrovascular diseases, like heart attacks or stroke
  • So the IR people may get diabetes first, but the insulin sensitive people may get macrovascular diseases first
• Peter says, “Which brings it right back to the observation of glucose versus insulin, micro versus macrovasculature…”

 

[mccoy]

Very interesting case of negative consequences (glucose intolerance) of hypoinsulinemia in elderly people. Is this the same mechanism of CR-induced GI ?

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But this is further complicated when you consider the following example:

• Elderly people in certain cases have enough insulin to suppress glucose production, but not enough insulin to increase glucose uptake
• So when you look at baseline glucose, they will look healthy
• But when they are fed, they fail and become glucose intolerant and diabetic
• And this is because the liver is more sensitive to insulin than the muscle.

 

[mccoy]

The amazing results of Bannister et al. 2014, where diabetics taking metformin displayed 17% less mortality than healthy control without metformin.

[mccoy]

[mccoy]

This is another staggering concept: markers of longevity in centenarians may be very tricky, since what you measure might be what's causing the centenarian's death.

 

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• Nir says it’s better to study offspring of centenarians rather than the centenarians themselves because you don’t know if their phenotype is what protected them or if it is a marker of their impending death (since statistically, they will die within a couple years)

 

[mccoy]

The part on IGF-1 is also extremely interesting, but maybe suited to another specific thread.

[Clinton]

McCoy,

Are you familiar with the paper that discussed potential natural metformin and rapamycin mimetics?

 I can post the article tomorrow when I get to work...

One of the natural substances that was similar to metformin was glucosamine sulfate- and another epidemiological study showed that it is both safe and seems to have profound impacts on all-cause mortality in humans (long Washington State study which followed thousands of people).

Clinton

 

[drcha]

The way we are heading, it will not surprise me if they put metformin and statins in the water supply one day. We are already putting fluoride in it, which would presumably be unnecessary if children did not eat crap. We seem to adjust our ideas of what is normal. As a society and a planet, we need to change our mindset. 

Is there an international body that is trying to change this? I see our government trying and I appreciate that. But, as usual they are operating with strained budgets and are 10 or 20 years behind on the science all the time and in bed with the food conglomerates, so people have stopped believing them. There are any number of people trying to sell you nutritional information or supplements, most of whom are making up lies. Someone please tell me who is dispensing sound and contemporary nutritional advice without trying to make a profit from it.

[mccoy]

10 hours ago, Clinton said:

Are you familiar with the paper that discussed potential natural metformin and rapamycin mimetics?

 I can post the article tomorrow when I get to work...

One of the natural substances that was similar to metformin was glucosamine sulfate- and another epidemiological study showed that it is both safe and seems to have profound impacts on all-cause mortality in humans (long Washington State study which followed thousands of people).

Clinton

Clinton, that 's very interesting and as a matter of fact, while hearing the podcast I was thinking about the natural molecule contained in the French Lily and if there are any supplements around. That would be a very feasible choice for those who are not diabetiscs or prediabetics and don't want to mess with a drug.

Ditto for Rapamacyn.

 

[mccoy]

6 hours ago, drcha said:

The way we are heading, it will not surprise me if they put metformin and statins in the water supply one day. ...

In the podcast Barzilai recounts that the prime minister of Singapore asked him about that very possibility (adding metformin in tap water and mineral waters).

[Clinton]

I’m having problems posting from my PC at work... maybe I’m supposed to be doing other things 😄

The paper is entitled ‘Towards natural mimetics of metformin and rapamycin’ by Aliper, Jellen ... Aging 2017 vol 9 No 11

The epidemiological study on glucosamine is ‘Total mortality risk in relation to use of less-common dietary supplements ‘  American Journal of clinical nutrition April 2010 by Pocobelli, Kristal, et al

[TomBAvoider]

Seems TAME will happen, though it seems to me suspiciously underpowered - unless it's going to be done with a single dose, which in turn would be super disappointing. So it'll be 1500 on met and 1500 placebo - but what I want to know is how are they going to test dosages (and maybe even timing) - I mean, "dose makes the poison". We know for a fact that f.ex. rapa must be carefully dosed and the timing is critical - apparently you shouldn't be taking rapa on a daily basis (for anti-aging effects), but in a pulsatile fashion. 

So how do they propose to test metformin for dosage and timing? If they do a fairly comprehensive test - divide the 1500 on metformin to various dosages, say 250mg, 500mg, 750mg, 1000mg, 1.5g, 2g, 2.5 g etc, once daily or broken into twice daily etc. - well that's quite a few groups - each would have to be pretty small to make up the 1500 in aggregate, so what kind of numbers can they have in each group: possibly numbers that are too small to be valid as a statistical sample. 

Or do they propose to throw all 1500 on one dose - which, how would they know which is the best?

Hence I say the study design is either underpowered (if they test various dosages), or disappointing (if they test only one dose).

I agree with Barzilai that it is very important to have clinical outcomes - but I'm not sure that TAME settles anything.

OK, reading more about TAME, I see that it's a single dose - 1500mg - very, very disappointing. 

[mccoy]

Tomb, from what I remember of the discussion, they based that dose on the huge database available on metformin users, which is not stratified by dosage though.

So they had to choose an optimal quantity for longevity, which I reckon they did by bayesian methods (prior experience) and optimization. Maybe even targeted research. Given the experience Barzilai and others have on metformin, maybe we can trust the experimental choice of dosage for the purpose.

[mccoy]

16 hours ago, Clinton said:

I’m having problems posting from my PC at work... maybe I’m supposed to be doing other things 😄

The paper is entitled ‘Towards natural mimetics of metformin and rapamycin’ by Aliper, Jellen ... Aging 2017 vol 9 No 11

The epidemiological study on glucosamine is ‘Total mortality risk in relation to use of less-common dietary supplements ‘  American Journal of clinical nutrition April 2010 by Pocobelli, Kristal, et al

Tahnks Clinton, that's enough info, I'm already consulting the articles

[TomBAvoider]

9 hours ago, mccoy said:

Tomb, from what I remember of the discussion, they based that dose on the huge database available on metformin users, which is not stratified by dosage though.

So they had to choose an optimal quantity for longevity, which I reckon they did by bayesian methods (prior experience) and optimization. Maybe even targeted research. Given the experience Barzilai and others have on metformin, maybe we can trust the experimental choice of dosage for the purpose.

Nonsense. Trust? Certainly not. It has nothing to do with trust, and everything to do with evidence. This is science, not a religion, so trust and authority is of no use. The biggest databases of users are in people with DMT2, so not exactly the same group looking for the same effects as healthy people taking metformin hoping for life/health extension.  We have no such a database of such people. You wouldn't use the database of patients taking rapa for what it's usually taken for - suppression of immunity in transplant rejection patients - as a guideline for healthy people looking for life/health extension in dosage... in fact, that is explicitly discussed by Peter Attia and Nir Barzilai in this very podcast - Peter and Nir mentioned that there are a lot very bad side effects in rapa, and Peter says that that is based on patients taking rapa for medical reasons, and THAT THOSE DOSAGES ARE BAD for life extension!!! He mentions that explicity, and says you need COMPLETELY DIFFERENT dosages and timing for rapa in life extension! C'mon mccoy, are you paying attention to what they say in the podcast? Use your head, it's exactly the same situation with metformin, or any other medical drug! Bottom line - all those databases are USELESS, because those are for people - just like in the rapa case - of people who take metformin BECAUSE THEY ARE SICK!!! So no, they did not pick the dose "based on prior experience" because THERE IS NO PRIOR EXPERIENCE with metformin used in healthy people to extend life/health - the only prior experience is with sick people, which is nonsense (see: rapa).

Sorry, but the way to establish the effect of metformin (or any drug) is to do trials with differing dosages, not pull out a magical number out of your behind and TRUST(LOL!!!!) that it is somehow divine intervention. TEST DOSAGES!!! That is what science does - test.

That is why I am calling the TAME study highly disappointing. I stand by my statements. By the way, I rememeber when I was researching metformin that there was one paper where they identified some good health outcome of metformin, but only in dosages of 500mg daily and NOT higher - unfortunately I can't locate that paper at the moment, but I remember thinking that dosage is extremely important and by no means something that can simply be assumed. Again - this is science, don't assume, TEST!!! This they failed to do in the design of TAME. 

 

[TomBAvoider]

Btw., through bitter experience of disappointment through many decades of hype with numerous - numerous! - "wonder drugs", I have learned to carefully research claims and hype. I urge everyone to do the same. For example, the hype about metformin and reduction of cancer? In the podcast, Nir makes a claim for metformin being helpful in prevention (except prostate cancer). Well, look more closely. For example here cancer reduction is only in patients with type II diabetes WHO HAVE LOW HDL cholesterol - personally don't have diabetes, and my HDL is high - so how relevant is it to me? See here:

http://care.diabetesjournals.org/content/34/2/375

Low HDL Cholesterol, Metformin Use, and Cancer Risk in Type 2 Diabetes

"RESULTS During 13,808 person-years of follow-up (median 5.51 years), 129 patients developed cancer. HDL cholesterol <1.0 mmol/L was associated with increased cancer risk among those who did not use metformin, but the association was not significant among those who did. Use of metformin was associated with reduced cancer risk in patients with HDL cholesterol <1.0 mmol/L and, to a lesser extent, in patients with HDL cholesterol ≥1.0 mmol/L. HDL cholesterol <1.0 mmol/L plus nonuse of metformin was associated with an adjusted hazard ratio of 5.75 (95% CI 3.03–10.90) compared with HDL cholesterol ≥1.0 mmol/L plus use of metformin, with a significant interaction (AP 0.44 [95% CI 0.11–0.78]).

CONCLUSIONS The anticancer effect of metformin was most evident in type 2 diabetic patients with low HDL cholesterol."

Now, you should always be extremely careful when extrapolating from studies with mixed groups of patients. Imagine that they did NOT pay attention to the HDL status of these patients - they would report that ON AVERAGE metformin helped patients lower incidence of cancer. But the average obscures the fact that it only helps very specific people! 

Remember when there was hype that aspirin helped prevent cancer? Upon closer look, it was all mostly down to aspirin helping with colorectal cancer, and because colorectal cancer is one of the biggest cancers and causes of death from cancer (after lung cancer), of course when you said "aspirin helps cancer" it came up a big number. But it gets worse. It transpires, that aspirin only helped with colorectal cancer in people WITH SPECIFIC GENETIC VULNERABILITIES - if you didn't have those snps, aspirin did NOTHING for your odds of getting colorectal cancer. Meanwhile, taking aspirin caused internal bleeding and on balance the risks of bleeding were bigger than benefits. So if you only relied on the hype, you would be taking aspirin, bleeding and all FOR NO CANCER benefit, unless you had a specific genetic profile (which by the way, I do not, for colorectal cancer - so I don't take aspirin).

Again, and again, and again - "TRUST" only in science, not the opinion of anyone including Nir - because as you can see, all claims have to be examined carefully, including Nir's misleading claims about metformin and cancer. I am not saying he's intentionally misleading, but in his enthusiasm, you must be careful not to get caught up in the hype. Which Peter Attia is also prone to - getting caught up naively in the hype. I like Peter Attia very much, but he frequently gets over enthusiastic and then must change his opinion completely (f.ex. keto diets). An example of Peter being naive is right there in this podcast - he mentions the opinion of David Sinclair with whom he had dinner... well, David Sinclair in my opinion is a borderline huckster and a huge hype guy - for Peter not to see this is very naive... nobody should listen to David Sinclair. 

Sorry, again I have to stress: the bigger the hype, the more careful you have to be. ALWAYS remember: extraordinary claims require extraordinary evidence. And the evidence that can be gotten out of TAME is by design not extraordinary, in fact it is highly disappointing - NO DOSE TESTING!!! That's very bad. 

I am not interested in rats, flies, yeast, worms, and other nonsense discussed in this podcast. I am not a rat, fly, yeast or worm. I am a human, and so, interested in humans. And not all humans. I am not interested in result from T2DM humans, because I don't have T2DM. And as we have seen, not all results even apply to people with T2DM, because in one example, for cancer, it applies only to T2DM with LOW HDL. I am sure the more closely you look, the more specific the results get. 

Which is why for many years now, I have claimed that individual medicine is the holy grail. Because what is good for you may not be good for me, and vice versa. And rats? If the result is good for rats, I am very happy for the rats among us, but I am not celebrating for myself. And yes, TAME continues to be disappointing.

[Saul]

Hi Tom!

I agree with you about "wonder supplements"; I've always ignored them -- even rapamycin, which is still being studied by Luigi and others.  I believe that calorie restriction is the only safe lifestyle change that is likely to have desirable outcomes.

However, I don't entirely agree with you on the subject of the studies of David Sinclair.  Dr. Sinclair of Harvard gave a nice talk here at the University of Rochester, at our annual conference on aging in the biology department.  His talk was very interesting (he was not pushing a supplement).  I would much like to see him invited to a future meeting of the CR Society -- if there are any future meetings.

Here's a previous note of mine about the work  of Prof. Sinclair:

Dr. Sinclair was the principle speaker at the annual UR Conference on aging today!  He needs no introduction to long time members of the Society.

 

Some of what he talked about is not published yet, so I can't discuss some details; but I'll summarize a small part of it:  He presented, and seems to favor, the "epigenetic theory of aging":  this notes that, with aging, there are changes occurring in the epigenome -- he was concentrating (in his talk) mostly on groups adhering to chromosomes (phosphorolation, methylation, etc.).  He has done experiments on mice, in which he cut chromosomes, and repaired them, repeatedly, very carefully.  The usual chemical tests showed that the genes of these modified mice were identical to their litermates.  But, tests showed changes in their epigenome.  The modified mice performed identically to their litermates; equally intelligent, active, etc.

 

 But they aged faster.  After 6 or so months, they resembled 12 month old mice.

 

A molecule with the acronym NMN (which stimulates NAD+, which among other things seems to improve chromosomal repair) appears to help improve the aging rate of these epigenetically modified mice.  Phase I testing of the use of NMN in possible treatment of some human ailments is hoped to be underway soon.

 

During the question period, I asked Dr. Sinclair if the maximal lifespan of the modified mice differed from untreated mice.  He said that this was the case, in the tiny experiment that he has so far made -- 15 modified, 15 control mice:  The modified mice had significantly lower maximal lifespan -- but he intends to repeat the experiment, with a much larger cohort.

 

One other attendee asked questions about calorie restrction.

 

Perhaps more information is available at the Department of Biology website of the UR.

 

  --  Saul 

  --  Saul

 

[mccoy]

5 hours ago, TomBAvoider said:

C'mon mccoy, are you paying attention to what they say in the podcast? Use your head, it's exactly the same situation with metformin, or any other medical drug! Bottom line - all those databases are USELESS, because those are for people - just like in the rapa case - of people who take metformin BECAUSE THEY ARE SICK!!! So no, they did not pick the dose "based on prior experience" because THERE IS NO PRIOR EXPERIENCE with metformin used in healthy people to extend life/health - the only prior experience is with sick people, which is nonsense (see: rapa).

Tomb, although you have a point, metformin has a huge record of possible side effects due to the huge number of people who have been administered it, I believe not all with the same dosage.

Metformin is given to prediabetics as well. Of course the dosage for longevity purposes may be different, but that has been probably calculated from the human database and from studies on animals. Although it is not cited and this is purely speculation.

having listened to so many podcasts on mTOR and rapamycin, I give it for granted what you say. PA speaks about intermittent dosages which target mTOR1 and leave mTOR2 alone. Whereas as an immunosuppressant, high dosages of Rapa target both complexes and trouble occurs.

However, they already know the optimum rapa dosages for longevity, as we have been discussing in other threads. One or a few mg once a week or 10 days. How do they know that I have no idea, but that would be the approximate dosage chosen in a longevity study, should there be one.

Bottom line: 70 US$ million estimated cost for the TAME study, I strongly believe they have very well founded reasons for the chosen dosage. If not, welcome to the land of fairy tales.

[TomBAvoider]

Yes, metformin is given to pre-diabetics, but note, these are also special patients. These are not "healthy" in the sense of the average person who is not pre-diabetic (or CRONies), so I would really like to know why they picked 1500mg as dose. I mean, it is basic science to test different dosages for effect. After all, even for patients they don't all prescribe the same dose! Doses vary greatly. Some are as low as 250mg in many patients in India, all the way through 500mg, 750mg, 1g, 1.5g, 2g, 2.5g. Clearly, different doses are appropriate for different situations - so why would this not be true for health/life improvement in "healthy" subjects? Why would you NOT test for different dosages?? I believe the answer is quite practical - they don't have enough subjects. If you test 6 different doses - 500 mg, 750, 1, 1.5, 2, 2.5 - you will end up with 1500/6 = 250 patients per group - and that is if you don't also test for how it is taken (once a day, twice a day, with food without food, morning, evening etc.). That's a very low number. Instead, they would need 1500 x 6 = 9000 subjects taking metformin - that's a very different study. 

That is why I said - TAME is either underpowered (only 250 patients per dose), or disappointing (a single dose test). I guess the answer is "disappointing" . Btw. they don't know the optimal dose for rapa - they only speculate as PA himself acknowledges. In fact, different practitioners of rapa for that purpose use slightly different protocols and dosages. The truth is we don't know. As so often happens. I haveon these boards advocated for a long time that we pay extreme attention to PROTOCOL - dose, timing and so on. That's a very basic principle that has been true for literally centuries: "THE DOSE MAKES THE POISON". It has a very ancient history - and for good reason. Depending on dose, a medication can CURE, be a HORMETIC, or POISON. So it is super important. 

Which is why it is SO DISAPPOINTING that they don't test for different dosages. That - in my mind - is a serious criticism of TAME. You seem to trust that "they have very well founded reasons for the chose dosage". From my experience reading papers - and being around to see the effects of various interventions - I think that's a very optimistic view - in fact, I believe the opposite is true - well designed studies are the RARE exception, not the rule (see: Replication). Besides, science doesn't work like that - why do you have to "choose" only ONE dose? What you do is test MANY doses to find the best one. I'm sorry, but cut it any way you want - that is a SERIOUS FLAW of the TAME study. That is not good science.

[TomBAvoider]

And anyhow, it is very discouraging how people seem to abandon all principles when hype and hope strike for a new miracle drug. I mean, really, I wonder if I am in an Alice in Wonderland Upside Down world when I read how someone "trusts" that a dose was well chosen... how does TRUST enter science? Excuse me? It's as bizarre as if someone said "oh, I have a great mathematical proof!" and you say "OK, let's see!" and we hear back "No, TRUST me!". WHAT???

Sorry, this is science. It is inappropriate to ask for "trust" because the whole point of science is to ELIMINATE the variable of "trust" - it is PROOF, not "TRUST". That's what's Upside Down world about this.

Also, let us just think for one moment about this. You tell me that they somehow KNOW that 1500mg is the best dose. Umm... in science the only way you KNOW is if you perform a study that proves it. Where is the study for 1500mg being optimal? Well, there isn't because that is the whole POINT of the study - to show us what the effect is, and you can only show the effect by a STUDY. WHERE IS THE STUDY for 1500mg? There isn't. If you already know the best dosage, why do you need TAME? This is NOT SCIENCE. Which is why you must design a study that tests many different dosages. If you don't, your study is one of the thousands of studies that is badly designed:

Why Most Published Research Findings Are False

It is my strong opinion that the TAME study will be one of those "most" that give us false findings - as per the above link. With only ONE dose, chosen UNSCIENTIFICALLY (because no study), the TAME study is already doomed to be a failure. Very disappointing.

[mccoy]

Tomb, I concur that in this field some healthy skepticism is needed. Ioannidis is a formidable analyst of medical papers.

About the original issue, Metformin dosage in TAME, we should ask perhaps Dr Barzilai, or PA.