35 replies to this topic

[AgeVivo]

Dear All

Metformin seems to be the first drug that extend lives of worms, mice, human diabetics (compared to the other usual drugs)... and possibly healthy persons as well? Among other things it normalizes glucose and IGF-1 to low levels and inhibits mTOR (a bit like rapamycin; for clarity please find references below rather than here). Metformin is an old, very cheap and very widely used drug, and as long as it is taken along with vitamin B12 and not given to people with severe cardiac/liver/renal failure, after a diarrhea during the first days it appears to be particularly safe.

The project is bold in many ways. The metformin test should be double blind, lead by a medical doctor and approved by an ethics comittee. We would need to find a sufficiently large number of volunteers to do typically a 5 year mortality study (rather than an even much longer lifespan study; during 5 years they would not know if they take a placebo or metformin), that require many persons: depending on the target population, first estimates give 2000 people aged 65 to 80. One target population could be some retirement communities (http://www.55places.com/), to be discussed.

This is a question we must digg, not only for metformin but for other/future very-plausible life-extending drugs. If we are blocked by things we do not see yet, at least we would have investigated it. And if we succeed, i) this will clearly boost the image and force of the organisation; ii) people will start to realize that the concept of life extending drugs exists (even if it may be associated to specific environmental diseases, or then seem trivial or already known, as often in science) and will pave the road for further improvements.

Edited by AgeVivo, 13 December 2010 - 12:16 PM.

[AgeVivo]

Please use this thread to discuss Health Risks from Metformin: http://www.imminst.o...-from-metformin

[AgeVivo]

History
Simply from wikipedia: Metformin was first described in the scientific litterature in 1922, was first used in humans as a non-toxic agent against influenza, was authorized by the FDA in 1954 against diabetes type II and then sold under the name Glucophage by BMS. It is now off-patent and has many cheap generics, and is the drug of choice in case of diabetes type II.

Worm lifespan and healthspan extension: http://www.ncbi.nlm....les/PMC2807458/ (free full text)


In mice, several experiments indicated life extension http://www.imminst.o...h-on-metformin/ but in not in clear conditions so it is being redone in now hopefully good conditions: http://www.imminst.o...6918-metformin/

In humans
- in diabetics, 40% less overall mortality than the alternative treatment sylfonide !! (http://care.diabetes...5/12/2244.short, "The adjusted odds ratio (OR) for all-cause mortality for metformin monotherapy was 0.60 (95% CI 0.49–0.74) compared with sulfonylurea monotherapy.")
- used against different insulin resistance diseases: diabetes type II, polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD) and premature puberty
- seem to have positive cardiovascular (), cancer (http://www.imminst.o...ng-cancer-in-s/) and dementia () actions
- in prediabetics (people who are likely to develop diabetes), a Diabetes Prevention Program 3 year study found that people taking metformin had less chances to develop diabetes than those taking a placebo (http://www.nejm.org/...56/NEJMoa012512) and after a 10-year follow up there was still a clear effect (http://www.ncbi.nlm....pubmed/19878986) [having a better lifestyle is still better in terms of diabetes outcome of course]

Prediabetics is a first step towards healthy non-overweight persons. The papers about those prediabetics studies show some benefits in terms of cardiovascular indicators but the do not indicate mortality effects. I emailed authors to know more about potential reduced mortality from metformin in prediabetics - but I don't think I'll get it: the 2009 paper says "Further follow-up will provide crucial data for long-term clinical outcomes, including mortality".

Edited by AgeVivo, 13 December 2010 - 12:38 PM.

[AgeVivo]

There is a poll for those here who take metformin: http://www.imminst.o...king-metformin/

Having people already taking metformin is an additional reason to conduct the human metformin trial.
Any questions/comments/suggesions are welcome. Please consider this as your project too, not specifically mine as apart from a few recent readings I am not at all familiar with metformin and not very much about setting clinical trials.

[maxwatt]

Metformin is one of a number of substances that increase mitochondrial biogenesis via PGC-1 alpha. (PMID: 19084501). This should help counter age-related sarcopenia.

[AgeVivo]

4000 people aged 60 needed, or 2000 people aged 70 !
That may seems strange, so I explain the reasoning here below:

In the US, the mortality rate (risk to die within a year) at age 60 is around q=1% (http://upload.wikime...003_Table_1.png)
If we target a relatively high income population (retirement community), it is below: let us consider q1=0.7%.
Let us consider that metformin reduces mortality by 30% (we don't know, this needs to be tested): q2=0.5%

If we do a 5 year mortality study, the risk to die is approximately multiplied by 5: we want to have enough people such that we can empirically distinguish Q1=3.5% from Q2=2.5%. We will have quite a lot of persons so we can use a normal distribution of the estimation of Q1 and Q2, with a standard error sqrt(Q1/N1) and sqrt(Q2/N1). We want that standard error to be at most 0.4% for example, to statistically clearly distinguish Q1 and Q2. So we want typically want N=Q/0.4%^2=2000 persons in each group (metformin and placebo)

With people aged 70, the mortality rate is approx doubled and this leads to twice as less persons.
Doing less than 5 years would of course require more people.

Edited by AgeVivo, 13 December 2010 - 12:42 PM.

[AgeVivo]

Actually this reminds me the polypill. They have done such a study with 2000 volunteers and are starting one with 5000.

http://www.wellcome....s/WTX063678.htm

Cardiovascular diseases (CVD), predominantly heart disease and stroke, account for approximately 30 per cent of all deaths around the world. The Polycap ™ offers a primary prevention strategy to individuals who are at high risk for these illnesses.
(...)
The combination pill has already been tested in more than 2000 volunteers across 50 centres in India as part of the Indian Polycap Study (TIPS) published in the 'Lancet' in 2009. Results from that phase II trial found that use of the drug reduces the risk of coronary heart disease by 62 per cent and stroke by 48 per cent.
(...)
The new funding will support the study of at least 5000 individuals with no previous history of heart attack or stroke. The placebo-controlled trial will recruit men over the age of 55 and women over 60 that have been identified as being at increased risk of CVD through a questionnaire based on family history and lifestyle factors. The investigators will assess whether taking Polycap for a period of five years can cut the risk of CVD, by monitoring the incidence of death due to heart attack, non-fatal heart attack and non-fatal stroke.

Here is what the description of such a trial looks like: http://clinicaltrial...how/NCT00603590

My hope is that metformin would have a larger effect such that less people are needed; our first target would not be cardiovascular mortality but general mortality. The "good" (or biased?) thing about testing things in India is that mortality is naturally higher there than in the US so you probably need less people to detect prevention effects...

Edited by AgeVivo, 13 December 2010 - 01:09 PM.

[AgeVivo]

More positive news:
- metformin decreases mortality by approx 30% in types 2 diabetes heart failure patients (usual contrindication for metformin)
- metformin decreases mortality by approx 30% in types 2 diabetes cardiovascular disease patients (usual contrindication for metformin)
- metformin even decreases mortality in diabetics with kidney disease (but to a lower extend; kidney disease is a usual clear contrindication due to lactic acidosis)

- metformin, against cancer? (analysis limited to diabetics so far)
- metformin, against alzheimer? (very preliminary research)
- metformin, against metabolic syndrome
Almost seems to much to be true...

[james41]

I think your idea is really encouraging and good intentionated, but there are certain things that should be adressed before this,

I am personaly taking metformin, and I have treated many patients with it.

but I am concert about the age of the target group aiming , I think it is too risky.

Metformin even though I strongly believe by many evidence that it can prolong life.It has secundary side effects and contraidications.

the main problem is that people that are 60 or 70 specially 70 dont always have the best kidney function,and even if they do, they can suddenlly develop renal failure without even showing unnormal creatinine levels beforehand, in the even that this happends metformin can be fatal as it can accumulate rapidly in the system and cause lactic acidosis, that is fatal in 50% of the cases.
this brings already a lot of moral second thoughts to be use in healthy subjetcs.Even if in the long run it prevents cancer and cardiovascular death.

Also metformin cause some mild/severe secundary effects that can severely decrease the life quality of healthy subjects (at doses required to really affect Igf1, mitochondrial uncoupleing, ampk activation,Mtor inhibition ) it can cause orthostatic hypotension, that is already quite common in the eldery,this is the eldery can be dangerous as they may fall downn it can cause malaise (a general feeling of not feeling well),depresion rates also it cause some foggyness and lack of mental sharpness and a general feeling of tireness.All together I dont think it will be easily consider a perfect safe drug specially when used in such old subjects.


I thik we should study this in a well control healthy long life mice population.that surprisingly has never been done despite being such a cheap and available drug.

Sorry if this sounds discouraging, It was really not my intention.I think motivation is the key of any achivement.

[AgeVivo]

Thank you! I was not aware of many things that you wrote and I'm glad to have someone knowledgeable on the subject to progress concretely (stopping the initiative for a good reason would be a kind of progress).

study this in a well control healthy long life mice population.that surprisingly has never been done despite being such a cheap and available drug

it is actually probably finished but not published yet, or under way, as explained here: http://www.imminst.o...6918-metformin/ , so we should hopefully know results within a few months. And meanwhile we can already focus of what would make sense on humans.

the main problem is that people that are 60 or 70 specially 70 dont always have the best kidney function,and even if they do, they can suddenlly develop renal failure without even showing unnormal creatinine levels beforehand, in the even that this happends metformin can be fatal as it can accumulate rapidly in the system and cause lactic acidosis, that is fatal in 50% of the cases.

Wow. The negative side of metformin appears more dramatic than I thought... But the positive side must be also very good, otherwise how to explain the various all-cause mortality improvements reported in my latest post above, including for people with moderate kidney issues? (http://www.pharmacyn...min/525921.aspx)

So metformin generally helps in many ways, and sometimes suddenly BOOM lactic acidosis?!... Would there be a way to continuously monitor for lactic acidosis, so that one would stop taking metformin in case of non-detected sudden renal failure? It seems that would be the ideal thing to do, to benefit of the positive side and reduce the negative side.

Edited by AgeVivo, 13 December 2010 - 09:09 PM.

[s123]

I think your idea is really encouraging and good intentionated ... I am personaly taking metformin, and I have treated many patients with it.

but I am concert about the age of the target group aiming , I think it is too risky.

Metformin even though I strongly believe by many evidence that it can prolong life.It has secundary side effects and contraidications.

This is an exaggeration of the risks.

The drug advice says "GLUCOPHAGE (metformin hydrochloride) Tablets and GLUCOPHAGE XR (metformin hydrochloride) Extended-Release Tablets treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced" (*). Thus the trial should use people younger than 80 and every participant would be screened for kidney function before the start of the trial.

Risks must always be balanced against benefits. For example, aspirine can cause anaphylaxis which can result in death. Should we now stop prescribing this drug to people with CVD and stop using it when we have a headache?

The dosage for LE purposes should be lower than what is used in diabetics patients. I would say 425mg/day. At this dosage it would take several days after kidney failure before the metformin accumulation would result in levels high enough to cause lactic acidosis. By this time the patient must have noticed the symptoms of kidney failure and thus have stopped taking metformin and consulted their physician.

Every participant would of course also be screened by a supervising physician before the start of the trial. He will exclude everyone who has contra-indications for metformin use.

The risk for lactic acidosis is quite small. Salpeter et al. found no cases after 36000 patient years of exposure.

Salpeter et al. Risk of fatal and non-fatal lactic acidosis with metformin in type 2 diabetes. Archives Int Med, 2003, 163: 2294-2602.

(*) http://www.rxlist.co...ophage-drug.htm

Edited by Michael, 17 June 2011 - 11:35 PM.
trim quotes

[s123]

I have a list of things that should be thought about for this trial.

What exclusion criteria will be used for the participants of this study? First, what drugs can they use? If we say none that it might be difficult to find enough people especially in the older age categories. On the other hand if we allow the use of drugs than these might influence lifespan (e.g. statins). If we decide to exclude only a list of drugs that might influence the outcome then which drugs would that be (given that we have no idea which drugs might influence lifespan)? Maybe we can allow the use of drugs but record who uses drugs and then calculate the variables that we test in the whole group and then in the group with the people who use drugs excluded and compare if excluding the people who used drugs has an influence on the outcome. We should also decide what to do with people who are prescribed drugs during the study. Should we exclude those from the analysis? Or include them but do the calculation with them and without them included? Secondly, which diseases should lead to exclusion? It is clear that someone with renal disease cannot participate in the study. I suggest that people who have diabetes should also be excluded. We might also decide to exclude everyone who has a high risk of developing diabetes because if a participant is diagnosed with diabetes we should (for ethical reasons) allow this person to be treated but treatment might include metformin and thus pose a problem. If he is in the control group then we could no longer consider him to be in the control group since he started to take metformin during the trial. On the other hand if he was in the metformin group then he might be prescribed a higher dosage as the one that we test and furthermore he could no longer be considered to be tested in a double-blind way since he knows that his physician prescribed him the drug that was being tested. If we decide that people with a high risk of developing diabetes should be excluded then we have to decide upon how to decide when someone has a too high risk (e.g. decide upon a cut-off level for fasting blood glucose, HbA1c,…).

We should also correlate the data for sex, smoking, body weight, race and maybe socioeconomic status.

We should also decide in which age range we will recruit the volunteers. Too young will make it impossible to observe changes in mortality due to the slowing down of aging (thus no 40-year olds) but elderly people (above 80) are contraindicated for metformin use due to a normal decline in kidney function in old age.

We should also decide upon a dosage to use. Too low might not result in any measurable effect but too high might lead to side-effects that would be unacceptable if the purpose is to investigate if it could be used as an LE drug (e.g. use from quite a young age for the rest of the remaining lifespan). We might also decide to start the therapy gradually do decrease side effects such as diarrhea. For example we might start in the first week with 100mg, increasing it to 200mg in the next week, 400mg in the third week and so on until the desired dose is reached. Should we give B12 supplementation to both the treatment and control groups or only to the treatment groups? How much B12 should be given? Because metformin might decrease B12 absorption we might decide to give it on separate times during the day but this might increase the frequency at which the participants accidentally forget to take one of the pills. We should also think on what to use as a placebo? The placebo should be indistinguishable from the metformin, thus we need a white, bitter tasting powder that has no effects on aging rate (and preferably also no effects on disease incidence).
What biomarkers should we test? Triglycerides, cholesterol, LDL, HDL, glucose, HbA1c, body weight during the study, homocysteine, B12, creatinine clearance, CRP,…? Should we test all of these in all participants or should we randomly select a subset that will be tested for these biomarkers. We should probably test things such as creatinine clearance in at least all participants because it investigates kidney function that is important in the risk of lactic acidosis. Because differences in B12 status have an influence on homocysteine levels and homocysteine increases the risk of several diseases such as CVD it might be that differences in mortality and/or disease incidence are caused by differences in B12 levels and not the metformin an sigh. Thus it might be informing to test homocysteine levels in at least a small sample of individuals in the treatment and the control group and investigate if the mean levels is different between these two groups.

We should also keep track of all diseases that participants develop during thus study so that we can see if for example the cancer incidence is different between the treatment and the control group. The following diseases are in my opinion interesting: cancer, CVD, T2DM, lactic acidosis, heart failure, hypertension, hypotension, neurodegenerative diseases, and strokes.

[james41]

hi maybe because english is not my mother tongue I was not able to be clear enough.

1/metformin is in general a very safe drug and I am certain it would be effective.The 50%fatality is in case the patient develops lactic acidosis, but the risk of lactic acidosis is really really low,(although in patients that are over 70 it is higher)

2/the problem here is that I do believe that in order to really have a benefict in an adult with a normal body weight the dose needs to be in a dose not less than 1200 mg.In my post I said it can be dangerous at the dose necesary to affect aging disease.Ar the dose of 400mg I think is much less dangerous but I dont think it is efective neither.

3/ It is not an exageration of risk (the problem is that this are not sick people), the risk are low indeed but the problem is that you are seeing aging as an illness,but the current law doesnt agree with your view(I have the same view as you) the problem is not that I believe that in the long run metformin won´t safe more lives than kill them, the problem is that as it is right now the law, even if only 3 patients die of lactic acidosis out of 1000000 in a study, this are HEALTHY SUBJECTS so in the view of the law (as it is established now)this doctors would had killed this patients prescribing them drugs that they dont (legaly)need,(aging by law nowday is not an illness) the legal implication for this doctors can be terrible.And the family of this 3 death will be full of hate and in disposition of sueing this doctors.You guys have to understand that as they are healthy subjects they are seen in legal terms as inmortals, so the fact that metformin prevents cancer in most of them or early death has no weight in legal implications, as this patients are healthy.The law will only see 3 were killed.(And that others lost quality of life)

4/I believe metformin is actually a "poison" ,i use the word poison to explain this in a simple way, metformin works as a caloric restrictor mimetic, but in a tricky way, it is a mitochondrial uncompeling drug ,(as parraquat or 2-deoxy-D-glucose(that also inhibits glucogenesis, it actually is a "poison" the way it works is by preventing the production of ATP so then the cell sense the thread and induce defense mechanism that in the long run because of hormesis increase longevity, but it has been tested in animals lacking AMPK, that if AMPK is not activated then the metformin longevity beneficts are not only not existant but decrimental, they die sooner, they perform physical tast worst......metformin lets not forget it is a very mild "poison".This is also the reason it inhibits Mtor, when an organism is threaten by the enviroment it focus in surviving and not in growing(this is also the reason metformin delay the progresion of puberty in humans).
So to give a "poison" to patients that are otherwise healthy is a very complex subjetc, in moral terms.


I also believe that in order to really affect the aging progress one has to take the same dose that is necesary for diabetic patients, I dont belive 400mg is enough for any real effect, the reason is because at this dose the mitochondrial uncoupleing is not enought to induce a subtantial celular defense hormetic mechanism .So I think if this human study is well design the dose should have to be 1000 to 2250 mg(depending of body weight and so on) not less.And at this dose and in patients that are 70.....and healthy....

s123(I think in your case well your body weight is very low to begin with and you are very young so the dose you are taking may be still ok,at least to help you keep this low body weight(you are technicaly doing caloric restriction)

Edited by james41, 14 December 2010 - 06:45 PM.

[mikeinnaples]

2/the problem here is that I do believe that in order to really have a benefict in an adult with a normal body weight the dose needs to be in a dose not less than 1200 mg.In my post I said it can be dangerous at the dose necesary to affect aging disease.Ar the dose of 400mg I think is much less dangerous but I dont think it is efective neither.

Can you post links to actual studies concerning this? i asked you before where you came with up with this conclusion with no answer.

4/I believe metformin is actually a "poison" ,i use the word poison to explain this in a simple way, metformin works as a caloric restrictor mimetic, but in a tricky way [...] the way it works is by preventing the production of ATP so then the cell sense the thread and induce defense mechanism that in the long run because of hormesis increase longevity, but it has been tested in animals lacking AMPK, that if AMPK is not activated then the metformin longevity beneficts are not only not existant but decrimental, they die sooner, they perform physical tast worst..... This is also the reason it inhibits Mtor, when an organism is threaten by the enviroment it focus in surviving and not in growing [...]

Again, can you provide a link to this study and test results?

Edited by Michael, 17 June 2011 - 11:42 PM.
clarifying dialog

[kenj]

I've taken met for a couple years, at 750-1250mg/day, divided in 250mg doses with meals, and also just before bed, althou' I originally started at 250-500mg/day to minimize gastrointestinal effects. I'm not diabetic, so I guess you could say I'm taking it for its possible 'CR-mimicking' effects.
When you semi-restrict your calories as well, IME met 'intensifies' the restriction. I don't feel hypoglycemic per se or even physically weak (I can exercise moderately fine on the drug), but in 1500+mg dosing it somewhat 'narrows' my (visionary) thinking, my creativity.. it's hard to explain because it's NOT hypoglycemia, but it's like I nevertheless have less 'mental stamina' for stuff other than food and sleep... so for me, the met adventure stops at ~1 gram, FWIW.

[s123]

3/the problem is not that I believe that in the long run metformin won´t safe more lives than kill them, the problem is that as it is right now the law, even if only 3 patients die of lactic acidosis out of 1.000.000 in this study, this are HEALTHY SUBJECTS so in the view of the law (as it is established now)this doctors would had killed this patients prescribing them drugs that they dont (legaly)need,(aging by law nowday is not an illness) the legal implication for this doctors can be terrible.And the family of this 3 death will be full of hate and in disposition of sueing this doctors.You guys have to understand that as they are healthy subjects they are seen in legal terms as inmortals, so the fact that metformin prevents cancer in most of them or early death has no weight in legal implications, as this patients are healthy.The law will only see 3 were killed.(And that others lost quality of life)

All participants would have to sign a paper in which they state that they were taking this drug voluntarily and that they fully aware of the fact that it could result in death. The paper would state that the physicians are free of any prosecution in case of unexpected side effects.

4/I believe metformin is actually a "poison" ,i use the word poison to explain this in a simple way, metformin works as a caloric restrictor mimetic, but in a tricky way, it is a mitochondrial uncompeling drug ,(as parraquat or 2-deoxy-D-glucose(that also inhibits glucogenesis, it actually is a "poison" the way it works is by preventing the production of ATP so then the cell sense the thread and induce defense mechanism that in the long run because of hormesis increase longevity, but it has been tested in animals lacking AMPK, that if AMPK is not activated then the metformin longevity beneficts are not only not existant but decrimental, they die sooner, they perform physical tast worst......metformin lets not forget it is a very mild "poison".This is also the reason it inhibits Mtor, when an organism is threaten by the enviroment it focus in surviving and not in growing(this is also the reason metformin delay the progresion of puberty in humans).
So to give a "poison" to patients that are otherwise healthy is a very complex subjetc, in moral terms.

No, several lines of evidence suggest that metformin activates AMPK by influencing LKB-1 and not by increasing AMP levels.

I also believe that in order to really affect the aging progress one has to take the same dose that is necesary for diabetic patients, I dont belive 400mg is enough for any real effect, the reason is because at this dose the mitochondrial uncoupleing is not enought to induce a subtantial celular defense hormetic mechanism .So I think if this human study is well design the dose should have to be 1000 to 2250 mg(depending of body weight and so on) not less.And at this dose and in patients that are 70.....and healthy....

As said above, metformin probably activates an upstream kinase (also in an indirect way that is not fully understood) and thus you do not need to take the dose that causes inhibition of complex I. In fact AMPK over-activation might be detrimental.

s123(I think in your case well your body weight is very low to begin with and you are very young so the dose you are taking may be still ok,at least to help you keep this low body weight(you are technicaly doing caloric restriction)

Yes, I try to do CR.

[james41]

I've taken met for a couple years, at 750-1250mg/day, divided in 250mg doses with meals, and also just before bed, althou' I originally started at 250-500mg/day to minimize gastrointestinal effects. I'm not diabetic, so I guess you could say I'm taking it for its possible 'CR-mimicking' effects.
When you semi-restrict your calories as well, IME met 'intensifies' the restriction. I don't feel hypoglycemic per se or even physically weak (I can exercise moderately fine on the drug), but in 1500+mg dosing it somewhat 'narrows' my (visionary) thinking, my creativity.. it's hard to explain because it's NOT hypoglycemia, but it's like I nevertheless have less 'mental stamina' for stuff other than food and sleep... so for me, the met adventure stops at ~1 gram, FWIW.

completely agree.metformin at more than 1500mg produce mental secundary effect, produce mental impairment,lower energy ,mental concentration for me is difficult to increase this dose I can only take my dose mostly at night so my body process it while sleeping because otherwise I would not be able to work.But I dont think this is related to hypoglucemia(in fact metformin in healthy subjetcts doesnt produce hypoglucemia) I think it is related to the hypotension and the ATP production impairment it produce.

I certaily think this secundary effect will be much worst in the eldery were the mental function , histamina and concetration is already decreased.

Edited by james41, 15 December 2010 - 06:37 AM.

[james41]

Although I understand the disbelieve position and it is a very scientific position, you usually ask me for links to all my statements,and although I can understand it, one have to understand that I can not back up all the information that I had gathered trough decades,when i write by personal believed,they are basicaly based in research ,studies clinical experiece.If I really try to back up all my believes it would take me to post hundreds of links and book remarks basicaly it would required you to go trough college and get medical training yourself,I dont think i can do that.

Still my answers in blue.

2/the problem here is that I do believe that in order to really have a benefict in an adult with a normal body weight the dose needs to be in a dose not less than 1200 mg.In my post I said it can be dangerous at the dose necesary to affect aging disease.Ar the dose of 400mg I think is much less dangerous but I dont think it is efective neither.

Can you post links to actual studies concerning this? i asked you before where you came with up with this conclusion with no answer.

Dont get me wroung I still believe 500mg in better than nothing is a little help mainly to de
crease overall caloric intake,but one can not really expect a "benefic"from it.
I can answer you based on my experiece and other doctors treating diabetic patients,precocious puberty and policistic ovary syndrome,doses lower than 850mg are not efective in downregulate any of the pathways though metformin increase longevity(decrease ifg1,increase igf1BP1, body fat decrease, estrogen aromatization,basal insulin,glicosilated hemoglobin,basal glucose, insulin tolerance, triglicerides,increase in shbg ,
neither of this mesurable parameter significaly change in doses lower than 850mg in adults.This are important biomarkers of the drugg effect,as we dont have cost permited available test for
general population to measure more complex markers like AMPK,Kinase LKB1,FOXO transcription factor,Mtor and so onof hormesis increase longevity, but it has been tested in animals lacking AMPK, that if AMPK is not activated then the metformin longevity beneficts are not only not existant but decrimental, they die sooner, they perform physical tast worst......
Metformin-Induced Extended Median Lifespan Requires AMPK
We next took genetic approaches toward identifying molecules that mediate metformin healthspan benefits in physiological context. In mammals, energy sensor AMPK is activated by metformin [20], [21], and metformin-activated AMPK increases glucose uptake in muscle and inhibits gluconeogenesis in hepatocytes [19]. C. elegans aak-2 encodes one of two homologs of the catalytic α subunit of the AMPK heterotrimeric complex, and nematode AAK-2 is activated by AMP, as occurs for mammalian AMPK [55]. Overexpression of the catalytic AMPK α subunit AAK-2 increases C. elegans longevity [55], and aak-2 is required for the increased lifespan of several longevity mutants [56] and for lifespan extension under at least one tested mode of DR induction [34]. To investigate the role of AMPK in metformin-induced extended median lifespan in C. elegans, we tested for metformin effects in the backgrounds of two independent aak-2 alleles: aak-2(ok524), a presumed molecular null [55], and aak-2(rr48), which carries a point mutation predicted to disrupt the catalytic activity of the α subunit [57]. As shown in Fig. 3A, no tested metformin concentration significantly increased the median lifespan of either aak-2 mutant (in three repeated trials for each strain; Table S1E). Instead, metformin treatment decreased mid-life viability in aak-2 mutants in a dose-dependent manner (Table S1E) and reduced locomotory ability in both aak-2 strains (Fig. S2A). We conclude that the catalytic AMPK subunit is required for median lifespan extension and locomotory healthspan increase in metformin-treated C. elegans. Moreover, we note that in the absence of healthspan-promoting AMPK activity, metformin confers deleterious consequences on culture survival and swimming prowess. Interestingly, although we did not note statistically significant differences in Nile Red staining (Fig. S2B), we did find lower age pigments in aak-2(ok524) mutants treated with 50 mM metformin vs. controls (Fig. S2C, other allele not tested). This observation suggests age pigment changes might be conferred via an AMPK-independent mechanism.
Again, can you provide a link to this study and test results? I did in blue above

Edited by james41, 15 December 2010 - 08:07 AM.

[james41]

my answers in blue

3/the problem is not that I believe that in the long run metformin won´t safe more lives than kill them, the problem is that as it is right now the law, even if only 3 patients die of lactic acidosis out of 1.000.000 in this study, this are HEALTHY SUBJECTS so in the view of the law (as it is established now)this doctors would had killed this patients prescribing them drugs that they dont (legaly)need,(aging by law nowday is not an illness) the legal implication for this doctors can be terrible.And the family of this 3 death will be full of hate and in disposition of sueing this doctors.You guys have to understand that as they are healthy subjects they are seen in legal terms as inmortals, so the fact that metformin prevents cancer in most of them or early death has no weight in legal implications, as this patients are healthy.The law will only see 3 were killed.(And that others lost quality of life)

All participants would have to sign a paper in which they state that they were taking this drug voluntarily and that they fully aware of the fact that it could result in death. The paper would state that the physicians are free of any prosecution in case of unexpected side effects.
I am sorry I don´t see this that easy trust me I wish it was, medicine could make gigantic steps without this laws but it is not that easy.I had seen many doctors get into big problems for matter less moraly complex than this.I see this from the doctor perspective maybe I am wroung.

4/I believe metformin is actually a "poison" ,i use the word poison to explain this in a simple way, metformin works as a caloric restrictor mimetic, but in a tricky way, it is a mitochondrial uncompeling drug ,(as parraquat or 2-deoxy-D-glucose(that also inhibits glucogenesis, it actually is a "poison" the way it works is by preventing the production of ATP so then the cell sense the thread and induce defense mechanism that in the long run because of hormesis increase longevity, but it has been tested in animals lacking AMPK, that if AMPK is not activated then the metformin longevity beneficts are not only not existant but decrimental, they die sooner, they perform physical tast worst......metformin lets not forget it is a very mild "poison".This is also the reason it inhibits Mtor, when an organism is threaten by the enviroment it focus in surviving and not in growing(this is also the reason metformin delay the progresion of puberty in humans).
So to give a "poison" to patients that are otherwise healthy is a very complex subjetc, in moral terms.

No, several lines of evidence suggest that metformin activates AMPK by influencing LKB-1 and not by increasing AMP levels. yes this is right but at the end of the day the result is the same without AMPK activation there is no increase in longevity.
Metformin-Induced Extended Median Lifespan Requires AMPK
We next took genetic approaches toward identifying molecules that mediate metformin healthspan benefits in physiological context. In mammals, energy sensor AMPK is activated by metformin [20], [21], and metformin-activated AMPK increases glucose uptake in muscle and inhibits gluconeogenesis in hepatocytes [19]. C. elegans aak-2 encodes one of two homologs of the catalytic α subunit of the AMPK heterotrimeric complex, and nematode AAK-2 is activated by AMP, as occurs for mammalian AMPK [55]. Overexpression of the catalytic AMPK α subunit AAK-2 increases C. elegans longevity [55], and aak-2 is required for the increased lifespan of several longevity mutants [56] and for lifespan extension under at least one tested mode of DR induction [34]. To investigate the role of AMPK in metformin-induced extended median lifespan in C. elegans, we tested for metformin effects in the backgrounds of two independent aak-2 alleles: aak-2(ok524), a presumed molecular null [55], and aak-2(rr48), which carries a point mutation predicted to disrupt the catalytic activity of the α subunit [57]. As shown in Fig. 3A, no tested metformin concentration significantly increased the median lifespan of either aak-2 mutant (in three repeated trials for each strain; Table S1E). Instead, metformin treatment decreased mid-life viability in aak-2 mutants in a dose-dependent manner (Table S1E) and reduced locomotory ability in both aak-2 strains (Fig. S2A). We conclude that the catalytic AMPK subunit is required for median lifespan extension and locomotory healthspan increase in metformin-treated C. elegans. Moreover, we note that in the absence of healthspan-promoting AMPK activity, metformin confers deleterious consequences on culture survival and swimming prowess. Interestingly, although we did not note statistically significant differences in Nile Red staining (Fig. S2B), we did find lower age pigments in aak-2(ok524) mutants treated with 50 mM metformin vs. controls (Fig. S2C, other allele not tested). This observation suggests age pigment changes might be conferred via an AMPK-independent mechanism.

I also believe that in order to really affect the aging progress one has to take the same dose that is necesary for diabetic patients, I dont belive 400mg is enough for any real effect, the reason is because at this dose the mitochondrial uncoupleing is not enought to induce a subtantial celular defense hormetic mechanism .So I think if this human study is well design the dose should have to be 1000 to 2250 mg(depending of body weight and so on) not less.And at this dose and in patients that are 70.....and healthy....

As said above, metformin probably activates an upstream kinase (also in an indirect way that is not fully understood) and thus you do not need to take the dose that causes inhibition of complex I. In fact AMPK over-activation might be detrimental.

this is the same answer I gave to Mike, I mainly believe metformin cause because it creates a caloric restriction metabolic shifft , and I believe caloric restriction works maily(not only) because it cause a pseudo growth hormone insensibility)
I still believe 500mg in better than nothing is a little help mainly to de
crease overall caloric intake,but one can not really expect a "benefic"from it.
I can answer you based on my experiece and other doctors treating diabetic patients,precocious puberty and policistic ovary syndrome,doses lower than 850mg are not efective in downregulate any of the pathways though metformin increase longevity(decrease ifg1,increase igf1BP1, body fat decrease, estrogen aromatization,basal insulin,glicosilated hemoglobin,basal glucose, insulin tolerance, triglicerides,increase in shbg ,
neither of this mesurable parameter significaly change in doses lower than 850mg in adults.This are important biomarkers of the drugg effect,as we dont have cost permited available test for
general population to measure more complex markers like AMPK,Kinase LKB1,FOXO transcription factor,Mtor and so on

s123(I think in your case well your body weight is very low to begin with and you are very young so the dose you are taking may be still ok,at least to help you keep this low body weight(you are technicaly doing caloric restriction)

Yes, I try to do CR.

Edited by james41, 15 December 2010 - 08:26 AM.

[s123]

yes this is right but at the end of the day the result is the same without AMPK activation there is no increase in longevity.
Metformin-Induced Extended Median Lifespan Requires AMPK

Yes, I completely agree! In the paper that I'm writing and that will be submitted for publication (hopefully today or tomorrow) I describe that metformin activates AMPK and that AMPK has several downstream targets that are responsible for the life extending effects of metformin.

[color="#0000FF"]this is the same answer I gave to Mike, I mainly believe metformin cause because it creates a caloric restriction metabolic shifft , and I believe caloric restriction works maily(not only) because it cause a pseudo growth hormone insensibility)
I still believe 500mg in better than nothing is a little help mainly to de
crease overall caloric intake,but one can not really expect a "benefic"from it.
I can answer you based on my experiece and other doctors treating diabetic patients,precocious puberty and policistic ovary syndrome,doses lower than 850mg are not efective in downregulate any of the pathways though metformin increase longevity(decrease ifg1,increase igf1BP1, body fat decrease, estrogen aromatization,basal insulin,glicosilated hemoglobin,basal glucose, insulin tolerance, triglicerides,increase in shbg ,
neither of this mesurable parameter significaly change in doses lower than 850mg in adults.This are important biomarkers of the drugg effect,as we dont have cost permited available test for
general population to measure more complex markers like AMPK,Kinase LKB1,FOXO transcription factor,Mtor and so on

As you say yourself, AMPK might (is probably) activated to some extend when you take 400mg of metformin and thus also the downstream targets are inhibited and thus a low dose could be enough to increase lifespan. In fact AMPK over-activation might have negative effects!

[AgeVivo]

Thank you everyone, trying to intra/extrapolate from the discussions it seems there is some convergence on an expected optimal dose between say 400 and 800 mg.

(- identified life-extending pathway: AMK activation
- 400 mg per day expected to start to extend lifespan
- doses above 1g may induce undesirable effects)

It is interesting to have such an hypothesis in mind before the mouse lifespan results are published: we should soon be able to compare with actual mouse results. Btw we should also define NOW the method/indicator of the comparison, so that we won't "choose an indicator to be right" later. For example (and please do not hesitate to make a better proposition): the ratio of a life-extending dosage over some glycemic-normalizing dosage, both dosages under a given way of administration (the way of administration may not be comparable between mice and humans, but the hope is that the ratio should, much more).

[AgeVivo]

discussed with s123 elsewhere: Anisimov just published another badly done metformin mouse survival study: http://www.impactagi.../pdf/100245.pdf
- based on ill mice that naturally have renal failure (!!! to test lactic acidosis?)
- treated mice end-up having higher blood glucose (!!! perhaps the control and treated groups were exchanged by error?)
the context was good but in terms of practical experiment, difficult to do worse...

...let's wait for the better metformin mouse survival results to come: http://www.imminst.o...6918-metformin/

[s123]

- based on ill mice that naturally have renal failure (!!! to test lactic acidosis?)

The mice with the high risk for lactic acidosis are the FVB/N mice, this study was done in 129/Sv mice. Understandable error because Anisimov switches mice models every time he does a new study. It's good to test interventions in different genetic backgrounds but the strains chosen should be normal (not diseased) and an intervention should first be properly tested in one mice model before jumping to another one. Properly means in both genders (not always the case in Anisimov's studies), with different drug concentrations, in combination with different levels of CR (to investigate if the drug mimics CR or influences lifespan by an CR-independent mechanism,...

[james41]

- based on ill mice that naturally have renal failure (!!! to test lactic acidosis?)

The mice with the high risk for lactic acidosis are the FVB/N mice, this study was done in 129/Sv mice. Understandable error because Anisimov switches mice models every time he does a new study. It's good to test interventions in different genetic backgrounds but the strains chosen should be normal (not diseased) and an intervention should first be properly tested in one mice model before jumping to another one. Properly means in both genders (not always the case in Anisimov's studies), with different drug concentrations, in combination with different levels of CR (to investigate if the drug mimics CR or influences lifespan by an CR-independent mechanism,...

I agree and yes in fact this are not animals with high risk of renal failure.

I have a theory why metformin works much better on females than on males.It is just a theory based on my observation on males with a rare disease called aromatase deficiency.

Metformin act as an aromate inhibitor, therefor decreasing the conversion of testosterone to estrogens.
This is the reason, it delay the bone plates closure in puberty, it is also the reason,it cause male pattern baldness in many patients I treated, it decrease gynecomasty in males(male breast) and it is also the reason is the latest studies it seems as effective as tamoxifen in the prevention of breast cancer.
http://www.abstracts...BCS09L_1347(you can find many studies on the effect of metformin on aromatase).

Estrogens play an important role in mammals health in males too, they are specially important for cardiovascular health and ,blood presure, lipid healthy profile,and insulin sensibility , estrogens themself have antioxidat effects and growth hormone antagonism effects on the body(they decrease the biological effect of growth hormone creating a small pseudogrowth hormone resistance).individuals with aromatase deficiency have elevated LDL, triglycerides, and insulin levels, indicative of insulin resistance

This all together could be the reason the dramatic diference between some studies on males and females.

there are many studies proving the important role of estrogens in males.

The reason in females life span is actually longer on metformin group may be explained because females have enough ovarian estrogen production to overcome the aromatase inhibition and actually in females too much estrogen can be detrimental(obesity, breast,uterus cancer,blood clot), so the aromatase inhibition may be positive.

this is all a theory of course.

[AgeVivo]

The mice with the high risk for lactic acidosis are the FVB/N mice, this study was done in 129/Sv mice.

true, though 129/Sv mice are considered particularly sensitive to certain renal models (http://cat.inist.fr/...cpsidt=17589189) and it remains very strange that a drug that is supposed to lower glucose level ("GLUCOPHAGE") actually increase it !?! if that very basic is not met it suggests that something went strong with the experiment. So i'm not sure to what to conclude (animals treated or not, lived longer or not, aromase mechanism or not)... hopefully next mouse metformin lifespan results will be better

Edited by AgeVivo, 21 December 2010 - 08:58 PM.

[brunotto]

Yes, I completely agree! In the paper that I'm writing and that will be submitted for publication (hopefully today or tomorrow) I describe that metformin activates AMPK and that AMPK has several downstream targets that are responsible for the life extending effects of metformin.
In fact AMPK over-activation might have negative effects!

For instance ERK (p44/p42)... it look like metformin in some tissue activates it (adipose, mucular) and in other suppresses it... do I understand something wrong ?

These results suggest that metformin may attenuate the inflammatory responses, at least in part, by suppressing the production of both TNF and TF through the inhibition of the ERK1/2-Egr-1 pathway in human monocytes.
http://www.ncbi.nlm....pubmed/20371705

The findings demonstrate that in muscle AICAR and metformin activate aPKC via sequential activation of AMPK, ERK, and PDK1 and the AMPK/ERK/PDK1/aPKC pathway is required for metformin- and AICAR-stimulated increases in glucose transport.
http://www.ncbi.nlm....pubmed/19887597

A time-dependent activation of AMPK was observed in response to a number of stimuli, including globular adiponectin, 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), or metformin. All these compounds significantly inhibited platelet-derived growth factor (PDGF)-stimulated proliferation and migration of human HSCs and reduced the secretion of monocyte chemoattractant protein-1.
http://www.ncbi.nlm....pubmed/18098312

Metformin dose-dependently inhibited IL-1beta-induced release of the pro-inflammatory cytokines IL-6 and IL-8 in human vascular smooth muscle cells (SMCs), macrophages (Mphis), and endothelial cells (ECs).... metformin suppressed IL-1beta-induced activation of the pro-inflammatory phosphokinases Akt, p38, and Erk, but did not affect PI3 kinase (PI3K) activity.
http://www.ncbi.nlm....pubmed/16385087

Treatment of HASMCs (human aortic smooth muscle cell) with metformin decreased leptin-induced ROS production and activation of PKC, ERK1/2, and NF-kappaB. Metformin also inhibited the effect of leptin on HASMC proliferation and MMP-2 expression. Overall, these results demonstrate that leptin induced HASMC proliferation and MMP-2 expression through a PKC-dependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-kappaB pathways and that therapeutic metformin concentrations effectively inhibit these biological effects.

http://www.ncbi.nlm....pubmed/15983226

Metformin acutely stimulated p44/p42 mitogenactivated protein (MAP) kinase in a dose- (3·2-fold at 1 mmol/l, P<0·05) as well as time-dependent (3·8-fold at 5 min, P<0·05) manner. This stimulation was highly selective since phosphorylation of intermediates in thestress kinase, janus kinase (JAK)–signal transducer and activator of transcription (STAT), and phosphatidylinositol (PI) 3-kinase signalling pathways such as p38 MAP kinase, STAT3, and Akt was unaltered.

http://joe.endocrino.../full/183/2/299

[maxwatt]

Lactic acidosis should not be a problem for healthy people who take metformin. Based on the paper below, the correlation is confounded by the concomitant use of metformin by diabetics: the risk factor is diabetes, not metformin. The incidence of lactic acidosis in diabetics is the same whether or not they use metformin.

Clin Endocrinol (Oxf). 2010 Oct 11. doi: 10.1111/j.1365-2265.2010.03891.x. [Epub ahead of print]
Diabetes, metformin and lactic acidosis.
Scale T, Harvey JN; Wrexham Academic Unit.

Centre for Endocrinology and Diabetes
Wales College of Medicine
Cardiff University.
Abstract
Objective  Metformin has long been thought to cause lactic acidosis but evidence from various sources has led researchers to question a direct causative relationship. We assessed the relationship of metformin prescription and other factors to the incidence of lactic acidosis. Methods  All cases of lactic acidosis at a single hospital were identified from laboratory lactate measurements. We compared patients classified as Cohen & Woods class A & B, patients with and without diabetes, and those taking metformin or not. Results  Lactic acidosis was more common than in published analyses based on hospital coding of diagnoses. The incidence of lactic acidosiswas greater in diabetes than in the non-diabetic population but with no further increase in patients taking metformin. Lactate levels were no greater in patients on metformin than in type 2 diabetic patients not on metformin even if patients with acute cardiorespiratory disturbance (Cohen & Woods class A) were excluded. Acidosis was greater in diabetes (hydrogen ion 94.9+4.6 v 83.2+2.3 10(-9) mol/l, p=0.027) but factors besides lactate contributed. Acute cardiorespiratory illness, acute renal impairment and sepsis were the most common of the recognised precipitating factors. Age (p=0.01), acute renal failure (p=0.015) and sepsis (p=0.005) were associated with mortality. Conclusions  Diabetes rather than metformin therapy is the major risk factor for the development of lactic acidosis. Lactic acidosis occurs in association with acute illness particularly in diabetes. Current guidance for the prevention of lactic acidosis may overemphasise the role of metformin.

© 2010 Blackwell Publishing Ltd.
PMID: 21039727

[AgeVivo]

A study (http://www.ncbi.nlm....pubmed/21186350) found 2 new things concerning metformin:
- depending on your genetic SNIP rs11212617, metformin should more or less normalize your glycemic index
- a new mechanism: through the gene called ATM that is already known to reduce DNA damage and reduce risks of cancer.

[AgeVivo]

More positive news : http://articles.lati...cancer-20100902

A study in mice exposed to tobacco carcinogens shows that the drug can reduce the development of lung tumors by more than 70%, and results from a small clinical trial in Japan suggest it can reduce rates of colorectal tumors in humans. The National Cancer Institute is now organizing a clinical trial to test the drug in people who smoke, and other trials are testing it against breast and prostate cancer
(...)
"Among the various treatment options for type 2 diabetes, if all other things are equal, early evidence that metformin might have benefit on the oncology side may play a role in decision-making," said Dr. Michael Pollak, a medical oncologist at McGill University in Montreal who surveyed recent metformin research in an article in the journal Cancer Prevention Research.The drug is particularly promising, he added, because unlike use of finasteride for preventing prostate cancer or tamoxifen for breast cancer, metformin appears to act across a broad spectrum of cancers
(...)
"The epidemiologic evidence in diabetic humans is convincing and strong," said Dr. Phillip A. Dennis, a medical oncologist at the National Cancer Institute. "It is real, and the reduction in risk ranges from 30% to 70%," depending on the type of cancer, he said."

From that web page I'm not sure whether the clinical trials may be done in diabetics or not, perhaps we should contact those persons (now or when we have clear mouse lifespan results).

Edited by AgeVivo, 09 January 2011 - 09:47 PM.

[s123]

A study (http://www.ncbi.nlm....pubmed/21186350) found 2 new things concerning metformin:
- depending on your genetic SNIP rs11212617, metformin should more or less normalize your glycemic index
- a new mechanism: through the gene called ATM that is already known to reduce DNA damage and reduce risks of cancer.

It was already known that ATM is an upstream kinase of AMPK.

http://www.ncbi.nlm....pubmed/15485651
http://www.ncbi.nlm....pubmed/17786544

Why metformin might be bad in young males:

http://www.impactagi...ull/100264.html

I don't really follow Blagosklonny's explanation here... If done properly, deaths due to external factors should be really low in the lab. I agree that sick mice do not get treatment but certainly the number of sick young animals in the lab should be extremely small. Too small to obscure the potential life extension benefits. In my opinion it was either the mouse model or the experimental procedure that failed. Don't forget, metformin, a drug designed to lower blood glucose, increased blood glucose in this study! This makes me doubt the results.