26 replies to this topic

[EmbraceUnity]

Are there any?

Edited by EmbraceUnity, 29 June 2010 - 01:36 PM.

[KimberCT]

The only one I'm aware of... it lowers testosterone levels.

[tintinet]

B12 depletion, potentially.

[s123]

The only one I'm aware of... it lowers testosterone levels.

And how exactly is this a health risk?

Lactic acidosis is a rare but dangerous side effect that can happen when you have certain diseases that predispose you to it (e.g. decreased renal function). About 30% of treated patients have in inhibition of B12 absorption. Beta-cell apoptosis has been found in cell culture studies but there’s little or no indication of impaired beta-cell function in treated humans.

Other side effects include: diarrhea, flatulence, abdominal bloating, anorexia, nausea, abdominal discomfort, metallic taste in the mouth, erythema, pruritus, urticaria, abnormal liver function tests and hepatitis.

[KimberCT]

The only one I'm aware of... it lowers testosterone levels.

And how exactly is this a health risk?

Low Serum Testosterone and Mortality in Older Men


Results: During an average 11.8-yr follow-up, 538 deaths occurred. Men whose total testosterone levels were in the lowest quartile (<241 ng/dl) were 40% [hazards ratio (HR) 1.40; 95% confidence interval (CI) 1.14–1.71] more likely to die than those with higher levels, independent of age, adiposity, and lifestyle.

[s123]

The only one I'm aware of... it lowers testosterone levels.

And how exactly is this a health risk?

Low Serum Testosterone and Mortality in Older Men


Results: During an average 11.8-yr follow-up, 538 deaths occurred. Men whose total testosterone levels were in the lowest quartile (<241 ng/dl) were 40% [hazards ratio (HR) 1.40; 95% confidence interval (CI) 1.14–1.71] more likely to die than those with higher levels, independent of age, adiposity, and lifestyle.

But is the higher mortality due to low testosterone levels or do low testosterone levels indicate bad overall health?

[KimberCT]

Low Serum Testosterone and Mortality in Older Men

Results: During an average 11.8-yr follow-up, 538 deaths occurred. Men whose total testosterone levels were in the lowest quartile (<241 ng/dl) were 40% [hazards ratio (HR) 1.40; 95% confidence interval (CI) 1.14–1.71] more likely to die than those with higher levels, independent of age, adiposity, and lifestyle.

But is the higher mortality due to low testosterone levels or do low testosterone levels indicate bad overall health?

It could go either way, but without knowing which, it is definitely a health risk to take a drug known to lower testosterone levels.

Edited by Michael, 18 June 2011 - 05:21 PM.
trim quotes

[capsun]

Yes, search the forums. Metformin without insulin potentially creates beta amyloid plaque! Be careful!

[mikeinnaples]

Yes, search the forums. Metformin without insulin potentially creates beta amyloid plaque! Be careful!

300 mg/kg/day was used in that study I believe.

A 76kg male would have to take 22.8 grams of Metformin to meet dosage in the study. That is a far cry above the 1.5g or so that seems to be the normal clinical dose.

[mikeinnaples]

Yes, search the forums. Metformin without insulin potentially creates beta amyloid plaque! Be careful!

300 mg/kg/day was used in that study I believe.

A 76kg male would have to take 22.8 grams of Metformin to meet dosage in the study. That is a far cry above the 1.5g or so that seems to be the normal clinical dose.

"A direct measurement of the metformin concentration in these mice showed that it reaches 2 μM and 1 μM in the plasma and forebrain region, respectively (Table S1); Considering that the steady-state plasma level of metformin in patients is reported to be from 10 μM to as high as 40 μM (32) and we achieved the maximum effect of metformin on BACE1 levels and AMPK activation in primary cultured neurons at 1–10 μM, the potential side-effects of metformin on accelerating AD pathogenesis must be taken seriously."

This threw the whole study off for me. They are comparing brain levels of metformin in the mice to serum levels in humans. To me this is a rather large flaw in logic.

[capsun]

Actually, with metabolic scaling, the dose they used could potentially mimic a ~2g human dose.

Notice I did use the word potentially. But I really don't think that kind of evidence should be discarded.

[capsun]

This threw the whole study off for me. They are comparing brain levels of metformin in the mice to serum levels in humans. To me this is a rather large flaw in logic.

Yes, the study leaves large gaps that need to be filled. I'm not satisfied by it at all. But my goodness, nobody had mentioned this *potential* side effect in the thread. This thread would be incomplete without it.

[mikeinnaples]

Also:

"Our data suggest that the potentially deleterious effects of metformin to AD patients may be avoided by using it in combination with insulin; the combination may result in a beneficial effect in treating both type 2 DM and in mitigating AD progression. "

To me, it would stand to reason that a normal healthy individual with normal insulin levels may not even experience this problem. I believe the mice study was comparing base to 25% of base regarding insulin levels... with the base mitigating AD progression and the 25% of base assisting AD progression. So the way I see these results is that normal insulin levels + metformin are likely to decrease AD progression ...but if you have screwed up insulin secretion, arent taking insulin to compensate, and take metformin ...you can increase AD progression *MAYBE* (see next post for clarification).

Ahh yes here it is:

Edited by mikeinnaples, 29 June 2010 - 05:39 PM.

[mikeinnaples]

Looking at the figure ...you can see metformin alone is huge in increasing AD risk/progression, but Met + Insulin at even a LOW level drastically decreases it from control.

[s123]

Yes, search the forums. Metformin without insulin potentially creates beta amyloid plaque! Be careful!

Metformin has is not evenly distributed through the whole body. When given 50mg/kg body weight the highest metformin concentration in the brain of rats was only 17µM compared to 182µM in the liver. The in vitro study of Chen used found that 10mM increased Abeta in primary neurons while 5mM had almost no effect. Thus if we assume that the increase in brain concentration is a linear dose-dependent relationship than 15mg/kg would give a brain concentration of 5,1µM (the safe dose). Thus 15mg/kg should be safe, this would mean 1050mg for a person of 70kg, which is much higher than what I would advise for life extension purposes.

Insulin and IGF-1 speed up aging and thus I would completely advise against the idea of increasing insulin or IGF-1 to protect against the increase in Abeta by metformin.

[mikeinnaples]

Actually, with metabolic scaling, the dose they used could potentially mimic a ~2g human dose.

Notice I did use the word potentially. But I really don't think that kind of evidence should be discarded.

They said the human equivolent was 300mg / kg / day verbatim in the paper. To me this reads as them already doing the metabolic conversion, but who knows.

[mikeinnaples]

Insulin and IGF-1 speed up aging and thus I would completely advise against the idea of increasing insulin or IGF-1 to protect against the increase in Abeta by metformin.

I contend from looking at the study that metformin + normal insulin production by the body could be more likely to reduce AD risk than increase it given normal metformin dosing. (just from extrapolating from the results).

[krillin]

Thus 15mg/kg should be safe, this would mean 1050mg for a person of 70kg, which is much higher than what I would advise for life extension purposes.

Do we have any positive life extension studies on normal rodents by people who are good at animal husbandry? Michael's recent article doesn't list any.

http://www.sens.org/...science-caf/738

A common rejoinder to the good husbandry stipulation is that we might not know how to do proper human husbandry. Could it be that the secret sauce is as simple as not letting the animals eat themselves into obesity?

Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6127-33. Epub 2010 Mar 1.
"Control" laboratory rodents are metabolically morbid: why it matters.
Martin B, Ji S, Maudsley S, Mattson MP.
Metabolism Unit, Laboratory of Clinical Investigation, Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Abstract

Failure to recognize that many standard control rats and mice used in biomedical research are sedentary, obese, glucose intolerant, and on a trajectory to premature death may confound data interpretation and outcomes of human studies. Fundamental aspects of cellular physiology, vulnerability to oxidative stress, inflammation, and associated diseases are among the many biological processes affected by dietary energy intake and exercise. Although overfed sedentary rodents may be reasonable models for the study of obesity in humans, treatments shown to be efficacious in these animal models may prove ineffective or exhibit novel side effects in active, normal-weight subjects.

PMID: 20194732

A blog comment on the subject:

I mentioned this to my fiancee, who worked as a vet tech in a university mouse facility, and she mentioned that ad libitum feeding is simply cheap and easy. It takes an animal tech a lot less time to just top off the food on a semi-regular basis. Measuring out food every day for every cage takes a lot more time and manual labor, and would thus cost a lot more. Plus that introduces the risk that someone will forget to feed the mice one day; my fiancee mentioned that this happened once every few weeks for the calorie restricted mice.

[Michael]

All:

Thus 15mg/kg should be safe, this would mean 1050mg for a person of 70kg, which is much higher than what I would advise for life extension purposes.

Do we have any positive life extension studies on normal rodents by people who are good at animal husbandry? Michael's recent article doesn't list any.

http://www.sens.org/...science-caf/738

Presuming that you mean, " positive life extension studies of metformin in normal rodents by people who are good at animal husbandry", then AFAIK there are none. That was rather the point of that post .

FWIW, labs whose controls consistently reach a respectable benchmark (mean and max LS of ~900 and ≥1100 d, respectively), include Spindler, Weindruch, and Richard Miller; Arlen Richardson does pretty well too.

A common rejoinder to the good husbandry stipulation is that we might not know how to do proper human husbandry. Could it be that the secret sauce is as simple as not letting the animals eat themselves into obesity? [1]

That's a hell of a lot of it; even some otherwise very respectable researchers, like Christian Leeuwenburgh, generally fail on this front. The animals (especially CR animals (2)!) are also often malnourished, or they don't keep a good lid on pathogens (as in the aspartame cancer scare study, and the SkQ1 bunk (maximum LS 800 d, almost all the "life extension" from preventing death from prevalent infectious disease -- and the TREATED animals got a HIGHER incidence of mammary gland adenocarcinoma!).

References
1. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6127-33. Epub 2010 Mar 1.
"Control" laboratory rodents are metabolically morbid: why it matters.
Martin B, Ji S, Maudsley S, Mattson MP.
PMID: 20194732

2. Cerqueira FM, Kowaltowski AJ. Commonly adopted caloric restriction protocols often involve malnutrition. Ageing Res Rev. 2010 May 20. [Epub ahead of print] PubMed PMID: 20493280.

[AgeVivo]

bumping this thread as more and more elements suggest that metformin could be an evidence-based life extension drug. will write more on this later

[AgeVivo]

Side effects reported by people taking glucophage (name of drug containing metformin): http://www.askapatie...name=GLUCOPHAGE

[JKDC]

How necessary is it if people are taking resveratrol,cinnulin pf,carnosine etc? Unless it is a money issue of course since Metformin is dirt cheap. The less man-made chems in your body the better IMO.

[smithx]

The less man-made chems in your body the better IMO.

Actually it was "originally derived from the French lilac (Gallega officianalis), which has had a place in folk medicine for hundreds of years".

http://www.lef.org/m...or-About_01.htm

[tunt01]

This is an old thread, but I was looking at the Chen paper again and some papers on metformin.

 

I think one of the problems with this Chen paper is the method of administration.  The fact that metformin was administered on a near continuous basis through drinking water, rather than on a pulsatile manner is part of the problem with this study.  I don't doubt that continuous metformin elicits beta-amyloid, but I think a pulsatile administration concurrent with a meal (and insulin release) probably wouldn't see the same effects.  Any thoughts?

 

Also, if anyone knows how Chen gets the math from 2 mg/mL in mouse drinking water to 300 mg/kg per day (in C57/BL6 mice?), I'd love some help with the math there.  I guess that translates to a HED of ~1,700 mg per day in a 70 kg adult.  Seems like s123's prior comments in the thread make sense.  A lower ~500 mg per day dose of metformin is probably fine.

 

EDIT:

 

This Senesi paper suggests that C57/BL6 drink 7 mL per day.  Therefore, the Chen mice probably got about 14 mg of metformin throughout the day, meaning the mice must weigh about 21.4 g.  That is relatively in-line with this data.

 

 

That still suggests ~1,700 per day for a 70 kg is the level on a continuous dose basis is what produced amyloid beta.

 

 

 

 

Chen, Y., Zhou, K., Wang, R., Liu, Y., Kwak, Y., & Ma, T. et al. (2009). Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proceedings Of The National Academy Of Sciences, 106(10), 3907-3912. doi:10.1073/pnas.0807991106

 

Senesi, P., Montesano, A., Luzi, L., Codella, R., Benedini, S., & Terruzzi, I. (2016). Metformin Treatment Prevents Sedentariness Related Damages in Mice. Journal Of Diabetes Research, 2016, 1-11. doi:10.1155/2016/8274689

 

Edited by prophets, 30 June 2017 - 05:37 PM.

[Michael]

I think one of the problems with this Chen paper  is the method of administration.  The fact that metformin was administered on a near continuous basis through drinking water, rather than on a pulsatile manner is part of the problem with this study.  I don't doubt that continuous metformin elicits beta-amyloid, but I think a pulsatile administration concurrent with a meal (and insulin release) probably wouldn't see the same effects.  Any thoughts?

 
Metformin is normally dosed several times a day and/or in extended-release forms, so this seems reasonable. One might expect the drug to work better the more evenly it were spread out.
 

Also, if anyone knows how Chen gets the math from 2 mg/mL in mouse drinking water to 300 mg/kg per day (in C57/BL6 mice?), I'd love some help with the math there.  I guess that translates to a HED of ~1,700 mg per day in a 70 kg adult.  Seems like s123's prior comments in the thread make sense.  A lower ~500 mg per day dose of metformin is probably fine.

Ideally, they would have weighed their mice and measured their water consumption, but if that's what they did they don't seem to have documented it. However, a young C57Bl/6J mouse is typically 25 g, and per several websites mice can be expected to consume 4-5 mL water/day, so that's 320-400 mg/kg/d. The supplemental info on this study indicates that 2 mg/mL fluoxetine in the drinking water yielded ~300 mg/kg/day. This PowerPoint of studies on antibiotics gives doses like Enrofloxacin or Amoxicillin 50 mg/kg/day = 0.25 mg/mL and Doxycycline 10 mg/kg/day = 0.05 mg/mL, any of which would mean 2 mg/mL = 400 mg/kg/day.This study of relatively small numbers of mice aged 65-74 days reports 25 g mice consumed 6.2 mL/d.

[tunt01]

 

Metformin is normally dosed several times a day and/or in extended-release forms, so this seems reasonable. One might expect the drug to work better the more evenly it were spread out.
 

Also, if anyone knows how Chen gets the math from 2 mg/mL in mouse drinking water to 300 mg/kg per day (in C57/BL6 mice?), I'd love some help with the math there.  I guess that translates to a HED of ~1,700 mg per day in a 70 kg adult.  Seems like s123's prior comments in the thread make sense.  A lower ~500 mg per day dose of metformin is probably fine.

Ideally, they would have weighed their mice and measured their water consumption, but if that's what they did they don't seem to have documented it. However, a young C57Bl/6J mouse is typically 25 g, and per several websites mice can be expected to consume 4-5 mL water/day, so that's 320-400 mg/kg/d. The supplemental info on this study indicates that 2 mg/mL fluoxetine in the drinking water yielded ~300 mg/kg/day. This PowerPoint of studies on antibiotics gives doses like Enrofloxacin or Amoxicillin 50 mg/kg/day = 0.25 mg/mL and Doxycycline 10 mg/kg/day = 0.05 mg/mL, any of which would mean 2 mg/mL = 400 mg/kg/day.This study of relatively small numbers of mice aged 65-74 days reports 25 g mice consumed 6.2 mL/d.

 

 

Thx Michael.  Insightful, as always.  

 

It just seems to me like the issue with AMPK activators is the dose/duration makes the poison.  A pulsatile release or very low dose, extended/continuous dose seems to be the only plausible route with Metformin.  In agreement with others in the thread, the ~1700 mg dose seems high to me, compared to what a preventive, life extension dose might be.

 

Thx again.

[Michael]

In agreement with others in the thread, the ~1700 mg dose seems high to me, compared to what a preventive, life extension dose might be.
 
Thx again.

Metformin does not extend lifespan in normal, otherwise-healthy (but aging) mammals.