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Metformin, a Review

Metformin is a drug that shows up in discussion here every so often. It is thought to be a calorie restriction mimetic, recapitulating some of the metabolic changes caused by the practice of calorie restriction. Its effects on life span in laboratory animals are up for debate and further accumulation of evidence - the results are on balance more promising than the generally dismal situation for resveratrol, but far less evidently beneficial than rapamycin. Like rapamycin, metformin isn't something you'd want to take as though it were candy, even if the regulators stood back to make that possible, as the side effects are not pleasant and potentially serious.

I should note as an aside that while ongoing research into the effects of old-school drugs of this nature is certainly interesting, it doesn't really present a path to significantly enhanced health and longevity. It is a pity that such research continues to receive the lion's share of funding, given that the best case outcome is an increase in our knowledge of human metabolism, not meaningful longevity therapies. Even if the completely beneficial mechanism of action is split out from the drug's actions - as seems to be underway for rapamycin - the end results will still only be a very modest slowing of aging. You could do better by exercising, or practicing calorie restriction.

For the billions in funding poured into these drug investigation programs, there should be a better grail at the end of the road - such as that offered by the SENS vision of rejuvenation biotechnology. Targeted repair of the biological damage of aging is a far, far better strategy than gently slowing the pace of damage accumulation through old-style drug discovery programs. This is a biotechnology revolution: time to start acting like it.

Anyway, aside done, let me point you to a recent open access review on metformin: the interesting work that won't really be in any way relevant to the future of your longevity, but which I'll wager has raised more funding as an object of study than the entire present extant SENS program and directly related scientific studies:

Metformin, an oral anti-diabetic drug, is being considered increasingly for treatment and prevention of cancer, obesity as well as for the extension of healthy lifespan. Gradually accumulating discrepancies about its effect on cancer and obesity can be explained by the shortage of randomized clinical trials, differences between control groups (reference points), gender- and age-associated effects and pharmacogenetic factors. Studies of the potential antiaging effects of antidiabetic biguanides, such as metformin, are still experimental for obvious reasons and their results are currently ambiguous.

...

The wave of interest, with periodical decays and increasing surges, was associated with the attempts to use antidiabetic biguanides [such as metformin] to control body weight and tumor growth. Another facet of the situation is that almost 45 years ago these drugs were suggested to promote longevity. Over the last years, the expanding bodies of relevant evidence, which mainly related to metformin, started to merge and occupy increasing place in current literature. The objective of the present essay is to attract more attention to accumulating inconsistencies. The first two sections of the essay, which are related to obesity and cancer, are based mostly on clinical data. The third section, which is related to aging or, rather, antiaging, is based predominately on experimental evidence obtained in rodents. Clearly, obesity and cancer have numerous interrelationships with aging, [however], we will separate these aspects for the sake of clarity in discussing the relevant effects of metformin.

See what you think; it makes for an interesting read - and includes a table of results from a number of life span studies that are, indeed, all over the map. It somewhat reinforces the point that unambiguous success in extending healthy life is not going to arrive from this quarter. Think SENS, not drug discovery - what will come from the drug discovery clade is a slow, grinding, and expensive cataloging of the fine details of genetics, metabolism, and aging in mammals.

Comments

1. Thanks for this great post. I agree that SENS deserves more money than old fashioned pills.
2. Reason, do you take rapamycin or recommend taking it? If so, where do you recommend purchase?
3. Are you on facebook? Please feel free to add me as a friend, if you like (if not, no worries!).

Posted by: Kip Werking at May 11th, 2012 6:28 PM

A little about myself, I walk every week day and exercise (sit up, push up) every night. I am in ok shape (155 lbs, 5 ft 10 in). I am normal and don't have diabetes.

I eat pretty healthy but I like ice cream and cookies too :)

I have been taking Metformin for about 2 weeks now. 500 mg per day (build up 1/4 4 days, now 250mg at lunch, 250mg at dinner). My first try (125mg) caused me to lose my appetite, diarrhea. But now I think I tolerate it well. I don't get sick and I don't lose my appetite. (Maybe that means it is losing effectiveness?)

I continue to exercise and it has lowered my weight some (maybe 5 pounds?) but it seems to be levelling off. I think it reduces both fat and muscle. Metformin blocks sugar so your body is going to get it from your body one way or another. My exercises are mostly about pushing my own weight around so I don't have an objective measure. I can tell I need less effort to do push ups since my body weight is lower. My skin improved some. Glucose is not the friend of your skin so reducing glucose helps. Might also be the weight loss.

Take B12 as well. I usually take 1000mcg B12 in the morning (when metformin concentration is lowest for me) then take the metformin at lunch and then at dinner. Metformin blocks B12. Lack of B12 can harm your neurons (neuropathy).

I read that Metformin also lowers testosterone which I am beginning to feel. Metformin has also been linked to reducing amyloid beta levels in people with normal insulin. I don't feel any different (headaches or such) but it does worry me a little. Reducing amyloid beta too low can interfere with memory and learning. Metformin alone in diabetics actually increases amyloid beta which can contribute to alzheimers.

I noticed pin prick kind of sensation every now and then in my feet. I have heard that diabetics can get this with lowered B12 and get numbness in their feet. That is why I take lots of B12. It might be fat loss in my feet? Somehow I doubt it.

Anyway, I think Metformin can help reduce glucose levels in your body which can be helpful. Maybe like orlistat with a greasy meal, it will block the grease (and cause you to poop it out). Metformin can block the sugar and you pee it out.

I noticed I also smell worse when exercising (excreting metformin?). I noticed my shoulder ached pretty bad doing my normal routine initially which I believe was attributable to lactic acid buildup. With lactic acid from strained muscles, your body will generate sugars to help. With Metformin, you don't have as much sugar around so your kidneys have to filter the lactic acid. I would not do muscle tearing exercise (sore muscle inducing) while taking metformin. I have felt some slight discomfort in my kidney one time.

So, I believe metformin might be good for 2-3 weeks for a normal person as a sugar "purge" and then lay off it for a while. Personally, I would not take it for years and years as a healthy person. If you really want to take it I would say 250 mg per day with meal (like maybe 1 hour before a dessert). A diabetic person is about 3x less sensitive to glucose than a normal person so I would take their lowest effective dose (1000mg) and divide by 3.

Posted by: Tesseract at May 12th, 2012 12:51 AM

Thanks for that on Metformin.

The quote box refers to a longer article (as does your following comment). But I cannot see any link to this. I would appreciate that link please.

Posted by: Ian at May 14th, 2012 8:37 AM

(Repeating: posted separately on a followup post, but equally or more relevant here).

The data on metformin's (in)ability to slow aging and extend life in mammals is not really mixed at all. There are a whole bunch of studies in diabetic and/or obese and/or cancer-prone and/or toxin-administered and/or otherwise buggered-with mice. None of these are informative on this question. Then there is a reasonably good negative result in rats, and two excellent negative results from the NIA's Interventions Testing Protocol and the intrepid Dr. Stephen Spindler, reporting jointly that metformin has a very slight effect on mean life expectancy, but none on maximum lifespan.

In sum: consistently, metformin does not retard aging in otherwise-normal, healthy mammals.

Smith, DL Jr, Elam CF Jr, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB. Metformin supplementation and life span in Fischer-344 rats. 2010 May; J Gerontol A Biol Sci Med Sci 65 (5): 468–74. doi:10.1093/gerona/glq033. PMID 20304770

Martin-Montalvo, A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. 2013 Jul;Nature Communications 4: 2192. doi:10.1038/ncomms3192. PMID 2390024.

Posted by: Michael at June 8th, 2014 6:45 PM

"You could do better by exercising, or practicing calorie restriction."

Yes, of course. But exercising and (especially) calorie restriction are rigorous disciplines, requiring great power of will. Taking a few metformin tablets requires almost no power of will. It is easy.

"the side effects are not pleasant and potentially serious."

What side effects do you have in mind? Diarrhea? That goes away in a few days. B12 deficit? Just take extra B12. Lower free testosterone? Take stuff that increases free testosterone, like mesterolone or avena extracts. Higher homocysteine? Take some homocysteine detoxifiers. Etcetera. Metformin has no side effects that cannot easily be averted or that do not go away spontaneously.

The potential of metformin as a longevity drug may be modest or even non-existent, but so what? That's not, primarily, what it is for*, based on information presently available. It has plenty of benefits and will extend the healthspan of most users. The negativity about metformin in these parts is strange and out of touch with practical reality for people for whom healthspan is more important than lifespan. Metformin is obviously a great drug for almost anyone who wants to max-out health and functionality for as long as they are alive.

.................

* "Not, primarily, what it is for" -- for the average person. But for some individuals, metformin might prevent cancer or some other killer disease, and thus greatly extend life. That's a nice extra potential bonus.

Posted by: alan2102 at August 5th, 2015 4:53 PM

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