Metformin: hype and reality

Metformin, a drug for anti-aging

The anti-diabetic drug metformin has been in the news a lot lately, because clinical trials for the purpose of anti-aging are under way. See for example, Diabetes drug metformin could increase human lifespan to 120 years.

Some of this news is not really new, since we’ve known for a number of years that metformin increases lifespan in worms and mice. (1)

But a clinical trial of metformin for human anti-aging is news, as this is the first time any drug has been tested for this purpose on humans. It may sound strange, but because the FDA doesn’t consider aging to be a disease, clinical anti-aging trials have not been permitted, until now.

What metformin does

Metformin is a cheap, off-patent, generic drug marketed under the trade name Glucophage and is used to treat diabetes. The plant known as French lilac is the original source of metformin, and was used to treat diabetes since at least the Middle Ages if not earlier.

Metformin decreases blood glucose by repressing glucose production in the liver. It increases insulin sensitivity and reduces hyperinsulinemia (high blood insulin).

Perhaps most importantly for its mechanism of action, it activates AMPK. See the following illustration, and note the presence of metformin at the top.

 

AMPK is a highly evolutionarily conserved cellular energy sensing mechanism. By evolutionarily conserved is meant that it is found in a wide range of organisms, from worms to humans, the forces of natural selection having preserved it for its great usefulness.

Activation of AMPK tells the organism that energy levels are low, and puts all cellular machinery into a state of energy conservation. Fat storage is blocked, muscle synthesis stops, and glucose is burned.

AMPK activation by metformin or any other means

  • increases autophagy
  • decreases fat storage
  • decreases inflammation
  • increases insulin sensitivity

Metformin results are not impressive

Metformin, by activating AMPK, functions as a fasting mimetic, since fasting is perhaps the most potent activator of this mechanism. Exercise also activates it, so it might be said that metformin also acts as an exercise mimetic. (2)

What else activates AMPK? Aspirin, resveratrol, tea and chocolate polyphenols, and coffee (3), all activate AMPK.

The question is how much and how long do these processes and substances activate AMPK, and whether metformin or something else is the best AMPK activator.

Does metformin add to the beneficial effects of a low-carbohydrate diet, fasting, and exercise on longevity?

Is it better than aspirin for lifespan extension? (At least one study, using a peculiar type of lab animal, found that aspirin works better for lifespan extension and with fewer side effects – “cost-free” –  than metformin. (4))

All of these questions make me skeptical of the potential of metformin.

In the mouse study, metformin caused an increase of just under 6% in mean lifespan. (5) Maximum lifespan was apparently not increased at all.

These results aren’t all that impressive.

Metformin is for fat, sick people

As is the case with normal lab reference ranges, metformin may help people who are fat and sick, which is almost everyone these days. Two thirds of the people in the U.S. are overweight or obese, most don’t exercise, and they eat processed junk out of boxes and bags. They take lots of prescription drugs.

These people aren’t capable of fighting aging and disease except with a pill.

If you exercise vigorously and regularly (especially strength training), incorporate an intermittent fasting regimen into your health practices, drink coffee, tea, and red wine, take supplements like aspirin and curcumin, and eat a relatively low-carbohydrate diet, is metformin going to increase your lifespan? That seems very doubtful.

If you’re fat, diabetic, and sedentary, and totally unwilling to make any changes in your lifestyle, will metformin help? Probably yes.

Metformin also has side effects, including “nausea, vomiting, stomach upset, diarrhea, weakness, or a metallic taste in the mouth”. (7) These are relatively common. No thank you, I say.

Most of the other processes and substances I outlined above, aspirin being a notable exception, have no side effects other than some occasional discomfort and testing of willpower. And personally, I live for those side effects.

Metformin: hype and reality – the bottom line

The bottom line (according to me) is that metformin is highly overrated.

Most people in this country, and increasingly the world, are fat, don’t exercise and are quite frankly lazy and unwilling to change. They want a pill, and the doctors and scientists want to give it to them. That pill is metformin.

Those of us who exercise, fast, watch our diets, maintain a normal body weight, and take select supplements don’t need metformin. It will do next to nothing for us and give us unwanted side effects like nausea. And while metformin is inexpensive, you do need to see a doctor at least once a year for a prescription, and this costs plenty. Furthermore, it’s entirely possible, indeed likely, that if you’re not diabetic, your doctor won’t give it to you.

Unless and until further strong evidence arrives, forget about metformin, and concentrate on the lifestyle factors that you can control.

P.S.: Check out the supplements page for all the supplements listed above.

 

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14 comments
u.betcha says December 10, 2015

Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2656178/

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Rob H says January 23, 2016

Good morning Dennis, my wife is a doctor and receives the ‘BMJ’ magazine (ie British Medical Journal) each week. There was a really interesting article on Metformin last week – unfortunately I can’t link to it online, but to quote from the article:

“The impressive results of Metformin (in treating type 2 diabetes) were obtained in a randomised subgroup of obese patients…and have never been reproduced. Meta-analyses of randomised controlled trials evaluating the effectiveness of Metformin in patients with type 2 diabetes found that Metformin DID NOT (my emphasis) significantly modify clinically relevant outcomes. The analysis of all types of trial shows no efficacy of Metformin at all…It is not possible to draw a definitive conclusion regarding the efficacy of Metformin on clinically important outcomes because of the lack of adequately designed randomised clinical trials”.

Hmm: it doesn’t seem to me that the case for Metformin is very strong – particularly as you mention in your article for non-obese individuals who have already been ‘Manganed-up’.

PS on a completely different note: I’m starting the 97% whey protein isolate and glycine shakes this morning: plan is to take one each morning to break my overnight fast on my 4 x non-fast/ non-workout days. Might add some creatine at some later point…

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    P. D. Mangan says January 23, 2016

    Timely comment, Rob, as I was just reading again about metformin, specifically an article by Anisimov and Bartke, 2 big names in aging science, on growth hormone, insulin signaling, and aging. I figure I want to get the best anti-GH case possible from the horses’ mouth. Anyway, they discuss metformin a lot and how it prevents cancer. (BTW, paper is this one: The key role of growth hormone — insulin — IGF-1 signaling in aging and cancer.) For instance, in mice, metformin caused a 70% drop in tobacco-induced lung cancer. So I’m very interested to hear about the BMJ article, and I think I’ll need to read it.

    I was all set by this article to have my mind changed about metformin, but maybe they’ll have to try harder.

    Also, nothing by Anisimov and Bartke has changed my mind that actions of GH, insulin, and metformin may all be tied in with iron.

    One last thing: your wife is a doctor and knows that you read my site? Or do you read it furtively? (j/k)

    P.S.: Must be this article? Metformin as firstline treatment for type 2 diabetes: are we sure?

    Reply
      Rob H says January 23, 2016

      Hi Dennis, thanks for sending the link for that article through, I’ll have to have a look at that one. I have to say the British Medical Association are not anywhere near as ‘cutting edge’ as your stuff, they tend to wait around until they have gathered a lot of evidence before making any comments, so I usually find their dietary opinion is very behind the times, however recently it does seem they have been catching up a bit. Yes, the article you mention at the end is the one. The thrust of this piece though is all around using Metformin solely as a treatment for type 2 diabetes (not for cancer or any other life extension effects). It appears that the recommendation to use Metformin is based solely on the “supposedly conclusive results of the UK Prospective Diabetes Study (UKPDS) published in 1998”. Their view is not that Metformin has major negative effects as such, just that there is little evidence of it benefiting type 2 patients.. The site given for the article is as follows, but it wouldn’t work for me: http://dx.doi.org/10.1136/bmj.h6748

      Oh and your last comment really made me smile! Yes, if I mention any of the stuff from your site to my wife she generally just gives me one of those looks… She is 100% dedicated to treating her patients, but like most doctors doesn’t really see the need for prevention. Her view is that she’d rather eat whatever she wants and take the consequences – although I have at least persuaded her to really cut down on sugar, and even ‘processed’ meat recently, so I have made a bit of progress..

      Reply
Allan Silliphant says January 23, 2016

I’m a 74 year old U.S. Veteran’s admin. medical patient. I’ve had diagnosed T2D for 18 years. Let me preface what I’ll say here, by a comment on a poor choice I made maybe 50 years ago, at about age 25. I was a relatively strong 6′ 1.7″ tall fellow who weighed perhaps 168 lbs. As a body type I saw myself as 60% ectomorphic, & 40% mesomophic . I wanted appear as a balanced blend between these two body types, so I resolved to gain 5 to 10 lbs. weight more than my healthy slim body actually should weigh with moderate workout, at home, only. Hand weights & little jogging, fast walking, and yes, sex with the girls I dated. It all seemed to work for the next ten or so years. When I took
stock of my physique as I approached 40, I realized that I had padded myself out
to something over 200 lbs. by just carrying a useless layer of under-skin fat. Fast
forward another decade, & I found myself diagnosed with atrial fibrillation, &
diabetes 2. That was 18 years ago. In that state of affairs, I sometimes got up to 245 lbs. but typically was around 215 to 220. Finally I got dangerous weakened
2 years ago with seriously blocked carotid arteries on both sides of my neck.
The VA/UCLA surgery team did world class carotid clearance on the right side.
That allowed eye/cat. & lasik surgery , that restored my former acute vision. I
wanted to do the left side arteries, but the VA doctor kept putting me off to due
the weight that increased the surgical risk. So finally, I took some action on my own part. And after studying a lot of options, on line, resolved to control the
diabtes 2, & the health issues stemming for the long term obesity. In late december of 2014 I had an A1c of 7.9%, and weighed about 217 Lbs. I was on metformin extended release version for a least 7 years, and started taking
resveratrol and 6 months ago a similar sirtunin called pterostilbene. This seemed
to be the “game changer”! Within 6 days my finger stick numbers went down 30,
then 40, than 50 points. My weight plummeted as well. I’m now down 35 lbs. My
present weight is 181, and my A1c% is well within normal range now. I have formed a little group of fellow vets with diabetes and are testing several nutritional substances that along with metformin are promising anti-aging,
pro health-span extending, food, medicine, & workout efforts. Collectively they
are working, very very well. Now, they VA doctors are willing to operate on the other side of my arterial blockage. We are testing Nr (Niagen) precursor to NAD+. As well as quercetin, which will hopeful, kill off some of our senescent
cells that contribute to aging & eventually, cancer, or dementia onset.

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Allan Silliphant says January 23, 2016

P.D. , I forgot in my lengthy comment just made, how much I admire the message and tone of what you’re saying on your excellent site. I thought the unintentional
results of my choice to fake part of my “buffness”, with some gratuitous body fat
turned out to be a near deadly choice as I got into an unhealthy state with the
ons4et of middle age. There is a lesson to be learned, even in this foolish choice…
If you were never meant to be a full fledged mesomorph, you will likely find it
easier, with sufficient work-out, healthy food, meds like metformin, & these new
nutritional substances that are influencing “gene expression”, to make the most
of what nature endowed you with, a good body to weather the gales of the
last decade, or two or three, of your remaining life, with a bit less effort than
a more impression mid-life body for the person who must now adjust downward
to rig his physical “craft” for long term survival in the gales to come.

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    P. D. Mangan says January 24, 2016

    Allan, thanks for that informative comment. Very interesting that adding resveratrol to your metformin made such a huge difference to your HbA1c.

    Reply
Drifter says January 24, 2016

This article and the podcast with Jay Campbell, caused me to go back and look at Metformin in more detail, and while I agree with the conclusion that it is unlikely to help people who already have a fat-centric metabolism, it seems from what I can tell that people who may have a degree of “damage” or other desire to try metformin, would be well advised to look in Berberine instead. As far as I can tell it seems to have all the benefits of metformin and more (e.g. improvement in gut biome) , without some of the downsides. My current approach is to use berberine in moderate amounts when my travel circumstances take me away from my ideal diet toward something a bit higher- carb beyond just post-exercise carbs. I haven’t noticed any subjective downsides yet.

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    P. D. Mangan says January 24, 2016

    Yes, I’ve seen that berberine is pretty effective, although most people that I’ve read seem to think it’s better than metformin because it’s “natural”, which is bollocks. Lots of things that will kill you are natural, and any chemical substance that has a physiological effect is a drug, whether natural or not. Nothing against either berberine or metformin, I just get tired of reading about something being natural.

    Anyway, berberine does indeed appear as or nearly as effective as metformin. One of berberine’s main advantages is that you don’t need a scrip for it.

    But I have been reviewing metformin again. The drop in cancer rates in lab animals with it is truly astonishing, in some cases up to 75% less. It’s reviewed in a paper I recently mentioned, The key role of growth hormone — insulin — IGF-1 signaling in aging and cancer. Whether we’re like lab mice in this regard is an open question – in humans, some of the metformin reviews have found only 10% less cancer. (see for example: http://cancerpreventionresearch.aacrjournals.org/content/early/2014/08/06/1940-6207.CAPR-13-0424.short) Also, they feed lab mice absolute crap in most cases, loaded with sugar, omega-6 oils, and iron among other things. So again, whether metformin is effective in humans who are already optimizing diet, exercise, and supplements is an open question to my mind.

    Reply
Allan Silliphant says January 24, 2016

P.D., thanks for the kind words, and again, thanks for the broad spectrum health
journalism I’m finding on your site. One of the things that has inspired me on this
quest to become what amounts to a “body re-builder”…I certainly wish I had wised
up on the extreme value of systematic physical training…at your tender ago. This 140 day transformation largely came about because of that factor. I’d rank this as the most “transformative” of all, ( about 50% ) of the whole input! My family, the
Silliphant’s. who immigrated from the west country (UK) back shortly after the
defeat of Napoleon, settled on Prince Edward Is. in eastern Canada. My dad”s
older brother, Stirling served as a WW1 fighter pilot for the Canadian part of
the Royal Flying Corps. Later in life he started one of first food supplement
businesses. He lived till the age of 97. His older sister worked as head nurse in
a Burbank CA small hospital until age 95, and lived on the celebrate her 100th
birthday. Their mother, my grandma “Tilly” was actually born before Abe Lincoln,
ran for office. She survived til almost 94, when I was 12. My oldest brother was
an a WW2 U.S. naval officer, California state fencing champ, and in later life was
an academy award winning screenwriter (In the Heat of the Night) and screen
writer for the movie version of Ray Bradbarry’s sci-fi novel “Flowers for Algernon”
called “Charley” in Stirling’s film. He wrote 41 feature films, 1000 hours of prime
time TV, and was Bruce Lee’s closest friend in America. “Algernon, was of course,
a very brilliant lab rat, who was destined to die like any other lab rat. My dad’s
cousin, Rear Ad. Dr. William Merril Silliphant was an internee in the P.I. of the Japanese invaders. He stayed in the navy as director of the Armed Forces Inst.
of Pathology, and retired to the Pathology Chair at Standford U. Medical school,
dying of cancer while conduction cancer research. I chose to be a film and TV
documentary producer, director, and developed the second generation of 3D
film cameras & projection technology for both 35 & 70 3D. Along the way I also
started an airline that is still flying after 48 years with a little fleet of Boeing jets,
mostly serving the US government’s needs. My main efforts now relate to my
status as a VA medical activist. The US has 26,000,000 veterans. 40% make use
of the VA medical system. I’m lobbying the Congressional Oversight Committee,
face to face where possible to link that huge medical service into the current
reality of these “Health-Span Extension” research activities. I see the great potential of the bravest of our sometimes poorly served Vet to take on another
somewhat risky challenge to put themselves into some degree of personal risk
by being the first humans to test the promising results from the lab rats. This
can greatly speed up the introduction of the first generation of real anti-aging
medications & therapies. They would be acting in the critical role of RECON,
before the systematic, double blind, randomized, large scale, costly, & slow
clinical trials begin. This can save hundreds of billions, put diabetes, & many
cancers, & dementia under some degree of control. Probably, a similar thing
might be helpful for British & Commonwealth Vets to consider, as well.
P.D. , thanks for letting me put this issue before your readers. My email address:
sharper3d@yahoo.com I’d be so delighted to hear from you, or a few of your readers.

Reply
    P. D. Mangan says January 24, 2016

    Alan, thank you. What a family and what a record of achievement! Your own achievements as well. As an aside, In the Heat of the Night is a great movie, your brother did well, to put it mildly.

    That’s great that you’re lobbying the VA system, truly a worthwhile effort, and I wish you all success. Glad you like the site. I’m currently trying to figure out ways to expand its reach and to refine my message. I’d like to have a program or book (or both, and maybe a video series) based on the 20 Principles of Rogue Health.

    Thanks for reading, please keep in touch.

    Reply
Allan Silliphant says January 24, 2016

Thanks again P.D… for the very kind words. As you probably see, I’m very much
an Anglophile, greatly appreciating the things our two related cultures continue
to do in this profoundly promising time in history, with the internet and all forms
of media going great guns , and now affordable to creative people who have something to say to the extended English speaking world out there, which now
takes in a lot of Continental European readers as well. One of the historical documentaries I’ve done in the last 20 years, was one on which I was co-director.
It was called Navajo Code Talkers, about the special unit in our Marine Corp in the Pacific. It was one of two that inspired the feature film “Wind Talkers”. I do have reasonably up to date video production cameras, sound, German microphones, lighting, dollies, & advanced post production gear. Contact me on
my E-mail to possibly exchange phone contacts, should you think we might be
able to work out a mutually useful connection…Best wishes. Allan in California

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The most potent life extension substance ever - Rogue Health and Fitness says March 21, 2016

[…] These compounds may be much more potent than the two most widely touted anti-aging drugs, rapamycin and metformin. […]

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Berberine for Lifespan and Fat Loss - Rogue Health and Fitness says May 25, 2016

[…] Metformin is a cheap, un-patented, prescription drug that is the first-line choice in diabetes. Its mechanisms are many, but lowering blood sugar appears to be due to lowering gluconeogenesis in the liver. That’s the process by which the liver makes glucose from fats and protein when no carbohydrate sources, whether from the diet or glycogen stores, are available. […]

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