Metformin: an anti-diabetic drug that is also anti-aging?

To the growing list of small-molecule drugs that have a measurable effect on lifespan or healthspan (e.g., resveratrol and rapamycin) we should add metformin, an anti-diabetic drug that has shown promise as a calorie restriction mimetic. Onken & Driscoll determined some of the genetic requirements for metformin’s anti-aging properties in the worm C. elegans:

Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1

Metformin, a biguanide drug commonly used to treat type-2 diabetes, has been noted to extend healthspan of nondiabetic mice, but this outcome, and the molecular mechanisms that underlie it, have received relatively little experimental attention. To develop a genetic model for study of biguanide effects on healthspan, we investigated metformin impact on aging Caenorhabditis elegans. We found that metformin increases nematode healthspan, slowing lipofuscin accumulation, extending median lifespan, and prolonging youthful locomotory ability in a dose-dependent manner. Genetic data suggest that metformin acts through a mechanism similar to that operative in eating-impaired dietary restriction (DR) mutants, but independent of the insulin signaling pathway. Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla. We also show that the conserved oxidative stress-responsive transcription factor SKN-1/Nrf2 is essential for metformin healthspan benefits in C. elegans, a mechanistic requirement not previously described in mammals. skn-1, which functions in nematode sensory neurons to promote DR longevity benefits and in intestines for oxidative stress resistance lifespan benefits, must be expressed in both neurons and intestines for metformin-promoted healthspan extension, supporting that metformin improves healthy middle-life aging by activating both DR and antioxidant defense longevity pathways. In addition to defining molecular players operative in metformin healthspan benefits, our data suggest that metformin may be a plausible pharmacological intervention to promote healthy human aging.

Some of those genes might sound familiar…

SKN-1 encodes a transcription factor required for longevity enhancement by calorie restriction (CR) (but not intermittent fasting) in worms and flies. The observation that metformin requires SKN-1 in order to extend median lifespan strongly suggests that the drug is acting via the same metabolic pathway as CR.

AMP kinase, a target of resveratrol and exercise mimetics, has also been implicated in the genetics of CR lifespan extension.

A quick aside about model systems: As it says in the first sentence of the abstract, metformin has already been studied in mice — so, why go “backward” to a simpler, smaller, and more divergent model system? Why not move forward, into humans? The answer has to do with the comparative ease with which certain types of genetic experiments can be performed in different systems; it’s simply easier in worms. Now that the genetics have been worked out, it will be more straightforward to do meaningful experiments in mammalian systems that are closer to our beloved H. sapiens.

ResearchBlogging.org

Onken, B., & Driscoll, M. (2010). Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1 PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008758

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18 comments

  1. Goodness, these drugs are just popping up everywhere and it is getting a bit tempting to try some. Especially resveratrol, which I think used to be expensive but now retails at WalGreens for $4.99 per 60 pill bottle.

    Are you willing to share if you take anything yourself Chris? I remember you wrote a review about resveratrol somewhere in the archives that had like 30+ comments, but I cannot find it again for the life of me…

  2. I think it will probably take a while before this new finding with metformin is confirmed as there are many confounding variables with ageing.

    What is surprising is why there is a delay in moving the research to mammals and humans subsequently. Why it is surprising to me is that, metformin is a drug that is already in use and indeed has been in use for decades.

    We know metformin being a biguanide increases insulin sensitivity peripherally thereby promoting glucose use by tissues.

    This very fact should actually qualify metformin as an anti-ageing agent as it helps to reduce diabetic complications in the long term.

  3. By doing simple things such as reading food labels before dec iding what to eat to lose weight can make a huge difference in the amount of calories a person eats in a day. Many foods have hidden calories in them that you may not even realize you are consuming them if you do not read the labels.

  4. A quick and cursory web search also indicates that metformin interferes with mTOR and NF-kappaB signalling, both implicated in aging.

  5. Metformin should we taken for what it is. It’s a b adrenergic blocker reducing Sympathetic Nervous System stimulation and abrogating BAT (Brown Adipose Tissue) Thermogenesis, thus lowering neuron inflammatory impact. CR does the same. That’s why there are similarities in their protruded effect- aging.

  6. Ilya, you might want to check the current pharmacology of beta blockers — well established epinephrine and lipolysis inhibitors, with weight gain and insulin resistance common side effects –just the opposite of Metformin!

  7. i take 500 mg of metformin daily in the hope that it helps. It is very cheap as a generic. about 4 bucks for 90 days under my insurance. no side effects and no discernable effect

  8. Ilya B Says:

    October 18, 2010 at 5:00 pm
    @Dakine Being more specific won’t hurt. No such effects as far as I googled it up. Pls. elaborate.

    Ilya,

    You are the one who made claims inconsistent with beta-blocker and metformin pharmacolgy profiles. Google “pharmacology of beta-blockers” or online “Physician’s Desk Reference” (PDR), or “rxlist.com”, etc., etc., etc.

    I look forward to your acknowledgement of lesson learned–to check YOUR facts before spewing ignorant bluster, let alone expecting others to do that work for you.
    –Dakine

  9. @Dakine Just google “metformin side effects” , check also Wikipedia and kindly STFU. No more comments. “Don’t argue with imbeciles”- Lesson learned.

  10. @Dakine Oooops, I deeply apologize as you referred to my wrong classification of Metformin as a beta blocker, not biguanide and ascribing Metformin properties of a beta blocker. I’m sorry about that it was long time ago and erred there.

  11. I currently have a friend taking metformin, and this is information she did not know. She is diabetic has been taking this for quite some time, but I guess it is to early for me to notice these results.

    There is always a new coming into the market and I don’t know if that is a good thing or a bad thing. Has anybody heard or experience any negative results from taking metformin???

  12. I have started Metformin as an anti aging agent. The results are not good. My fasting glucose previousily in the mid 80s and now are high 90s. I also feel at times like I have vertigo, but usually just a dizzy feeling. Is this response common at first? My doctor is cooperating with me in this “experiment” and we don’t have an answer yet why the strange affect.

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