Activating AMPK for lifespan extension

Caenorhabditis elegans

AMPK senses the energy status of cells

AMPK is a highly evolutionarily conserved energy sensor. By evolutionarily conserved is meant that essentially all living organisms, including of course humans, have it. Increased AMPK activation is associated with longer lifespan and better health; AMPK causes a signaling cascade that promotes fat oxidation, increases cellular stress defenses and autophagy, and decreases inflammation.

Some scientists go so far as to say that AMPK controls aging: AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.

Efficient control of energy metabolic homeostasis, enhanced stress resistance, and qualified cellular housekeeping are the hallmarks of improved healthspan and extended lifespan. AMPK signaling is involved in the regulation of all these characteristics via an integrated signaling network. Many studies with lower organisms have revealed that increased AMPK activity can extend the lifespan. Experiments in mammals have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling which augment the quality of cellular housekeeping. Moreover, AMPK-induced stimulation of FoxO/DAF-16, Nrf2/SKN-1, and SIRT1 signaling pathways improves cellular stress resistance. Furthermore, inhibition of NF-κB signaling by AMPK suppresses inflammatory responses. Emerging studies indicate that the responsiveness of AMPK signaling clearly declines with aging. The loss of sensitivity of AMPK activation to cellular stress impairs metabolic regulation, increases oxidative stress and reduces autophagic clearance. These age-related changes activate innate immunity defence, triggering a low-grade inflammation and metabolic disorders. We will review in detail the signaling pathways of this integrated network through which AMPK controls energy metabolism, autophagic degradation and stress resistance and ultimately the aging process.

The image below shows what can activate AMPK and in turn the effects of activation and inactivation of AMPK.

Activation of AMPK is crucial for health and long life. The question is, how do you activate it? Following are a number of ways.

Activating AMPK for lifespan extension – how to do it

  1. Curcumin: In a head-to-head comparison with metformin, the most widely prescribed anti-diabetes drug and an AMPK activator, “curcuminoids increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase (ACC) in H4IIE and Hep3B cells with 400 times (curcumin) to 100,000 times (THC) the potency of metformin.”

2. Aspirin: Aspirin is a known life-extender, and it is no coincidence that it activates AMPK. “At concentrations corresponding to plasma concentrations in humans treated with high doses of aspirin or salsalate, salicylate activated wild-type AMPK… There have been numerous observational studies suggesting that metabolic parameters improved in diabetic patients who were taking salicylate-based drugs.”

3. Fasting and exercise: “…AMPK acts as the primordial trigger for fasting- and exercise-induced adaptations in skeletal muscle and that activation of SIRT1 and its downstream signaling pathways are improperly triggered in AMPK-deficient states.”

4. Resveratrol: “Resveratrol induces mitochondrial biogenesis and protects against metabolic decline… Mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased NAD+ levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits.”

5. Tea and chocolate polyphenols: “… we found that mice administered Mitochondria Activation Factor (MAF) combined with exercise training could run longer distances and for a longer time compared with the exercise only group; MAF is a high-molecular-weight polyphenol purified from black tea. Furthermore, MAF intake combined with exercise training increased phosphorylation of AMPK and mRNA level of glucose transporter 4 (GLUT4).”

The common mechanism that ties together a number of processes (fasting and exercise) and chemical compounds (the rest) is the activation of the energy sensor AMPK.

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  1. Simon says:

    Great summary.

    Presumably, it wouldn’t be too difficult or expensive to incorporate all of these into a daily regimen of fasting/exercise/supplementation.

    Do you personally supplement with resveratrol/curcumin?

    • P. D. Mangan says:

      Simon, yes I do. I take resveratrol daily, curcumin 3x week. The curcumin is sort of an “extra”, since many of those processes/compounds activate the same things, such as we see above, AMPK. So I’d say there’s overlap, and trying to say definitively what the best combination is, or which supplements best, will involve lots of speculation. Curcumin has somewhat better bioavailability than resveratrol. I also, of course, fast, exercise, take baby aspirin (though not daily) and eat chocolate and drink tea!

      • Baron says:

        What are your recommendations for taking aspirin?

        • P. D. Mangan says:

          Currently, the medical establishment only recommends aspirin for those with >1.5% (I think it is) risk of heart attack annually (, since it comes with side effects, mainly bleeding. There’s been lots of discussion about changing that recommendation, because the fact that aspirin appears now to have a substantial benefit for cancer risk means that the risk/benefit ratio has changed in its favor. Also, I’ve read that risk of bleeding is actually quite low. But that is the current state of thinking.

  2. Joshua says:

    Any thoughts on ibuprofen vs aspirin? My understanding is that ibuprofen has a lesser risk of causing stomach bleeding. But I wonder if it carries the same effects on AMPK.

    • P. D. Mangan says:

      Apparently it’s the salicylate that aspirin metabolizes into that inhibits AMPK. Ibuprofen is a COX2 inhibitor, as is aspirin, but it looks like ibuprofen doesn’t activate AMPK. From what I’m seeing, medical researchers don’t think too highly of ibuprofen in preventing heart disease either, though I believe it has some anti-platelet and possibly anti-cancer activity. But it looks like for AMPK activation, aspirin beats ibuprofen.

      Interestingly, some acne medications and soaps contain salicylic acid, and I’m wondering if the mechanism of action isn’t activation of AMPK, which might stop bacteria from growing, and might do the same to skin cells, preventing pores clogging up.

  3. sam silk says:

    im 90 years of age and have been taking 650 mg of enteric covered asperins fo the past 28 years. i always believed that aspirin was an anti aging drug. now with the knowledge that 600 mg of aspirin taken daily stimulates the enzyme AMPK. which in turn keeps the cells from aging it fortifies my belief. i still work everyday i do not look or act 90 years i also read a study that if the aspirins desolve in the intestines it helps produce AMPK in the brain.

  4. David Nystrom says:

    I’m 30 years of age and take 500mg of aspirin every day.

    Of course, that’s because I’m hungover every day, but now I know I’m going to live forever.

    Thank you Mr. Silk.

  5. David Nystrom says:

    Kidding–I stopped abusing alcohol at 28!

    Keep up the great work Mr. Mangan, and I hope Mr. Silk lives to 120.

    I own your supplement book and will be purchasing your new life extension book. I also plan on gifting a copy to my 65 year old father. He is on a LCHF diet and looks 50, but he doesn’t supplement (other than vitamin D) or pursue any other anti-aging strategies.

    It would be wonderful if he could somehow still be alive when I am 65–at which time he’d be 100 years old!

  6. meera says:

    I use a lot of turmeric (curcumin) in cooking? how much are you taking as a supplement?

    • P. D. Mangan says:

      I use 500 mg curcumin several times a week, but note that curcumin and turmeric are not the same. Curcumin is a constituent of turmeric at about 2 to 8 % of total weight. My supplement is 95% curcuminoids.

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