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Dr. Barry Sears

Dr. Barry Sears

The Ultimate Anti-Viral Drug: AMPK

What if you had a drug that would stop the replication of viruses and whose only know side-effect would be to extend your healthspan?  Would you use it?  Of course, you would.  Such a drug is already inside every cell in your body just waiting to be activated.

That “drug” is AMPK, the genetic master switch of your metabolism.  AMPK is under significant dietary control, and in particular, it can be activated by using the Pro-Resolution Nutrition system. 

AMPK works at many levels of the body’s numerous anti-viral defenses (1).  It is critical for maintaining the physical barriers to prevent the virus from reaching the target tissue (2-4).  Likewise, it is essential for presenting viral antigens to the adaptive immune system to make antibodies (5,6).  However, its most important role is that it can prevent the virus itself from replicating so that it can’t infect other cells (7-10).  How AMPK works as an anti-viral drug is complicated but elegant. 

Most viruses are composed of a lipid envelope the surrounds the genetic core of the virus.  Viruses that have a lipid envelope include retroviruses such as those that cause AIDS,  DNA viruses such as those that cause smallpox, herpes, and hepatitis, RNA viruses such as those that cause West Nile fever, dengue fever, encephalitis, yellow fever, Zika, influenza, and of course Covid-19.  What this means is that the enveloped virus can’t replicate inside the infected cell unless it can hijack the machinery in the infected cell to make new lipid envelopes for themselves as they replicate.  This critical point is where the activation of AMPK comes in.  Once AMPK is activated, it dramatically reduces the formation of that last necessary step in viral replication. 

As I stated earlier, AMPK is the master switch for your metabolism and, in particular, the synthesis of lipids.  Increased lipid synthesis is controlled by another enzyme known as ACC.  However, that process is inhibited if you can activate AMPK (11,12).  Every cell in your body carries the molecular mechanism to stop viral replication if you can only activate AMPK.

Dietary Activation of AMPK  

AMPK is under profound dietary control.  It is activated by calorie-restricted diets like the Zone diet (13, 14).  AMPK is also activated by the hormones known as resolvins that are generated from omega-3 fatty acids (15-17).  However, the best way to activate AMPK is via water-soluble polyphenols (18), as shown below. 

Not surprisingly, the three dietary components that activate AMPK are the nutritional pillars of the Pro-Resolution Nutrition system.  However, they are all not equal in their abilities to activate AMPK, as water-soluble polyphenols will be the most significant effect of the three.

The reason that polyphenols are so beneficial in the activation of AMPK is that they work through a complicated pathway that activates the SIRT enzyme which activates LKB1 by deacylation, which in turn enables AMPK to be activated (19).  One unique aspect of AMPK activation is the increase of the activity of the enzyme (Nampt) that makes NAD+ that in turn activates the SIRT enzyme, as shown below.  

Thus, the cycle continues in a chain reaction as long as you maintain a consistent intake of polyphenols to recharge the system continuously.  This complex biochemistry is all explained in greater detail in my book, The Resolution Zone (14).  The bottom line is that water-soluble polyphenols can be a wonder “drug” for shutting down the replication of new enveloped viruses.   

Unfortunately, there are a few problems to be overcome.  First, most polyphenols are not very water-soluble, meaning they will not enter the blood at high enough levels to get into the cells to initially activate SIRT enzymes.  Second, the polyphenols have to possess a unique structure to bind the SIRT enzyme (20).  Of the 8,000 known polyphenols, only a specific subclass of anthocyanins known as delphinidins meet both criteria.  

OK, where do you find delphinidins because you will need a daily intake of about 100-500 mg?  Red wine contains some delphinidins but you would have to consume about 50 glasses of red wine per day to get enough delphinidins just to begin to activate AMPK.   Blueberries are a more abundant source, but to get enough delphinidins, you would need to consume about two pounds of blueberries per day that would also supply a large amount of glucose that inhibits AMPK activity (21).  

I believe the answer is finding highly purified extracts that are rich in delphinidins and devoid of glucose. Such products do exist, and they have demonstrated numerous clinical benefits that you would expect of an activator of AMPK (22-25).  When highly refined delphinidin extracts are used as part of the Pro-Resolution Nutrition system, you have done your best to prepare your body to mitigate the potential damage of any virus that has lipid envelope, and that includes the SARS-CoV-2 virus that causes Covid-19.

References

1.  Silwal P, Kim JK, Yuk JM, Jo EK. “AMP-Activated Protein Kinase and Host Defense against Infection.” Int J Mol Sci 19: E3495 (2018)

2.  Sun X and, Zhu MJ. “AMP-activated protein kinase: a therapeutic target in intestinal diseases.” Open Biol 7: 170104 (2017)

3.  Rowart P, Wu J, Caplan MJ, and Jouret F. “Implications of AMPK in the Formation of Epithelial Tight Junctions.” Int J Mol Sci 19: E2040 (2018)

4.  Zhu MJ, Sun X, and Du M. “AMPK in regulation of apical junctions and barrier function of intestinal epithelium.” Tissue Barriers 6: 1-13 (2018)

5. Fullerton MD and Steinberg GR. “Presenting an adaptive role for AMPK.”  J Leukoc Biol 94:1099-1101 (2013)

6.  Carroll KC, Viollet B, and Suttles J. “AMPKα1 deficiency amplifies proinflammatory myeloid APC activity and CD40 signaling.” J Leukoc Biol 94: 1113-1121 (2013)

7. Moser TS, Schieffer D, Cherry S. AMP-activated kinase restricts Rift Valley fever virus infection by inhibiting fatty acid synthesis.  PLoS Pathog 8: e1002661 (2012)

8.  Jiménez de Oya N, Blázquez AB, Casas J, Saiz JC, and Martín-Acebes MA. “Direct activation of adenosine monophosphate-activated protein kinase (AMPK) by PF-06409577 inhibits flavivirus infection through modification of host cell lipid metabolism.” Antimicrob Agents Chemother 62: e00360-18 (2018)

9.  Singh S, Singh PK, Suhail H, Arumugaswami V, Pellett PE, Giri S, and Kumar A. “AMP-activated protein kinase restricts Zika virus replication in endothelial cells by potentiating innate anti-viral responses and inhibiting glycolysis.” J Immunol 204:1810-1824 (2020)

10.  Martín-Acebes MA, Jiménez de Oya N, and Saiz JC. “Lipid metabolism as a source of druggable targets for anti-viral discovery against Zika and other flaviviruses.  Pharmaceuticals 12: E97 (2019)

11.  Saha AK, Ruderman NB. “Malonyl-CoA and AMP-activated protein kinase: an expanding partnership.” Mol Cell Biochem 253: 65-70 (2003)

12.  Foretz M and Viollet B. “Measurement of AMPK-induced inhibition of lipid synthesis flux in cultured cells.  Methods Mol Biol 1732:363-371 (2018)

13. Sears B.  The Zone.  Regan Books.  New York, NY (1995)

14. Sears B.  The Resolution Zone.  Zone Press.  Palm City, FL (2019)  

15.  Jung TW, Ahn SH, Shin JW, Kim HC, Park ES, Abd El-Aty AM, Hacımüftüoğlu A, Song KH, Jeong JH.  Protectin DX ameliorates palmitate-induced hepatic insulin resistance through AMPK/SIRT1-mediated modulation of fetuin-A and SeP expression.  Clin Exp Pharmacol Physiol. 2019 Oct;46(10):898-909.

16.  Jung TW, Kyung EJ, Kim HC, Shin YK, Lee SH, Park ES, Hacımüftüoğlu A, Abd El-Aty AM, Jeong JH.  Protectin DX Ameliorates Hepatic Steatosis by Suppression of Endoplasmic Reticulum Stress via AMPK-Induced ORP150 Expression.  J Pharmacol Exp Ther. 2018 Jun;365(3):485-493.

17.  Piao S, Du W, Wei Y, Yang Y, Feng X, Bai L.  Protectin DX attenuates IL-1β-induced inflammation via the AMPK/NF-κB pathway in chondrocytes and ameliorates osteoarthritis progression in a rat model.  Int Immunopharmacol. 2019 Dec 11;78:106043.

18.  Momtaz S, Salek-Maghsoudi A, Abdolghaffari AH, Jasemi E, Rezazadeh S, Hassani S, Ziaee M, Abdollahi M, Behzad S, and Nabavi SM. “Polyphenols targeting diabetes via the AMP-activated protein kinase pathway; future approach to drug discovery.”  Crit Rev Clin Lab Sci 56: 472-492 (2019)

19.  Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, and Ido Y. “AMPK and SIRT1: a long-standing partnership?” Am J Physiol Endocrinol Metab 298: E751-60 (2010)

20.  Rahnasto-Rilla M, Tyni J, Huovinen M, Jarho E, Kulikowicz T, Ravichandran S, A Bohr V, Ferrucci L, Lahtela-Kakkonen M, and Moaddel R. “Natural polyphenols as sirtuin 6 modulators.” Sci Rep 8: 4163 (2018)

21.  Viollet B, Horman S, Leclerc J, Lantier L, Foretz M, Billaud M, Giri S, and Andreelli F. “AMPK inhibition in health and disease.” Crit Rev Biochem Mol Biol 45: 276–295 (2010)

22. Alvarado JL, Leschot A, Olivera-Nappa Á, Salgado AM, Rioseco H, Lyon C, Vigil P. “Delphinidin-rich maqui berry extract (Delphinol®) lowers fasting and postprandial glycemia and insulinemia in prediabetic individuals during oral glucose tolerance tests.”  Biomed Res Int. 2016: 9070537 (2016)

23.  Alvarado J, Schoenlau F, Leschot A, Salgad AM, Vigil Portales P.  “Delphinol® standardized maqui berry extract significantly lowers blood glucose and improves blood lipid profile in prediabetic individuals in three-month clinical trial.”  Panminerva Med 58(3 Suppl 1):1-6 (2016)

24.  Davinelli S, Bertoglio JC, Zarrelli A, Pina R, and Scapagnini G.  “A randomized clinical trial evaluating the efficacy of an anthocyanin-maqui berry extract (Delphinol®) on oxidative stress biomarkers.”  J Am Coll Nutr. 2015;34 Suppl 1:28-33 (2015)

25.  Hidalgo J, Flores C, Hidalgo MA, Perez M, Yañez A, Quiñones L, Caceres DD, and Burgos RA.  “Delphinol® standardized maqui berry extract reduces postprandial blood glucose increase in individuals with impaired glucose regulation by novel mechanism of sodium glucose cotransporter inhibition.”  Panminerva Med 56(2 Suppl 3):1-7 (2014)

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7 replies
  1. Al
    Al says:

    Hi Dr. Sears, hope you and yours are alright and staying safe! Do you have any thoughts on fasting and it’s effects on AMPK? Also, other than cortisol rising during fasting, do you have any other thoughts on fasting in general…or a fasting-combined with the Zone Diet protocol, perhaps? Thank you Doctor and be well.

    Reply
    • Barry Sears
      Barry Sears says:

      Calorie restriction is defined as lowering calorie intake without malnutrition. Fasting is defined as consuming only water. There is a vast gulf between these two definitions. Although both can increase AMPK activity, continuous calorie-restriction will have the most significant therapeutic benefits. Unlike fasting, calorie-restriction can be maintained indefinitely as long as it is protein-adequate, carbohydrate-moderate, low-fat, and rich in micronutrients (vitamins, minerals, omega-3 fatty acids, and polyphenols) as well as fermentable fiber. Human physiology requires constant degradation of damaged cells and rebuilding new cells. Calorie-restriction allows that to be maintained as you are activating AMPK. The Zone diet is a continuous calorie-restriction program that requires some discipline. One addition to the Pro-Resolution Nutrition system that would add the benefits of fasting is practice 12-hour fasting. This type of “fasting” means eating within one hour after waking and consuming your last meal no later than 12 hours after waking to be in better alignment with your circadian rhythms, which are driven by daylight exposure.

      Reply
  2. Carla
    Carla says:

    hi Dr Sears, i want to knows some tips about anxiety disorder, in a way you feel cronic tension in your body, glucose levels are high

    , you dont rest well, abdominal inflammation, I avoid flours…

    I hope to receive news soon,

    Sinceraly Carla M.

    Reply
    • Barry Sears
      Barry Sears says:

      Anxiety is usually associated with decreased levels of the neurotransmitter GABA. Certain bacteria can manufacture much of the GABA in the gut that can travel to the brain via the vagus nerve (Stradwitz. Brain Research 15: 128 (2018)). Furthermore, neuroinflammation in the brain can be another contributing factor by causing by disrupting signaling pathways. These two factors are why I feel that a Pro-Resolution Nutrition program could have significant benefits not only on your anxiety but also in reducing your elevated glucose levels and abdominal inflammation.

      Reply
  3. kevin ByrkeT
    kevin ByrkeT says:

    Being pre diabetic im afraid to take the zone shakes. The carbs and sugars are high with each serving.

    I love the taste and they sastify my hunger cravings. Not sure what to do. Maybe its bettter to take the shakes and cut something else out ? Please advise. My fasting glucose is ave 104 every morning

    Reply
    • Barry Sears
      Barry Sears says:

      The lack of appetite is because the shakes are providing significantly better hormonal control leading to a reduction in insulin resistance. You can use the insulin resistance quiz on this site to determine that from subject parameters, but your TG/HDL is a better marker, and HOMA-IR being the best. If you are not as hungry, you will reduce calorie intake, thereby increasing AMPK activity. One of many of the benefits of AMPK activation is the reduction of blood glucose by increasing the activity of the GLUT-4 glucose transport protein in every insulin-sensitive tissue. The higher the levels of glucose in the blood, the more AMPK is inhibited. As always, a strict Zone diet will be primary dietary choice supplemented with adequate levels of omega-3 fatty acid to make the hormones (i.e., resolvins) needed to resolve existing cellular inflammation that is the underlying cause of insulin resistance.

      Reply
  4. Barry Sears
    Barry Sears says:

    Fasting will activate AMPK. However, you have to maintain protein intake to maintain muscle mass and the immune system. The Zone diet is a controlled way to maintain adequate levels of AMPK activation without compromising immune and hormonal response because even though it is a calorie-restricted diet, it is also protein-adequate at every meal. The two dietary factors that decrease AMPK activity are excess calories and excess glucose. That’s why calorie restriction also has to be glucose restricted. Not too low to compromise brain function (which needs about 130 grams of glucose per day) or increase cortisol levels, but not too high to inhibit AMPK. My general rule on calorie intake is never to try to consume more than 400 calories per meal and to keep the total carbohydrate intake under 40 grams. Also, try never to eat after 7 pm. It has been shown that your circadian rhythms tend to convert late-night calorie intake into fat storage more effectively. Therefore, you might consider the Zone diet to be a 12-hour fast. Although intermittent fasting is widely discussed, it appears to have no benefits compared to continuous calorie restriction. Yet diet is only one dietary avenue to increase AMPK activity. Resolvins derived from EPA and DHA are also useful, but the most effective way appears to be the intake of water-soluble polyphenol extracts that are free of glucose. I explain these hormonal and genetic pathways in greater detail in The Resolution Zone.

    Reply

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