Long COVID and Metabolism: How AMPK Activation May Reduce Risk

Key Takeaways

• Long COVID affects about 7% of infected individuals and can produce more than 200 symptoms across multiple organs.
• COVID-19 appears to suppress AMPK, the master regulator of cellular energy and metabolism.
• AMPK activation may help prevent long COVID, as demonstrated by studies showing metformin reduces long COVID incidence by more than 60%.
• Metabolic Engineering® is a dietary strategy designed to activate AMPK through calorie control, balanced macronutrients, omega-3 fatty acids, and polyphenols.
• Protein balance and calorie control are critical, with roughly 30 g of protein per meal helping maintain satiety while supporting metabolic efficiency.
• Omega-3 fatty acids help resolve inflammation, particularly by lowering the AA/EPA ratio to a healthier range.
• Polyphenols further enhance metabolic health by reducing oxidative stress and indirectly activating AMPK.

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It has been nearly five years since COVID-19 first appeared.  However, for many, the consequences of initial infection remain with them for years.  About 7 percent of people infected with COVID-19 end up with long COVID-19 (1).  Long COVID has more than 200 symptoms associated with it, affecting multiple organs (2).  Such widespread symptoms suggest a global disruption of metabolism, most likely involving the inhibition of AMPK.(3). 

One known drug that activates AMPK is metformin, which is the primary drug used to treat diabetes.  A recent study has found that administering metformin to overweight or obese COVID-19 patients within three months after infection reduces the incidence of long COVID by more than 60 percent (4).  Pretty good results. But why? 

First, individuals who are overweight and obese tend to have low AMPK activity, hence their increased body fat percentage.  Second is that COVID-19 inhibits AMPK activity (3).  This inhibition of AMPK activity is crucial in allowing the virus to continue replicating. Third, it has been demonstrated that direct pharmacological activation of AMPK with experimental compounds inhibits COVID-19 infection (5).  Although metformin has some effect on relieving AMPK inhibition, it primarily acts in the liver.  On the other hand, more powerful experimental AMPK-activating compounds can increase AMPK activity in all organs, including the lungs (5). 

Is there a better way to prevent and treat long COVID or avoid reinfection with new strains of COVID-19 for which there are no vaccines?  I think the answer is yes, and the solution is surprisingly simple.  It starts with following Metabolic Engineering® to keep AMPK continually activated. 

The most powerful way to activate AMPK is through constant calorie restriction, but without hunger.  That requires a calorie-restricted program with enough protein to maintain satiety.  I believe that the data strongly indicates that consuming approximately 30 grams of protein at every meal, providing a minimum of 90 grams of protein throughout the day, is essential for reaching that goal. 

Then you must balance that amount of protein at every meal with adequate carbohydrates to maintain stable blood glucose levels.  That will be about 40 grams of carbohydrates at every meal. The best types of carbohydrates will be non-starchy vegetables.  Why? They contain far fewer simple sugars that will inhibit AMPK (6, 7). 

Finally, you add just enough fat for flavor, but not too much that it increases your calorie intake and reduces AMPK activity.  About 15 grams of fat per meal, ideally from monounsaturated sources like olive oil or nuts, is the correct balance. This will provide approximately 1,200 to 1,500 calories per day, which is similar to the calorie intake of individuals using GLP-1 drugs (8).  This single component of Metabolic Engineering will have the most significant impact on reducing the cytokine storms associated with COVID-19 infection, as increasing AMPK activity inhibits the key gene transcription factor responsible for generating cytokines (9).  

If you want even better results, add adequate levels of omega-3 fatty acids to resolve the inflammation associated with COVID-19 infection (10).  To be successful, you will need at least 2.5 grams of EPA and DHA daily to get your AA/EPA ratio between 1.5 and 3.  Finally, add some additional polyphenols to help reduce oxidative stress and also indirectly activate AMPK.

Putting all of these together, you have Metabolic Engineering®.  This will be your best “drug” to not only treat long COVID-19, but also to reduce any significant impact of new COVID-19 mutants that will most likely arise in the future.  

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FAQ

What is long COVID?

Long COVID refers to persistent symptoms that continue for weeks or months after an initial COVID-19 infection. These symptoms can affect multiple organs and may include fatigue, brain fog, shortness of breath, and inflammation.

How common is long COVID?

Research suggests that about 7 percent of people infected with COVID-19 develop long COVID, although estimates vary depending on population and study design.

What role does AMPK play in COVID-19?

AMPK is a key regulator of cellular energy. COVID-19 appears to suppress AMPK activity, which may allow the virus to replicate more easily and contribute to the widespread metabolic disruption seen in long COVID.

Can metformin reduce the risk of long COVID?

Some studies show that metformin reduces the incidence of long COVID by more than 60 percent when given early after infection. This benefit may be related to metformin’s ability to activate AMPK.

How can diet help activate AMPK?

A calorie-controlled diet with balanced protein, carbohydrates, and healthy fats can help activate AMPK. The Metabolic Engineering® approach combines dietary balance, omega-3 fatty acids, and polyphenols to support metabolic health and reduce inflammation.

• References
• 1.  CDC.  Long COVID in Adults: United States, 2022.  https://www.cdc.gov/nchs/products/databriefs/db480.htm
• 2.  Davis HE, McCorkell L, Vogel JM, Topol EJ.  Long COVID:  Major findings, mechanisms and recommendations. Nat Rev Microbiol. 21:133-146 (2023) doi: 10.1038/s41579-022-00846-2. 
• 3.  Ashraf MS, Tuli K, Moiz S, Sharma SK, Sharma D, Adnan M.  AMP kinase:  A promising therapeutic drug target for post-COVID-19 complications.  Life Sciences. 359: 123202 (2024) doi.org/10.1016/j.lfs.2024.123202.
• 4.  Chaichana U, Man KKC, Ju C, Makaronidis J, Wei L.  Effect of metformin on the risk of post-coronavirus disease 2019 condition among individuals with overweight or obese:  A population-based retrospective cohort study.  Clin Infect Dis. ciaf429 (2025). doi: 10.1093/cid/ciaf429. 
• 5.  Cottignies-Calamarte A, Marteau F, He F, Belouzard S, Dubuisson J, Tudor D, Viollet B, Bomsel M.  Direct pharmacological AMPK activation inhibits mucosal SARS-CoV-2 infection by reducing lipid metabolism, restoring autophagy flux and the type I IFN response.  J Virol. 99:e0039425 (2025). doi: 10.1128/jvi.00394-25. 
• 6.  Steinberg GR, Hardie  DG. New insights into the activation and function of the AMPK. Nat Rev Mol Cell Biol. 24:255–272 (2023). doi.org/10.1038/s41580-022-00547-x.
• 7.  Gugliucci, A. The hepatic axis fructose-methylglyoxal-AMPK:  Starring or secondary role in chronic metabolic disease? J. Clin. Med. 14:3559 (2025). https://doi.org/10.3390/jcm14103559
• 8.  Anyiam O, Phillips B, Quinn K, Wilkinson D, Smith K, Atherton P, Idris K.  Metabolic effects of very-low calorie diet, semaglutide, or combination of the two, in individuals with type 2 diabetes mellitus.  Clinical Nutrition. 2024; 43:1907-1913.  doi: 10.1016/j.clnu.2024.06.034.
• 9.  Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-κB signaling and inflammation:  Impact on healthspan and lifespan.  J Mol Med.  89:667-676 (2011). doi: 10.1007/s00109-011-0748-0. 
• 10.  Arnardottir H, Pawelzik SC, Ohlund Wistbacka U, Artiach G, Hofmann R, Reinholdsson I, Braunschweig F, Tornvall P, Religa D, Back M.  Stimulating the resolution of inflammation through omega-3 polyunsaturated fatty acids in COVID-19:  Rationale for the COVID-Omega-F Trial. Front Physiol. 11:624657 (2021). doi: 10.3389/fphys.2020.624657.