The Establishment of a New Metabolic Reprogramming through Calorie Control, Combined with Methionine Restriction and Nutritive Ketogenic Therapy, Has the Potential to be the First Effective Measure to the Next COVID-19-like Pandemic
Currently and in the future, especially for scientific and technologic workers and public health professionals in the world, there are two challenging issues:
1. Will we be ready for the next plague (COVID-19-like) pandemic? How to deal with it?
2. Or at least make more adequate preparations than when the COVID-19 epidemic disaster comes?
Introduction
On December 19, 2024, the United States reported its first severe case of human infection with avian influenza (H5N1). Subsequently, California, the most populous state in the United States, declared a state of emergency. Recently, United Nations health officials announced that the avian influenza epidemic is raging globally, causing the death of over 300 million birds and warning that the virus is "increasingly crossing species boundaries" and posing a serious threat to wildlife, livestock, and public health. This situation raises a very important question: Will avian influenza evolve from an ecological disaster to a comprehensive pandemic?
The bird flu epidemic has brought the COVID-19 back to public view. Since the outbreak of COVID-19 at the end of 2019, the world has rapidly plunged into an unprecedented health crisis. This crisis has not only had a serious impact on the public health systems of various countries, but also had a profound impact on the world economy, social order, and international relations.
In response to a wave of ongoing viral infections, researchers and health professionals need to answer and solve the following two challenging problems:
1. Will we be ready for the next plague (COVID-19-like) pandemic? How to deal with it?
2. Or at least make more adequate preparations than when the COVID-19 epidemic disaster comes?
Simulate these two challenging topics. Time goes back to the beginning of the COVID-19 pandemic at the end of 2019. In view of the fact that there was no effective drug treatment or specific vaccine for the new virus at that time, how to minimize the occurrence of severe cases and deaths? How to try to control COVID-19 virus infection into seasonal flu cases. Let scientific research professionals have time to develop effective preventive vaccines and drugs to prevent SARS-CoV-2 -like infection from becoming a worldwide plague.
A series of basic scientific research and clinical medical research results have been obtained in the past 4-5 years for scientific research and discussion in the fields of COVID-19 etiology, pathogenicity, pathophysiology of human infection virus, immunology, drugs and vaccines, and clinical treatment. These studies show that at the beginning of the COVID-19 outbreak, there was no effective drug and vaccine use due to insufficient scientific knowledge of COVID-19.
According to the results of basic and clinical medical research in recent years: by changing the dietary structure, implementing metabolic reprogramming measures, and changing the metabolic pathway of human susceptible cells, the growth and reproduction of viruses can be slowed down, the efficacy of human immune cells in killing viruses can be increased, the cytokine storm effect can be weakened, and the occurrence of severe cases can be controlled, making it possible for SARS-CoV-2 infection to become a seasonal viral infection case, so as to have time for developing effective drugs and vaccines.
Based on a series of basic and clinical achievements in the prevention and treatment of SARS-CoV-2 infection by means of total calorie control of diet, methionine restricted diet and nutritional ketogenesis therapy for the public and patients with viral infection, the three dietary therapies are matched to overcome their own shortcomings and side effects, and form a combined treatment of total calorie control-methionine restricted- nutritional ketogenic therapy, which might become an effective response to the next outbreak of SARS-CoV-2-like infection.
The following review summarizes the research achievements of basic and clinical research on SARS-CoV-2 infection in recent years, which to some extent support the application of total calorie control-methionine restriction-nutritional ketogenesis combination therapy to the prevention and treatment of SARS-CoV-2 infection.
I. Ketogenic diet therapy helps fight against SARS-CoV-2 infection. The following research papers and reviews study and analyze how ketogenic diet can combat SARS-CoV-2 infection from different perspectives.
Fig.1. Ketogenic Diet for Obese COVID-19 Patients: Is Respiratory Disease a Contraindication? (Ref.: A Narrative Review of the Literature on Ketogenic Diet and Respiratory Function.)
1. Ketogenic diet as a therapeutic strategy to enhance antiviral immunity.
A significant study in 2022 showed that unlike other types of viral infections, SARS-CoV-2 infection inhibits β - hydroxybutyrate synthesis and impairs the immune function of CD4+T cells in patients with acute respiratory distress syndrome (ARDS). Proving that ketogenic diet (KD) or BHB supplementation during severe viral infection can restore mitochondrial metabolism and immune function of CD4+T cells, thereby reducing the severity and mortality of SARS-CoV-2 infection in mice.
Studies have shown that the production of β - hydroxybutyrate (BHB) is damaged in patients with COVID-19 induced acute respiratory distress syndrome (ARDS), but not affected by influenza virus induced ARDS. BHB promotes the survival and production of interferon gamma through CD4+T cells. The results show that BHB is an alternative carbon source, which promotes T cell response in pulmonary virus infection, and emphasizes that impaired ketogenesis is a potential interference factor in severe patients with COVID-19.(Ref.: Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19. Nature. 2022 ;609:801-807)
2. Ketogenic diet may prevent influenza and enhance antiviral immunity. A ketogenic diet can promote the release of a special type of immune cell, γδT cells, improve lung barrier function, and enhance antiviral immunity. Compared to mice fed a regular diet, mice fed a ketogenic diet showed significantly stronger resistance to influenza virus infection. Researchers found that the virus titers in the lungs of mice on a ketogenic diet were significantly lower, indicating that the survival benefits of mice do indeed come from the enhancement of antiviral immunity.
（Ref.:1. Ketogenic diet activates protective γδ T cell responses against influenza virus infection. Sci Immunol.2019 Nov 15;4(41):2. Obesogenic and Ketogenic Diets Distinctly Regulate the SARS-CoV-2 Entry Proteins ACE2 and TMPRSS2 and the Renin-Angiotensin System in Rat Lung and Heart Tissues. Nutrients 2021, 13, 3357.）
3. New research has found that ketones can enhance the ability of T cells to fight infections and diseases.
Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. ΒOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. (Ref.:Ketolysis drives CD8+ T cell effector function through effects on histone acetylation)
4. Severe COVID-19 is characterized by severe impairment of CD8+T cell function. The ability of CD8+T cells can be significantly increased through a ketogenic diet. At this time, ketone body BHB can reprogram such T cells to improve the immune function of patients with COVID-19.
Ketone Bodies Improve Human CD8+ Cytotoxic T-Cell Immune Response During COVID-19 Infection. Front Med. 2022.
4. Clinical study on the treatment results of ketogenic therapy
Clinical efficacy of eucaloric ketogenic nutrition in the Covid-19 cytokine storm (CSS): a retrospective analysis of mortality and Intensive Care Unit admission. Nutrition, 2021: 111236.
5. One of the proposed nutritional therapies to support drug therapy in COVID-19 is the use of a ketogenic diet (KD) or ketone bodies.
KD increased survival, reduced the need for hospitalization for COVID-19, and showed a protective role against metabolic abnormalities after COVID-19. It appears that the use of KD and ketone bodies may be considered as a clinical nutritional intervention to assist in the treatment of COVID-19, despite the fact that numerous studies indicate that SARS-CoV-2 infection alone may induce ketoacidosis. However, the use of such an intervention requires strong scientific validation.(Ref.:Ketogenic Diet and Ketone Bodies as Clinical Support for the Treatment of SARS-CoV-2—Review of the Evidence. 2. Inactivation of lipid-enveloped viruses in proteins by caprylate. Vox Sang. 1991;60(2):75-81)
II. Methionine restricted diet therapy for COVID-19 infection
1. the SARS-CoV-2 is a single stranded RNA positive virus that uses its genomic RNA for translation and replication. In order to perform correct RNA replication and translation, the cap RNA of the virus must be methylated. Methyltransferase uses S-adenosylmethionine (SAM) as a universal methyl donor for transferring the genome of methylviruses. The synthesis of SAM depends on the availability of methionine. If the concentration of methionine is low, viral methyltransferase cannot complete the reaction due to the lack of SAM. Each time a methyl group is transferred to SAM, the resulting product is a methylated molecule, such as S-adenosyl-homocysteine (SAH). (Ref.: Oral Methioninase for Covid-19 Methionine-restriction Therapy.No relevant final clinical outcome research reports were found.)
2、A high SAM level and high methylation index are associated with the risk of lung injury in patients with COVID-19. The association of SAM with IL-6 and glutathione indicates an important role of transmethylation in the development of cytokine imbalance and oxidative stress in patients with COVID-19.
3. Methionine restriction can inhibit the activity of EB virus by affecting its epigenome and viral latency.
These results highlight epigenetic/immunometabolism crosstalk supporting the EBV B cell lifecycle and suggest therapeutic approaches.
Methionine metabolism also shaped EBV latency gene regulation required for B cell immortalization. Dietary methionine restriction altered murine Burkitt xenograft metabolomes and de-repressed EBV immunogens in vivo. These results highlight epigenetic/immunometabolism crosstalk supporting the EBV B cell lifecycle and suggest therapeutic approaches.
III. Ketogenic therapy inhibits cytokine storm effect
Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism.
(Ref.: COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm. 2023. Immunity 56(9)
IV. Constructing a calorie total control- methionine restriction - nutritional ketogenic combination therapy to respond to the next critical illness caused by a COVID-19- like epidemic in the shortest possible time. This therapy might be effective, operable, and adhesive.
1. Acquisition of micronutrients.
The Arctic Skim people and polar bears eat food, first of all, the liver of seals, which contains abundant B group water-soluble vitamins as mitochondrial oxidative phosphorylation coenzymes, as well as fat soluble vitamins and other micronutrients.
Unlike fat soluble vitamins, water-soluble vitamins are stored less in the human body, and the excess water-soluble vitamins absorbed from the intestine and entering the body are mostly excreted in urine. Water soluble vitamins are almost non-toxic, and high intake generally does not cause poisoning. If the intake is too low, deficiency symptoms will appear quickly.
The ketogenic diet results in a lower intake of these vitamins due to the low total amount of carbohydrates in cereal foods. Supplementing animals such as pig liver powder is an option, but due to customs and high cholesterol, alternative ingredients need to be found.
2.The ratio of protein to fat.
The meat that Inuit eat is fatty meat from wild animals. The Inuit and other hunter-gatherer people tend to eat no more than 40 percent protein. Too much protein can stress the liver until ill health or death occurs, according to evolutionary nutritionist Loren Cordain in "Discover Magazine." Approximately 50 percent of the Inuit's calories are derived from fat. The nutritional profile of the fat that these animals provide is significantly different from that of the farm-raised animals that are consumed by the average American, however. Wild mammals and cold water fish are rich in healthy monounsaturated fat and omega-3 fatty acids. This may partially account for the health that the Inuit enjoy on this diet.
Fig.2.Inuit eat animal liver first.
Fig.3. Polar bears first eat seals' liver
2. Using yeast protein as a high-quality protein:
The content of L-methionine is relatively low. According to the latest medical research results, a new dietary plan: limiting the increase of L-methionine to compensate for the weight of folic acid, prolonging life and improving fertility, Nature Aging .). Yeast whole protein can be labeled as a "nutritious and life extending food", and a series of high value-added and healthy products can be developed to further promote the rapid and healthy development of the yeast whole protein industry.
3. Satisfy the use of the highest quality fat MLCT for nutritional ketogenesis
Based on human safety, clinical efficacy, human tolerance, and patient convenience, medium -long chain fatty acid triglycerides have become the most superior product for low glycemic ketogenic therapy. Indirect studies have shown that when the human body uses triglycerides rich in medium chain fatty acids (8C octanoic acid) in a ketogenic state, it can enter the optimal ketogenic state after more than 30 minutes. Ketones can replace glucose for energy supply, greatly reducing the occurrence of serious side effects caused by insufficient energy supply(Fig4.). Eating medium chain fatty acid triglycerides can cause gastrointestinal discomfort and side effects, with severe symptoms such as diarrhea and vomiting. Rich in medium chain fatty acids, medium-long chain fatty acid triglycerides have better gastrointestinal tolerance.
Fig4: nutritional ketogenesis(The Art and Science of Low Carbohydrate Living. Stephen D. Written by Phinney and Jeff S. Volek. 2011. )
V. The methionine restricted diet is feasible in eliminating the accelerated aging side effects caused by ketogenic diet therapy.
1. Animal experiments have shown that a ketogenic diet can induce cellular aging in both young and old mice, indicating that the effect of a ketogenic diet on cellular aging is independent of age factors.
Although a ketogenic diet can effectively reduce fat, it has multiple side effects, including decreased glucose tolerance, increased fat oxidation, and altered diversity of gut microbiota. Long term ketogenic diet can also induce cellular aging. In a Science Advances article, researchers delved into the effects of a ketogenic diet on organ cell aging in mice and elucidated the relevant molecular mechanisms. This article was published by the David Gius team and titled "Ketogenic diet induces p53 dependent cellular senescence in multiple organs".
2.Methionine Restriction can attenuate oxidative stress through multiple mechanisms, consequently associating with lifespan extension and metabolic health.
3. Based on the unique characteristics of amino acid composition and vitamin abundance of yeast whole protein, L-methionine content is relatively low, while folate content is high (the highest among all foods). According to the latest medical research results, a new dietary plan: limiting L-methionine to increase could be prolonging life and improving fertility ("Separation of productive decline from life span extension during methionine restriction", July 26, 2024), Nature Aging .）. Yeast protein can be labeled as a "nutritious and life extending food", and a series of high value-added and healthy products can be developed to further promote the rapid and healthy development of the yeast whole protein industry.
VI. Specific implementation method of calorie control- methionine restricted- nutrient ketogenic therapy
When the human body begins to break down fat instead of glucose, nutritional ketosis occurs. Ketones are intermediate metabolites produced by the breakdown of fats into fatty acids in the liver, including acetoacetic acid, beta hydroxybutyric acid, and acetone. Under normal circumstances, the body produces a small amount of ketone bodies, which are transported to tissues such as the heart, kidneys, and skeletal muscles through the bloodstream and utilized as an energy source. Ketones are products of normal human metabolism and are a general term for acetoacetic acid, β - hydroxybutyric acid, and acetone. Ketones are mainly generated in the liver when fat metabolism is not complete, but they can generally be quickly utilized, so the concentration of ketones in the blood is relatively constant.
The patient is unable to eat, leading to a state of hunger and a gradual decrease in glycogen levels in the liver, resulting in exhaustion. On the one hand, there is a lack of carbohydrate supplementation in food, and on the other hand, the glucose stored in the liver is depleted. The body needs to find another "pathway" for energy, which is to replace it with fat stored in the body. However, when fat breakdown metabolism is enhanced, it is often accompanied by incomplete oxidation, which can easily produce excessive intermediate products such as acetoacetic acid B-hydroxybutyric acid, etc., collectively known as ketone bodies.
(Ref: Ketogenic nutritional therapy (KeNuT)—a multi‑step dietary model with meal replacements for the management of obesity and its related metabolic disorders: a consensus statement from the working group of the Club of the Italian Society of Endocrinology (SIE)—diet therapies in endocrinology and metabolism. Journal of Endocrinological Investigation . 2024. 47:487–500)
Fig.5: Burger model with 500 kilocalorie and a diet structure meeting the requirements of total calorie control- methionine restriction- nutritional ketogenic therapy
According to the implementation method of nutritional ketogenesis mentioned above, considering the maximum calorie requirement of normal people and the needs of work and life, the initial calorie provided at the beginning of ketogenesis is set at 1000 kcal. To facilitate the implementation of nutritional ketogenesis, consume 2-3 500 calorie burgers per day.
Each burger containing 500 calories increases the amount of three main nutrients, carbohydrates, proteins, and fats:
Carbohydrates: 17-25g
Protein: 16-24g
Fat: 34-41g
Carbohydrates use high levels of resistant starch, which increases the total amount of carbohydrates and can be made into regular food. Protein: The main component is yeast protein with low methionine content. Fat: mainly composed of medium chain fatty acids and medium long chain fatty acid triglycerides.
VII. Summary
Relying on the low methionine content related characteristics of yeast protein for anti-aging nutritional properties, correcting the side effects of promoting multi organ premature aging in the human body caused by ketogenic diet. By rapidly replacing glucose with keto bodies for energy supply, a safe, reliable, and quality controlled calorie total control- methionine restriction- nutritional ketogenic therapy is constructed to alleviate side effects such as ketogenic colds. Furthermore, high content resistant starch is used as a carbohydrate food raw material to make conventional edible foods, increasing the convenience and adhesion of this diet therapy application.
The purpose of applying this calorie total control- methionine restriction -nutritional ketogenic therapy is to reprogram the metabolic pattern of the human body, further changing the metabolic pattern of organs and tissues, using fat as the main energy source instead of glucose as the main energy source. This metabolic reprogramming can improve immunity and prevent inflammatory damage. KD induced systemic reprogramming may improve the multi organ pathogenicity of COVID-19 or COVID-19-like, further reduce the incidence of severe infections, and make it possible.
Note: This article is my understanding and supposition of COVID-19 etiology, pathogenicity, pathophysiology of human infection virus, immunology, drugs and vaccines, and clinical treatment. The etiology of COVID-19, pathophysiology caused by viral infection, immunology, clinical treatment, vaccine development and other fields are very complex and there are still many challenges that need to be discussed by scientific and technical professionals and medical professionals. There should be many shortcomings in my understanding of these. Therefore, there might be inaccuracies in the expression of this article, and even errors in the expression of basic concepts and professional terminology. Please understand and support it.
Thank you for your reading.
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