WO2024215786A2

WO2024215786A2 - Compositions and methods for improving autophagy activity and inhibiting dysfunction

Info

Publication number: WO2024215786A2
Application number: PCT/US2024/023910
Authority: WO
Inventors: Nancy Starkey FLYNN; David Flynn
Original assignee: Warrior Essentials LLC
Current assignee: Warrior Essentials LLC
Priority date: 2023-04-12
Filing date: 2024-04-10
Publication date: 2024-10-17
Anticipated expiration: 2025-10-12
Also published as: WO2024215786A3

Abstract

Compositions and methods for activation of autophagy, or suppression of autophagy dysregulation, in the body are provided, the composition including an exogenous polyamine including spermidine, spermine, putrescine, or a combination thereof; a precursor to the exogenous polyamine; and a cofactor that increases production of endogenous polyamines, the cofactor comprising Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, copper, manganese, or a combination thereof. The exogenous polyamine suppresses autophagy dysregulation.

Description

COMPOSITIONS AND METHODS FOR IMPROVING AUTOPHAGY ACTIVITY

AND INHIBITING DYSFUNCTION

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/495740, filed on April 12, 2023, the content of which is hereby incorporated by reference in its entirety.

BACKGROUND

[0002] Autophagy is a conserved cellular process by which cells degrade and recycle their own damaged or unnecessary components, such as misfolded proteins, damaged organelles, and/or intracellular pathogens. Autophagy plays a crucial role in maintaining cellular homeostasis, as well as in responding to stress, starvation, and/or infection. The process of autophagy involves the formation of a double-membrane vesicle called an autophagosome, which engulfs cytoplasmic cargo and fuses with a lysosome to form an autolysosome, where the cargo is degraded by lysosomal enzymes and recycled. Autophagy is regulated by a complex network of signaling pathways, including the mTOR pathway and the AMPK pathway, which respond to nutrient availability and energy status. Dysfunction in the autophagy process has been implicated in a range of human diseases, including cancer, neurodegeneration, and metabolic disorders. Understanding the autophagy process and its regulation has important implications for the development of compositions and methods for improving harmful effects of these disorders.

SUMMARY

[0003] The compositions and methods disclosed herein each have several aspects, no single one of which is solely responsible for their desirable attributes. Without limiting the scope of the claims, some prominent features will now be discussed briefly. Numerous other embodiments are also contemplated, including embodiments that have fewer, additional, and/or different components, steps, features, objects, benefits, and advantages. The components, aspects, and steps may also be arranged and ordered differently. After considering this discussion, and particularly after reading the section entitled “Detailed Description,” one will understand how the features of the compositions and methods disclosed herein provide desirous properties over other known compositions and methods.

[0004] Some embodiments provided herein relate to compositions including one or more exogenous polyamine; one or more endogenous polyamine producing agent; and one or more autophagy dysregulation suppressing agent. In some embodiments, the one or more exogenous polyamines include spermidine, spermine, and/or putrescine. In some embodiments, the one or more exogenous polyamine is present in an amount between 250 pg and 50 mg. In some embodiments, the one or more endogenous polyamine producing agent includes a precursor to spermidine, spermine, putrescine, or a combination thereof. In some embodiments, the precursor includes ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, y- aminobutyric acid, hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof.

[0005] In some embodiments, the compositions include one or more cofactor. In some embodiments, the one or more cofactor includes Vitamin B6 Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof. In some embodiments, the compositions include one or more activator. In some embodiments, the one or more activator includes one or more polyphenol. In some embodiments, the one or more polyphenol includes resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, Fisetin, luteolin, Epigallocatechin gallate (EGCG), or combinations thereof. In some embodiments, the EGCG includes green tea powders and extracts. In some embodiments, the compositions include one or more synthesizer. In some embodiments, the one or more synthesizer includes a probiotic. In some embodiments, the probiotic includes Lactobacillus, Bifidobacterium, Streptococcus, Thermophilus, Enterococcus faecalis, Escherichia coli, or a combination thereof. In some embodiments, the Lactobacillus includes Lactobacillus acidophilus. In some embodiments, the Lactobacillus includes Lactobacillus plantarum. In some embodiments, the Bifidobacterium includes Bifidobacterium lactis. In some embodiments, the one or more synthesizer includes a prebiotic. In some embodiments, the one or more synthesizer is present in an amount between 100 million CFU’s and 50 billion CFU’s. In some embodiments, the one or more autophagy dysregulation suppressing agent includes spermidine, spermine, resveratrol, putrescine, or a combination thereof. [0006] In some embodiments, the compositions include an antioxidant precursor. In some embodiments, the antioxidant precursor includes N-acctyl-L-cystcinc (NAC). In some embodiments, the antioxidant precursor includes a derivative of NAC. In some embodiments, the derivative of NAC includes N-acetylcysteine methyl ester, N-acetylcysteine ethyl ester (NACET), N-acetylcysteine propyl ester, or N-acetylcysteine butyl ester.

[0007] In some embodiments, the compositions are oral dosage formulations. In some embodiments, the oral dosage formulations include one or more capsules, one or more tablets, one or more gummies, one or more granules, one or more stick packs, a powder, a beverage, a syrup, a suspension, or a food.

[0008] Some embodiments provided herein relate to compositions for activation of autophagy in the body. In some embodiments, the compositions include an exogenous polyamine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; and a cofactor that increases production of the endogenous polyamine, the cofactor including Vitamin B6, Vitamin B9, Vitamin B 12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof, wherein the exogenous polyamine suppresses autophagy dysregulation. In some embodiments, the precursor increases the production of the endogenous polyamines. In some embodiments, the precursor includes ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, y- aminobutyric acid, hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof. In some embodiments, an amount of the exogenous polyamine is between 250 pg to 50 mg.

[0009] In some embodiments, the compositions include an activator that increases production of the endogenous polyamines. In some embodiments, the activator includes a polyphenol. In some embodiments, the polyphenol includes resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, fisetin, luteolin, or epigallocatechin gallate (EGCG), or a combination thereof. In some embodiments, the EGCG includes green tea powders and extracts. In some embodiments, the composition includes a synthesizer that increases production of the endogenous polyamines. In some embodiments, the synthesizer includes a probiotic. In some embodiments, the probiotic includes Lactobacillus, Bifidobacterium, Streptococcus thermophilus, Enterococcus faecalis, Escherichia coli, or a combination thereof. In some embodiments, the Lactobacillus includes Lactobacillus acidophilus. In some embodiments, the Lactobacillus includes Lactobacillus plantarum. In some embodiments, the Bifidobacterium includes Bifidobacterium lactis. In some embodiments, an amount of the synthesizer is between 1 x 10⁸ to 5 x IO¹⁰ CFU.

[0010] In some embodiments, the compositions include an AKT inhibitor. In some embodiments, the compositions include a Beclin-1 stabilizing agent.

[0011] In some embodiments, the compositions include an antioxidant precursor. In some embodiments, the antioxidant precursor includes NAC. In some embodiments, the antioxidant precursor includes a NAC derivative. In some embodiments, the derivative of NAC includes N-acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N- acetylcysteine butyl ester.

[0012] Some embodiments provided herein relate to oral formulations. In some embodiments, the oral formulations include a base composition including a precursor to an exogenous polyamine and a cofactor and an activator that increases production of endogenous poly amines; and an exogenous poly amine including spermidine, spermine, putrescine, or a combination thereof, wherein the formulation is formulated as a capsule, a tablet, a gummy, a granule, a stick pack, a powder, a beverage, a syrup, a suspension, or a food.

[0013] In some embodiments, the precursor includes ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, y- aminobutyric acid, hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof. In some embodiments, the cofactor includes Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof.

[0014] In some embodiments, the activator includes a polyphenol. In some embodiments, the polyphenol includes resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, fisetin, luteolin, or epigallocatechin gallate (EGCG), or a combination thereof. In some embodiments, the EGCG includes green tea powders and extracts. In some embodiments, the oral formulations include a probiotic that increases production of the endogenous polyamines. In some embodiments, the probiotic includes Lactobacillus, Bifidobacterium, Streptococcus thermophilus, Enterococcus faecalis, Escherichia coli, or a combination thereof. In some embodiments, the Lactobacillus includes Lactobacillus acidophilus. In some embodiments, the Lactobacillus includes Lactobacillus plantarum. In some embodiments, the Bifidobacterium includes Bifidobacterium lactis. In some embodiments, an amount of the probiotic is between 1 x 10⁸ to 5 x IO¹⁰ CFU.

[0015] In some embodiments, the oral formulations include an AKT inhibitor. In some embodiments, the oral formulations include a Beclin-1 stabilizing agent.

[0016] In some embodiments, the oral formulations include an antioxidant precursor. In some embodiments, the antioxidant precursor includes NAC. In some embodiments, the antioxidant precursor includes a NAC derivative. In some embodiments, the derivative of NAC includes N-acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N-acetylcysteine butyl ester.

[0017] In some embodiments, an amount of the exogenous polyamine is between 250 pg to 50 mg. In some embodiments, the oral formulation inhibits mammalian target of rapamycin (mTOR). In some embodiments, the oral formulation activates AMP-protein activated kinase (AMPK). In some embodiments, the oral formulation inhibits mTOR and activates AMPK.

[0018] In some embodiments, the oral formulations are formulated for ingestion by a subject. In some embodiments, the subject has cancer. In some embodiments, the subject has a neurodegenerative disease. In some embodiments, the subject has a metabolic disorder. In some embodiments, the oral formulation is formulated for ingestion by subjects having a respiratory illness or symptoms of the respiratory illness. In some embodiments, the respiratory illness is caused by a Coronavirus. In some embodiments, the Coronavirus is SARS-2-CoV. In some embodiments, the oral formulation is formulated for ingestion by subjects having symptoms from a vaccine. In some embodiments, the vaccine includes a Coronavirus vaccine. In some embodiments, the Coronavirus vaccine causes spike protein expression in the subject. In some embodiments, the Coronavirus vaccine includes a SARS-CoV-2 vaccine. In some embodiments, the SARS-CoV-2 vaccine causes SARS-CoV-2 spike protein expression in the subject. In some embodiments, the SARS-CoV-2 spike protein causes Post-COVID symptoms in the subject.

[0019] In some embodiments, the oral formulations activate autophagy. In some embodiments, the oral formulations suppress autophagy dysregulation. In some embodiments, the oral formulations activate autophagy and suppress autophagy dysregulation. [0020] Some embodiments provided herein relate to methods of activating autophagy or suppressing autophagy dysrcgulation in a subject. In some embodiments, the methods include providing an effective amount of a formulation to the subject, wherein the formulation includes an exogenous polyamine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; and a cofactor that increases production of the endogenous polyamine, the cofactor including Vitamin B6, Vitamin B9, Vitamin B 12, Vitamin C, Vitamin D, zinc, magnesium, selenium, copper, manganese, lithium, or a combination thereof.

[0021] In some embodiments, the effective amount of the formulation provided to the subject is in an amount ranging from about 500 pg to about 3000 mg. In some embodiments, the subject suffers from cancer. In some embodiments, the subject suffers from a neurogenerative disease. In some embodiments, the neurogenerative disease is Alzheimer’s disease. In some embodiments, the neurogenerative disease is Parkinson’s disease. In some embodiments, the subject suffers from a metabolic disorder. In some embodiments, the subject suffers from anorexia nervosa. In some embodiments, the subject suffers from a viral infection. In some embodiments, the viral infection includes a respiratory infection. In some embodiments, the respiratory infection includes COVID-19. In some embodiments, the subject suffers from symptoms associated with Post-COVID. In some embodiments, the subject suffers symptoms from a vaccine.

[0022] In some embodiments, the vaccine includes a Coronavirus vaccine. In some embodiments, the Coronavirus vaccine causes spike protein expression in the subject. In some embodiments, the Coronavirus vaccine includes a SARS-CoV-2 vaccine. In some embodiments, the SARS-CoV-2 vaccine causes SARS-CoV-2 spike protein expression in the subject. In some embodiments, the subjects have Post-COVID symptoms.

[0023] In some embodiments, the methods include orally ingesting the formulation by the subject. In some embodiments, the oral ingesting occurs daily. In some embodiments, the oral ingesting occurs prior to a meal.

[0024] Some embodiments provided herein relate to methods of activating autophagy or suppressing autophagy dysregulation in a subject. In some embodiments, the methods include providing one or more formulations to a subject, wherein the one or more formulations includes a first formulation, the first formulation including an exogenous polyamine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyaminc; and a cofactor that increases production of the endogenous polyamine, the cofactor including Vitamin B6, Vitamin B9, Vitamin B 12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof.

[0025] In some embodiments, the methods include ingesting the one or more formulations by the subject. In some embodiments, the one or more formulations include a second formulation, and wherein the second formulation includes nattokinase. In some embodiments, the one or more formulations include a second formulation, and wherein the second formulation includes nattozime. In some embodiments, the second formulation includes bromelain.

[0026] In some embodiments, the one or more formulations include a third formulation. In some embodiments, the third formulation includes lunasin.

[0027] In some embodiments, the one or more formulations include a fourth formulation. In some embodiments, the fourth formulation includes an antioxidant precursor. In some embodiments, the antioxidant precursor includes NAC. In some embodiments, the antioxidant precursor includes a derivative of NAC. In some embodiments, the derivative of NAC includes N-acetylcysteine methyl ester, NACET, N- acetylcysteine propyl ester, or N- acetylcysteine butyl ester. In some embodiments, the derivative of NAC is converted to the NAC following an intracellular esterase contacting the derivative of NAC. In some embodiments, the methods include directing the NAC to neutralize one or more SARS-CoV- 2 spike proteins.

[0028] Some embodiments provided herein relate to methods of activating autophagy or suppressing autophagy dysregulation in a subject. In some embodiments, the methods include providing one or more formulations to a subject, wherein the one or more formulations includes a first formulation, the first formulation including an exogenous polyamine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; a cofactor that increases production of the endogenous polyamine, the cofactor including Vitamin B6, Vitamin B9, Vitamin B 12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof; and an antioxidant precursor. [0029] In some embodiments, the antioxidant precursor includes NAC. In some embodiments, the antioxidant precursor includes a derivative of NAC. In some embodiments, the derivative of NAC includes N-acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N-acetylcysteine butyl ester. In some embodiments, the derivative of NAC is converted to the NAC following an intracellular esterase contacting the derivative of NAC. In some embodiments, the methods include directing the NAC to neutralize one or more SARS- CoV-2 spike proteins.

[0030] In some embodiments, the methods include ingesting the one or more formulations by the subject. In some embodiments, the one or more formulations include a second formulation, and wherein the second formulation includes nattokinase. In some embodiments, the one or more formulations include a second formulation, and wherein the second formulation includes nattozime. In some embodiments, the second formulation includes bromelain. In some embodiments, the one or more formulations include a third formulation. In some embodiments, the third formulation includes lunasin.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to describe the manner in which the above-recited and other advantages and features of the invention can be obtained, a more particular description will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. Understanding that these drawings depict only typical embodiments and are not therefore to be considered to be limiting of its scope, the invention will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

[0032] FIG. 1 illustrates a spike protein interfering with an intracellular autophagy process.

[0033] FIG. 2 illustrates a composition restoring the autophagy process according to some embodiments.

[0034] FIG. 3 is a schematic diagram illustrating a method of activating autophagy or suppressing autophagy dysregulation according to some embodiments.

[0035] FIG. 4 is a schematic diagram illustrating a method of activating autophagy or suppressing autophagy dysregulation according to some embodiments. DETAILED DESCRIPTION

[0036] In the Summary Section above and the Detailed Description Section, and the claims below, reference is made to particular features of the invention. It is to be understood that the disclosure of the invention in this specification includes all possible combinations of such particular features. For example, where a particular feature is disclosed in the context of a particular aspect or embodiment of the invention, or a particular claim, that feature can also be used, to the extent possible, in combination with and/or in the context of other particular aspects and embodiments of the invention, and in the invention generally.

[0037] Several studies have demonstrated the role of autophagy in human health and disease. For example, autophagy dysfunction has been linked to neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, as well as liver damage in patients with anorexia nervosa. On the other hand, upregulation of autophagy has been shown to promote longevity and improve overall health span. Mizushima, 2008; Rubinsztein, 2011; Rautou, 2008; Komatsu, 2010.

[0038] Autophagy plays a critical role in the removal of cellular debris, including damaged organelles, misfolded proteins, and other intracellular components. This process is essential for maintaining cellular homeostasis and preventing the accumulation of toxic molecules, damaged proteins, and/or organelles that can contribute to the development of diseases.

[0039] An important function of autophagy is the removal of toxins and harmful agents from the body. Toxins and other harmful agents can be internalized by cells and may accumulate over time, leading to cellular damage and dysfunction. Autophagy plays a crucial role in removing these harmful agents by engulfing and degrading them within the lysosome. This process is especially important in the liver and other organs responsible for detoxification, where autophagy helps to clear out unwanted or harmful substances.

[0040] Autophagy also plays a critical role in removing damaged and diseased cells from the body. In some cases, cells can become damaged due to oxidative stress, DNA damage, or other factors. These damaged cells can become a source of chronic inflammation and contribute to the development of various diseases. Autophagy helps to remove these cells from the body by recognizing and engulfing them within an autophagosome. This process is known as selective autophagy and is important for maintaining tissue homeostasis and preventing the accumulation of damaged cells.

[0041] Furthermore, autophagy plays an important role in removing viral components and other intracellular pathogens from the body. Many viruses rely on host cells to replicate and spread, and some can evade the immune system by replicating within cells. Autophagy can recognize and target viral components within infected cells, leading to their degradation within the lysosome. This process is important for limiting viral replication and spreading within the body.

[0042] Autophagy is a critical process for maintaining cellular homeostasis and removing harmful substances, damaged cells, viral components, and other debris from the body. Dysregulation of autophagy can contribute to the development of various diseases, highlighting the importance of understanding and regulating this process for therapeutic interventions.

[0043] A non-limiting example of the type of dysregulation caused by viruses and viral components is that the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may interfere with the autophagy process in human cells. Specifically, with reference to FIG. 1, the spike protein 122 within the cell 100 (the latter indicated by the lipid bilayer cellular membrane 110) may induce the formation of autophagosomes 120, but inhibits the fusion of these autophagosomes with lysosomes 130, thereby preventing the degradation of their contents. Without being bound by theory, it is believed that the cytokine storm responsible for disease severity and death in COVID-19 patients may result from SARS-CoV- 2-induced autophagy dysfunction. Zhou, May 2021. Zhou, July 2021. Lakshmana, 2022. The SARS-CoV-2 spike protein in the coronavirus, SARS-CoV-2, (hereinafter, “viral spike protein”) is a trimeric glycoprotein that consists of three identical protein subunits, each with a molecular weight of approximately 180 kDa. The viral spike protein is responsible for binding to the ACE2 receptor on the surface of human cells, facilitating viral entry into the host cell. The viral spike protein has two subdomains: the SI subunit, which contains the receptor-binding domain (RBD), and the S2 subunit, which contains the fusion peptide and transmembrane domain. The RBD of the SI subunit binds to the ACE2 receptor, triggering a conformational change in the viral spike protein that exposes the fusion peptide of the S2 subunit. This enables the coronavirus to fuse with the host cell membrane and enter the cell. The viral spike protein is heavily glycosylated, meaning that it is covered in sugar molecules. These sugar molecules may help to shield the protein from recognition by the host immune system, which can make it more difficult for the immune system to mount an effective response against the virus.

[0044] In some embodiments, the SARS-CoV-2 spike protein that is expressed by the mRNA pay load provided by the SARS-CoV-2 vaccine is a modified form of the viral spike protein that has been stabilized in its prefusion conformation. The stabilized spike protein used in SARS-CoV-2 vaccines include the SI and S2 subunits, with the RBD of the SI subunit being the primary target for neutralizing antibodies. The stabilized spike protein is produced by expressing the DNA sequence encoding the protein in cells, such as mammalian cells or insect cells, and then purifying the protein from the cell culture supernatant. The stabilized spike protein used in the Pfizer-BioNTech and Moderna mRNA vaccines, as well as the Novavax protein subunit vaccine, contains two proline mutations (P986 and P987) that help to stabilize the protein in its prefusion conformation. The stabilized spike protein used in the Johnson & Johnson adenoviral vector vaccine, on the other hand, uses a similar stabilizing mutation (P708) as well as a modification to the furin cleavage site, which helps to enhance the immunogenicity of the protein.

[0045] Embodiments provided herein relate to composition and methods for targeting the mTOR signaling pathway, which regulates various cellular processes including autophagy and endolysosome function. In some embodiments, the compositions and methods are used as a therapeutic approach to suppress SARS-CoV-2 infection and COVID- 19 pathogenesis. In some embodiments, suppression is achieved through the inhibition of Mammalian target of rapamycin (mTOR) and activation of AMP-activated Protein Kinase (AMPK), a protein kinase that regulates energy homeostasis and is involved in the induction of autophagy. In some embodiments, the compositions include natural compounds, which are used to enhance endolysosome function and autophagy by inhibiting mTOR and activating AMPK. In some embodiments, the natural compounds include resveratrol and/or spermidine.

[0046] Accumulating evidence suggests potential inhibitory regulation by multiple CoVs on autophagy mechanism. For example, as similar to IBV and MERS-CoV, recently a preprint article demonstrated that the novel SARS-CoV-2 infection in bronchial epithelial cells (NCI-H1299) and monkey kidney cells (VeroFM) inhibits autophagy flux by limiting the activation of AMP-protein activated kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORCl), and thereby protecting viral particles from subsequent lysosomal degradation and assisting in replication process (Gassen et al., 2020). Moreover, SARS-CoV- 2 infection leads to downregulation of autophagy-inducing spermidine, and AKT1/SKP2- mediated proteasomal degradation of Beclin-1 (Gassen et al., 2019). Accordingly, embodiments provided herein relate to compositions and methods that specifically target these pathways using aliphatic polyamines, such as spermidine, used as dietary supplement and/or combination of AKT inhibitor and Beclin-1 stabilizing agent. In some embodiments, the compositions and methods are used in a subject in need thereof. In some embodiments, the subject is a COVID-19 patient. Non-selective cation channel inhibitors, such as ruthenium red or polyamine spermidine, block SARS-CoV-2 open reading frame 3a (ORF3a)-mediated ion conductance with IC50 of 90 ± 10 pM or 10 mM, respectively, in a manner that is unique from those of other known channels (Kern et al., 2021; Khan, 2021).

[0047] Without being bound by theory, the expression of the viral protein, ORF3a, from SARS-CoV-2 induces incomplete autophagy. SARS-CoV-2 encodes 28 viral proteins, including 16 non-structural proteins (nspl to nspl6), four structural proteins [glycoprotein spike (S), membrane (M), envelope (E), and nucleocapsid (N)], and 8 accessory proteins (ORF3a, ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORF9c, and ORF10) (Qu et al., 2021). According to Qu, SARS-CoV-2 ORF3a targets the autophagy regulator UV radiation resistance-associated gene protein (UVRAG) to module Beclin 1 complexes by disrupting PI3KC3-C2 (Beclin 1-Vps34-UVRAG) and facilitating PI3KC3-C1, thereby elevating autophagosome formation and blocking autophagosome maturation. Mechanistically, with reference to FIG. 1, the activity of SARS-CoV-2 ORF3a results in the generation of doublemembrane autophagosome vesicles to facilitate viral replication but arrests the autophagosomes prior to lysosome fusion to avoid succumbing to lysosomal degradation (Qu et al., 2021).

Definitions

[0048] Terms used herein will be understood to take on their ordinary meaning in the relevant art unless specified otherwise. Several terms used herein and their meanings are set forth below. [0049] The section headings used herein are for organizational purposes only and arc not to be construed as limiting the subject matter described.

[0050] As used herein, term “and/or” shall be taken to provide explicit support for both meanings or for either meaning.

[0051] As used herein, the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0052] The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The singular forms “a,” “an,” and “the” refer to one or more than one, unless the context clearly dictates otherwise. For example, the term “comprising a nucleic acid molecule” includes single or plural nucleic acid molecules and is considered equivalent to the phrase “comprising at least one nucleic acid molecule.” The term “or” refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, “comprises” means “includes.” Thus, “comprising A or B,” means “including A, B, or A and B,” without excluding additional elements. Unless otherwise specified, the definitions provided herein control when the present definitions may be different from other possible definitions.

[0053] As used herein, the term “exogenous” refers to something that originates outside of the organism or system that it affects. As used herein, the term “polyamines” refer to compounds that contain two or more amino groups (-NH2). As used herein, the “exogenous polyamines” refer to compounds that contain two or more amino groups and originate outside of an organism or system into which these compounds are introduced. The exogenous polyamines may be synthetic. The exogenous polyamines may be synthetically made. The exogenous polyamines may be synthesized in organisms, where the organisms are genetically modified or not.

[0054] As used herein, the term “precursor” refers to a substance that is converted into another substance by a series of reactions. In other words, it is a substance that serves as a building block or starting material for the synthesis of other molecules, such as proteins, hormones, neurotransmitters, and enzymes. In some non- limiting examples, amino acids are precursors for protein synthesis, while cholesterol is a precursor for the synthesis of steroid hormones, such as testosterone and estrogen. The availability and regulation of precursors play a crucial role in various biological processes and metabolic pathways in living organisms.

[0055] As used herein, the term “cofactor” refers to a non-protein compound that is required for the proper functioning of certain enzymes in biological systems. These cofactors are often inorganic ions, such as magnesium, zinc, and iron, or organic molecules, such as vitamins or coenzymes. Cofactors work by binding to enzymes and modifying their activity, either by facilitating substrate binding, stabilizing the transition state of the reaction, or donating or accepting chemical groups during the reaction. In a non-limiting example, the enzyme lactase requires zinc as a cofactor for its enzymatic activity, while the enzyme pyruvate dehydrogenase requires the coenzyme thiamine pyrophosphate (TPP) for its activity. Cofactors are essential for the proper functioning of many biological processes, including metabolism, DNA synthesis, and cell signaling, and their deficiency or absence can lead to various diseases and disorders.

[0056] As used herein, the term “activator” refers to a substance that enhances the activity of an enzyme or metabolic pathway. While an activator is not always required for enzyme activity, activators can increase the rate of the reaction. Activators can be small molecules, that include (but are not limited to) metabolites, polyphenols, allosteric modulators or inhibitors; or larger molecules that include (but are not limited to) other enzymes or proteins. Polyphenols are a group of organic compounds characterized by the presence of two or more phenolic hydroxyl groups (-OH) in their molecular structure.

[0057] As used herein, the term “synthesizer” refers to a biological system or organism that is capable of synthesizing complex molecules or compounds using biological processes. These synthesizers can be natural, such as plants and microorganisms, or genetically engineered organisms that are designed to produce specific molecules. Biological synthesizers work by using enzymes, metabolic pathways, and cellular machinery to convert simple molecules or precursors into complex molecules. In a non-limiting example, bacteria such as Escherichia coli can be engineered to produce insulin or other therapeutic proteins through recombinant DNA technology.

[0058] As used herein, the term “probiotics” refers to live microorganisms that are beneficial to human health when consumed in adequate amounts. These microorganisms are typically bacteria or yeasts that are similar to those found naturally in the human gut. Some of the potential health benefits of probiotics include improved digestion and bowel regularity, reduced inflammation, enhanced immune function, and decreased risk of certain diseases such as diarrhea, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD).

[0059] In some embodiments, compositions for activation of autophagy in the body are provided. In some embodiments, the compositions include one or more exogenous polyamine, one or more precursor to the endogenous polyamine, and one or more cofactor that increases production of endogenous poly amines. In some embodiments, the exogenous polyamine includes spermidine, spermine, putrescene, or a combination thereof. In some embodiments, the exogenous polyamine suppresses autophagy dysregulation. With reference to FIG. 2, in some embodiments, the composition 230 suppresses autophagy dysregulation by removing the inhibition of fusion between the autophagosome and lysosome, as illustrated in FIG. 1, that is induced by the spike protein 222. With the suppression of the inhibitory effects of the spike protein 222, the merging 200 of the autophagosome and lysosome can occur as illustrated by the autophagosome-lysosome complex 220. As shown, the lysosomal enzymes 232 responsible for the hydrolysis of many different kinds of biomolecules, including but not limited to the spike protein 222, are allowed to enter the autophagosome and hydrolyze, thus degrading, the contents of the autophagosome. Accordingly, the spike protein 222 is degraded and can no longer disrupt the cell’s autophagy process.

[0060] In some embodiments, an amount of the exogenous polyamine in the composition is between 250 pg to 50 mg, such as 250, 260, 270, 280, 290, 300, 325, 350, 375, 400, 450, 500, 550, 600, 700, 800, 900, or 1000 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg, or an amount within a range defined by any two of the aforementioned values. In some embodiments, the composition is formulated as a capsule, a tablet, a gummy, a granule, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. In some embodiments, a subject may ingest one or more of the capsule, tablet, gummy, granule, stick pack, powder, beverage, syrup, suspension, or food. In some embodiments, the capsule is a vegetable capsule, including, for example, water and hypromellose. In some embodiments, the formulations further include rice hull. In some embodiments, the composition is orally ingested. In some embodiments, the composition is ingested daily. In some embodiments, the composition is ingested daily at the same time. In some embodiments, the composition is ingested prior to a meal. In some embodiments, the composition is ingested about 1 to about 60 minutes prior to the meal, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes or within a time frame defined by any two of the aforementioned values, prior to the meal.

[0061] In some embodiments, the precursor increases the production of the endogenous poly amines. In some embodiments, the one or more precursor is ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, y- aminobutyric acid (GABA), hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof. In some embodiments, an amount of the precursor is between 125 pg to 500 mg, such as 125, 130, 135, 140, 145, 150, 155, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 325, 350, 375, 400, 450, 500, 550, 600, 700, 800, 900, or 1000 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 mg, or an amount within a range defined by any two of the aforementioned values. In some embodiments, a ratio of the precursor to the exogenous polyamine is between l:10 to 1:1, such as 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, or an amount within a range defined by any two of the aforementioned ratios. Ornithine is a precursor of polyamines, and its conversion to putrescine is a step in polyamine biosynthesis. Arginine is an amino acid that can be converted to ornithine by the enzyme arginase, where the ornithine then serves as a precursor for poly amines. Proline is an amino acid that can be converted to pyrroline-5 -carboxylate, which is a precursor of ornithine (conversion to ornithine is catalyzed by the enzyme ornithine aminotransferase (OAT)) and, therefore, polyamines. Glutamine is an amino acid can provide the amine group required for the synthesis of ornithine and, subsequently, polyamines. Methionine can be converted to S-adenosylmethionine (SAM), which is a methyl donor for the synthesis of the polyamines spermidine and spermine. Alanine and serine are amino acids that are involved in the synthesis of pyrimidine nucleotides, which are important for DNA and RNA synthesis. Polyamines are also involved in DNA and RNA synthesis, and therefore, the increased production of nucleotides can indirectly increase polyamine synthesis. Lysine is a precursor of cadaverine, which is a polyamine. GABA can be converted to polyamines through the action of the enzyme diamine oxidase. Hydroxyproline is a precursor of ornithine and, therefore, polyamines. Malic acid can increase the activity of ornithine decarboxylase (ODC), which is the rate-limiting enzyme in polyamine biosynthesis. ODC catalyzes the conversion of ornithine to putrescine, which is the first step in the biosynthesis of polyamincs. Aspartic acid is an amino acid that can provide the amine group required for the synthesis of ornithine and, subsequently, polyamines. Isoleucine, tyrosine, valine, and leucine are amino acids that can be converted to acetyl-CoA, which is a precursor of SAM and, therefore, poly amines. Adenine is a precursor of S-adenosyladenosine, which is a methyl donor for the synthesis of spermidine and spermine.

[0062] In some embodiments, the one or more cofactor includes Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, chromium, copper, manganese, lithium, or a combination thereof. In some embodiments, an amount of the cofactor is between 10 pg to 500 mg, such as 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 325, 350, 375, 400, 450, 500, 550, 600, 700, 800, 900, or 1000 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 mg, or an amount within a range defined by any two of the aforementioned values. In some embodiments, a ratio of the cofactor to the exogenous polyamine is between 1: 10 to 1:1, such as 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, or an amount within a range defined by any two of the aforementioned ratios. Vitamin B6, also known as pyridoxine, is a cofactor for the enzyme ODC, which catalyzes the conversion of ornithine to putrescine, an early step in the biosynthesis of polyamines. Vitamin B9, or folate, is also important for polyamine biosynthesis. Folate is involved in the transfer of one-carbon units in various metabolic pathways, including the biosynthesis of purines and thymidine, which are precursors for DNA synthesis. Folate is also involved in the biosynthesis of SAM, which is a methyl donor for the biosynthesis of polyamines. Vitamin B12, or cobalamin, is a cofactor for the enzyme methionine synthase, which catalyzes the conversion of homocysteine to methionine, a precursor for SAM synthesis. SAM is a methyl donor for the biosynthesis of polyamines, and adequate levels of Vitamin B12 are necessary for the activity of methionine synthase and subsequent SAM and polyamine biosynthesis. Vitamin C, also known as ascorbic acid, is an antioxidant that can stimulate polyamine biosynthesis by increasing the activity of ODC. Vitamin C can also increase the activity of the enzyme spermidine synthase, which catalyzes the conversion of spermidine to spermine. Vitamin D has been shown to increase the expression of ODC and spermidine synthase, leading to increased polyaminc biosynthesis. Zinc is a trace element that is involved in numerous biochemical pathways. Zine can increase the activity of ODC, which leads to increased polyamine biosynthesis. Zinc can also increase the expression of the genes encoding ODC and spermidine synthase, further stimulating polyamine biosynthesis. Magnesium can increase the activity of ODC, leading to increased polyamine biosynthesis. Selenium can increase the activity of ODC and spermidine synthase, leading to increased polyamine biosynthesis. In some embodiments, an amount of selenium is present in an amount ranging from about 15 pg to about 500 pg, such as 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 pg, or an amount within a range defined by any two of the aforementioned values. Copper can increase the activity of ODC, leading to increased polyamine biosynthesis. Manganese can increase the activity of ODC and spermidine synthase, leading to increased polyamine biosynthesis. Chromium may indirectly modulate polyamine synthesis through its influence on insulin sensitivity and glucose metabolism.

[0063] Lithium is used as a mood stabilizing drug to treat psychological disorders, such as bipolar disorders. Lithium also counteracts the neuroinllammatory effects of the SARS-CoV-2 spike protein. Brain fog, often experienced by individuals suffering from long COVID or vaccine injuries, is thought to result from neuroinflammatory damage inflicted by the spike protein. The spike protein triggers a series of immune responses in brain immune cells, culminating in the production of pro-inflammatory cytokines. Glycogen synthase kinase- 3 (GSK-3), a highly active kinase, plays a pivotal role in regulating the balance between pro- and anti-inflammatory cytokine production. Moreover, GSK-3 governs gene expression by modulating the levels of transcription factors in neural progenitors. Lithium, a natural inhibitor of GSK-3, holds potential in mitigating this cascade of events. At an amount from about 0.5 to about 10 mg, lithium thwarts cytokine storms and alleviates the inflammatory response. Additionally, in neurodegenerative diseases like Parkinson’s and Alzheimer’s, lithium supplementation may activate adult hippocampal neurogenesis, facilitating the generation of new brain cells in the adult brain. This multifaceted mechanism underscores the therapeutic effect of lithium in addressing both acute and chronic neurological conditions. In some embodiments, an amount of lithium is present in the composition in an amount ranging from about 0.1 mg to about 20 mg, such as 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg, or an amount within a range defined by any two of the aforementioned values. In some embodiments, the amount of lithium is present in an amount ranging from about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg, or an amount within a range defined by any two of the aforementioned values.

[0064] In some embodiments, the compositions further include an activator that increases production of the endogenous polyamines. In some embodiments, the activator includes a polyphenol. In some embodiments, the polyphenol includes resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, fisetin, luteolin, or epigallocatechin gallate (EGCG), or a combination thereof. In some embodiments, an amount of the activator is between 125 pg to 1000 mg, such as 125, 130, 135, 140, 145, 150, 155, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 325, 350, 375, 400, 450, 500, 550, 600, 700, 800, 900, or 1000 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, or 1000 mg, or an amount within a range defined by any two of the aforementioned values. In some embodiments, a ratio of the activator to the exogenous polyamine is between 1:10 to 1:1, such as 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, or an amount within a range defined by any two of the aforementioned ratios. In some embodiments, the EGCG includes green tea powders and extracts. Resveratrol is a polyphenol that has been shown to increase polyamine levels by stimulating the expression of ODC and spermidine synthase. Quercetin is a flavonoid found in various fruits and vegetables that has been shown to increase polyamine levels by inhibiting the activity of polyamine oxidase, the enzyme that degrades polyamines. Berberine is an alkaloid found in various plants, including barberry and goldenseal, which has been shown to increase polyamine levels by stimulating the expression of ODC and spermidine synthase. Lipoic acid is a compound that is involved in various metabolic processes and has been shown to increase polyamine levels by stimulating the expression of ODC and spermidine synthase. Curcumin is a polyphenolic compound found in turmeric that has been shown to increase polyamine levels by stimulating the expression of ODC and spermidine synthase. Grape seed extract is a rich source of polyphenolic compounds, including proanthocyanidins, that have been shown to increase polyamine levels by stimulating the expression of ODC and spermidine synthase. Fisetin is a flavonoid found in various fruits and vegetables that has been shown to increase polyamine levels by inhibiting the activity of polyaminc oxidase. Lutcolin is a flavonoid found in various plants, including parsley and celery, which has been shown to increase polyamine levels by stimulating the expression of ODC and spermidine synthase. EGCG is a catechin found in green tea that has been shown to increase polyamine levels by stimulating the expression of ODC and spermidine synthase.

[0065] In some embodiments, the compositions further include a synthesizer that increases production of the endogenous poly amines. In some embodiments, an amount of the synthesizer is between 1 x 10⁸ to 5 x IO¹⁰ CFU, such as 2 x 10⁸, 3 x 10⁸, 4 x 10⁸, 5 x 10⁸, 6 x

10⁸, 7 x 10⁸, 8 x 10⁸, 9 x 10⁸, 1 x 10⁹, 2 x 10⁹, 3 x 10⁹, 4 x 10⁹, 5 x 10⁹, 6 x 10⁹, 7 x 10⁹, 8 x

10⁹, 9 x 10⁹, 1 x IO¹⁰, 2 x IO¹⁰, 3 x IO¹⁰, 4 x IO¹⁰, or 5 x IO¹⁰ CFU, or an amount within a range defined by any two of the aforementioned values. As used herein, “CFU” stands for Colony-Forming Units. In some embodiments, the synthesizer includes a probiotic. In some embodiments, the probiotic includes Lactobacillus, Bifidobacterium, Streptococcus thermophilus, Enterococcus faecalis, Escherichia coli, or a combination thereof. In some embodiments, an amount of the probiotic is between 1 x 10⁸ to 5 x IO¹⁰ CFU, such as 2 x 10⁸, 3 x 10⁸, 4 x 10⁸, 5 x 10⁸, 6 x 10⁸, 7 x 10⁸, 8 x 10⁸, 9 x 10⁸, 1 x 10⁹, 2 x 10⁹, 3 x 10⁹, 4 x 10⁹, 5 x 10⁹, 6 x 10⁹, 7 x 10⁹, 8 x 10⁹, 9 x 10⁹, 1 x IO¹⁰, 2 x IO¹⁰, 3 x IO¹⁰, 4 x IO¹⁰, or 5 x IO¹⁰ CFU, or an amount within a range defined by any two of the aforementioned values. Lactobacillus and Bifidobacterium are able to produce putrescine, spermidine, and spermine. Some non-limiting examples of species from Lactobacillus and Bifidobacterium include Lactobacillus acidophilus, Lactobacillus plantarum, and Bifidobacterium lactis. Streptococcus thermophilus is a lactic acid bacteria that produces arginine decarboxylase (ADC), which is capable of converting arginine into the polyamine putrescine. While a polyamine, putrescine serves as a precursor to other polyamines such as spermidine and spermine. When putrescine is produced by Streptococcus thermophilus, the produced- putrescine is taken up by the host’s cells and can be used for the synthesis of other polyamines. Further, Streptococcus thermophilus can stimulate the growth of other bacteria that are known to produce polyamines, such as Escherichia coli, through the production of various compounds like lactic acid and acetic acid. These compounds can create a favorable environment for the growth of these bacteria, leading to an increase in polyamine production. Enterococcus faecalis produces an enzyme called agmatine deiminase, which is capable of converting the amino acid arginine into agmatine, and then converting agmatine into putrescine, a polyamine, and a precursor to other polyamincs. Additionally, Enterococcus faecalis stimulates growth of other bacteria that promotes polyamine production such as Escherichia coli. Similarly to Streptococcus thermophilus. Enterococcus faecalis creates a favorable environment for the growth of these polyamine producing/stimulating bacteria by production of various compounds such as lactic acid. Further, Enterococcus faecalis is involved in various catabolic pathways that break down complex proteins and peptides, which can lead to increased bioavailability of amino acids such as arginine that is used to produce polyamines. Escherichia coli produces the enzymes ODC and ADC, which convert ornithine and arginine, respectively, into putrescine and agmatine, the latter being a precursor in the synthesis of the polyamine putrescine. Escherichia coli can also increase polyamine levels by producing compounds that enhance the growth of other polyamine-producing bacteria, such as Streptococcus thermophilus and Enterococcus faecalis . These compounds include short-chain fatty acids like acetate and butyrate, which can create a favorable environment for the growth of these bacteria. Additionally, Escherichia coli can increase the availability of amino acids via the breakdown of complex proteins and peptides into individual amino acids.

[0066] In some embodiments, the synthesizer includes a prebiotic. As used herein, the term “prebiotic” refers to a type of non-digestible fiber found in various foods that promotes the growth of beneficial bacteria in the gut. Without being bound by theory, prebiotics promote this growth by serving as food for these bacteria, whereby the fermentation of prebiotics by these bacteria can lead to the production of beneficial short-chain fatty acids and other metabolites that support gut health and function. In some embodiments, the prebiotic includes fructooligosaccharides (FOS). FOS are a type of carbohydrate, specifically a prebiotic fiber, composed of short chains of fructose molecules. They are found naturally in various plants, including onions, garlic, asparagus, bananas, and leeks. FOS serves as a food source for beneficial gut bacteria, such as Bifidobacterium and Lactobacillus species, thereby promoting their growth and activity in the digestive system. In some embodiments, the prebiotic includes an inulin. Inulins are a type of soluble fiber that promotes the growth of beneficial bacteria in the gut and are found in chicory root, asparagus, leeks, onions, garlic, and artichokes. In some embodiments, the prebiotic includes galactooligosaccharides (GOS). GOS arc found in dairy products and are known for their bifidogenic effects, which includes supporting the growth of Bifidobacteria in the gut. In some embodiments, the prebiotic includes isomaltooligosaccharidcs (IMO). IMO’s arc produced from starch and found in honey and fermented foods and are a type of prebiotic fiber that can stimulate the growth of beneficial gut bacteria. In some embodiments, the prebiotic includes beta-glucans. Beta-glucans are found in cereal grains including, but not limited to, oats and barley. Beta-glucans are soluble fibers that promote the growth of healthy gut bacteria. In some embodiments, the prebiotic includes pectin. Pectin is a heteropolysaccharide rich in galacturonic acid that is a soluble fiber. In the gut, the dissolved pectin forms a gel-like substance that helps slow down the absorption of glucose and bind to cholesterol. Additionally, pectin promotes the growth of beneficial bacteria. In some embodiments, an amount of the prebiotic is between 1 x 10⁸ to 5 x IO¹⁰ CFU, such as 2 x 10⁸, 3 x 10⁸, 4 x 10⁸, 5 x 10⁸, 6 x 10⁸, 7 x 10⁸, 8 x 10⁸, 9 x 10⁸, 1 x 10⁹, 2 x 10⁹, 3 x 10⁹, 4 x 10⁹, 5 x 10⁹, 6 x 10⁹, 7 x 10⁹, 8 x 10⁹, 9 x 10⁹, 1 x IO¹⁰, 2 x IO¹⁰, 3 x IO¹⁰, 4 x IO¹⁰, or 5 x IO¹⁰ CFU, or an amount within a range defined by any two of the aforementioned values. [0067] In some embodiments, the compositions further include an AKT inhibitor. As used herein, “AKT” is a family of serine/threonine protein kinases encoded by three genes AKT1, AKT2, and AKT3. All three AKT proteins have an N-terminal PH (pleckstrin homology) domain, a serine/threonine- specific kinase domain and a C-terminal regulatory domain. These proteins are phosphorylated by phosphoinositide 3-kinase (PI3K). AKT/PI3K forms a key component of many signaling pathways that involve the binding of membranebound ligands such as receptor tyrosine kinases, G-protein coupled receptors, and integrin- linked kinase. In some embodiments, the AKT inhibitor is orally active. In some embodiments, the AKT inhibitor includes MK-2206, perifosine, GSK690693, AZD5363, A-443654, or a combination thereof. In some embodiments, an amount of the AKT inhibitor is 125 pg to 50 mg, such as 125, 130, 135, 140, 145, 150, 155, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 325, 350, 375, 400, 450, 500, 550, 600, 700, 800, 900, or 1000 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg, or an amount within a range defined by any two of the aforementioned values. In some embodiments, a ratio of the AKT inhibitor to the exogenous polyamine is between 1:10 to 1:1, such as 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, or an amount within a range defined by any two of the aforementioned ratios. MK-2206 and perifosine is an orally active allosteric inhibitor of AKT. GSK690693 is a potent and selective inhibitor of AKT. AZD5363 is an orally active inhibitor of all three isoforms of AKT. A-443654 is a selective inhibitor of AKT1 isoform.

[0068] In some embodiments, the compositions further include a Beclin-1 stabilizing agent. In some embodiments, an amount of the Beclin-1 stabilizing agent is 125 pg to 50 mg, such as 125, 130, 135, 140, 145, 150, 155, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 325, 350, 375, 400, 450, 500, 550, 600, 700, 800, 900, or 1000 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg, or an amount within a range defined by any two of the aforementioned values. In some embodiments, a ratio of the Beclin-1 stabilizing agent to the exogenous polyamine is between 1:10 to 1:1, such as 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, or an amount within a range defined by any two of the aforementioned ratios. In some embodiments, the Beclin-1 stabilizing agent includes lithium. In some embodiments, the Beclin-1 stabilizing agent includes curcumin, which is found in the spice turmeric. In some embodiments, the Beclin-1 stabilizing agent includes the polyphenol resveratrol. In some embodiments, the Beclin-1 stabilizing agent includes rapamycin. Rapamycin is a macrolide that has been found to inhibit the mTOR pathway, a key regulator of autophagy. Macrolides are compounds that feature large (14-16-membered) lactone rings and reduced saccharide substituents.

[0069] In some embodiments, the composition includes an antioxidant precursor. In some embodiments, the antioxidant precursor includes N-Acetyl-L-cysteine (NAC) or any derivative of NAC, including, for example, N-acetylcysteine methyl ester, N-acetylcysteine ethyl ester, N-acetylcysteine propyl ester, or N-acetylcysteine butyl ester. NAC itself is a derivative of the amino acid L-cysteine. Without being bound by theory, NAC combines in the body with glycine to create glutathione, an antioxidant that is useful in conditions associated with oxidative stress and inflammation. In view of SARS-CoV-2 spike proteins, the function and activity of these spike proteins are impaired by disulfide-bond disruption with mutation at cysteine-488 and by thiol-reactive NAC and glutathione. However, the ability of NAC to cross cellular membranes and the blood-brain barrier is poor. To improve the bioavailability of NAC, a derivative of NAC is preferred. In some embodiments, the derivative of NAC includes NAC ethyl ester (NACET). Without being bound by theory, NACET is 1000 times more permeable to cells, and up to 20 times more bioavailable than NAC, due to the ability of NACET to cross cellular membranes and the blood-brain barrier. After NACET enters into the cell, intracellular esterases cleave the ethyl ester group from the NACET to yield NAC and ethanol in a hydrolysis reaction: NACET + H2O — > NAC + Ethanol. Thereafter, the freed NAC can exert its antioxidant effects within the cell at least by increasing/replenishing intracellular glutathione levels. In some embodiments, the NACET is an amount ranging from about 50 mg to about 400 mg, such as 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, and 400 mg, or an amount within a range defined by any two of the aforementioned values.

[0070] In some embodiments, the compositions are formulated as an oral formulation. In some embodiments, the oral formulation includes a base composition which includes a precursor to an endogenous polyamine and a cofactor and an activator that increases production of endogenous polyamines. In some embodiments, the precursor includes ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, GABA, hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof. As set forth above, any of these precursors, or combinations thereof, can increase the production of endogenous polyamines. In some embodiments, the cofactor includes Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, copper, manganese, or a combination thereof. As set forth above, any of these cofactors, or combinations thereof, can increase the production of endogenous polyamines. In some embodiments, the one or more activator includes a polyphenol. In some embodiments, the polyphenol includes resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, fisetin, luteolin, or EGCG, or a combination thereof. In some embodiments, the EGCG includes green tea powders and extracts. As set forth above, any of these activators, or combinations thereof, can increase the production of endogenous poly amines.

[0071] In some embodiments, the oral formulation further includes an exogenous polyamine. In some embodiments, the exogenous polyamine includes spermidine, spermine, putrescine, or a combination thereof. In some embodiments, an amount of the exogenous polyamine in the oral formulation is between 250 pg to 50 mg. In some embodiments, the oral formulation is formulated as a capsule, a tablet, a gummy, a granule, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. In some embodiments, the oral formulation is orally ingested. In some embodiments, the oral formulation is orally ingested daily. In some embodiments, the oral formulation is orally ingested daily at the same time of the day. In some embodiments, the oral formulation is ingested prior to a meal. In some embodiments, the oral formulation is ingested about 1 to about 60 minutes prior to the meal, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes or within a time frame defined by any two of the aforementioned values, prior to the meal.

[0072] In some embodiments, the oral formulation further includes a probiotic that increases production of the endogenous polyamines. In some embodiments, the probiotic includes Lactobacillus, Bifidobacterium, Streptococcus thermophilus, Enterococcus faecalis, Escherichia coli, or a combination thereof. In some embodiments, an amount of the probiotic in the oral formulation is between 1 x 10⁸ to 5 x 10¹⁰ CFU. As set forth above, any of these probiotics, or a combination thereof, can increase the production of endogenous polyamines. In some embodiments, the oral formulation further includes a prebiotic that fosters the growth of probiotics in the gut. In some embodiments, the prebiotic includes FOS, inulin, GOS, IMO, beta-glucan, pectin, or a combination thereof. In some embodiments, an amount of the prebiotic in the oral formulation is between 1 x 10⁸ to 5 x 10¹⁰ CFU.

[0073] In some embodiments, the oral formulation further includes an AKT inhibitor. In some embodiments, the AKT inhibitor MK-2206, perifosine, GSK690693, AZD5363, A-443654. In some embodiments, the oral formulation further includes a Beclin-1 stabilizing agent. In some embodiments, the oral formulation inhibits mammalian target of rapamycin (mTOR). In some embodiments, the oral formulation activates AMP-protein activated kinase (AMPK). In some embodiments, the oral formulation inhibits mTOR and activates AMPK. In some embodiments, the oral formulation activates autophagy. In some embodiments, the oral formulation suppresses autophagy dysregulation. In some embodiments, the oral formulation activates autophagy and suppresses autophagy dysregulation.

[0074] In some embodiments, the compositions include a physiologically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the ail, and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, and flavoring agents may be provided in the therapeutic composition. For example, sodium benzoate and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. The physiologically acceptable carrier may also include, for example, one or more of the following: antioxidants including ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, such as serum albumin, gelatin, immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids, carbohydrates including glucose, mannose, or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, salt-forming counter ions such as sodium, and nonionic surfactants such as Tween™, polyethylene glycol (PEG), and Pluronics™. Auxiliary, stabilizer, emulsifier, lubricant, binder, pH adjustor controller, isotonic agent and other conventional additives may also be added to the carriers.

[0075] The carrier may include other compounds known to be beneficial to an impaired situation of the GI tract, (for example, antioxidants, such as Vitamin C, Vitamin E, Selenium or Zinc); or a food composition. The food composition can be, but is not limited to, milk, yogurt, curd, cheese, fermented milks, milk based fermented products, ice-creams, fermented cereal based products, milk based powders, infant formulae, tablets, liquid bacterial suspensions, dried oral supplement, or wet oral supplement.

[0076] In some embodiments, the oral formulation is formulated for ingestion of the oral formulation by a subject. In some embodiments, the subject has cancer. In some embodiments, the subject has a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the subject has a metabolic disorder. In some embodiments, the subject has anorexia nervosa. In some embodiments, the subject has a viral infection. In some embodiments, the viral infection includes a respiratory illness or symptoms of the respiratory illness. In some embodiments, the respiratory illness is caused by a Coronavirus. In some embodiments, the Coronavirus is SARS-2-CoV. In some embodiments, the subjects have Post-COVID symptoms. In some embodiments, the subject was previously provided a vaccine. In some embodiments, the subject is about to receive a vaccine. In some embodiments, the subject is receiving a vaccine. In some embodiments, the vaccine includes a Coronavirus vaccine. In some embodiments, the Coronavirus vaccine causes spike protein expression in the subject. In some embodiments, the Coronavirus vaccine includes a SARS-CoV-2 vaccine. In some embodiments, the SARS-CoV- 2 vaccine causes SARS-CoV-2 spike protein expression in the subject. In some embodiments, the SAR-CoV-2 spike protein expressed by an mRNA payload provided by the SAR-CoV-2 vaccine is modified from the SARS-CoV-2 spike protein found in the coronavirus, SARS- CoV-2. In some embodiments, the Post-COVID symptoms are caused by the SARS-CoV-2 vaccine.

[0077] With reference to FIG. 3, in some embodiments, a method 300 to activate autophagy and suppress autophagy dysregulation in a subject in need is provided, the method 300 including providing 310 a formulation to the subject for improving effects of a disorder, wherein the formulation includes an exogenous polyamine including spermidine, spermine, putrescine, or a combination thereof; a precursor to the endogenous polyamine; and a cofactor that increases production of endogenous polyamines, the cofactor including Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, copper, manganese, or a combination thereof. In some embodiments, the method 300 includes the subject orally ingesting 320 the formulation. In some embodiments, the oral ingesting step 320 occurs daily. In some embodiments, the oral ingesting step 320 occurs daily at the same time of the day. In some embodiments, the oral ingesting step 320 occurs prior to a meal. In some embodiments, the oral ingesting step occurs about 1 to about 60 minutes prior to the meal, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes or within a time frame defined by any two of the aforementioned values, prior to the meal.

[0078] In some embodiments, an effective amount of the formulation provided to the subject is an amount greater than about 500 pg, such as greater than 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 pg, or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, or 3000 mg.

[0079] In some embodiments, an effective amount of the formulation provided to the subject is an amount ranging from about 500 pg to about 3000 mg, such as 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, or 3000 mg, or an amount within a range defined by any two of the aforementioned values.

[0080] In some embodiments, an effective amount of the formulation is an amount of at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 950, or at least 1000 pg; or at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40 at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1050 mg, at least 1100 mg, at least 1150 mg, at least 1200 mg, at least 1250 mg, at least 1300 mg, at least 1350 mg, at least 1400 mg, at least 1450 mg, at least 1500 mg, at least 1550 mg, at least 1600 mg, at least 1650 mg, at least 1700 mg, at least 1750 mg, at least 1800 mg, at least 1850 mg, at least 1900 mg, at least 1950 mg, at least 2000 mg, at least 2050 mg, at least 2100 mg, at least 2150 mg, at least 2200 mg, at least 2250 mg, at least 2300 mg, at least 2350 mg, at least 2400 mg, at least 2450 mg, at least 2500 mg, at least 2550 mg, at least 2600 mg, at least 2650 mg, at least 2700 mg, at least 2750 mg, at least 2800 mg, at least 2850 mg, at least 2900 mg, at least 2950 mg, or at least 3000 mg, or an amount within a range defined by any two of the aforementioned values.

[0081] In some embodiments, the subject suffers from cancer. In some embodiments, the subject suffers from a neurogenerative disease. In some embodiments, the subject suffers from a metabolic disorder. In some embodiments, the subject suffers from COVID-19. In some embodiments, the subject suffers symptoms associated with Post-CO VID.

[0082] In some embodiments, a method 400 to activate autophagy and suppress autophagy dysregulation in a subject in need is provided as shown in FIG. 4. The method 400 includes providing 410 one or more formulations to the subject for improving effects of a disorder, wherein the one or more formulations includes a first formulation comprising: an exogenous polyamine including spermidine, spermine, putrescine, or a combination thereof; a precursor to the endogenous polyamine; and a cofactor that increases production of endogenous polyamines, the cofactor including Vitamin B6, Vitamin B9, Vitamin B 12, Vitamin C, Vitamin D, zinc, magnesium, selenium, copper, manganese, or a combination thereof. In some embodiments, the first formulation is formulated as a capsule, a tablet, a gummy, a granule, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. In some embodiments, the first formulation is formulated as one or more capsules, tablets, gummies, granules, or stick packs.

[0083] In some embodiments, an effective amount of the first formulation provided to the subject is an amount greater than 500 pg, such as greater than 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 pg, or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, or 3000 mg.

[0084] In some embodiments, an effective amount of the first formulation provided to the subject is an amount ranging from about 500 pg to about 3000 mg, such as 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, or 3000 mg, or an amount within a range defined by any two of the aforementioned values.

[0085] In some embodiments, an effective amount of the first formulation is an amount of at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 950, or at least 1000 pg; or at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40 at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1050mg, at least HOOmg, at least 1150mg, at least 1200mg, at least 1250mg, at least 1300mg, at least

1350mg, at least HOOmg, at least 1450mg, at least 1500mg, at least 1550mg, at least

1600mg, at least 1650mg, at least 1700mg, at least 1750mg, at least 1800mg, at least

1850mg, at least 1900mg, at least 1950mg, at least 2000mg, at least 2050mg, at least 2100mg, at least 2150mg, at least 2200mg, at least 2250mg, at least 2300mg, at least

2350mg, at least 2400mg, at least 2450mg, at least 2500mg, at least 2550mg, at least

2600mg, at least 2650mg, at least 2700mg, at least 2750mg, at least 2800mg, at least

2850mg, at least 2900mg, at least 2950mg, or at least 3000 mg, or an amount within a range defined by any two of the aforementioned values.

[0086] In some embodiments, the one or more formulations includes a second formulation. In some embodiments, the second formulation includes nattozimes. As used herein, the term “nattozime” refers to a nattokinase replacement, wherein a nattozime is created by fermenting natto with the bacterium, Aspergillus oryzae. As used herein, the term “nattokinase” refers to an enzyme found in natto, a traditional Japanese food produced from the fermentation of soybeans, wherein the fermentation process involves the bacterium, Bacillus subtilis natto. Nattokinase is a serine protease having a catalytic triad consisting of three highly conserved amino acid residues, Ser32, His64, and Asp221. Additionally, the S3 binding of this enzyme play a crucial role in the enzyme’s fibrinolytic and proteolytic functions. The fibrinolytic functions of nattokinase helps break down the fibrin found in blood clots. In some embodiments, the second formulation includes nattokinase. Nattozimes is a 1:1 nattokinase replacement. In some embodiments, the formulations include nattokinase. In some embodiments, the formulations include nattozimes. In some embodiments, nattozimes and nattokinase are used interchangeably.

[0087] In some embodiments, the second formulation includes bromelain. As used herein, the term “bromelain” refers a group of proteolytic enzymes that are commonly associated with endopeptidases present in the tissue of the Bromeliaceae plant family. Pineapple (Ananas comosus) is one of the more popular members of this plant family. In some embodiments, bromelain from different locations in the Bromeliaceae plant family may exhibit different levels of protease activity. In some embodiments, the protease activity of bromelain is higher in the stem of the pineapple than it is in the fruit thereof. In some embodiments, the bromelain is derived from a stem of a pineapple. While it is preferable that bromelain is extracted from a stem of the pineapple (stem bromelain) than extracted from the fruit of the pineapple (fruit bromelain), mixtures of stem and fruit bromelain extracts at various ratios are contemplated with a ratio between stem bromelain and fruit bromelain being greater than 1:1. [0088] In some embodiments, the second formulation includes a prebiotic. In some embodiments, the prebiotic includes inulin. In some embodiments, the second formulation includes rice hull. In some embodiments, the second formulation is in a form of a capsule, a tablet, a gummy, a granule, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. In some embodiments, the first formulation is formulated as one or more capsules, tablets, gummies, granules, or stick packs. In some embodiments, the second formulation is in a form of one or more vegetable capsules. In some embodiments, the one or more vegetable capsules include, for example, purified water and hypromellose. In some embodiments, the second formulation is orally ingested one or more times daily. In some embodiments, the second formulation is orally ingested two or more times daily.

[0089] In some embodiments, an effective amount of the second formulation provided to the subject is an amount ranging from about 500 pg to about 1000 mg, such as 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 4050, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg, or an amount within a range defined by any two of the aforementioned values. In some embodiments, an effective amount of the first formulation is an amount of at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 950, or at least 1000 pg; or at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40 at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, or at least 1000 mg, or an amount within a range defined by any two of the aforementioned values. In some embodiments, these amounts are serving amounts.

[0090] In some embodiments, the effective amount of the second formulation is measured by the respective enzymatic activities of the nattozimes and the bromelain. In some embodiments, the effective amount of the nattozimes is measured by FU (enzyme activity in Fibrinolytic Units). In some embodiments, the effective amount of the nattozimes is an FU ranging from about 500 to about 5000 FU, such as 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 FU, or an FU within a range defined by any two of the aforementioned values. In some embodiments, the effective amount of the bromelain is measured by GDU (enzyme activity in Gelatin Digestive Units). In some embodiments, the effective amount of the bromelain is a GDU ranging from about 100 GDU per serving amount to about 500 GDU per serving amount, such as 100, 150, 200, 250, 300, 350, 400, 450, or 500 GDU per serving amount, or a GDU within a range defined by any two of the aforementioned values.

[0091] In some embodiments, the one or more formulations includes a third formulation. In some embodiments, the third formulation includes lunasin. Lunasin is a 43- chain polypeptide that contains nine Asp residues at its carboxyl end, an Arg-Gly-Asp cell adhesion motif, and a predicted helix with structural homology to a conserved region of chromatin-binding proteins. Without being bound by theory, lunasin exhibits the ability to promote cellular growth, improve epigenomic function, improve immune response, management of cholesterol, and reduce inflammation, which are achieved, at least in part, by inhibition of telomere and DNA shortening that promotes heterochromatin stability. In some embodiments, lunasin is derived from soybean, barley, wheat, rye, or a combination thereof. In some embodiments, lunasin is derived from concentrates of soybean barley, wheat, rye, or a combination thereof. In some embodiments, lunasin is derived from a soybean concentrate. In some embodiments, the third formulation includes calcium phosphate. In some embodiments, the third formulation is in a form of a capsule, a tablet, a gummy, a granule, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. In some embodiments, the third formulation is in a form of one or more capsules, tablets, gummies, granules, or stick packs. In some embodiments, the one or more capsules includes one or more vegetable capsules. In some embodiments, the one or more vegetable capsules includes, for example, hypromellose and purified water. In some embodiments, the third formulation is orally ingested one or more times daily. In some embodiments, the third formulation is orally ingested two or more times daily.

[0092] In some embodiments, an effective amount of the third formulation provided to the subject is an amount ranging from about 500 pg to about 1000 mg, such as 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 pg, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 4050, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg, or an amount within a range defined by any two of the aforementioned values. In some embodiments, an effective amount of the first formulation is an amount of at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 950, or at least 1000 pg; or at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40 at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, or at least 1000 mg, or an amount within a range defined by any two of the aforementioned values.

[0093] In some embodiments, the one or more formulations include a fourth formulation. In some embodiments, the fourth formulation includes NAC, or a derivative of NAC, including, for example, N-acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N-acetylcysteine butyl ester. NAC itself is a derivative of the amino acid L-cysteine. Without being bound by theory, NAC combines in the body with glycine to create glutathione, an antioxidant that is useful in conditions associated with oxidative stress and inflammation. In view of SARS-CoV-2 spike proteins, the function and activity of these spike proteins are impaired by disulfide-bond disruption with mutation at cysteine-488 and by thiol-reactive NAC and glutathione. However, the ability of NAC to cross cellular membranes and the bloodbrain barrier is poor. To improve the bioavailability of NAC, a derivative of NAC is preferred. In some embodiments, the derivative of NAC includes NACET. Without being bound by theory, NACET is 1000 times more permeable to cells, and up to 20 times more bioavailable than NAC, due to the ability of NACET to cross cellular membranes and the blood-brain barrier. After NACET enters into the cell, intracellular esterases cleave the ethyl ester group from the NACET to yield NAC and ethanol in a hydrolysis reaction: NACET + H2O — »■ NAC + Ethanol. Thereafter, the freed NAC can exert its antioxidant effects within the cell.

[0094] In some embodiments, an effective amount of the fourth formulation provided to the subject is an amount ranging from about 50 mg to about 800 mg, such as 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250,

260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440,

450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630,

640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, or 800 mg, or an amount within a range defined by any two of the aforementioned values. In a non-limiting example, 100-200 mg of NACET per serving would be equivalent to 1000-4000 mg of NAC per serving in terms of intracellular bioavailability. That is, at least 10 times to 20 times the amount of NAC is required to achieve a similar effect for a given amount of NACET due to the poor cell permeability and bioavailability of the former. However, intake or administration of 1000-4000 mg of NAC elicits negative side effects, whereas lower equivalent comparative doses of NACET do not.

[0095] In some embodiments, the first, second, third, and fourth formulations are combined in a single formulation. In some embodiments, the single formulation is in a form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. In some embodiments, the first, second, third, and fourth formulations are individual formulations, wherein each of the individual formulations is in a form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. In some embodiments, the form of the individual formulations is the same. In some embodiments, the form of the individual formulations is not all the same. In some embodiments, a combined formulation includes the first, second, third, fourth, or a combination of any two or more thereof. In some embodiments, the formulation includes a combined formulation and an individual formulation, wherein the combined formulation includes the first, second, third, fourth, or a combination of any two or three thereof, and wherein the individual formulation is one or more formulations from the first, second, third, and fourth formulations that were not included in the combined formulation. In some embodiments, the combined formulation is in a form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. In some embodiments, the individual formulation is in a form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food.

[0096] In some embodiments, the method 400 includes the subject orally ingesting 420 the one or more formulations. In some embodiments, the oral ingesting step 420 occurs daily. In some embodiments, the oral ingesting step 420 occurs daily at the same time of the day. In some embodiments, the oral ingesting step 420 occurs daily at different times for the one or more formulations. In some embodiments, the oral ingesting step 420 occurs prior to a meal. In some embodiments, the oral ingesting step occurs about 1 to about 60 minutes prior to the meal, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes or within a time frame defined by any two of the aforementioned values, prior to the meal. In some embodiments, in the oral ingesting step 420, the subject orally ingests the first formulation one or more times daily. In some embodiments, in the oral ingesting step 420, the subject orally ingests the first formulation one or more times daily at the same time, or times, of the day. In some embodiments, in the oral ingesting step 420, the subject orally ingests the first formulation one or more times daily prior to a meal. In some embodiments, in the oral ingesting step 420, the subject orally ingests the first formulation one or more times daily about 1 to about 60 minutes prior to each meal, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes or within a time frame defined by any two of the aforementioned values, prior to each meal.

[0097] In some embodiments, in the oral ingesting step 420, the subject orally ingests the second formulation one or more times daily. In some embodiments, in the oral ingesting step 420, the subject orally ingests the second formulation one or more times daily at the same time, or times, of the day. In some embodiments, in the oral ingesting step 420, the subject orally ingests the second formulation one or more times daily without a meal or between meals. In some embodiments, in the oral ingesting step 420, the subject orally ingests the third formulation one or more times daily. In some embodiments, in the oral ingesting step 420, the subject orally ingests the third formulation one or more times daily at the same time, or times, of the day. In some embodiments, in the oral ingesting step 420, the subject orally ingests the third formulation one or more times daily with food.

[0098] In some embodiments, in the oral ingesting step 420, the subject orally ingests the first and second formulations daily. In some embodiments, in the oral ingesting step 420, the subject orally ingests the first and second formulations daily at different times. In some embodiments, in the oral ingesting step 420, the subject orally ingests the first, second, and third formulations daily, at different times. In some embodiments, the oral ingesting step 420, the subject orally ingests the first, second, and third formulations daily, wherein the first formulation is ingested prior to a meal, the second formulation is ingested without food, and the third formulation is ingested with food. In some embodiments, the subject ingests the first and third formulations daily.

[0099] In some embodiments, the method 400 includes imprinting a frequency to the intracellular NAC-payload from NACET by a device configured to emit one or more frequencies. In some embodiments, the one or more frequencies are within a frequency range. In some embodiments, the one or more frequencies are emitted in a frequency pattern. In some embodiments, the device is configured to imprint an oscillatory frequency rate onto the intracellular NAC to further direct the NAC to neutralize the SARS-CoV-2 spike proteins.

[0100] Additional non-limiting embodiments of the present disclosure are provided in the following numbered alternatives.

[0101] 1. A composition, comprising: one or more exogenous polyamine; one or more endogenous polyamine producing agent; and one or more autophagy dysregulation suppressing agent.

[0102] 2. The composition of alternative 1, wherein the one or more exogenous polyamines comprise spermidine, spermine, and/or putrescine.

[0103] 3. The composition of alternative 2, wherein the one or more exogenous polyamine is present in an amount between 250 pg and 50 mg.

[0104] 4. The composition of any one of alternatives 1-3, wherein the one or more endogenous polyamine producing agent comprises a precursor to spermidine, spermine, putrescine, or a combination thereof.

[0105] 5. The composition of alternative 4, wherein the precursor comprises ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, y-aminobutyric acid, hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof.

[0106] 6. The composition of any one of alternatives 1-5, further comprising one or more cofactor.

[0107] 7. The composition of alternative 6, wherein the one or more cofactor comprises Vitamin B6 Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof. [0108] 8. The composition of any one of alternatives 1 -7, further comprising one or more activator.

[0109] 9. The composition of alternative 8, wherein the one or more activator comprises one or more polyphenol.

[0110] 10. The composition of alternative 9, the one or more polyphenol comprises resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, Fisetin, luteolin, Epigallocatechin gallate (EGCG), or combinations thereof.

[0111] 11. The composition of alternative 10, wherein the EGCG comprises green tea powders and extracts.

[0112] 12. The composition of any one of alternatives 1-11, further comprising one or more synthesizer.

[0113] 13. The composition of alternative 12, wherein the one or more synthesizer comprises a probiotic.

[0114] 14. The composition of alternative 13, wherein the probiotic comprises

Lactobacillus, Bifidobacterium, Streptococcus, Thermophilus, Enterococcus faecalis, Escherichia coli, or a combination thereof.

[0115] 15. The composition of alternative 14, wherein the Lactobacillus comprises

Lactobacillus acidophilus.

[0116] 16. The composition of alternative 14 or 15, wherein the Lactobacillus comprises Lactobacillus plantarum.

[0117] 17. The composition of any one of alternatives 14-16, wherein the

Bifidobacterium, comprises Bifidobacterium lactis.

[0118] 18. The composition of any one of alternatives 12-17, wherein the one or more synthesizer comprises a prebiotic.

[0119] 19. The composition of any one of alternatives 12-18, wherein the one or more synthesizer is present in an amount between 100 million CFU’s and 50 Billion CFU’s.

[0120] 20. The composition of any one of alternatives 1-18, wherein the one or more autophagy dysregulation suppressing agent comprises spermidine, spermine, resveratrol, putrescine, or a combination thereof.

[0121] 21. The composition of any one of alternatives 1-20, further comprising an antioxidant precursor. [0122] 22. The composition of alternative 21 , wherein the antioxidant precursor comprises N-acctyl-L-cystcinc (NAC).

[0123] 23. The composition of alternative 21, wherein the antioxidant precursor comprises a derivative of NAC.

[0124] 24. The composition of alternative 23, wherein the derivative of NAC comprises N-acetylcysteine methyl ester, N- acetylcysteine ethyl ester (NACET), N- acetylcysteine propyl ester, or N-acetylcysteine butyl ester.

[0125] 25. The composition of any one of alternatives 1-24, wherein the composition is an oral dosage formulation.

[0126] 26. The composition of alternative 25, wherein the oral dosage form comprises one or more capsules, one or more tablets, one or more gummies, one or more granules, one or more stick packs, a powder, a beverage, a syrup, a suspension, or a food.

[0127] 27. A composition for activation of autophagy in the body, the composition comprising: an exogenous poly amine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; and a cofactor that increases production of the endogenous polyamine, the cofactor comprising Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof, wherein the exogenous poly amine suppresses autophagy dysregulation.

[0128] 28. The composition of alternative 27, wherein the precursor increases the production of the endogenous poly amines.

[0129] 29. The composition of alternative 27 or 28, wherein the precursor comprises ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, y- aminobutyric acid, hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof.

[0130] 30. The composition of any one of alternative 27-29, further comprising an activator that increases production of the endogenous polyamines. [0131] 31. The composition of alternative 30, wherein the activator comprises a polyphenol.

[0132] 32. The composition of alternative 31, wherein the polyphenol comprises resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, fisetin, luteolin, or epigallocatechin gallate (EGCG), or a combination thereof.

[0133] 33. The composition of alternative 32, wherein the EGCG comprises green tea powders and extracts.

[0134] 34. The composition of any one of alternatives 27-33, further comprising a synthesizer that increases production of the endogenous polyamines.

[0135] 35. The composition of alternative 34, wherein the synthesizer comprises a probiotic.

[0136] 36. The composition of alternative 35, wherein the probiotic comprises

Lactobacillus, Bifidobacterium, Streptococcus, Thermophilus , Enterococcus faecalis, Escherichia coli, or a combination thereof.

[0137] 37. The composition of alternative 36, wherein an amount of the synthesizer is between 1 x 10⁸ to 5 x 10¹⁰ CFU.

[0138] 38. The composition of any one of alternatives 27-37, further comprising an

AKT inhibitor.

[0139] 39. The composition of any one of alternatives 27-38, further comprising a

Beclin-1 stabilizing agent.

[0140] 40. The composition of any one of alternatives 27-39, further comprising an antioxidant precursor.

[0141] 41. The composition of alternative 40, wherein the antioxidant precursor further comprises NAC.

[0142] 42. The composition of alternative 40, wherein the antioxidant precursor further comprises a NAC derivative.

[0143] 43. The composition of alternative 42, wherein the derivative of NAC comprises N-acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N- acetylcysteine butyl ester.

[0144] 44. The composition of any one of alternatives 27-43, wherein an amount of the exogenous polyamine is between 250 pg to 50 mg. [0145] 45. An oral formulation of the composition of any one of alternatives 27-

44.

[0146] 46. The oral formulation of alternative 45, formulated as one or more capsules, one or more tablets, one or more gummies, one or more granules, one or more stick packs, a powder, a beverage, a syrup, a suspension, or a food.

[0147] 47. An oral formulation, comprising: a base composition comprising a precursor to an exogenous polyamine and a cofactor and an activator that increases production of endogenous poly amines; and an exogenous polyamine comprising spermidine, spermine, putrescine, or a combination thereof, wherein the formulation is formulated as one or more capsules, one or more tablets, one or more gummies, one or more granules, one or more stick packs, a powder, a beverage, a syrup, a suspension, or a food.

[0148] 48. The oral formulation of alternative 47, wherein the precursor comprises ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, y-aminobutyric acid, hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof.

[0149] 49. The oral formulation of alternative 47 or 48, wherein the cofactor comprises Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof.

[0150] 50. The oral formulation of any one of alternatives 47-49, wherein the activator comprises a polyphenol.

[0151] 51. The oral formulation of alternative 50, wherein the polyphenol comprises resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, fisetin, luteolin, or epigallocatechin gallate (EGCG), or a combination thereof.

[0152] 52. The oral formulation of alternative 51, wherein the EGCG comprises green tea powders and extracts.

[0153] 53. The oral formulation of any one of alternatives 47-52, further comprising a probiotic that increases production of the endogenous poly amines. [0154] 54. The oral formulation of alternative 53, wherein the probiotic comprises

[0155] 55. The oral formulation of alternative 54, wherein an amount of the probiotic is between 1 x 10⁸ to 5 x IO¹⁰ CFU.

[0156] 56. The oral formulation of any one of alternatives 47-55, further comprising an AKT inhibitor.

[0157] 57. The oral formulation of any one of alternatives 47-56, further comprising a Beclin-1 stabilizing agent.

[0158] 58. The oral formulation of any one of alternatives 47-57, further comprising an antioxidant precursor.

[0159] 59. The oral formulation of alternative 58, wherein the antioxidant precursor comprises NAC.

[0160] 60. The oral formulation of alternative 58, wherein the antioxidant precursor comprises a NAC derivative.

[0161] 61. The oral formulation of alternative 60, wherein the derivative of NAC comprises N-acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N- acetylcysteine butyl ester.

[0162] 62. The oral formulation of any one of alternatives 47-61, wherein an amount of the exogenous polyamine is between 250 pg to 50 mg.

[0163] 63. The oral formulation of any one of alternatives 47-62, wherein the oral formulation inhibits mammalian target of rapamycin (mTOR).

[0164] 64. The oral formulation of any one of alternatives 47-63, wherein the oral formulation activates AMP-protein activated kinase (AMPK).

[0165] 65. The oral formulation of any one of alternatives 47-62, wherein the oral formulation inhibits mTOR and activates AMPK.

[0166] 66. The oral formulation of any one of alternatives 47-65, wherein the oral formulation is formulated for ingestion by a subject.

[0167] 67. The oral formulation of alternative 66, wherein the subject has cancer.

[0168] 68. The oral formulation of alternative 66 or 67, wherein the subject has a neurodegenerative disease. [0169] 69. The oral formulation of any one of alternatives 66-68, wherein the subject has a metabolic disorder.

[0170] 70. The oral formulation of alternative 65, wherein the oral formulation is formulated for ingestion by subjects having a respiratory illness or symptoms of the respiratory illness.

[0171] 71. The oral formulation of alternative 70, wherein the respiratory illness is caused by a Coronavirus.

[0172] 72. The oral formulation of alternative 71, wherein the Coronavirus is

SARS-2-CoV.

[0173] 73. The oral formulation of alternative 65, wherein the oral formulation is formulated for ingestion by subjects having symptoms from a vaccine.

[0174] 74. The oral formulation of alternative 73, wherein the vaccine comprises a

Coronavirus vaccine.

[0175] 75. The oral formulation of alternative 74, wherein the Coronavirus vaccine causes spike protein expression in the subject.

[0176] 76. The oral formulation of alternative 74, wherein the Coronavirus vaccine comprises a SARS-CoV-2 vaccine.

[0177] 77. The oral formulation of alternative 76, wherein the SARS-CoV-2 vaccine causes SARS-CoV-2 spike protein expression in the subject.

[0178] 78. The oral formulation of alternative 77, wherein the SARS-CoV-2 spike protein causes Post-COVID symptoms in the subject.

[0179] 79. The oral formulation of any one of alternatives 47-78, wherein the oral formulation activates autophagy.

[0180] 80. The oral formulation of any one of alternatives 47-79, wherein the oral formulation suppresses autophagy dysregulation.

[0181] 81. The oral formulation of any one of alternatives 47-78, wherein the oral formulation activates autophagy and suppresses autophagy dysregulation.

[0182] 82. A method of activating autophagy or suppressing autophagy dysregulation in a subject, comprising: providing an effective amount of a formulation to the subject, wherein the formulation comprises: an exogenous polyamine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; and a cofactor that increases production of the endogenous polyamine, the cofactor including Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, copper, manganese, lithium, or a combination thereof.

[0183] 83. The method of alternative 82, wherein the effective amount of the formulation provided to the subject is in an amount ranging from about 500 pg to about 3000 mg.

[0184] 84. The method of alternative 82 or 83, wherein the subject suffers from cancer.

[0185] 85. The method of any one of alternatives 82-84, wherein the subject suffers from a neurogenerative disease.

[0186] 86. The method of alternative 85, wherein the neurogenerative disease is

Alzheimer’s disease.

[0187] 87. The method of alternative 86, wherein the neurogenerative disease is

Parkinson’s disease.

[0188] 88. The method of any one of alternatives 82-87, wherein the subject suffers from a metabolic disorder.

[0189] 89. The method of any one of alternatives 82-88, wherein the subject suffers from anorexia nervosa.

[0190] 90. The method of any one of alternatives 82-89, wherein the subject suffers from a viral infection.

[0191] 91. The method of alternative 90, wherein the viral infection comprises a respiratory infection.

[0192] 92. The method of alternative 91, wherein the respiratory infection comprises CO VID-19.

[0193] 93. The method of any one of alternatives 82-88, wherein the subject suffers from symptoms associated with Post-COVID. [0194] 94. The method of any one of alternatives 82-89, wherein the subject suffers symptoms from a vaccine.

[0195] 95. The method of alternative 94, wherein the vaccine comprises a

Coronavirus vaccine.

[0196] 96. The method of alternative 95, wherein the Coronavirus vaccine causes spike protein expression in the subject.

[0197] 97. The method of alternative 95, wherein the Coronavirus vaccine comprises a SARS-CoV-2 vaccine.

[0198] 98. The method of alternative 97, wherein the SARS-CoV-2 vaccine causes

SARS-CoV-2 spike protein expression in the subject.

[0199] 99. The method of alternative 97 or 98, wherein the subjects have Post-

COVID symptoms.

[0200] 100. The method of any one of alternatives 82-99, further comprising orally ingesting the formulation by the subject.

[0201] 101. The method of alternative 100, wherein the oral ingesting occurs daily.

[0202] 102. The method of alternative 100 or 101, wherein the oral ingesting occurs prior to a meal.

[0203] 103. A method of activating autophagy or suppressing autophagy dysregulation in a subject, comprising: providing one or more formulations to a subject, wherein the one or more formulations comprises a first formulation, the first formulation comprising: an exogenous poly amine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; and a cofactor that increases production of the endogenous polyamine, the cofactor including Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof. [0204] 104. The method of alternative 103, further comprising ingesting the one or more formulations by the subject.

[0205] 105. The method of alternative 103 or 104, wherein the one or more formulations further comprise a second formulation, and

[0206] wherein the second formulation comprises nattokinase.

[0207] 106. The method of alternative 103 or 104, wherein the one or more formulations further comprise a second formulation, and

[0208] wherein the second formulation comprises nattozime.

[0209] 107. The method of alternative 105 or 106, wherein the second formulation further comprises bromelain.

[0210] 108. The method of any one of alternatives 105-107, wherein the one or more formulations further comprise a third formulation.

[0211] 109. The method of alternative 108, wherein the third formulation comprises lunasin.

[0212] 110. The method of alternatives 108 or 109, wherein the one or more formulations further comprise a fourth formulation.

[0213] 111. The method of alternative 110, wherein the fourth formulation comprises an antioxidant precursor.

[0214] 112. The method of alternative 111, wherein the antioxidant precursor comprises NAC.

[0215] 113. The method of alternative 111, wherein the antioxidant precursor comprises a derivative of NAC.

[0216] 114. The method of alternative 113, wherein the derivative of NAC comprises N-acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N- acetylcysteine butyl ester.

[0217] 115. The method of alternative 113 or 114, wherein the derivative of

NAC is converted to the NAC following an intracellular esterase contacting the derivative of NAC.

[0218] 116. The method of alternative 112 or 115, further comprising directing the NAC to neutralize one or more SARS-CoV-2 spike proteins. [0219] 1 17. A method of activating autophagy or suppressing autophagy dysrcgulation in a subject, comprising: providing one or more formulations to a subject, wherein the one or more formulations comprises a first formulation, the first formulation comprising: an exogenous poly amine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; a cofactor that increases production of the endogenous polyamine, the cofactor including Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof; and an antioxidant precursor.

[0220] 118. The method of alternative 117, further comprising ingesting the one or more formulations by the subject.

[0221] 119. The method of alternative 117 or 118, wherein the one or more formulations further comprise a second formulation, and

[0222] wherein the second formulation comprises nattokinase.

[0223] 120. The method of alternative 117 or 118, wherein the one or more formulations further comprise a second formulation, and

[0224] wherein the second formulation comprises nattozime.

[0225] 121. The method of alternative 119 or 120, wherein the second formulation further comprises bromelain.

[0226] 122. The method of any one of alternatives 119-121, wherein the one or more formulations further comprise a third formulation.

[0227] 123. The method of alternative 122, wherein the third formulation comprises lunasin.

[0228] 124. The method of any one of alternatives 117-123, wherein the antioxidant precursor comprises NAC.

[0229] 125. The method of any one of alternatives 117-123, wherein the antioxidant precursor comprises a derivative of NAC. [0230] 126. The method of alternative 125, wherein the derivative of NAC comprises N-acctylcystcinc methyl ester, NACET, N-acctylcystcinc propyl ester, or N- acetylcysteine butyl ester.

[0231] 127. The method of alternative 125 or 126, wherein the derivative of

[0232] 128. The method of alternative 124 or 127, further comprising directing the NAC to neutralize one or more SARS-CoV-2 spike proteins.

[0233] It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein. In particular, all combinations of claimed subject matter appearing at the end of this disclosure are contemplated as being part of the inventive subject matter disclosed herein. It should also be appreciated that terminology explicitly employed herein that also may appear in any disclosure incorporated by reference should be accorded a meaning most consistent with the particular concepts disclosed herein.

EXAMPLES

[0234] Some aspects of the embodiments discussed above are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the present disclosure. Those in the art will appreciate that many other embodiments also fall within the scope of the invention, as it is described herein above and in the claims.

EXAMPLE 1

[0235] A formulation includes a biogenic polyamine, an AMPK blend, one or more co-factors, and a synthesizer blend. In this example, the biogenic polyamine includes spermidine. The AMPK blend includes resveratrol, curcumin, berberine, green tea extract, red wine extract (Vi s vinifera, grape skin), grapeseed extract (Vili.s vinifera). dandelion extract Taraxacum officinale), L-Ornithine, and pepper (black) (Piper nigrum).

[0236] The one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), and zinc (zinc sulfate). The chromium is in the form of chromium chloride, the magnesium is in the form of magnesium glycinate and carbonate, the selenium is in the form of sodium selenite, and zinc is in the form of zinc sulfate.

[0237] The synthesizer blend includes prebiotics and probiotics. In this example, the prebiotic includes FOS. In this example, the probiotic includes L. acidophilus, L. plantarum, and Bifidobacterium lactis.

[0238] As shown in Table 1, the formulation includes the polyamine, AMPK blend, co-factors, and a synthesizer blend. The formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The formulation is orally ingested at least once a day prior to a meal, preferably at the same time daily.

Table 1: Formulation

EXAMPLE 2

[0239] A formulation includes a biogenic polyamine, an AMPK blend, one or more co-factors, and a synthesizer blend. In this example, the biogenic polyamine includes spermidine. The AMPK blend includes resveratrol, curcumin, berberine, green tea extract, red wine extract (Vitis vinifera, grape skin), grapeseed extract (Vitis vinifera), dandelion extract (Taraxacum officinale), L-Ornithine, and pepper (black) (Piper nigrum).

[0240] The one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), and zinc (zinc sulfate). The chromium is in the form of chromium chloride, the magnesium is in the form of magnesium glycinate and carbonate, the selenium is in the form of sodium selenite, and zinc is in the form of zinc sulfate.

[0241] The synthesizer blend includes prebiotics and probiotics. In this example, the prebiotic includes FOS. In this example, the probiotic includes L. acidophilus, L. plantarum, and Bifidobacterium lactis.

[0242] As shown in Table 2, the formulation includes the polyamine, AMPK blend, co-factors, and a synthesizer blend. The formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The formulation is orally ingested at least once a day prior to a meal, preferably at the same time daily.

Table 2: Formulation

EXAMPLE 3

[0243] A formulation includes a biogenic polyamine, an AMPK blend, one or more co-factors, and a synthesizer blend. In this example, the biogenic polyamine includes spermidine. The AMPK blend includes resveratrol, curcumin, berberine, green tea extract, red wine extract (Vitis vinifera, grape skin), grapeseed extract (Vitis vinifera), dandelion extract (Taraxacum officinale), L-Ornithine, and pepper (black) (Piper nigrum).

[0244] The one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), lithium, and zinc (zinc sulfate). The chromium is in the form of chromium chloride, the magnesium is in the form of magnesium glycinate and carbonate, the selenium is in the form of sodium selenite, and zinc is in the form of zinc sulfate.

[0245] The synthesizer blend includes prebiotics and probiotics. In this example, the prebiotic includes FOS. In this example, the probiotic includes L. acidophilus, L. plantarum, and Bifidobacterium lactis.

[0246] As shown in Table 3, the formulation includes the polyamine, AMPK blend, co-factors, and a synthesizer blend. The formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The formulation is orally ingested at least once a day prior to a meal, preferably at the same time daily.

Table 3: Formulation

EXAMPLE 4

[0247] A formulation includes a biogenic polyamine, an AMPK blend, one or more co-factors, a synthesizer blend, and a NAC. In this example, the biogenic polyamine includes spermidine. The AMPK blend includes resveratrol, curcumin, berberine, green tea extract, red wine extract (Vids vinifera, grape skin), grapeseed extract (Vitis vini/era). dandelion extract (Taraxacum officinale), L-Ornithine, and pepper (black) (Piper nigrum).

[0248] The one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), and zinc (zinc sulfate). The chromium is in the form of chromium chloride, the magnesium is in the form of magnesium glycinate and carbonate, the selenium is in the form of sodium selenite, and zinc is in the form of zinc sulfate.

[0249] The synthesizer blend includes prebiotics and probiotics. In this example, the prebiotic includes FOS. In this example, the probiotic includes L. acidophilus, L. plantarum, and Bifidobacterium lactis.

[0250] The antioxidant in this example is NACET, which is converted into NAC after crossing the cell membrane, wherein the intracellular NAC at least increases/replenishes the levels of the antioxidant glutathione.

[0251] As shown in Table 4, the formulation includes the polyaminc, AMPK blend, co-factors, a synthesizer blend, and an antioxidant. The formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The formulation is orally ingested at least once a day prior to a meal, preferably at the same time daily. Table 4: Formulation

EXAMPLE 5

[0252] A formulation includes a biogenic polyamine, an AMPK blend, one or more co-factors, a synthesizer blend, and an antioxidant precursor. In this example, the biogenic polyamine includes spermidine. The AMPK blend includes resveratrol, curcumin, berberine, green tea extract, red wine extract ( Vitis vinifera, grape skin), grapeseed extract ( Vitis vinifera), dandelion extract (Taraxacum officinale), L-Omithine, and pepper (black) (Piper nigrum).

[0253] The one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), lithium, and zinc (zinc sulfate). The chromium is in the form of chromium chloride, the magnesium is in the form of magnesium glycinate and carbonate, the selenium is in the form of sodium selenite, and zinc is in the form of zinc sulfate.

[0254] The synthesizer blend includes prebiotics and probiotics. In this example, the prebiotic includes FOS. In this example, the probiotic includes L. acidophilus, L. plantarum, and Bifidobacterium lactis. [0255] The antioxidant precursor in this example is NACET, which is converted into NAC after crossing the cell membrane, wherein the intracellular NAC at least increases/replenishes the levels of the antioxidant glutathione.

[0256] As shown in Table 5, the formulation includes the poly amine, AMPK blend, co-factors, a synthesizer blend, and an antioxidant precursor. The formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The formulation is orally ingested at least once a day prior to a meal, preferably at the same time daily.

Table 5: Formulation

EXAMPLE 6

[0257] As shown in Tables 1-3, the first formulations include the polyamine, AMPK blend, co-factors, and a synthesizer blend. A first formulation includes a biogenic polyamine, an AMPK blend, one or more co-factors, and a synthesizer blend. In this example, the biogenic polyamine includes spermidine. The AMPK blend includes resveratrol, curcumin, berberine, green tea extract, red wine extract (Vitis vinifera, grape skin), grapeseed extract (Vitis vinifera), dandelion extract (Taraxacum officinale), L-Omithine, and pepper (black) (Piper nigrum). The one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), and zinc (zinc sulfate) as shown in Tables 1 and 2. Alternatively, as shown in Table 3, the one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), lithium, and zinc (zinc sulfate). The chromium is in the form of chromium chloride, the magnesium is in the form of magnesium glycinate and carbonate, the selenium is in the form of sodium selenite, and zinc is in the form of zinc sulfate. The synthesizer blend includes prebiotics and probiotics. In this example, the prebiotic includes FOS. In this example, the probiotic includes L. acidophilus, L. plantarum, and Bifidobacterium lactis. The first formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The one or more capsules is a vegetable-based capsule that includes, for example, purified water and hypromellose. The formulation is orally ingested once a day prior to a meal, preferably at the same time daily.

[0258] As shown in Table 6, a second formulation includes nattozimes, bromelain, and a prebiotic. The enzymatic activity of the nattozimes is measured by FU, which is enzyme activity in Fibrinolytic Units. The enzymatic activity of the nattozimes is 2000 FU. The effective amount of nattozimes is 58 mg per serving. The bromelain is obtained from a pineapple, where preferably most, if not all, of the bromelain is extracted from the stem of a pineapple where the enzymatic activity of the bromelain is 2400 GDU/g (GDU is the enzyme activity in Gelatin Digestive Units), which provides 250 GDU per serving. The effective amount of bromelain is 105 mg per serving. The prebiotic is inulin, where the effective amount of inulin is 30 mg. The second formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The one or more capsules is a vegetable-based capsule that includes, for example, purified water and hypromellose. The second formulation is orally ingested once a twice a day without food, or between meals.

Table 6. Second formulation

+ = Enzyme activity in Gelatin Digestive Units; 250 GDU / serving obtained from 2400 GDU / g of pineapple stem

[0259] A third formulation includes lunasin. The effective amount of lunasin is 420 mg daily. The third formulation also includes calcium phosphate. The third formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The one or more capsules is a vegetable -based capsule that includes, for example, purified water and hypromellose. The third formulation is orally ingested once a day with food.

EXAMPLE 7

[0260] As shown in Tables 1-3, first formulations include the polyamine, AMPK blend, co-factors, and a synthesizer blend. A first formulation includes a biogenic polyamine, an AMPK blend, one or more co-factors, and a synthesizer blend. In this example, the biogenic polyamine includes spermidine. The AMPK blend includes resveratrol, curcumin, berberine, green tea extract, red wine extract ( Vitis vinifera, grape skin), grapeseed extract ( Vitis vinifera), dandelion extract (Taraxacum officinale , L-Omithinc, and pepper (black) (Piper nigrum). The one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), and zinc (zinc sulfate) as shown in Tables 1 and 2. Alternatively, as shown in Table 3, the one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), lithium, and zinc (zinc sulfate). The chromium is in the form of chromium chloride, the magnesium is in the form of magnesium glycinate and carbonate, the selenium is in the form of sodium selenite, and zinc is in the form of zinc sulfate. The synthesizer blend includes prebiotics and probiotics. In this example, the prebiotic includes FOS. In this example, the probiotic includes L. acidophilus, L. plantarum, and Bifidobacterium lactis. The first formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The one or more capsules is a vegetable-based capsule that includes, for example, purified water and hypromellose. The formulation is orally ingested once a day prior to a meal, preferably at the same time daily.

[0261] As shown in Table 6, the second formulation includes nattozimes, bromelain, and a prebiotic. The enzymatic activity of the nattozimes is measured by FU, which is enzyme activity in Fibrinolytic Units. The enzymatic activity of the nattozimes is 2000 FU. The effective amount of nattozimes is 58 mg per serving. The bromelain is obtained from a pineapple, where preferably most, if not all, of the bromelain is extracted from the stem of a pineapple where the enzymatic activity of the bromelain is 2400 GDU/g (GDU is the enzyme activity in Gelatin Digestive Units), which provides 250 GDU per serving. The effective amount of bromelain is 105 mg per serving. The prebiotic is inulin, where the effective amount of inulin is 30 mg. The second formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The one or more capsules is a vegetable-based capsule that includes, for example, purified water and hypromellose. The second formulation is orally ingested once a twice a day without food, or between meals.

[0262] The third formulation includes lunasin. The effective amount of lunasin is 420 mg daily. The third formulation also includes calcium phosphate. The third formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, a stick pack, a powder, a beverage, a syrup, a suspension, or a food. The one or more capsules is a vegetable-based capsule that includes, for example, purified water and hypromellose. The third formulation is orally ingested once a day with food.

[0263] A fourth formulation includes an antioxidant precursor. The antioxidant precursor in this example is NACET at 100-200 mg per serving, which is equivalent to 1000- 4000 mg of NAC. After crossing the cell-membrane, the NACET is converted to NAC, wherein the intracellular NAC at least increases/replenishes the levels of the antioxidant glutathione. The fourth formulation is orally ingested once a day.

EXAMPLE 8

[0264] As shown in Tables 4 and 5, first formulations include the polyamine, AMPK blend, co-factors, a synthesizer blend, and an antioxidant precursor. A first formulation includes a biogenic poly amine, an AMPK blend, one or more co-factors, a synthesizer blend, and an antioxidant. In this example, the biogenic polyamine includes spermidine. The AMPK blend includes resveratrol, curcumin, berberine, green tea extract, red wine extract (Vitis vinifera, grape skin), grapeseed extract (Vitis vinifera), dandelion extract (Taraxacum officinale), L-Ornithine, and pepper (black) (Piper nigrum). The one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), and zinc (zinc sulfate) as shown in Table 4. Alternatively, as shown in Table 5, the one or more co-factors include chromium, magnesium, selenium, vitamin d (cholecalciferol), lithium, and zinc (zinc sulfate). The chromium is in the form of chromium chloride, the magnesium is in the form of magnesium glycinate and carbonate, the selenium is in the form of sodium selenite, and zinc is in the form of zinc sulfate. The synthesizer blend includes prebiotics and probiotics. In this example, the prebiotic includes FOS. In this example, the probiotic includes L. acidophilus, L. plantarum, and Bifidobacterium lactis. In this example, the antioxidant precursor is NACET. The first formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, one or more stick packs, a powder, a beverage, a syrup, a suspension, or a food. The one or more capsules is a vegetable -based capsule that includes, for example, purified water and hypromellose. The formulation is orally ingested once a day prior to a meal, preferably at the same time daily.

[0265] As shown in Table 6, the second formulation includes nattozimes, bromelain, and a prebiotic. The enzymatic activity of the nattozimes is measured by FU, which is enzyme activity in Fibrinolytic Units. The enzymatic activity of the nattozimes is 2000 FU. The effective amount of nattozimes is 58 mg per serving. The bromelain is obtained from a pineapple, where preferably most, if not all, of the bromelain is extracted from the stem of a pineapple where the enzymatic activity of the bromelain is 2400 GDU/g (GDU is the enzyme activity in Gelatin Digestive Units), which provides 250 GDU per serving. The effective amount of bromelain is 105 mg per serving. The prebiotic is inulin, where the effective amount of inulin is 30 mg. The second formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, one or more stick packs, a powder, a beverage, a syrup, a suspension, or a food. The one or more capsules is a vegetable-based capsule that includes, for example, purified water and hypromellose. The second formulation is orally ingested once a twice a day without food, or between meals. [0266] The third formulation includes lunasin. The effective amount of lunasin is 420 mg daily. The third formulation also includes calcium phosphate. The third formulation may be in the form of one or more capsules, one or more tablets, one or more gummies, one or more granules, one or more stick packs, a powder, a beverage, a syrup, a suspension, or a food. The one or more capsules is a vegetable-based capsule that includes, for example, purified water and hypromellose. The third formulation is orally ingested once a day with food.

EXAMPLE 9

[0267] The following example describes the use of the formulations presented herein to treat or prevent symptoms and conditions associated with autophagy dysfunction in subjects. The formulation as described in Examples 1, 2, 3, 4, 5, 6, 7, or 8 is used to treat or prevent symptoms and conditions associated with autophagy dysfunction, particularly autophagy dysfunction caused by SAR-CoV-2 spike protein.

[0268] The formulation is in the form of one or more capsules. That is, the amount per serving can be in a single capsule or in multiple smaller capsules. The capsules are vegetable-based, which includes, for example, purified water and Hypromellose. The serving amount will be similar across the subjects.

[0269] Subjects are selected who are suffering, or have suffered, from SARS-CoV- 2. The subjects are randomized into test (group A), placebo (group B), or control (group C) groups. Subjects in the test group are administered the formulation by ingesting the capsule containing the formulation. Subjects in the placebo group ingest a capsule containing an inert filler. Subjects in the control group do not receive a formulation. An Enzyme-Linked Immunosorbent Assay (ELISA) is used to determine the levels of the SARS-CoV-2 spike protein before, during, and after the study. The subjects also complete a health questionnaire and a symptoms log over the course of the study.

EXAMPLE 10

[0270] The following example describes the use of the formulation presented herein to treat or prevent symptoms and conditions associated with autophagy dysfunction in subjects. The formulation as described in Example 9 is used to treat or prevent symptoms and conditions associated with autophagy dysfunction, particularly autophagy dysfunction caused by SAR-CoV-2 spike protein. Additionally, a frequency imprint on the NAC of NACET will be provided by a device. The device is configured to imprint oscillatory frequency rates onto the intracellular NAC to further direct its contact with SAR-CoV-2 spike protein.

[0271] The formulation in this example is in the form of one or more capsules. That is, the amount per serving can be in a single capsule or in multiple smaller capsules. The capsules are vegetable-based, which includes, for example, purified water and Hypromellose. The serving amount will be similar across the subjects.

[0272] Subjects are selected who are suffering, or have suffered, from SARS-CoV- 2. The subjects are randomized into test (group A), placebo (group B), or control (group C) groups. Subjects in the test group are administered the formulation by ingesting the capsule containing the formulation. Subjects in the placebo group ingest a capsule containing an inert filler. Subjects in the control group do not receive a formulation. The test and placebo groups receive one or more imprinting sessions with a device that is configured to imprint oscillatory frequency rates onto the NAC. In this example, only the test group will have ingested the formulation from Example 4.

[0273] An Enzyme-Linked Immunosorbent Assay (ELISA) is used to determine the levels of the SARS-CoV-2 spike protein before, during, and after the study. The subjects also complete a health questionnaire and a symptoms log over the course of the study.

[0274] Reference throughout the specification to “one example”, “another example”, “an example”, and so forth, means that a particular element (e.g., feature, structure, and/or characteristic) described in connection with the example is included in at least one example described herein, and may or may not be present in other examples. In addition, it is to be understood that the described elements for any example may be combined in any suitable manner in the various examples unless the context clearly dictates otherwise. While several examples have been described in detail, it is to be understood that the disclosed examples may be modified. Therefore, the foregoing description is to be considered non-limiting.

[0275] Features, materials, characteristics, or groups described in conjunction with a particular aspect, or example are to be understood to be applicable to any other aspect or example described in this section or elsewhere in this specification unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps arc mutually exclusive. The protection is not restricted to the details of any foregoing examples. The protection extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0276] Furthermore, certain features that are described in this disclosure in the context of separate implementations can also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation can also be implemented in multiple implementations separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations, one or more features from a claimed combination can, in some cases, be excised from the combination, and the combination may be claimed as a sub-combination or variation of a sub-combination.

[0277] Moreover, while operations may be depicted in the drawings or described in the specification in a particular order, such operations need not be performed in the particular order shown or in sequential order, or that all operations be performed, to achieve desirable results. Other operations that are not depicted or described can be incorporated in the example methods and processes. For example, one or more additional operations can be performed before, after, simultaneously, or between any of the described operations. Further, the operations may be rearranged or reordered in other implementations. Those skilled in the art will appreciate that in some examples, the actual steps taken in the processes illustrated and/or disclosed may differ from those shown in the figures. Depending on the example, certain of the steps described above may be removed or others may be added. Furthermore, the features and attributes of the specific examples disclosed above may be combined in different ways to form additional examples, all of which fall within the scope of the present disclosure.

[0278] For purposes of this disclosure, certain aspects, advantages, and novel features are described herein. Not necessarily all such advantages may be achieved in accordance with any particular example. Thus, for example, those skilled in the art will recognize that the disclosure may be embodied or earned out in a manner that achieves one advantage or a group of advantages as taught herein without necessarily achieving other advantages as may be taught or suggested herein.

[0279] Conditional language, such as “can,” “could,” “might,” or “may,” unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain examples include, while other examples do not include, certain features, elements, and/or steps. Thus, such conditional language is not generally intended to imply that features, elements, and/or steps are in any way required for one or more examples or that one or more examples necessarily include logic for deciding, with or without user input or prompting, whether these features, elements, and/or steps are included or are to be performed in any particular example.

[0280] Conjunctive language such as the phrase “at least one of X, Y, and Z,” unless specifically stated otherwise, is otherwise understood with the context as used in general to convey that an item, term, etc. may be either X, Y, or Z. Thus, such conjunctive language is not generally intended to imply that certain examples require the presence of at least one of X, at least one of Y, and at least one of Z.

[0281] Language of degree used herein, such as the terms “approximately,” “about,” “generally,” and “substantially” represent a value, amount, or characteristic close to the stated value, amount, or characteristic that still performs a desired function or achieves a desired result.

[0282] The scope of the present disclosure is not intended to be limited by the specific disclosures of preferred examples in this section or elsewhere in this specification, and may be defined by claims as presented in this section or elsewhere in this specification or as presented in the future. The language of the claims is to be interpreted broadly based on the language employed in the claims and not limited to the examples described in the present specification or during the prosecution of the application, which examples are to be construed as non-exclusive.

[0283] The described embodiments and examples of the present disclosure are intended to be illustrative rather than restrictive, and are not intended to represent every embodiment or example of the present disclosure, and thus, are not to be limited in scope by the specific embodiments and examples described herein. While the fundamental novel features of the disclosure as applied to various specific embodiments thereof have been shown, described, and pointed out, it will also be understood that various omissions, substitutions, and changes in the details of the compositions and methods that arc disclosed, may become apparent and may be made by those skilled in the art without departing from the spirit of the disclosure. For example, it is expressly intended that all combinations of those method steps that perform substantially the same function in substantially the same way to achieve the same results are within the scope of the disclosure. Moreover, it should be recognized that method steps shown and/or described in connection with any disclosed form or embodiment of the disclosure may be incorporated in any other disclosed or described or suggested form or embodiment as a general matter of design choice. Further, various modifications and variations can be made without departing from the spirit or scope of the disclosure as set forth in the following claims both literally and in equivalents recognized in law.

References

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3. Gassen, N. C., Papies, J., Bajaj, T., Dethloff, F., Emanuel, J., Weckmann, K., et al., “Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics,” bioRxiv (2020).

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6. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, lemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keapl. Nat Cell Biol. 2010 Mar;12(3):213-23. Lakshmana MK. SARS-CoV-2-induced autophagy dysregulation may cause neuronal dysfunction in COVID-19. Neural Rcgcn Res. 2022 Jun;17(6): 1255-1256. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008 Feb 28;451(7182): 1069-75. Qu Y, Wang X, Zhu Y, et al. ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication. Front Cell Dev Biol. 2021 ;9:716208. Rautou PE, Cazals-Hatem D, Moreau R, Francoz C, Feldmann G, Lebrec D, Ogier- Denis E, Bedossa P, Valla D, Durand F. Acute liver cell damage in patients with anorexia nervosa: a possible role of starvation-induced hepatocyte autophagy. Gastroenterology. 2008 May; 134(5): 1369-79. Rubinsztein DC, Marino G, Kroemer G. Autophagy and aging. Cell. 2011 Nov l l;146(4):682-95. Singh, K„ Chen, Y. C., Judy, J. T„ Seifuddin, F„ Tunc, I., and Pirooznia, M. (2020). Network analysis and transcriptome profiling identify autophagic and mitochondrial dysfunctions in SARS-CoV-2 infection. bioRxiv. Zhou R, To KK, Wong YC, Liu L, Zhou B, Li X, Huang H, Mo Y, Luk TY, Lau TT, Yeung P, Chan WM, Wu AK, Lung KC, Tsang OT, Hung IF, Yuen KY, Chen Z. Acute SARS-CoV-2 Spike Impairs Dendritic Cell and T Cell Functions. Front Cell Infect Microbiol. 2021 May 26; 11:653517. Zhou S, Butler-Laporte G, Nakanishi T, Morrison DR, Afilalo J, Afilalo M, Laurent L, Pietropaolo M, Behlouli H, Pilote L, de Denus S, Tschopp J, Ma J, Manganas LN, Sabbagh S, Becerra B, Shalhoub J, 6 Omichessan H, Harray M, John AM, Arora RC, Gupta S, Juneau M, Rodger M, Wu J, Libman M, Brophy J, Tardif JC, Blondeau L, Gupta A, Frasure-Smith N, Kimmelman J, Thanassoulis G. SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2. Circulation. 2021 Jul 13;144(2):e7-el9.

Claims

WHAT TS CLAIMED TS:

1. A composition, comprising: one or more exogenous polyamine; one or more endogenous polyamine producing agent; and one or more autophagy dysregulation suppressing agent.

2. The composition of claim 1, wherein the one or more exogenous polyamines comprise spermidine, spermine, and/or putrescine.

3. The composition of claim 2, wherein the one or more exogenous poly amine is present in an amount between 250 pg and 50 mg.

4. The composition of claim 1, wherein the one or more endogenous poly amine producing agent comprises a precursor to spermidine, spermine, putrescine, or a combination thereof.

5. The composition of claim 4, wherein the precursor comprises ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, y-aminobutyric acid, hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof.

6. The composition of claim 1, further comprising one or more cofactor.

7. The composition of claim 6, wherein the one or more cofactor comprises Vitamin B6 Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof.

8. The composition of claim 1, further comprising one or more activator.

9. The composition of claim 8, wherein the one or more activator comprises one or more polyphenol.

10. The composition of claim 9, the one or more polyphenol comprises resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, Fisetin, luteolin, Epigallocatechin gallate (EGCG), or combinations thereof.

11. The composition of claim 10, wherein the EGCG comprises green tea powders and extracts.

12. The composition of claim 1, further comprising one or more synthesizer.

13. The composition of claim 12, wherein the one or more synthesizer comprises a probiotic.

14. The composition of claim 13, wherein the probiotic comprises Lactobacillus, Bifidobacterium, Streptococcus, Thermophilus, Enterococcus faecalis, Escherichia coli, or a combination thereof.

15. The composition of claim 14, wherein the Lactobacillus comprises

Lactobacillus acidophilus.

16. The composition of claim 14, wherein the Lactobacillus comprises

Lactobacillus plantarum.

17. The composition of claim 14, wherein the Bifidobacterium, comprises

Bifidobacterium lactis.

18. The composition of claim 12, wherein the one or more synthesizer comprises a prebiotic.

19. The composition of claim 12, wherein the one or more synthesizer is present in an amount between 100 million CFU’s and 50 Billion CFU’s.

20. The composition of claim 1, wherein the one or more autophagy dysregulation suppressing agent comprises spermidine, spermine, resveratrol, putrescine, or a combination thereof.

21. The composition of claim 1, further comprising an antioxidant precursor.

22. The composition of claim 21, wherein the antioxidant precursor comprises N- acetyl-L-cysteine (NAC).

23. The composition of claim 21, wherein the antioxidant precursor comprises a derivative of NAC.

24. The composition of claim 23, wherein the derivative of NAC comprises N- acetylcysteine methyl ester, N- acetylcysteine ethyl ester (NACET), N-acetylcysteine propyl ester, or N-acetylcysteine butyl ester.

25. The composition of claim 1, wherein the composition is an oral dosage formulation.

26. The composition of claim 25, wherein the oral dosage form comprises one or more capsules, one or more tablets, one or more gummies, one or more granules, one or more stick packs, a powder, a beverage, a syrup, a suspension, or a food.

27. A composition for activation of autophagy in the body, the composition comprising: an exogenous polyamine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; and a cofactor that increases production of the endogenous polyamine, the cofactor comprising Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof, wherein the exogenous polyamine suppresses autophagy dysregulation.

28. The composition of claim 27, wherein the precursor increases the production of the endogenous polyamines.

29. The composition of claim 27, wherein the precursor comprises ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, y-aminobutyric acid, hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof.

30. The composition of claim 27, further comprising an activator that increases production of the endogenous poly amines.

31. The composition of claim 30, wherein the activator comprises a polyphenol.

32. The composition of claim 31, wherein the polyphenol comprises resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, fisetin, luteolin, or epigallocatechin gallate (EGCG), or a combination thereof.

33. The composition of claim 32, wherein the EGCG comprises green tea powders and extracts.

34. The composition of claim 27, further comprising a synthesizer that increases production of the endogenous polyamines.

35. The composition of claim 34, wherein the synthesizer comprises a probiotic.

36. The composition of claim 35, wherein the probiotic comprises Lactobacillus, Bifidobacterium, Streptococcus thermophilus, Enterococcus faecalis, Escherichia coli, or a combination thereof.

37. The composition of claim 36, wherein an amount of the synthesizer is between 1 x 10⁸ to 5 x 10¹⁰CFU.

38. The composition of claim 27, further comprising an AKT inhibitor.

39. The composition of claim 27, further comprising a Beclin-1 stabilizing agent.

40. The composition of claim 27, further comprising an antioxidant precursor.

41. The composition of claim 40, wherein the antioxidant precursor further comprises NAC.

42. The composition of claim 40, wherein the antioxidant precursor further comprises a NAC derivative.

43. The composition of claim 42, wherein the derivative of NAC comprises N- acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N-acetylcysteine butyl ester.

44. The composition of claim 27, wherein an amount of the exogenous polyamine is between 250 pg to 50 mg.

45. An oral formulation of the composition of claim 27.

46. The oral formulation of claim 45, formulated as one or more capsules, one or more tablets, one or more gummies, one or more granules, one or more stick packs, a powder, a beverage, a syrup, a suspension, or a food.

47. An oral formulation, comprising: a base composition comprising a precursor to an exogenous polyamine and a cofactor and an activator that increases production of endogenous poly amines; and an exogenous polyamine comprising spermidine, spermine, putrescine, or a combination thereof, wherein the formulation is formulated as one or more capsules, one or more tablets, one or more gummies, one or more granules, one or more stick packs, a powder, a beverage, a syrup, a suspension, or a food.

48. The oral formulation of claim 47, wherein the precursor comprises ornithine, arginine, proline, glutamine, methionine, alanine, serine, lysine, y-aminobutyric acid, hydroxyproline, malic acid, aspartic acid, isoleucine, tyrosine, valine, leucine, adenine, or a combination thereof.

49. The oral formulation of claim 47, wherein the cofactor comprises Vitamin B6, Vitamin B9, Vitamin B 12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof.

50. The oral formulation of claim 47, wherein the activator comprises a polyphenol.

51. The oral formulation of claim 50, wherein the polyphenol comprises resveratrol, quercetin, berberine, lipoic acid, curcumin, grape seed, fisetin, lutcolin, or epigallocatechin gallate (EGCG), or a combination thereof.

52. The oral formulation of claim 51, wherein the EGCG comprises green tea powders and extracts.

53. The oral formulation of claim 47, further comprising a probiotic that increases production of the endogenous poly amines.

54. The oral formulation of claim 53, wherein the probiotic comprises Lactobacillus, Bifidobacterium, Streptococcus thermophilus, Enterococcus faecalis, Escherichia coli, or a combination thereof.

55. The oral formulation of claim 54, wherein an amount of the probiotic is between 1 x 10⁸ to 5 x 10¹⁰CFU.

56. The oral formulation of claim 47, further comprising an AKT inhibitor.

57. The oral formulation of claim 47, further comprising a Beclin-1 stabilizing agent.

58. The oral formulation of claim 47, further comprising an antioxidant precursor.

59. The oral formulation of claim 58, wherein the antioxidant precursor comprises NAC.

60. The oral formulation of claim 58, wherein the antioxidant precursor comprises a NAC derivative.

61. The oral formulation of claim 60, wherein the derivative of NAC comprises N- acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N-acetylcysteine butyl ester.

62. The oral formulation of claim 47, wherein an amount of the exogenous polyamine is between 250 pg to 50 mg.

63. The oral formulation of claim 47, wherein the oral formulation inhibits mammalian target of rapamycin (mTOR).

64. The oral formulation of claim 47, wherein the oral formulation activates AMP- protein activated kinase (AMPK).

65. The oral formulation of claim 47, wherein the oral formulation inhibits mTOR and activates AMPK.

66. The oral formulation of claim 47, wherein the oral formulation is formulated for ingestion by a subject.

67. The oral formulation of claim 66, wherein the subject has cancer.

68. The oral formulation of claim 66, wherein the subject has a neurodegenerative disease.

69. The oral formulation of claim 66, wherein the subject has a metabolic disorder.

70. The oral formulation of claim 65, wherein the oral formulation is formulated for ingestion by subjects having a respiratory illness or symptoms of the respiratory illness.

71. The oral formulation of claim 70, wherein the respiratory illness is caused by a Coronavirus.

72. The oral formulation of claim 71, wherein the Coronavirus is SARS-2-CoV.

73. The oral formulation of 65, wherein the oral formulation is formulated for ingestion by subjects having symptoms from a vaccine.

74. The oral formulation of claim 73, wherein the vaccine comprises a Coronavirus vaccine.

75. The oral formulation of claim 74, wherein the Coronavirus vaccine causes spike protein expression in the subject.

76. The oral formulation of claim 74, wherein the Coronavirus vaccine comprises a SARS-CoV-2 vaccine.

77. The oral formulation of claim 76, wherein the SARS-CoV-2 vaccine causes SARS-CoV-2 spike protein expression in the subject.

78. The oral formulation of claim 77, wherein the SARS-CoV-2 spike protein causes Post-COVID symptoms in the subject.

79. The oral formulation of claim 47, wherein the oral formulation activates autophagy.

80. The oral formulation of claim 47, wherein the oral formulation suppresses autophagy dysregulation.

81. The oral formulation of claim 47, wherein the oral formulation activates autophagy and suppresses autophagy dysregulation.

82. A method of activating autophagy or suppressing autophagy dysregulation in a subject, comprising: providing an effective amount of a formulation to the subject, wherein the formulation comprises: an exogenous poly amine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; and a cofactor that increases production of the endogenous polyamine, the cofactor including Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, copper, manganese, lithium, or a combination thereof.

83. The method of claim 82, wherein the effective amount of the formulation provided to the subject is in an amount ranging from about 500 pg to about 3000 mg.

84. The method of claim 82, wherein the subject suffers from cancer.

85. The method of claim 82, wherein the subject suffers from a neurogenerative disease.

86. The method of claim 85, wherein the neurogenerative disease is Alzheimer’s disease.

87. The method of claim 86, wherein the neurogenerative disease is Parkinson’s disease.

88. The method of claim 82, wherein the subject suffers from a metabolic disorder.

89. The method of claim 82, wherein the subject suffers from anorexia nervosa.

90. The method of claim 82, wherein the subject suffers from a viral infection.

91. The method of claim 90, wherein the viral infection comprises a respiratory infection.

92. The method of claim 91, wherein the respiratory infection comprises CO VID- 19.

93. The method of claim 82, wherein the subject suffers from symptoms associated with Post-CO VID.

94. The method of claim 82, wherein the subject suffers symptoms from a vaccine.

95. The method of claim 94, wherein the vaccine comprises a Coronavirus vaccine.

96. The method of claim 95, wherein the Coronavirus vaccine causes spike protein expression in the subject.

97. The method of claim 95, wherein the Coronavirus vaccine comprises a SARS- CoV-2 vaccine.

98. The method of claim 97, wherein the SARS-CoV-2 vaccine causes SARS-CoV- 2 spike protein expression in the subject.

99. The method of claim 97, wherein the subjects have Post-COVID symptoms.

100. The method of claim 82, further comprising orally ingesting the formulation by the subject.

101. The method of claim 100, wherein the oral ingesting occurs daily.

102. The method of claim 100, wherein the oral ingesting occurs prior to a meal.

103. A method of activating autophagy or suppressing autophagy dysregulation in a subject, comprising: providing one or more formulations to a subject, wherein the one or more formulations comprises a first formulation, the first formulation comprising: an exogenous poly amine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; and a cofactor that increases production of the endogenous polyamine, the cofactor including Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof.

104. The method of claim 103, further comprising ingesting the one or more formulations by the subject.

105. The method of claim 103, wherein the one or more formulations further comprise a second formulation, and wherein the second formulation comprises nattokinase.

106. The method of claim 103, wherein the one or more formulations further comprise a second formulation, and wherein the second formulation comprises nattozime.

107. The method of claim 105, wherein the second formulation further comprises bromelain.

108. The method of claim 105, wherein the one or more formulations further comprise a third formulation.

109. The method of claim 108, wherein the third formulation comprises lunasin.

110. The method of claim 108, wherein the one or more formulations further comprise a fourth formulation.

111. The method of claim 110, wherein the fourth formulation comprises an antioxidant precursor.

112. The method of claim 111, wherein the antioxidant precursor comprises NAC.

113. The method of claim 111, wherein the antioxidant precursor comprises a derivative of NAC.

114. The method of claim 113, wherein the derivative of NAC comprises N- acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N-acetylcysteine butyl ester.

115. The method of claim 113, wherein the derivative of NAC is converted to the NAC following an intracellular esterase contacting the derivative of NAC.

116. The method of claim 115, further comprising directing the NAC to neutralize one or more SARS-CoV-2 spike proteins.

117. A method of activating autophagy or suppressing autophagy dysregulation in a subject, comprising: providing one or more formulations to a subject, wherein the one or more formulations comprises a first formulation, the first formulation comprising: an exogenous poly amine including spermidine, spermine, putrescine, or a combination thereof; a precursor to an endogenous polyamine; a cofactor that increases production of the endogenous polyamine, the cofactor including Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, zinc, magnesium, selenium, lithium, copper, manganese, or a combination thereof; and an antioxidant precursor.

118. The method of claim 117, further comprising ingesting the one or more formulations by the subject.

119. The method of claim 1 17, wherein the one or more formulations further comprise a second formulation, and wherein the second formulation comprises nattokinase.

120. The method of claim 117, wherein the one or more formulations further comprise a second formulation, and wherein the second formulation comprises nattozime.

121. The method of claim 119, wherein the second formulation further comprises bromelain.

122. The method of claim 119, wherein the one or more formulations further comprise a third formulation.

123. The method of claim 122, wherein the third formulation comprises lunasin.

124. The method of claim 117, wherein the antioxidant precursor comprises NAC.

125. The method of claim 117, wherein the antioxidant precursor comprises a derivative of NAC.

126. The method of claim 125, wherein the derivative of NAC comprises N- acetylcysteine methyl ester, NACET, N-acetylcysteine propyl ester, or N-acetylcysteine butyl ester.

127. The method of claim 125, wherein the derivative of NAC is converted to the NAC following an intracellular esterase contacting the derivative of NAC.

128. The method of claim 127, further comprising directing the NAC to neutralize one or more SARS-CoV-2 spike proteins.