WO2021202245A1 - Régimes de traitement antiviral - Google Patents

Régimes de traitement antiviral Download PDF

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Publication number
WO2021202245A1
WO2021202245A1 PCT/US2021/024207 US2021024207W WO2021202245A1 WO 2021202245 A1 WO2021202245 A1 WO 2021202245A1 US 2021024207 W US2021024207 W US 2021024207W WO 2021202245 A1 WO2021202245 A1 WO 2021202245A1
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Prior art keywords
composition
subject
virus
acid
nmn
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PCT/US2021/024207
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English (en)
Inventor
Joel Timothy HUIZENGA
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Egaceutical Corporation
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Publication of WO2021202245A1 publication Critical patent/WO2021202245A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the disclosed subject matter generally relates to compositions for defending against and repairing the effects of aging and for treating viral infections, e.g., COVID-19.
  • Adverse effects of aging can be a result of accumulated unrepaired cellular damage.
  • Accumulated damage to one’s immune system may reduce or prevent a patient’s ability to mount an effective immune response to pathogens, including viruses.
  • New compositions and methods for repairing the effects of aging, including reversing accumulated cellular damage, and especially among cells of the immune system, are needed.
  • the present disclosure provides methods and compositions for repairing the effects of aging, including reversing accumulated cellular damage, and especially among cells of the immune system. These methods and compositions are particularly useful in treating, preventing, and/or reducing the ill effects of a viral infection, e.g, resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • An aspect of the present disclosure is a composition for administering to a subject.
  • the composition comprises: a repair system activator chosen from, nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, nicotinamide adenine dinucleotide (NAD+), nicotinamide riboside (NR), nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), nicotinic acid riboside (NAR), 1- methylnicotinamide (MNM), cyclic adenosine monophosphate (cAMP), and any combination thereof; a methyl donor chosen from, betaine, S-5’-adenosyl-L-methionine (SAM), methionine, choline, serine, folate, vitamin B 12, and any combination thereof; and an antioxidant defense activator chosen from
  • the repair system activator, the methyl donor, and the antioxidant defense activator are present in a combined amount of at least 5 wt.% of the composition.
  • the repair system activator is nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, nicotinamide riboside (NR), or both.
  • NMN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • the methyl donor is betaine, methionine, or both.
  • the antioxidant defense activator is Zinc (e.g., as zinc sulfate), calcium peroxide, N-Acetylcysteine, H2O2, H2S, orNaSH.
  • the repair system activator, methyl donor, and antioxidant defense activator are in an amount sufficient to beneficially change a surrogate marker for aging level in a human when compared to the surrogate marker level prior to administration.
  • the change in the level of the surrogate marker is lowered the surrogate marker is CMV IgG, C-Reactive Protein, Tumor Necrosis Factor-Alpha, or Interleukin-6.
  • the change in the level of the surrogate marker is increased.
  • the surrogate marker is DNA methylation.
  • the composition further comprises water. In embodiments, the composition comprises at least 1 x 10 8 moles of the repair system activator, at least 1 x 10 8 moles of the methyl donor, and at least 1 x 10 9 moles of the antioxidant defense activator.
  • the composition comprises nicotinamide mononucleotide (NMN) or the precursor or prodrug of NMN, Betaine, and zinc (e.g as zinc sulfate).
  • the composition comprises NMN, Betaine, and Zinc Sulfate in a ratio of from about 7 and 20: to from about 4 and 10; to about 1.
  • a unit dose of the composition comprises from about 0.8 grams and about 2.0 grams of NMN, from about 0.4 grams and 0.8 grams of Betaine, and from about 0.09 and 0.25 grams of Zinc Sulfate. In embodiments, the unit dose of the composition comprises from about 0.9 grams and about 1.1 grams of NMN, from about 0.45 grams and 0.55 grams of Betaine, and from about 0.1 and 0.12 grams of Zinc Sulfate. In embodiments, the unit dose of the composition comprises about 1 gram of NMN, 0.5 grams of Betaine, and about 0.11 grams of Zinc Sulfate.
  • the composition further comprises from about 25 mg to about 100 mg of NaCl. In embodiments, the composition further comprises about 50 mg of NaCl.
  • composition may be used in a method for reversing aging and/or for reversing accumulated cellular damage in a subject in need thereof.
  • compositions may comprise or administered contemporaneously with Na+ (e.g., as NaCl) to increase the absorption of NMN or Betaine.
  • Na+ e.g., as NaCl
  • NNN Cocktail The herein described “unit dose”, “formulation”, and/or “composition” may be referred to as an “NMN Cocktail”.
  • any herein-disclosed composition may be used in a method for treating, preventing, and/or reducing the ill effects of a viral infection in a subject in need thereof.
  • the viral infection is caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); an enterovirus A-J; a rhinovirus A-C; a rotavirus A-C; a norovirus; an influenza virus A-C and their types such as H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H7N9; a human papillomavirus; a polyomavirus: John Cunningham virus and Merkel cell virus; a poxvirus; a herpesvirus such as human simplex virus 1, human simplex virus 2, varicella zoster virus, Epstein-Barr virus or human herpesvirus 4; a human cytomegalovirus, Herpesvirus 6 (A
  • an injectable formulation a tablet, a powder, and a beverage, each comprising any herein-disclosed composition.
  • Another aspect of the present disclosure is a method for reducing inflammation in a subject in need thereof, for reversing aging and/or for reversing accumulated cellular damage in a subject in need thereof, and/or for treating, preventing, and/or reducing the ill effects of a viral infection in a subject in need thereof.
  • the method comprising: administering to the subject any herein-disclosed composition.
  • the composition is administered to a subject at a dosage of at least 1 x 10 6 moles /kg of the repair system activator to the subject, 1 x 10 6 moles /kg of the methyl donor to the subject, and 1 x 10 7 moles /kg of the antioxidant defense activator to the subject.
  • the composition is injected over 8-12 days.
  • the composition is in an aerosol, lyophilized, powder, or emulsion form.
  • the subject in need thereof is a human.
  • the composition is administered to the human for at least two months.
  • the composition is in a tablet that is administered orally at least once daily.
  • the composition further comprises water.
  • the composition is administered to the subject once daily.
  • the composition comprises nicotinamide mononucleotide (NMN) or the precursor or prodrug of NMN, Betaine, and Zinc ( e.g ., as zinc sulfate).
  • the composition comprises Na+ (e.g., as NaCl) or is administered contemporaneously with Na+ (e.g, as NaCl) to increase the absorption of NMN or Betaine.
  • the viral infection is caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); an enterovirus A-J; a rhinovirus A-C; a rotavirus A-C; a norovirus; an influenza virus A-C and their types such as H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H7N9; a human papillomavirus; a polyomavirus: John Cunningham virus and Merkel cell virus; a poxvirus; a herpesvirus such as human simplex virus 1, human simplex virus 2, varicella zoster virus, Epstein-Barr virus or human herpesvirus 4; a human cytomegalovirus, Herpesvirus 6 (A&B), herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus; a hepatitis A-E virus; Retroviruses like human
  • the composition comprises NMN, Betaine, and Zinc Sulfate in a ratio of from about 7 and 20: to from about 4 and 10; to about 1.
  • a unit dose of the composition comprises from about 0.8 grams and about 2.0 grams of NMN, from about 0.4 grams and 0.8 grams of Betaine, and from about 0.09 and 0.25 grams of Zinc Sulfate. In embodiments, the unit dose of the composition comprises from about 0.9 grams and about 1.1 grams of NMN, from about 0.45 grams and 0.55 grams of Betaine, and from about 0.1 and 0.12 grams of Zinc Sulfate. In embodiments, the unit dose of the composition comprises about 1 gram of NMN, 0.5 grams of Betaine, and about 0.11 grams of Zinc Sulfate.
  • the unit dose further comprises from about 25 mg to about 100 mg of NaCl. In embodiments, the unit dose further comprises about 50 mg of NaCl.
  • At least one unit of the composition is administered to the subject at each dosing. In embodiments, at least two units of the composition, at least three units of the composition, at least four units of the composition, or at least five units of the composition is administered to the subject at each dosing. In embodiments, the number of units of the composition per dosing relates in part to the weight of the subject. In embodiments, when a subject weighs 100 lbs or less, the subject is administered at least one unit of the composition per dosing and/or when a subject weighs over 100 lbs, the subject is administered at least one unit, at least two units, at least three units, or at least four units or at least five units of the composition per dosing. In embodiments, the subject receives at least one dosing per day, at least two dosings per day, at least three dosings per day, or at least four dosings per day.
  • NNN Cocktail The herein described “unit dose”, “formulation”, and/or “composition” may be referred to as an “NMN Cocktail”.
  • Yet another aspect of the present disclosure is a method for reducing inflammation in a subject in need thereof, for reversing aging and/or for reversing accumulated cellular damage in a subject in need thereof, and/or for treating, preventing, and/or reducing the ill effects of a viral infection in a subject in need thereof.
  • a repair system activator chosen from nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, nicotinamide adenine dinucleotide (NAD+), nicotinamide riboside (NR), nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), nicotinic acid riboside (NAR), 1- methylnicotinamide (MNM), cyclic adenosine monophosphate (cAMP), and any combination thereof; a methyl donor chosen from, betaine, S-5’-adenosyl-L-methionine (SAM), methionine, choline, serine, folate, vitamin B 12, and any combination thereof; and an antioxidant defense activator chosen from zinc (e.g ., as zinc sulfate, zinc (SAM), methionine
  • the repair system activator, the methyl donor, and the antioxidant defense activator are administered at approximately the same time.
  • the repair system activator is administered within 15, 30, 60, 90, or 120 minutes of the subject’s biological clock NAD+ peak. In embodiments, the repair system activator, the methyl donor, and the antioxidant defense activator are administered at different times.
  • the subject is a human.
  • the repair system activator, the methyl donor, and the antioxidant defense activator are administered to the human for at least two months.
  • the repair system activator, the methyl donor, and the antioxidant defense activator are administered to the human once daily.
  • Na+ e.g, as NaCl
  • NMN or Betaine is administered to increase the absorption of NMN or Betaine.
  • the viral infection is caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); an enterovirus A-J; a rhinovirus A-C; a rotavirus A-C; a norovirus; an influenza virus A-C and their types such as H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H7N9; a human papillomavirus; a polyomavirus: John Cunningham virus and Merkel cell virus; a poxvirus; a herpesvirus such as human simplex virus 1, human simplex virus 2, varicella zoster virus, Epstein-Barr virus or human herpesvirus 4; a human cytomegalovirus, Herpesvirus 6 (A&B), herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus; a hepatitis A-E virus; Retroviruses like human
  • the repair system activator, the methyl donor, and/or the antioxidant defense activator are each independently in the form of an injectable formulation, a tablet, a powder, and/or a beverage.
  • the repair system activator, the methyl donor, and the antioxidant defense activator are respectively NMN, Betaine, and Zinc Sulfate and in a ratio of from about 7 and 20: to from about 4 and 10; to about 1.
  • a unit dose of the repair system activator, the methyl donor, and the antioxidant defense activator comprises from about 0.8 grams and about 2.0 grams of NMN, from about 0.4 grams and 0.8 grams of Betaine, and from about 0.09 and 0.25 grams of Zinc Sulfate.
  • the unit dose comprises from about 0.9 grams and about 1.1 grams of NMN, from about 0.45 grams and 0.55 grams of Betaine, and from about 0.1 and 0.12 grams of Zinc Sulfate.
  • the unit dose comprises about 1 gram of NMN, 0.5 grams of Betaine, and about 0.11 grams of Zinc Sulfate.
  • the unit dose further comprises from about 25 mg to about 100 mg of NaCl. In embodiments, the unit dose further comprises about 50 mg of NaCl.
  • NNN Cocktail The herein described “unit dose”, “formulation”, and/or “composition” may be referred to as an “NMN Cocktail”.
  • At least one unit of the repair system activator, the methyl donor, and the antioxidant defense activator is administered to the subject at each dosing.
  • at least two units, at least three units, at least four units, or at least five units is administered to the subject at each dosing.
  • the number of units per dosing relates in part to the weight of the subject.
  • the subject receives at least one dosing per day, at least two dosings per day, at least three dosings per day, or at least four dosings per day.
  • the subject is at least 50 years old.
  • the subject has previously been treated with one or more of hydroxychloroquine, Zithromax, and zinc.
  • the subject is administered the composition in accordance with the subject’s circadian rhythm.
  • the subject is administered the composition to a substantially empty stomach.
  • the present disclosure provides a composition
  • a precursor or prodrug of nicotinamide mononucleotide (NMN) a methyl donor chosen from, betaine, S-5’-adenosyl-L-methionine (SAM), methionine, choline, serine, folate, vitamin B 12, and any combination thereof; and an antioxidant defense activator chosen from zinc (e.g as zinc sulfate), calcium peroxide, N- Acetyl cysteine, H 2 0 2 , H 2 S, NaSH, Na 2 S, ROS, RNS, RCS, RSOH, 0 2 ⁇ , OH ⁇ , x 0 2 , O3, HOC1, HOBr, HOI, ROOH, where R is alkyl, cycloalkyl, heteralkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, or hetercycloalkenyl,
  • NPN nic
  • the composition comprises NMN, Betaine, and Zinc Sulfate in a ratio of from about 7 and 20: to from about 4 and 10; to about 1.
  • a unit dose of the composition comprises from about 0.8 grams and about 2.0 grams of NMN, from about 0.4 grams and 0.8 grams of Betaine, and from about 0.09 and 0.25 grams of Zinc Sulfate. In embodiments, the unit dose of the composition comprises from about 0.9 grams and about 1.1 grams of NMN, from about 0.45 grams and 0.55 grams of Betaine, and from about 0.1 and 0.12 grams of Zinc Sulfate. In embodiments, the unit dose of the composition comprises about 1 gram of NMN, 0.5 grams of Betaine, and about 0.11 grams of Zinc Sulfate. In embodiments, the unit dose further comprises from about 25 mg to about 100 mg of NaCl. In embodiments, the unit dose further comprises about 50 mg of NaCl.
  • NNN Cocktail The herein described “unit dose”, “formulation”, and/or “composition” may be referred to as an “NMN Cocktail”.
  • Another aspect is a disposable waterproof and/or air proof container comprising any herein-disclosed composition.
  • the disposable waterproof and/or air proof container comprises instructions for use.
  • kits comprising at least ten of the disposable waterproof and/or air proof containers.
  • FIG. 1 is a schematic showing effects of lowered NAD+, SAM and Nrf2, which occurs as cells age. Proposed mechanisms for reversing aging and treating viral infections are shown.
  • the three components NMN, Betaine, and H2O2 are used as illustrative of the methods and compositions for reversing aging. Other components used in the methods and compositions of the present disclosure would likewise reverse aging.
  • FIG. 2 is a table showing patient characteristics for patients described in Example 1.
  • FIG. 3 is a table showing pre-treatment clinical conditions for patients described in Example 1.
  • FIG. 4 is a table showing patient outcomes for patients described in Example 1.
  • FIG. 5 to FIG. 9 are chest x-rays for Patient 1 described in Example 1.
  • FIG. 10 is a table showing vital signs of Patient 1 described in Example 1.
  • FIG. 11 is a table showing vital signs of Patient 2 described in Example 1.
  • FIG. 12 is a table showing vital signs of Patient 3 described in Example 1.
  • FIG. 13 to FIG. 16 are chest x-rays for Patient 4 described in Example 1.
  • FIG. 17 is a table showing vital signs of Patient 4 described in Example 1.
  • FIG. 18 and FIG. 19 are chest x-rays for Patient 5 described in Example 1.
  • FIG. 20 is a table showing vital signs of Patient 5 described in Example 1.
  • FIG. 21 is a chest x-ray for Patient 6 described in Example 1.
  • FIG. 22 is a table showing vital signs of Patient 6 described in Example 1.
  • FIG. 23 is a chest x-ray for Patient 6 described in Example 1.
  • FIG. 24 is a chest x-rays for Patient 7 described in Example 1.
  • FIG. 25 is a table showing vital signs of Patient 7 described in Example 1.
  • FIG. 26 to FIG. 28 are chest x-rays for Patient 7 described in Example 1.
  • FIG. 29 is a chest x-rays for Patient 8 described in Example 1.
  • FIG. 30 is a table showing vital signs of Patient 8 described in Example 1.
  • FIG. 31 is a chest x-rays for Patient 8 described in Example 1.
  • FIG. 32 to FIG. 35 are chest x-rays for Patient 10 described in Example 1.
  • FIG. 36 is a table showing vital signs of Patient 10 described in Example 1.
  • compositions are particularly useful in reversing cellular consequences of aging and in treating, preventing, and/or reducing the ill effects of a viral infection, e.g., resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • NADH is not used by sirtuins enzymes and is only inhibitory at concentrations far greater that those predicted for cells. NADH is also not used for generation of NADP+ by the cytosolic NADK enzyme and this generated NADP+ is rapidly turned into NADPH.
  • Caloric restriction induces a “nutritional stress” that results in a depletion of the cells energy stores (ATP, NADH, etc.). The “depleted energy forms” of this stored energy are cAMP and NAD+.
  • NAD+ activates a set of enzymes called Sirtuins as well as PARPs.
  • Sirtuins As well as PARPs.
  • What the data disclosed herein shows is that by providing NAD+ or compounds or compositions having a similar activity, immune system markers are reduced, which has been shown to be associated with anti-aging. These data are consistent with an increased activation of Sirtuins, through interaction with NAD+, or similar acting molecules.
  • the positive effect of NAD+ can level off, presumably because of other reactions taking place in the organism, including in the active site of the Sirtuins themselves.
  • compositions and formulations which contain three categories of compositions, or methods where three different categories of molecules are administered, alone, in conjunction, or in combination to a subject.
  • NAD+ should be available to turn on and be used by Sirtuins
  • methyl donors should be available to methylate DNA and other entities needing methylation like the reaction of nicotinamide to 1-methylnicotinamide by the nicotinamide-N-methyltransferase (NNMT) enzyme, and
  • a reducing balance should be provided so that important enzymes, such as Sirtuins, can have the thiol (sulfur) groups in their reactive sites maintained in a reduced state.
  • compositions, formulations, and methods that reduce markers of inflammation related to aging and are consistent with enhancing these three goals.
  • one provides enough oxidation from H2O2 to provide pre conditioning from signaling to turn on the anti-oxidant defense and repair system but not enough to create oxidized damage like oxidizing the thiol groups in the Sirtuin active site that turns the Sirtuin enzymes activities off.
  • the APE-1/ Ref-1 is a molecule that protects the thiol groups of amino acids in the Sirtuin active site from oxidation by H2O2. This can be kept active.
  • Nrf2 nicotinamide-N-methyltransf erase
  • compositions, formulations, and methods which turn on, enhance, and in some formulations keep on, the human defense and repair mechanisms involving the Sirtuin enzymes.
  • These compounds, compositions and formulations comprise one or more items from each of three (3) categories alone or in combination, and can be administered through ingestion, injection, inhalation, application to the skin, or any other means.
  • the disclosed compounds, compositions, and formulations can perform at least one of the following activities: Protect against further cellular damage from the aging process; Repair cellular damage from the aging process; Delay the onset of the diseases of aging where aging is a causal factor; Promote weight loss / reduce hunger; and Promote more productive sleep, waking more rested.
  • Diseases of aging include inflammation, heart disease (including heart attack and heart failure), stroke, neurodegenerative disease such as Alzheimer’s disease, diabetes, cancer, respiratory disease, systemic autoimmune disease (including arthritis) and muscle wasting.
  • the herein-disclosed methods and compositions are particularly useful in treating, preventing, and/or reducing the ill effects of a viral infection, e.g., resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Death from viral attacks correlates to the speed of activation of CD-8 T-Cells.
  • a viral infection e.g., resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • Death from viral attacks correlates to the speed of activation of CD-8 T-Cells.
  • the late rise of 11-6 in a “cytokine storm” may be due to this late start, since with early start IL-6 does not seem to have the late rise.
  • CD-8 T-cells with high CD38 expression have decreased cytotoxic capacity and higher rates of infections and increased propensity for infections.
  • the late rise of 11-6 may be due to the low ability of the T-Cells to kill viruses.
  • CD-8 T-Cells Activation of CD-8 T-Cells needs CD38 and CD-38 not only is correlated to the Adaptive Immune system CD-8 T-Cells but also the Innate Immune system Toll-like Receptors.
  • CD-38 Other correlations of CD-38 include:
  • NF-kB oxidation; CD-38 active; inflammation is increased; decreased methylation (like H3K9me3 & H3K27me3); increased LINE-1; and increased II- 6 gene transcription.
  • Nrf2 reduction; CD-38 inactive; increased methylation; endogenous (LINE-1) viruses are inactivated.
  • TNF-a modulates immune response to viral attack; an inducer of CD-38; CD- 38 has a TNF receptor; lowered by compositions and methods disclosed in below working examples.
  • IL-6 modulates immune response to viral attack; lowered by compositions and methods disclosed in below working examples; reduction of LINE-1 leads to reduction of 11-6; basal level correlates to favorable health-span and life-span.
  • NAD+ CD-38 rapidly degrades NAD+ and NMN its precursor; when CD-38 is active, NAD+ is less available to Sirtuins and Defense and Repair.
  • Tristetraprolin induced by CD-38 in the onset of acute inflammation; TTP-dependent degradation of CD-38 activates Sirtuin-1 at the onset of resolution; TTP controls the resolution of inflammation; Carbon monoxide (CO) inhibits inflammation by increasing TTP expression; a Phase 1 clinical trial with low dose inhaled carbon monoxide in (sepsis-induced) ARDS was successfully conducted showing it was feasible to give precise administration of CO, CO was well-tolerated and that CO was safe.
  • CO Carbon monoxide
  • Zinc (+2) inhibits Coronavirus RNA-synthesizing machinery and impairs a number of RNA viruses
  • Zinc (+2) is important in regulating the immune system.
  • zinc may be of benefit or harm due to its correlation to its turning on Nrf2 which correlates to the turning off of NF-kB (and vice versa) which at certain stages of certain viral replication can be of benefit.
  • zinc is provided as zinc acetate, zinc arginate, zinc aspartate, zinc chloride, zinc citrate, zinc difumarate hydrate, zinc gluconate, zinc glycinate, zinc methionine, zinc monomethionine, zinc muratab, zinc orotate picolinate, zinc oxide, zinc pyrithione, or zinc sulfate.
  • zinc is provided as zinc sulfate.
  • a unit dose of zinc comprises about 25 mg of zinc.
  • a patient experiencing a “cytokine storm syndrome” and the overwhelming oxidation and inflammation involved will lead to an active CD-38 that breaks down all NAD+ and its precursor NMN very rapidly.
  • levels of NAD+ via the methods and compositions of the present disclosure
  • the methods and compositions of the present disclosure are particularly useful in treating, preventing, and/or reducing the ill effects of a viral infection, e.g., resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the methods of the present disclosure include administering a composition in adherence to the Circadian rhythm. Without wishing to be bound by theory, such adherence makes for a better therapeutic outcome, especially against viral attacks, e.g., by SARS-CoV-2.
  • An advantage of the methods and compositions of the present disclosure is that they can provide a therapy against a viral attack (e.g, by SARS-CoV-2) in patients who cannot receive standard treatments, e.g, IL6 blockers or Remdesivir, due to sensitivity or allergy or adverse interactions with other therapies.
  • a viral attack e.g, by SARS-CoV-2
  • standard treatments e.g, IL6 blockers or Remdesivir
  • Illustrative viral infections may be caused by one or more of enteroviruses A-J; rhinoviruses A-C; rotaviruses A-C; norovirus; influenza virus A-C and their several types like H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H7N9, and their other relatives; human papillomaviruses (HPV); polyomaviruses like John Cunningham virus (JCV) and Merkel cell virus (MCV); poxviruses; herpesviruses such as human simplex virus 1 (HSV- 1), human simplex virus 2 (HSV-2), varicella zoster virus, Epstein-Barr virus (human herpesvirus 4; EBV/HHV-4), human cytomegalovirus (HHV-5), Herpesvirus 6 (A&B), herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus
  • Non-cancer diseases include (i) non-cancer diseases: enteritis (enteroviruses A-J); common cold (rhinoviruses A-C); gastroenteritis, diarrhoea (rotaviruses A-E, norovirus); gastroenteritis (norovirus); influenza (influenza virus A-C); progressive multifocal leukoencephalopathy (JCV), nephrophathy, Merkel cell cancer (MCV), smallpox (variola) (poxvirus); herpes (HSV-1, HSV-2); chicken-pox, herpes zoster (shingles) (varicella zoster virus); infectious mononucleosis (HHV-4); hepatitis A (hepatitis A virus); hepatitis B (hepatitis B virus); hepatitis C (hepatitis C virus); acquired immunodeficiency syndrome (HIV-1, HIV-2, and their subtypes); severe acute respiratory infections
  • Category 1 which are Repair System Activators
  • Category 2 which are Methyl Donors
  • Category 3 which are Antioxidant Defense Activators
  • compositions comprising a first compound, a second compound, and a third compound
  • the first compound comprises nicotinamide adenine dinucleotide (NAD+), NAD+ precursor such as nicotinamide mononucleotide (NMN), a precursor or prodrug of NMN, nicotinamide riboside (NR), nicotinic acid riboside (NAR), nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), analog of NAD+ that promotes NAD+ use such as 1-methylnicotinamide (MNM), cyclic adenosine monophosphate (cAMP)
  • the second compound comprises S-5’-adenosyl-L- methionine (SAM), SAM precursor such as methionine, betaine, choline, serine, folate, vitamin B12,
  • compositions wherein the first compound, comprises NAD+ NMN, NR, NaMN, NaAD, NAR, MNM, cAMP, alone or in combination. Also disclosed are compositions wherein the first compound comprises NMN. Also disclosed are compositions wherein the first compound comprises a precursor or prodrug of NMN, e.g., a compound that increases NMN production in the body.
  • compositions wherein the composition lowers a Surrogate Marker for Aging are also disclosed.
  • the surrogate marker is CMV IgG, C- Reactive Protein, Tumor Necrosis Factor-alpha, or Interleukin-6 Serum.
  • Na e.g, via NaCl
  • compositions wherein the composition is formulated for injection are also disclosed.
  • compositions wherein the composition is in tablet form or aerosol are also disclosed.
  • compositions wherein the composition comprises at least 1 x 10 8 moles of the first compound, at least 1 x 10 8 moles of the second compound, and at least 1 x 10 9 moles of the third compound.
  • NNN Cocktail The herein described “unit dose”, “formulation”, and/or “composition” may be referred to as an “NMN Cocktail”.
  • Sirtuins require NAD+.
  • Providing a repair system activator can turn on the Sirtuins.
  • Examples of a repair system activator include NAD+, NAD+ precursor such as NMN, NR, NaMN, NaAD, NAR, analog of NAD+ that promotes NAD+ use such as MNM, and cAMP, or any combination thereof.
  • a preferred repair system activator is the NAD+ precursor NMN (to make NAD+, to turn on, and be consumed by Sirtuins, which provides the benefit from Calorie Restriction).
  • NAD+ typically naturally peaks in the morning and the evening such as at 8 AM and 8 PM, and thus the addition of NAD+ or precursor that would turn into NAD+ would be added, for example, preferentially in the 7 AM to 8 AM and the 7 PM to 8 PM time frame.
  • Typical formulations provide greater or equal to 1.19 x 10 4 moles/kg-of-subject NMN, NAD+, or NAD+ precursor when administered (NMN is 334.22 grams / mole).
  • a preferred repair system activator is a precursor or prodrug of NMN, e.g, a compound that increases NMN production in the body.
  • NAD+ and NR are less preferred because NAD+ is not absorbed well through the digestive system and the enzymes that make NMN from NR are not found in every cell of the body.
  • Orally delivered NR has also been shown to largely not reach muscle.
  • NMN neurotinamide mononucleotide
  • the dosage can be adjusted for absorption and Na (e.g via NaCl) can be added for active transport absorption. It is preferred to administer the Repair System Activator such as NMN, through water and drinking. A precursor or prodrug of NMN can also be administered, in further examples.
  • repair system activators are administered for reducing inflammation markers related to aging.
  • repair system activators are any compound, composition, formulation, molecule, biologic, or substance, which activates sirtuin enzymes. These types of enzymes prefer a redox balance near or at reducing to be optimized. Examples of such molecules that activate Sirtuin are NAD+, NAD+ precursor such as NMN, NR, NaMN, NaAD, NAR, analog of NAD+ that promotes NAD+ use such as MNM, and cAMP.
  • SAM adenosyl-L-methionine
  • SAM can provide the methyl group for nicotinamide, which has aging properties by stopping Sirtuin enzymes from working. This methylation of nicotinamide occurs via N-methyltransferase (NNMT) N-m ethylation to 1- methylnicotinamide.
  • This nicotinamide with a methyl group attached provides competition to the available nicotinamide molecules that can get into the Sirtuin enzyme and decrease the Sirtuin enzyme’s reactive ability; thus, preventing this process from happening in proportion to the concentration of each of the two competitors.
  • the timing for giving would be with the Repair System Activator, such as NAD+ or NAD+ precursor.
  • SAM also provides the methyl groups to reduce the hypo-methylation seen in aging and in the right context it can to be used beneficially to combat aging, example: the need for H3K4me3 methylation of DNA found especially in older people.
  • Methyl Donors in addition to betaine, which can be used include SAM, methionine, choline, serine, folate, and B 12. Typically, these alternatives are less preferred because only about 2% of SAM get into the body when ingested; choline needs extra NAD+ to be made into betaine, which is in short supply in the body.
  • Serine helps make SAM from Methionine in two ways.
  • This dose can be given over 24 hours and can be divided into two approximately equal doses taken approximately 12 hours apart.
  • the dose can be dissolved in water and drunk by the subject.
  • the administration can be along with the administration of the category 1 compound or composition.
  • the methylation donors are administered to a subject, and these methylation donors are molecules, substances, compositions, compounds, and formulations, which increase the methylation of molecules or methylate molecules themselves.
  • methyl donors prefer a Redox balance to be near reduction for optimal activity.
  • S-5’Adenosyl -L- methionine (SAM) precursors include methionine, betaine, choline (a precursor of betaine), serine, folate, Vitamin B12 alone or in combination.
  • the antioxidant defense When providing a category 3 compound, composition, or formulation the antioxidant defense is turned on. Having the antioxidant defense enzymes working increases the reduction of the thiol (sulfur) groups in the reactive site of Sirtuin enzymes and others with similar regulation. This prevents the Sirtuin enzymes from turning off due to thiol oxidation.
  • One way to create a generally reducing environment is to “shock” the organism by a pulsed burst of oxidants, such as H2O2.
  • oxidants such as H2O2.
  • H2O2 oxidants
  • pre-conditioning with oxidants to shock on the system, and one keeps them on by additional timed shock pulses of oxidants prior to the antioxidant enzymes turning off due to their feedback loops that turn them off or down when they are not challenged by oxidants.
  • the pulse of oxidants for the preconditioning one uses a sufficient level of oxidants to turn on and keep on the antioxidant enzymes.
  • H2O2 hydrogen peroxide
  • H 2 O 2 can oxidize thiol groups on proteins / enzymes thereby changing their enzymatic properties.
  • This pre-conditioning low level oxidation by H 2 O 2 can be given in a pulsed, time controlled, and dose-controlled fashion to turn on enzymes and processes without providing oxidation in excess of what is needed to turn on enzymes including anti-oxidant defense and repair systems enzymes, because excess oxidation causes cellular damage and harm.
  • Any small molecule (non-enzyme) antioxidants should be taken at other time periods (other than the time period of the oxidative pulse) so as not to diminish this temporal effect of the oxidative pulse.
  • Hydrogen peroxide (H 2 O 2 ) is a ubiquitous oxidant present in all aerobic organisms. H 2 O 2 is now appreciated as a messenger molecule and it provides sensitivity to redox signaling. H 2 O 2 provides oxidative modification of amino acid side chains in proteins; in decreasing order of reactivity and biological reversibility, cysteine, methionine, proline, histidine and tryptophan. Thiol modification is key in H 2 O 2 sensing and perception in proteins. Hydrogen peroxide has been found to mimic insulin activity, elicit arterial pulmonary relaxation, stimulate cell proliferation, and activate NF-KB and AP-1. The functional consequences of H 2 O 2 signaling concern fundamental biological processes.
  • H 2 O 2 With recognition of the role of low-level oxidants stimuli for altering the set point of gene expression for batteries of enzymes, known as Hormesis.
  • Transcriptional factors effected by H 2 O 2 include AP-1, Nrf2, CREB, HSF1, HIF-1, TPSS, NF-KB, NOTCH, SP1, and SCREB- 1 most involved in regulation of cell damage response, cell proliferation (cell cycle regulation) differentiation and apoptosis.
  • Protein acetylation is regulated by H 2 O 2. Protein deacetylation is regulated by Sirtuins. H 2 O 2 increase acetylation and Sirtuins decrease acetylation, so H 2 O 2 and Sirtuins effects are in pushing acetylation reaction pathways in the opposite directions.
  • Sirtl is very sensitive to H 2 O 2 inhibition of 1 pmol of extracellular H 2 O 2.
  • Sirtl is protected by thiol oxidation from (APE1 / Ref-1). It governs the redox state and activity of Sirtl. It reduces the thiol groups in the active site of Sirtl, H 2 O 2 oxidizes the thiols in Sirtl’ s active site.
  • Sirtl is also regulated by redox-dependent phosphorylation. Need for pulsing of signaling oxidants
  • H 2 O 2 High levels of H 2 O 2 increase defenses by preconditioning and thus can ultimately protect against increase of oxidized thiols in Sirtuin’s active site and Sirtl’s decrease in activity by an oxidative challenge.
  • Adaptation to H 2 O 2 decrease H 2 O 2 permeability of plasma membranes. Different cell membranes have a full range of permeability to H 2 O 2.
  • Aquaporins also regulate H 2 O 2 transport across bio-membranes.
  • Metformin the most widely prescribed antidiabetic drug in the world, increases hydrogen peroxide (H 2 O 2 ); this upregulates peroxiredoxin-2 (PRDX-2). Metformin increases lifespan in C. elegans and taking away the PRDX-2 gene takes away this effect. PRDX-2 appears to have the role of translating oxidative stress into a downstream pro longevity signal. Treatment with N-acetylcysteine (NAC) and butylated hydroxyanisole (BHA), which are small molecule antioxidants, abolished the positive effect of metformin on lifespan. Pharmaceuticals that increase hydrogen peroxide in the body can also be used for this category either in addition to H 2 O 2 or as a substitute for adding hydrogen peroxide itself. Pharmaceuticals that increase H 2 O 2 in the body include metformin and acetaminophen.
  • H 2 O 2 in the body need also to be included in the calculation of the oxidative pulse given in category #3.
  • An example is Acetaminophen (the ingredient in Tylenol), which is a pharmaceutical that is known to increase H 2 O 2 in the body.
  • N-acetyl-l-cysteine (NAC) is a compound that is known to counter many effects of H 2 O 2 in the body.
  • the APE-1/ Ref-1 is a molecule that protects the thiol groups of the Sirtuin enzymes, which should remain active.
  • the same or similar process for the nicotinamide-N-methyltransferase (NNMT) enzyme is theorized.
  • H 2 O 2 hydrogen peroxide
  • approximately 100 mM concentration of food grade (commercial grade has acetanilide in it as a stabilizer) H 2 O 2 in the 400 to 500 mL of water per individual dose is preferred, which can be taken alone or with Category 1 and Category 2 compounds or compositions.
  • one drop of H2O2 is 0.05 mL.
  • a preferred method of administration is to ingest H2O2 by dissolving H2O2 in deionized / distilled water and drinking.
  • a preferred timing of dosage concentration, time taken and length of time taking is to use the same timing as #1 and #2 when in water.
  • H2O2 is partially enhanced from endurance exercise do exercise directly before or after.
  • metformin can come in liquid form, Riomet, as well as tablets.
  • liquid form 5 mL is equal to a 500 mg tablet. It reaches peak plasma concentrations in 1 to 3 hours in immediate release form and a steady state in one to two days. It is typically 50 to 60% bioavailable under fasting conditions. One would need to use this data to time and dose appropriately with Metformin.
  • Calcium peroxide turns into hydrogen peroxide when in water.
  • An advantage of using this compound is that it exists as a solid and can be combined with other dry compounds useful in compositions of the present disclosure.
  • a composition may be stored, shipped, and/or provided in a product sachet.
  • H2O2 can be replaced with calcium peroxide.
  • Hydrogen Sulfide (H2S) Hydrogen Sulfide
  • H2S hydrogen peroxide
  • NaSH a H2S donor
  • H2O2 hydrogen sulfide
  • Plasma H2S levels decrease in humans over 50 to 80 years of age and plasma levels of 3 ⁇ 4S in patients with cardiovascular disease (CHD) show a significant inverse correlation with severity of CHD and changes in the coronary artery.
  • NaSH decreases ROS and enhances SOD, GPx and GST expression.
  • Exogenous 3 ⁇ 4S has a protective effect on maintaining the circadian rhythm of clock genes by changing the NAD+/NADH ratio and enhancing the Sirtl protein.
  • H2S is also an important endogenous inhibitor of key elements of acute inflammatory reactions by down regulating NF-kB or upregulating heme oxygenase 1 expression.
  • 3 ⁇ 4S can activate ATP-sensitive, intermediate-conductance and small-conductance potassium channels through cysteine S-sulfhydration causing endothelial and smooth muscle cell hyperpolarization which intern causes vasorelaxation of vascular endothelium and lowering of blood pressure.
  • 3 ⁇ 4S has a direct inhibitory effect on angiotensin-converting enzyme (ACE) activity.
  • ACE angiotensin-converting enzyme
  • NaSH increases the expression of eNOS and PGC-1 Alpha, which both play a role in mitochondria biogenesis and function.
  • 3 ⁇ 4S upregulates the MAPK pathway. It has been inferred that calorie restriction may help maintain 3 ⁇ 4S signaling.
  • GYY4237 a slow releasing 3 ⁇ 4S donor can kill seven different human cancer cell lines in a concentration- dependent manner.
  • Sulforaphane also a 3 ⁇ 4S donor, has dose-dependent antiprostate cancer (PC-3) properties.
  • H2S is a gasotransmitter. Gasotransmitters are endogenously produced at low levels and are able to freely diffuse through cell membranes to invoke cellular signaling. The three gasotransmitters are nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S).
  • NO nitric oxide
  • CO carbon monoxide
  • H2S hydrogen sulfide
  • Hydrogen sulfide is synthesized from L-cysteine.
  • Cystathionine gamma-lyase CSE
  • cystathionine beta-synthase CBS
  • cysteine aminotransferase CAT
  • 3- mercaptopyruvate sulfurtransferase MST
  • H2S 3- mercaptopyruvate sulfurtransferase
  • 3 ⁇ 4S regulates lipid peroxidation and antioxidant enzyme (GPx, T- SOD, Cu/Zn-SOD, and Mn-SOD) activities in the liver, by administration of 3 ⁇ 4S donor NaSH to the mice by injection of 0.05 mM of NaSH / kg body weight / day dissolved in 10 mL / kg body weight saline.
  • Mitochondria are able to use ThS under hypoxia and stress conditions to produce ATP.
  • ThS antioxidant ability
  • ThS can scavenge superoxide and ThS can upregulate glutathione.
  • ThS has been shown to activate Nuclear factor-erythroid 2-related factor 2 (Nfr2), which turns on antioxidant genes.
  • Na?S for 7 days increased Nrf2 expression in both cytosolic and nuclear fractions.
  • Nrf2 which up regulates expression of antioxidant response element-regulated genes, is upregulated by ThS.
  • ThS activation causes Nrf2 to separate itself from its adherent inhibitor, Kelch-like ECH- associated protein 1 in the cytosol then translocate to the nucleus and bind to a specific enhancer sequence, known as the antioxidant responsive element, in the promoter region of antioxidant genes, including HO-1 and thioredoxin 1.
  • ThS exhibits effects on mitochondria function antioxidant stress apoptosis, inflammation angiogenesis, sepsis and shock and blood pressure.
  • ThS protects against NO3 , as does glutathione. ThS also significantly reduces the toxic effects of HOC1. ThS enhances the antioxidant effects of N-acetyl-l-cysteine (NAC).
  • NAC N-acetyl-l-cysteine
  • ThS therapeutic effects have been most studied to date in regard to heart disease. ThS effects on heart disease include macrophages are able to produce ThS endogenously. NaHS (a ThS donor) inhibited pro-atherogenic oxidized low-density lipoproteins induced foam cell formation in macrophages. ThS is able to down regulate ROS at the mitochondria, providing protection through reduced respiration. ThS production (10-100 nM) enhanced mitochondrial electron transport and cellular bioenergetics however at high concentrations ThS is toxic. ThS in the diet decreased adverse left ventricle (LV) remodeling during heart failure. ThS can upregulate endothelial nitric oxide synthase which makes NO and NO can upregulate the ThS synthesis enzyme CSE.
  • LV adverse left ventricle
  • ThS phosphorylation effecting eNOS suggesting active cross talk between ThS and NO. There also appears to be cross talk between CO and ThS. ThS induces vasodilation, leading to reduced blood pressure. ThS in the form of Na2S (10 minutes prior) prevents reperfusion injury. Exogenous ThS also led to improved renal function.
  • ThS under in vivo conditions has an extremely short half-life which is estimated to be between seconds and minutes.
  • Plasma concentrations of ThS is in the range of 0.034 to 0.065 mM, in the brain it is three-fold higher than the plasma.
  • ThS concentration are inversely related to O2 concentration and ThS decrease cellular O2 consumption.
  • ThS concentrations of between 0.030 and 0.300 have also been reported in the blood and plasma.
  • H2S donors NaHS and Na?S increase H2S concentration within seconds to minutes.
  • H2S The physiological range of H2S is widely variable from 0.005 to 0.300 mM. Endogenous levels of EES in the brains of humans have been detected at from 0.05 to 0.16 mM; in the brains of Alzheimer’s patients, the EES concentration is lower. Diallyl trisulfide (DATS) is a stable EES donor and shows effects 30 minutes after injection and is longer lasting. NaHS can be taken in drinking water. NaHS (H2S donor), in aqueous solution releases 3 ⁇ 4S, in drinking water for 6 weeks. There was an increase in plasma 3 ⁇ 4S concentration with exogenous supplementation. There was no difference in the consumption of water among the groups of mice treated with NaHS and untreated groups.
  • DATS Diallyl trisulfide
  • 3 ⁇ 4S donors include GYY 4137 (CAS# 106740-09-4) a water soluble 3 ⁇ 4S donor that slowly releases 3 ⁇ 4S over the course of hours and SG 1002 from Sulfagenix, Inc.
  • AP97, AP39, AP67, and AP105 are also 3 ⁇ 4S donors with slower release.
  • 3 ⁇ 4S can be ingested with foods containing organosulfides, who’s polysulfides can be 3 ⁇ 4S donors.
  • 3 ⁇ 4S can be inhaled and inhalation increases blood 3 ⁇ 4S levels (40 ppm for 8 hours for 7 days was used with mice). Inhalation can also be combined with ingestible H2S donors such as Na2S and NaHS. Measurement of H2S in blood and tissue has been done with a sensitive and reliable means.
  • H2S can also be stored in cells in the form of sulfane sulfur and transported and released in response to physiological stimulus.
  • FW1256 is a phenyl analogue and a slow-releasing hydrogen sulfide (H2S) donor. FW1256 inhibits NF-KB activity and induces cell apoptosis. FW1256 exerts potent anti inflammatory effects and has the potential for cancer and cardiovascular disease treatment.
  • H2S hydrogen sulfide
  • Nrf2 The transcription factor NF-E2 p45-related factor 2 (Nrf2: gene name NFE212) regulates the expression of networks of genes encoding proteins with diverse cytoprotective activities. Nrf2 itself is controlled primarily at the level of protein stability. Nrf2 is a short lived protein subjected to continuous ubiquitination and protease degradation. There are three known ubiquitin ligase systems that contribute to the degradation of Nrf2 a) Keap-1, a substrate adaptor protein for Cullin-3, b) glycogen synthase kinase, and c) E3 ubiquitin ligase Hrdl. Keap-1 is also a sensor for a wide array of small-molecule activators also called inducers.
  • Nrf2 When Nrf2 is not degraded and is translocated to the nucleus it forms a heterodimer with a small Maf protein, binds to antioxidant-response elements which are the upstream regulatory regions of its target genes and initiates transcription.
  • Nrf2 is a master regulator of cellular redox homeostasis. Over 50 genes are regulated by Nrf2 in humans. In a direct effect of inflammation genes, without a Redox mechanism, Nrf2 also binds to the upstream region of the IL6 gene and when bound can significantly disrupt the recruitment of RNA polymerase II to regulate the transcription of IL6 in human macrophage cells.
  • Nrf2 signaling is regulated by transcriptional, translational, posttranslational, and epigenetic mechanisms as well as by other protein partners including p62, p21 and IQ motif containing GTPase activating protein 1.
  • Nuclear factor erythroid 2 (Nrf2) activators include classes of activators with activities that: induce nuclear translocation of Nrf2, increase Nrf2 mRNA transcription, increase protein expression of Nrf2 and increase Nrf2 downstream target genes. There are also Nrf2 inhibitors (Bach 1, caveolae, TGF-beta). The Keapl-Nrf2 pathway acts in concert with autophagy to combat proteotoxicity.
  • Keap-1 is a zinc metalloprotein that is localized near the plasma membrane. It has three functional domains, at least 25 reactive thiols most of which are found in the intervening linker region. Keap-1 has an Nrf2 binding site on each dimer subunit forming a “latch and hinge.” Keap-1 is highly sensitive to oxidation and its different thiol groups have different redox potentials. These different cysteine residues create a sensor system.
  • Nrf2 is a 605 amino acid transcription factor composed of six domains.
  • the N- terminal Neh2 domain is the binding site for the inhibitory protein Keap-1.
  • the half-life of Nrf2 when separated from Keap-1 is 20 minutes.
  • Keap-1 is exported out of the nucleus in 0.5 hours. Nrf2 activations enhances Sirtl activity in mice fibroblasts cell culture.
  • Nrf2 When Nrf2 releases Keap-1 it is available to capture IKKBeta thus inhibiting NF-KB target genes. This interaction correlates the expression of antioxidant enzymes by NrF2 and the turning on and off of the immune system by NF-KB.
  • Nrf2 and NF-kB compete for CREB-binding protein (CBP).
  • CBP CREB-binding protein
  • Phenolics that appear to act most directly on Nrf2 are ortho- or para- dihydroxyphenols which can be oxidized to quinones.
  • Quinones are oxidized derivatives of aromatic compounds and are often readily made from reactive aromatic compounds with electron-donating substituents such as phenols and catechols, which increase the nucleophilicity of the ring and contributes to the large redox potential needed to break aromaticity.
  • Quinones are conjugated but not aromatic.
  • Quinones are electrophilic Michael acceptors stabilized by conjugation. Depending on the quinone and the site of reduction, reduction can either re-aromatize the compound or break the conjugation. Conjugate addition nearly always breaks the conjugation.
  • Nrf2 activators listed separately above. Everything mentioned that is aNrf2 activator, is also an antioxidant defense system activator although some things activated by Nrf2 may be seen as additional to antioxidant defense system activation. The activation comes from the multiple ways listed above of keeping the Nrf2 system on.
  • One form of regulation of Nrf2 is reversible phosphorylation.
  • Sirtl and PARP1 as discussed before can also be reversibly phosphorylated.
  • Nrf2 activation and the turning on of the antioxidant defense system needs to be correlated in timing to NAD+ availability and methylation availability and be synced with the biological clock NAD+ peaks of the person.
  • the Nrf2 system does need to turn off (example: around 2 pm when NAD+ concentrations normally are at their daily biological clock low) so one’s body can do the things it needs to do under a redox balance when that leans towards oxidation.
  • Antioxidant defense activators such as Nuclear factor erythroid 2 (Nrf2) activators (including activities such as: nuclear translocation of Nrf2, increasing Nrf2 mRNA transcription, increasing protein expression of Nrf2 and increasing Nrf2 downstream target genes), zinc, calcium peroxide, N-Acetylcysteine, H2O2, ROS, RNS, RCS, RSOH, O2 1 , O2, EES, O3, HOC1, HOBr, HOI, ROOH, where R is alkyl, cycloalkyl, heteralkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, or hetercycloalkenyl, H2O2 generator, such as metformin or acetaminophen, ortho hydroxyphenols which can be oxidized to quinones, para dihydroxyphenols which can be oxidized to quinones, quinones (are oxidized derivatives of aromatic compounds), hydrogen sulfide (H2
  • the disclosed compositions can comprise nicotinamide adenine dinucleotide (NAD+), Betaine, and Zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), folate + Vitamin B12, and Zinc (e.g, as zinc sulfate).
  • the disclosed compositions e.g, nutritional compositions
  • the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and Zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Choline, and Zinc (e.g, as zinc sulfate).
  • the disclosed compositions can comprise nicotinamide adenine dinucleotide (NAD+), Betaine, and H2O2.
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), folate + Vitamin B 12, and H2O2.
  • the disclosed compositions e.g, nutritional compositions
  • the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and H2O2.
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Choline, and H2O2.
  • the disclosed compositions can comprise nicotinamide adenine dinucleotide (NAD+), Betaine, and NaHS.
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Folate + Vitamin B 12, and NaHS.
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Methionine, and NaHS.
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Choline, and NaHS.
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Betaine, and Na2S.
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Folate + Vitamin B12, and Na2S.
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Methionine, and Na2S.
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Choline, and Na2S.
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Betaine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3 ,4-dihyfroxyphenyl ethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Folate + Vitamin B12, and any one or more of H?S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4- dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl-l, 2, 4-triazole derivatives, 6-Shogaol, Acetyl
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Methionine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2,3- triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acety
  • the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Choline, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1,4- diphenyl-1, 2, 3-triazoles, 15 -deoxy-D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3 -alkyl amino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl- 11
  • the disclosed compositions can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and zinc (e.g, as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • Betaine a precursor or prodrug of NMN
  • zinc e.g, as zinc sulfate
  • the disclosed composition can comprise nicotinamide riboside (NR), Betaine, and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), with Betaine, and zinc ( e.g ., as zinc sulfate).
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and zinc (e.g., as zinc sulfate).
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • Betaine Betaine
  • zinc e.g., as zinc sulfate
  • compositions wherein the first compound comprises NMN.
  • compositions wherein the first compound comprises a precursor or prodrug of NMN, e.g, a compound that increases NMN production in the body.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, folate + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • folate + Vitamin B12 a precursor or prodrug of NMN
  • zinc e.g, as zinc sulfate
  • the disclosed composition can comprise nicotinamide riboside (NR), folate + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), folate + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), folate + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • Betaine + Vitamin B12 a precursor or prodrug of NMN
  • zinc e.g, as zinc sulfate
  • the disclosed composition can comprise nicotinamide riboside (NR), Betaine + Vitamin B 12, and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • NaMN nicotinic acid adenine mononucleotide
  • NaAD nicotinic acid adenine dinucleotide
  • NAR nicotinic acid riboside
  • Betaine + Vitamin B12 e.g, as zinc sulfate
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • MNM 1-methylnicotinamide
  • cAMP cyclic adeno
  • the disclosed compositions can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and zinc (e.g, as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • Methionine nicotinamide riboside
  • zinc e.g, as zinc sulfate
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), with Methionine, and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and zinc (e.g., as zinc sulfate).
  • the disclosed composition can comprise nicotinamide riboside (NR), Choline, and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Choline, and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl-methionine (SAM), and zinc (e.g, as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • SAM S-Adenosyl-methionine
  • zinc e.g, as zinc sulfate
  • the disclosed composition can comprise nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and zinc (e.g, as zinc sulfate).
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), S-Adenosyl-methionine (SAM), and zinc (e.g, as zinc sulfate).
  • NaMN nicotinic acid adenine mononucleotide
  • NaAD nicotinic acid adenine dinucleotide
  • NAR nicotinic acid riboside
  • SAM S-Adenosyl-methionine
  • zinc e.g, as zinc sulfate
  • the disclosed composition can comprise 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl- methionine (SAM), and zinc (e.
  • the disclosed compositions can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and H2O2.
  • the disclosed composition can comprise nicotinamide riboside (NR), Betaine, and H2O2.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), with Betaine, and H2O2.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and H2O2.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • Betaine Betaine
  • H2O2O2 H2O2
  • compositions wherein the first compound comprises NMN Also disclosed are compositions wherein the first compound comprises a precursor or prodrug of NMN, e.g, a compound that increases NMN production in the body.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, folate + Vitamin B12, and H2O2.
  • the disclosed composition can comprise nicotinamide riboside (NR), folate + Vitamin B12, and H2O2.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), folate + Vitamin B12, and H 2 O 2.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), folate + Vitamin B 12, and H 2 O 2.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine + Vitamin B12, and H 2 O 2.
  • the disclosed composition can comprise nicotinamide riboside (NR), Betaine + Vitamin B12, and H 2 O 2.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine + Vitamin B12, and H 2 O 2.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine + Vitamin B12, and H2O2.
  • the disclosed compositions can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and H 2 O 2.
  • the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and H 2 O 2.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), with Methionine, and H 2 O 2.
  • the disclosed composition can comprise 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and H2O2.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and H 2 O 2.
  • the disclosed composition can comprise nicotinamide riboside (NR), Choline, and H 2 O 2.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Choline, and H 2 O 2.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and H 2 O 2.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl-methionine (SAM), and H 2 O 2.
  • the disclosed composition can comprise nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and H 2 O 2.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), S- Adenosyl-methionine (SAM), and H2O2.
  • NaMN nicotinic acid adenine mononucleotide
  • NaAD nicotinic acid adenine dinucleotide
  • NAR nicotinic acid riboside
  • SAM S- Adenosyl-methionine
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • SAM S-Adenosyl-methionine
  • H2O2 can be replaced with calcium peroxide or N-Acetylcysteine.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and NaHS.
  • the disclosed composition can comprise nicotinamide riboside (NR), Betaine, and NaHS.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine, and NaHS.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and NaHS.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Folate + Vitamin B12, and NaHS.
  • the disclosed composition can comprise nicotinamide riboside (NR), Folate + Vitamin B12, and NaHS.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Folate + Vitamin B12, and NaHS.
  • the disclosed composition can comprise 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate + Vitamin B 12, and NaHS.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine + Vitamin B12, and NaHS.
  • the disclosed composition can comprise nicotinamide riboside (NR), Betaine + Vitamin B 12, and NaHS.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine + Vitamin B12, and NaHS.
  • the disclosed composition can comprise 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine + Vitamin B 12, and NaHS.
  • MNM 1- methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and NaHS.
  • the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and NaHS.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Methionine, and NaHS.
  • NaMN nicotinic acid adenine mononucleotide
  • NaAD nicotinic acid adenine dinucleotide
  • NAR nicotinic acid riboside
  • Methionine Methionine
  • NaHS NaHS
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and NaHS.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and NaHS.
  • the disclosed composition can comprise nicotinamide riboside (NR), Choline, and NaHS.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Choline, and NaHS.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and NaHS.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl-methionine (SAM), and NaHS.
  • the disclosed composition can comprise nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and NaHS.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), S-Adenosyl-methionine (SAM), and NaHS.
  • NaMN nicotinic acid adenine mononucleotide
  • NaAD nicotinic acid adenine dinucleotide
  • NAR nicotinic acid riboside
  • SAM S-Adenosyl-methionine
  • NaHS NaHS
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and NaHS.
  • MNM 1-methylnicotinamide
  • cAMP cyclic aden
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and Na?S.
  • the disclosed composition can comprise nicotinamide riboside (NR), Betaine, and Na2S.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine, and Na?S.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and Na?S.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Folate + Vitamin B12, and Na2S.
  • the disclosed composition can comprise nicotinamide riboside (NR), Folate + Vitamin B12, and Na2S.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Folate + Vitamin B12, and Na2S.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate + Vitamin B12, and Na2S.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine + Vitamin B12, and Na2S.
  • the disclosed composition can comprise nicotinamide riboside (NR), Betaine + Vitamin B12, and Na2S.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine + Vitamin B12, and Na2S.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine + Vitamin B12, and Na 2 S.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and Na2S.
  • the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and Na2S.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Methionine, and Na2S.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and Na2S.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and Na2S.
  • the disclosed composition can comprise nicotinamide riboside (NR), Choline, and Na2S.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Choline, and Na2S.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and Na2S.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl-methionine (SAM), and Na2S.
  • the disclosed composition can comprise nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and Na?S.
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), S- Adenosyl-methionine (SAM), and Na?S.
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and Na?S.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and any one or more of IBS, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1,4- diphenyl-1, 2, 3-triazoles, 15 -deoxy-D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol
  • the disclosed composition can comprise nicotinamide riboside (NR), Betaine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1,4- diphenyl-1, 2, 3-triazoles, 15 -deoxy-D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl- 11 -keto ⁇ -bos
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-al
  • the disclosed composition can comprise 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shoga
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Folate + Vitamin B12, and any one or more of H?S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4- dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl-l, 2, 4-triazole derivatives, 6-S
  • the disclosed composition can comprise nicotinamide riboside (NR), Folate + Vitamin B12, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2,3- triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl- 1 l-
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Folate + Vitamin B12, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxypheny
  • the disclosed composition can comprise 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate + Vitamin B12, and any one or more of FhS, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl- 1,2, 4-triazole derivatives,
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine + Vitamin B12, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-
  • the disclosed composition can comprise nicotinamide riboside (NR), Betaine + Vitamin B12, and any one or more of FhS, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2,3- triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl- 1 l-
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine + Vitamin B12, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxypheny
  • the disclosed composition can comprise 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine + Vitamin B12, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl- 1,2, 4-triazole derivatives, 6-
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4- dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl-l, 2, 4-triazole derivatives, 6-Shoga
  • the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl-1 l-keto ⁇ -bo
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Methionine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4- dihyfroxyphenylethanol, 3-
  • the disclosed composition can comprise 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shog
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1,4- diphenyl-1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3 -alkyl amino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shog
  • the disclosed composition can comprise nicotinamide riboside (NR), Choline, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1,4- diphenyl-1, 2, 3-triazoles, 15 -deoxy-D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3 -alkyl amino- IH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl- 11 -keto ⁇ -bos
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Choline, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-
  • the disclosed composition can comprise 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogao
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl-methionine (SAM), and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl-
  • the disclosed composition can comprise nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1,4- diphenyl-1, 2, 3-triazoles, 15 -deoxy-D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3 -alkyl amino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogao
  • the disclosed composition can comprise one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), S- Adenosyl-methionine (SAM), and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-
  • the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2,3- triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino- lH-indole acrylates, 4-phenyl- 1,
  • the combined amounts of compounds of category 1, 2, and 3 in the composition can be at least 5 wt.% of the composition.
  • the repair system activator, the methyl donor, and the antioxidant defense activator can be at least 5 wt.% of the composition.
  • the combined amount of compounds of category 1, 2, and 3 in the composition can be at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or 100 wt.% of the composition, where any of the stated values can form an upper or lower endpoint of a range.
  • NNN Cocktail The herein described “unit dose”, “formulation”, and/or “composition” may be referred to as an “NMN Cocktail”.
  • Formulations which can be packaged in a powder or lyophilized form, which can then have either hot or cold liquid added to them for reconstituting into a solution are disclosed.
  • the disclosed compositions could be mixed with compositions, such as is done in personal beverage systems, which make hot or cold coffee or tea or hot chocolate from individually packaged components and the addition of water.
  • the disclosed compositions can be administered in vivo either alone or in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject, along with the composition disclosed herein, without causing any undesirable biological effects.
  • the carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.
  • the materials can be in solution, suspension (for example, incorporated into microparticles, liposomes, or cells).
  • the mammalian intestinal microbiota is composed of up to 100 trillion microbes from over 500 genera of bacteria from two main phyla, namely Bacteroidetes and Firmicutes.
  • a well-studied mammalian probiotic Lactobacillus rhamnosus GG is a potent inducer of ROS.
  • Redox signaling mediates symbiosis between the gut microbiota and the intestine. In flies, increase in life span is correlated to increase formation of the oxidant H2O2 in the gut.
  • FhS protects the mucosal lining of the gastrointestinal tract against oxidative stress as well as regulates various functions including fluid transport, inflammation, acid induced HCO3 secretion.
  • Gut microbiota composition in the elderly has been correlated to plasma 11-6 levels.
  • Crtc A fasting molecule Crtc enhances immunity by making the gut barrier less permeable to bacteria. Gut bacteria that get across the gut barrier cause inflammation. This Crtc is a genetic switch in the brain that controls energy balance. This constant communication between the brain and the GI tract allows the body to keep tract of energy expenditures and stores. Crtc interacts with CREB (cAMP response element-binding protein). A partner of Crtc in the human brain is neuropeptide Y, which causes mammals to search for food. CREB activity is regulated by energy sensing Sirtl and its ability to deacetylate CREB. This links the level of NAD+ and the feeling of hunger.
  • CREB cAMP response element-binding protein
  • the glucose- regulated antagonism between (yet coordinated with) CREB and Sirtl for Hes-1 transcription participates in the metabolic regulation of neurogenesis, this is important since a decline in neurogenesis accompanies brain aging and CREB transcription factor is activated by nutrient deprivation which is correlated to Sirtuin enzyme activity.
  • TNF in the circulation of humans that occurs as part of the aging process impairs inflammatory monocyte development function and is detrimental to anti -pneumococcal immunity. This is reversed with pharmacological reduction of TNF.
  • the formulation could have organisms such as bacteria in the microbiome extrude any or all of these three categories of compounds that are desired and add them directly into the gut. These organisms could extrude the desired compounds in the quantity and with the timing desired. These organisms could be introduced to the microbiome either from a selection of organisms that naturally occur in the microbiome or by the engineering of organisms that naturally occurs in the microbiome. The engineered organisms could be engineered to extrude these compounds in accordance to the introduced organism’s and or the host’s biological clock. The introduced organism could be engineered to extrude the desired amount of compound or compounds. Gene-drive could be used to switch all of the species in the gut of this type used to the introduced organism’s gene type desired. A kill switch could be engineered into this introduced species as well to allow an elimination of these engineered species if they were not desired later.
  • compositions disclosed herein can be used therapeutically in combination with a pharmaceutically acceptable carrier.
  • Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (22nd ed.) ed. L.V. Loyd Jr., CBS Publishers & Distributors Grandville MI USA 2012.
  • an appropriate amount of a pharmaceutically acceptable salt is used in the formulation to render the formulation isotonic.
  • the pharmaceutically acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution.
  • the pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5.
  • Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers can be more preferable depending upon, for instance, the route of administration and concentration of composition being administered.
  • compositions can be administered intramuscularly or subcutaneously. Other compounds will be administered according to standard procedures used by those skilled in the art.
  • compositions can include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.
  • Pharmaceutical compositions can also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.
  • the pharmaceutical composition can be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration can be topically (including ophthalmically, vaginally, rectally, intranasally), orally, by inhalation, or parenterally, for example by intravenous drip, subcutaneous, intraperitoneal or intramuscular injection.
  • the disclosed compounds can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives can also be present such as, for example, antimicrobials, chelating agents, and inert gases and the like.
  • Formulations for topical administration can include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders may be desirable.
  • compositions can be administered as a pharmaceutically acceptable acid- or base- addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines and substituted ethanolamines.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, glycolic
  • the various compounds and compositions of categories 1, 2, and 3, can be taken at the same time or in proximity, such as within 1, 5, 10, 30, 60, 90, or 120 minutes.
  • the disclosed composition can comprise nicotinamide mononucleotide (NMN), Betaine, and Zinc Sulfate in a ratio of from about 7 and 20: to from about 4 and 10; to about 1.
  • the composition further comprises about a ratio of NaCl (to the other components) of from about 0.25 and about 1.25.
  • a unit dose of the composition comprises from about 0.8 grams and about 2.0 grams of NMN, from about 0.4 grams and 0.8 grams of Betaine, and from about 0.09 and 0.25 grams of Zinc Sulfate. In embodiments, the unit dose of the composition comprises from about 0.9 grams and about 1.1 grams of NMN, from about 0.45 grams and 0.55 grams of Betaine, and from about 0.1 and 0.12 grams of Zinc Sulfate. In embodiments, the unit dose of the composition comprises about 1 gram of NMN, 0.5 grams of Betaine, and about 0.11 grams of Zinc Sulfate. In embodiments, the unit dose further comprises from about 25 mg to about 100 mg of NaCl. In embodiments, the unit dose further comprises about 50 mg of NaCl.
  • NNN Cocktail The herein described “unit dose”, “formulation”, and/or “composition” may be referred to as an “NMN Cocktail”.
  • At least one unit of a composition is administered to the subject at each dosing.
  • at least two units of the composition, at least three units of the composition, at least four units of the composition, or at least five units of the composition is administered to the subject at each dosing.
  • the number of units of the composition per dosing relates in part to the weight of the subject.
  • the subject when a subject weighs 100 lbs or less, the subject is administered at least one unit of the composition per dosing and/or when a subject weighs over 100 lbs, the subject is administered at least one unit, at least two units, at least three units, or at least four units or at least five units of the composition per dosing.
  • the subject receives at least one dosing per day, at least two dosings per day, at least three dosings per day, or at least four dosings per day.
  • a delivery system in water is preferable if the preferred ingredient of category 1, 2 and 3 are used. This will help elicit the correct timing (all 3 preferred ingredients are easily absorbed and soluble in water). For some other less preferred ingredients, which are not as water soluble or are not as easily absorbed their delivery would result in a reduced benefit with respect to the pulse timing of these three categories of ingredients.
  • a viral infection e.g caused by SARS-CoV-2
  • Illustrative viral infections may be caused by one or more of enteroviruses A-J; rhinoviruses A-C; rotaviruses A-C; norovirus; influenza virus A-C and their several types like H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H7N9, and their other relatives; human papillomaviruses (HPV); polyomaviruses like John Cunningham virus (JCV) and Merkel cell virus (MCV); poxviruses; herpesviruses such as human simplex virus 1 (HSV- 1), human simplex virus 2 (HSV-2), varicella zoster virus, Epstein-Barr virus (human herpesvirus 4; EBV/HHV-4), human cytomegalovirus (HHV-5), Herpesvirus 6 (A&B), herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus
  • composition in accordance with the subject is administered the composition in accordance with the subject’s circadian rhythm.
  • compositions are administered to a subject a dosage of at least 1 x 10 8 moles of the first compound to the subject, 1 x 10 8 moles of the second compound to the subject, and 1 x 10 9 moles of the third compound to the subject.
  • composition is injected over 8-12 days.
  • composition is an aerosol, lyophilization, powder, or emulsion.
  • composition is a tablet that is administered orally at least once daily.
  • composition is administered once daily.
  • compositions can be administered at a variety of dosages.
  • category 1 compounds like Nicotinamide Mononucleotide (NMN), can be at dosages per day of 1 x 10 6 moles/kg to 1 x 10 2 moles/kg or 1 x 10 5 moles/kg to 1 x 10 3 moles/kg or 1 x 10 4 moles/kg to 1 x 10 3 moles/kg or 2 x 10 4 moles/kg to 7 x 10 4 moles/kg.
  • NPN Nicotinamide Mononucleotide
  • the dosages per day of the category 1 molecule can be at least 1 x 10 6 moles/kg, 1 x 10 5 moles/kg, 1 x 10 4 moles/kg, 1 x 10 3 moles/kg or 1 x 10 2 moles/kg.
  • the dosages can also be at least 2.38 moles/kg per day.
  • the same dosages are contemplated herein for other category 1 compounds NAD+, NR, NaMN, NaAD, NAR, MNM, and cAMP.
  • the dosage of category 2 compounds can be at dosages per day of 1 x 10 6 moles/kg to 1 x 10 2 moles/kg or 1 x 10 5 moles/kg to 1 x 10 3 moles/kg or 1 x 10 4 moles/kg to 1 x 10 3 moles/kg or 2 x 10 4 moles/kg to 7 x 10 4 moles/kg.
  • the dosages per day of the category 2 compound can be at least 1 x 10 6 moles/kg, 1 x 10 5 moles/kg, 1 x 10 4 moles/kg, 1 x 10 3 moles/kg or 1 x 10 2 moles/kg.
  • the dosages can also be at least 5.82 x 10 4 moles / kg body weight / day.
  • the dosages of category 3 compounds can be at dosages per day of 1 x 10 7 moles/kg to 1 x 10 2 moles/kg or 1 x 10 6 moles/kg to 1 x 10 3 moles/kg or 1 x 10 5 moles/kg to 1 x 10 4 moles/kg or 1 x 10 5 moles/kg to 7 x 10 5 moles/kg.
  • the dosages per day of the category 3 compound can be at least 1 x 10 7 moles/kg, 1 x 10 6 moles/kg, 1 x 10 5 moles/kg, 1 x 10 4 moles/kg or 1 x 10 3 moles/kg.
  • the dosages can also be at least dosage 2.34 x 10 5 moles / kg body weight / day.
  • the dosages of category 3 compounds can be at dosages per day of 1 x 10 7 moles/kg to 1 x 10 2 moles/kg or 1 x 10 6 moles/kg to 1 x 10 3 moles/kg or 1 x 10 5 moles/kg to 1 x 10 4 moles/kg or 1 x 10 5 moles/kg to 7 x 10 5 moles/kg.
  • the dosages per day of the category 3 compound can be at least 1 x 10 7 moles/kg, 1 x 10 6 moles/kg, 1 x 10 5 moles/kg, 1 x 10 4 moles/kg or 1 x 10 3 moles/kg.
  • the dosages can also be at least dosage 2.34 x 10 5 moles / kg body weight / day.
  • the dosages of category 3 compounds can be at dosages per day of 1 x 10 7 moles/kg to 1 x 10 2 moles/kg or 1 x 10 6 moles/kg to 1 x 10 3 moles/kg or 1 x 10 5 moles/kg to 1 x 10 4 moles/kg or 1 x 10 5 moles/kg to 7 x 10 5 moles/kg.
  • the dosages per day of the category 3 compound can be at least 1 x 10 7 moles/kg, 1 x 10 6 moles/kg, 1 x 10 5 moles/kg, 1 x 10 4 moles/kg or 1 x 10 3 moles/kg.
  • the dosages can also be at least dosage 2.34 x 10 5 moles / kg body weight / day.
  • the dosages of category 3 compounds, such as H2O2 can be at dosages per day of 1 x 10 7 moles/kg to 1 x 10 2 moles/kg or 1 x 10 6 moles/kg to 1 x 10 3 moles/kg or 1 x 10 5 moles/kg to 1 x 10 4 moles/kg or 1 x 10 5 moles/kg to 7 x 10 5 moles/kg.
  • the dosages per day of the category 3 compound can be at least 1 x 10 7 moles/kg, 1 x 10 6 moles/kg, 1 x 10 5 moles/kg, 1 x 10 4 moles/kg or 1 x 10 3 moles/kg.
  • the dosages can also be at least dosage 2.34 x 10 5 moles / kg body weight / day.
  • the dosages of category 3 compounds can be at dosages per day of 1 x 10 8 moles/kg to 1 x 10 3 moles/kg or 1 x 10 7 moles/kg to 1 x 10 4 moles/kg or 1 x 10 6 moles/kg to 1 x 10 5 moles/kg or 1 x 10 6 moles/kg to 7 x 10 6 moles/kg.
  • the dosages per day of the category 3 compound can be at least 1 x 10 8 moles/kg, 1 x 10 7 moles/kg, 1 x 10 6 moles/kg, 1 x 10 4 moles/kg or 1 x 10 3 moles/kg.
  • the dosages can also be at least 3.02 x 10 6 moles / Kg body weight / day.
  • a viral infection e.g caused by SARS-CoV-2
  • Illustrative viral infections may be caused by one or more of enteroviruses A-J; rhinoviruses A-C; rotaviruses A-C; norovirus; influenza virus A-C and their several types like H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H7N9, and their other relatives; human papillomaviruses (HPV); polyomaviruses like John Cunningham virus (JCV) and Merkel cell virus (MCV); poxviruses; herpesviruses such as human simplex virus 1 (HSV- 1), human simplex virus 2 (HSV-2), varicella zoster virus, Epstein-Barr virus (human herpesvirus 4; EBV/HHV-4), human cytomegalovirus (HHV-5), and Herpesvirus 6 (A&B), herpesvirus 7, Kaposi's sarcoma-associated herpesvirus
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), S-Adenosyl-methionine (SAM), and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), S-Adenosyl-methionine (SAM), and H2O2.
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), S-Adenosyl-methionine (SAM), and NaSH.
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), S-Adenosyl-methionine (SAM), and Na2S.
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), S-Adenosyl-methionine (SAM), and any one or more of 3 ⁇ 4S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles,
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Betaine, and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), folate + Vitamin B12, and zinc (e.g., as zinc sulfate).
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Methionine, and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Methionine, and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Choline, and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Betaine, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), folate + Vitamin B12, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Methionine, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Methionine, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Choline, and H 2 O 2.
  • H 2 O 2 can be replaced with calcium peroxide or N-Acetylcysteine.
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Betaine, and NaHS. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Folate + Vitamin B 12, and NaHS. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Methionine, and NaHS. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Choline, and NaHS.
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Betaine, and Na 2 S. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Folate + Vitamin B12, and Na 2 S. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Methionine, and Na 2 S. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Choline, and Na 2 S.
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Betaine, and any one or more of IBS, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1,4- diphenyl-1, 2, 3-triazoles, 15 -deoxy-D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3 -alkyl amino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Folate + Vitamin B12, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2,3- triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-S, nic
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Methionine, and any one or more of FhS, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl- 1,2, 4-triazole derivatives, 6-Shogaol
  • the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Choline, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Ace
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and zinc (e.g, as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • Betaine a precursor or prodrug of NMN
  • zinc e.g, as zinc sulfate
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine, and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), with Betaine, and zinc (e.g, as zinc sulfate).
  • NaMN nicotinic acid adenine mononucleotide
  • NaAD nicotinic acid adenine dinucleotide
  • NAR nicotinic acid riboside
  • the disclosed methods can comprise administering to a subject 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and zinc (e.g, as zinc sulfate).
  • MNM methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • Betaine cyclic a
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, folate + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), folate + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), folate + Vitamin B 12, and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), folate + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • Betaine + Vitamin B12 e.g., as zinc sulfate
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • NaMN nicotinic acid adenine mononucleotide
  • NaAD nicotinic acid adenine dinucleotide
  • NAR nicotinic acid riboside
  • Betaine + Vitamin B12 e.g, as zinc sulfate
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine + Vitamin B12, and zinc (e.g, as zinc sulfate).
  • MNM 1-methylnicotinamide
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and zinc ( e.g ., as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • Methionine e.g., as zinc sulfate
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), with Methionine, and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and zinc (e.g, as zinc sulfate).
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • Methionine Methionine
  • zinc e.g, as zinc sulfate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and zinc (e.g, as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • NR nicotinamide riboside
  • zinc e.g, as zinc sulfate
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Choline, and zinc (e.g, as zinc sulfate).
  • NaMN nicotinic acid adenine mononucleotide
  • NaAD nicotinic acid adenine dinucleotide
  • NAR nicotinic acid riboside
  • Choline e.g, as zinc sulfate
  • the disclosed methods can comprise administering to a subject 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and zinc (e.g, as zinc sulfate).
  • MNM methylnicotinamide
  • cAMP cyclic aden
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl- methionine (SAM), and zinc (e.g, as zinc sulfate).
  • NMN nicotinamide mononucleotide
  • SAM S-Adenosyl- methionine
  • zinc e.g, as zinc sulfate
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), S-Adenosyl- methionine (SAM), and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), S-Adenosyl-methionine (SAM), and zinc (e.g, as zinc sulfate).
  • the disclosed methods can comprise administering to a subject 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl- methionine (SAM), and zinc (e.g, as zinc sulfate).
  • MNM methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • SAM S-Adenosyl- methionine
  • zinc e.g, as zinc sulfate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and H2O2.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), with Betaine, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and H 2 O 2.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, folate + Vitamin B12, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), folate + Vitamin B 12, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), folate + Vitamin B12, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), folate + Vitamin B 12, and H 2 O 2.
  • MNM 1-methylnicotinamide
  • cAMP cyclic
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine + Vitamin B12, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine + Vitamin B 12, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine + Vitamin B12, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine + Vitamin B 12, and H 2 O 2.
  • MNM methylnicotinamide
  • cAMP cycl
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Methionine, and H 2 O 2.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), with Methionine, and H 2 O 2.
  • NaMN nicotinic acid adenine mononucleotide
  • NaAD nicotinic acid adenine dinucleotide
  • NAR nicotinic acid riboside
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and H 2 O 2.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and H 2 O 2 .
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Choline, and H 2 O 2 .
  • NR nicotinamide riboside
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Choline, and H 2 O 2 .
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and H 2 O 2 .
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl- methionine (SAM), and H 2 O 2 .
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and H 2 O 2 .
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), S-Adenosyl-methionine (SAM), and H 2 O 2 .
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S- Adenosyl-methionine (SAM), and H 2 O 2 .
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • SAM S- Adenosyl-methionine
  • H 2 O 2 can be replaced with calcium peroxide or N-Acetylcysteine.
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and NaHS.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine, and NaHS.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine, and NaHS.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and NaHS.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Folate + Vitamin B12, and NaHS.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Folate + Vitamin B12, and NaHS.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Folate + Vitamin B12, and NaHS.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate + Vitamin B12, and NaHS.
  • MNM 1-methylnicotinamide
  • cAMP cyclic a
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine + Vitamin B12, and NaHS.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine + Vitamin B12, and NaHS.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine + Vitamin B12, and NaHS.
  • the disclosed methods can comprise administering to a subject 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine + Vitamin B 12, and NaHS.
  • MNM methylnicotinamide
  • cAMP cyclic a
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and NaHS.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Methionine, and NaHS.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Methionine, and NaHS.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and NaHS.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and NaHS.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Choline, and NaHS.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Choline, and NaHS.
  • NaMN nicotinic acid adenine mononucleotide
  • NaAD nicotinic acid adenine dinucleotide
  • NAR nicotinic acid riboside
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and NaHS.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl- methionine (SAM), and NaHS.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and NaHS.
  • NR nicotinamide riboside
  • SAM S-Adenosyl-methionine
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), S-Adenosyl-methionine (SAM), and NaHS.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S- Adenosyl-methionine (SAM), and NaHS.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • SAM S- Adenosyl-methionine
  • NaHS NaHS
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and Na2S.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine, and Na2S.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine, and Na?S.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and Na?S.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Folate + Vitamin B12, and Na?S.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Folate + Vitamin B 12, and Na?S.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Folate + Vitamin B12, and Na?S.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate + Vitamin B12, and Na?S.
  • MNM 1-methylnicotinamide
  • cAMP cycl
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine + Vitamin B12, and Na2S.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine + Vitamin B 12, and Na?S.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine + Vitamin B12, and Na?S.
  • the disclosed methods can comprise administering to a subject 1- methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine + Vitamin B 12, and Na?S.
  • MNM methylnicotinamide
  • cAMP cycl
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and Na2S.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Methionine, and Na?S.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Methionine, and Na?S.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and Na?S.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and Na2S.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Choline, and Na2S.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Choline, and Na2S.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and Na2S.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl- methionine (SAM), and Na2S.
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and Na2S.
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), S-Adenosyl-methionine (SAM), and Na2S.
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S- Adenosyl-methionine (SAM), and Na2S.
  • MNM 1-methylnicotinamide
  • cAMP cyclic adenosine monophosphate
  • SAM S- Adenosyl-methionine
  • Na2S Na2S.
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and any one or more of H?S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4- dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl-l, 2, 4-triazole derivatives
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2,3- triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl- 1
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphen
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2,3- triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Folate + Vitamin B12, and any one or more of FhS, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl- 1,2, 4-tri
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Folate + Vitamin B12, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl-
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Folate + Vitamin B12, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihy
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate + Vitamin B12, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl- 1,2, 4-tri
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine + Vitamin B12, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl- 1,2, 4-triazo
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine + Vitamin B12, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl-
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine + Vitamin B12, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihy
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine + Vitamin B12, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl- 1,2, 4-tri
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl- 1,2, 4-triazole
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Methionine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1,4- diphenyl-1, 2, 3-triazoles, 15 -deoxy-D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3 -alkyl amino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Methionine, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfr
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and any one or more of FhS, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2,3- triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino- lH-indole acrylates, 4-phenyl- 1,2, 4-triadi
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetyl cysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4- dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4-phenyl-l, 2, 4-triazole derivatives,
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Choline, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2,3- triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivatives, 6-Shogaol, Acetyl- 1 l
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Choline, and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphen
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2,3- triazoles, 15-deoxy-D12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino- lH-indole acrylates, 4-phenyl- 1,2, 4-triazole derivative
  • the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl- methionine (SAM), and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates,
  • the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3-alkylamino-lH-indole acrylates, 4- phenyl- 1,2, 4-triazole derivatives, 6-Shog
  • the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), S- Adenosyl-methionine (SAM), and any one or more of H2S, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, b- lapachone, pterostilbene, resveratrol, apigenin, zinc, 1, 4-diphenyl- 1, 2, 3-triazoles, 15-deoxy- D 12, 14-prostaglan
  • the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and any one or more of FES, O3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N- Acetylcysteine, DHEA, garlic, b-lapachone, pterostilbene, resveratrol, apigenin, zinc, 1,4- diphenyl-1, 2, 3-triazoles, 15 -deoxy-D 12, 14-prostaglandin J2, 3,4-dihyfroxyphenylethanol, 3 -alkyl amino- lH-indole
  • MNM
  • compositions comprising “a” compound of category 3, as an example, can include more than one compound of category 3.
  • preventing is meant, at least, avoiding the occurrence of a disease and/or reducing the likelihood of acquiring the disease.
  • treating is meant, at least, ameliorating or avoiding the effects of a disease, including reducing a sign or symptom of the disease.
  • a “subject” is meant an individual.
  • the “subject” can include domesticated animals (e.g, cats, dogs, etc.), livestock (e.g, cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g, mouse, rabbit, rat, guinea pig, etc.), and birds.
  • “Subject” can also include a mammal, such as a primate or a human.
  • NMN cocktail comprises any NMN containing unit dose, composition, or formulation as disclosed herein.
  • Illustrative NMN cocktails include at least one compound from category 1, at least one compound from category 2, and at least one compound from category 3. Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.
  • Example 1 Dramatic clinical improvement in ten consecutive acutely ill elderly patients with presumed COVID-19 treated with a cocktail of nicotinamide mononucleotide (NMN), betaine, sodium chloride and zinc sulfate:
  • NAD+ is a critical cellular “currency”, facilitating metabolism, oxidation reduction, circadian rhythm, DNA repair, control of aging and the immune system.
  • intra-cellular NAD+ drops, with 50-year-old individuals having only half the quantity of NAD+ compared to healthy young individuals. This age associated NAD+ depletion appears to be exacerbated during COVID-19 infections, especially when complicated by cytokine storm.
  • Results Patients 1, 4, 7, and 10 were critically ill with documented worsening oxygenation, increasing levels of inflammation biomarkers, and worsening chest x-ray appearance immediately prior to administration of the NMN cocktail. These patients exhibited prompt post treatment clinical improvement, namely 2-3 days till temperature resolution (4 out of 4 patients), ⁇ 5 days until discharge (3 out of 3 patients), prompt chest x-ray improvement (4 out of 4 patients) and dramatic drops in cytokine levels (3 out of 4 patients) within 3 days. Patients 5 and 8 had double pneumonia but no prior films or inflammation tests. Patients 2 and 3 were severely symptomatic outpatient status post failed hydroxychloroquine (HC), Zithromax (Z) and Zinc (Zc) with no chest x-rays performed.
  • HC hydroxychloroquine
  • Z Zithromax
  • Zinc Zinc
  • NAD+ the cell’s hydrogen carrier
  • redox oxidation -reduction
  • Patient 1 was a rapidly deteriorating SARS-CoV-2 positive woman who needed hospitalization. Her room air (RA) O2 saturation suddenly dropped, her pulmonary infiltrates increased and cytokine levels spiked. The experimental remdesivir or any experimental anti-IL6 drug was unavailable for what appeared to be an obvious cytokine storm. With no other treatment available, after signed informed consent from the patient and family, oral NMN was administered with three additional OTC food supplement boosters (the NMN cocktail). Patient 1 dramatically improved within 48 hours. Based on this surprisingly prompt and dramatic result, these OTC products were further studied in the next nine consecutive patients who were over 50 years old and with presumptive diagnosis of COVID-19.
  • RA room air
  • ARDS Acute respiratory distress syndrome
  • ARDS was defined as bilateral pulmonary opacities on chest radiograph, arterial hypoxemia (partial pressure of arterial oxygen [Pa02] to fraction of inspired oxygen [Fi0 2 ] ratio ⁇ 300), and exclusion of cardiac failure - at time of treatment (See, Bernard etal. The American-European Consensus Conference on ARDS. Am J Respir Crit Care Med. 1994; 149: 818-824).
  • FIG. 2 Eight patients (FIG. 2) had positive PCR-based diagnosis from nasal swabs for SARS-CoV-2, Patient 3 had classic Covid-19 clinic presentation (cough, daily fevers to 102°F, severe fatigue and anosmia) and Patient 9 was ruled out for COVID- 19 based on three negative PCR-based nasal swabs for SARS-CoV-2, one negative serologic test for antibodies directed against the virus (day 18 post symptom onset) together with a normal chest x-ray and chest computerized tomography (CT) scan.
  • CT computerized tomography
  • the nine Covid-19 infected patients were on average 65 years old with frequent co morbidities -two with diabetes, five with pre-diabetes, two with known significant Coronary Artery Disease (CAD), three on baseline meds for Hypertension (HTN), and six with body mass index (BMI) in the overweight category.
  • CAD Coronary Artery Disease
  • HTN three on baseline meds for Hypertension
  • BMI body mass index
  • Patient 1 previously were administered hydroxychloroquine plus Zithromax and zinc.
  • Patient 10 took a six-day course of hydroxychloroquine.
  • Patient 4 received an experimental course of convalescent plasma.
  • Chest x-ray improvement was noted in every patient with pneumonia at the onset of treatment (six out of six patients), specifically those with worsening bilateral pulmonary infiltrates (Patients 1, 4, 7 and 10) and bilateral pulmonary infiltrates of unknown onset (Patients 5 and 8) with significant improvement at the first follow-up film (4, 4, 10, 17, 10 and 9 days respectively).
  • oral administration of a composition of the present disclosure which included nicotinamide mononucleotide/betaine/Zinc Sulfate (with NaCl to aid absorption), possesses important immune “anti-aging” properties vital in reversing cytokine storm associated with COVID-19.
  • Patient 1 A 55-year-old white female presented with a one-day history of body aches, choking cough and fever to 100.2°F. The SARS-CoV-2 PCR test was positive.
  • her fever increased to 102.5° F. She was prescribed Zithromax, hydroxychloroquine and zinc sulfate.
  • her temp increased to 103° F, she had debilitating body aches, dyspnea at rest, a RA O2 % sat of 90 and chest x-ray with bilateral patchy infiltrates throughout both lungs (FIG. 6) consistent with new onset acute respiratory distress syndrome (ARDS).
  • ARDS new onset acute respiratory distress syndrome
  • her body mass index was 30 and her history was positive for a recent uneventful elective arm plastic surgery and a past history of episodic hives and allergic reactions to Ivermectin and Keflex.
  • Admission labs suggested poor prognosis (CRP (217 mg/L), 11-6 (56 pg/mL), TNF-alpha (7.4 ng/mL) and myoglobin (>500 ng/mL) with absolute lymphopenia (490 cells/pL)).
  • CRP prognosis
  • 11-6 56 pg/mL
  • TNF-alpha 7.4 ng/mL
  • myoglobin >500 ng/mL
  • absolute lymphopenia 490 cells/pL
  • Tocilizumab - a humanized monoclonal antibody that inhibits ligand binding to the human interleukin-6 receptor (IL-6R) - was requested for presumptive cytokine storm, however, strict hospital protocol prohibited the use of this intravenous drug outside of the ICU - and because her O2 % sat on high flow nasal O2 was still > 90, she did not meet criteria for ICU transfer. She therefore agreed to continue Zinc Sulfate and begin NMN, Betaine, Sodium Chloride and zinc (the NMN cocktail) twice a day diluted in 500cc water and timed in sync with the her presumed diurnal circadian rhythm peaks. (Table 4).
  • her absolute lymphocyte count increased by 85%. Then, after two weeks of continuous fever, the patient turned afebrile at 5 am on day 14, 36 hours after the NMN cocktail was begun. On day 17 she was discharged home on oral NMN, betaine, NaCl and Zinc Sulfate twice a day; her clinical signs (fever, shortness of breath, body aches) were remarkably better, her room air % O2 sat (up from 84 to 96) and chest x-ray (FIG. 8) also dramatically improved over just 4 days, and showing improved interstitial and alveolar opacities compared with the chest x-ray of day 13. Her laboratory markers (CRP and IL6) simultaneously dropped approximately 80% during the 5 days of in hospital NMN cocktail administration.
  • Her third day home she felt stronger and walked multiple times a day.
  • Her nasopharyngeal SARS-CoV-2 test was negative.
  • Her CRP and IL-6 decreased to 7.4 and 3.2 respectively.
  • Her CXR revealed a small amount of residual peripheral infiltrates (FIG. 9) but had dramatically improved interstitial and alveolar opacities
  • FIG. 10 lists Patient l’s medical history over the course the study.
  • Patient 2 A 60-year-old SARS-CoV-2 NAA positive man with cough, chest tightness, dyspnea, diarrhea and HA was prescribed HCQ, AZ and Zn as an outpatient on his 15th consecutive day of fever. At the completion of the 6-day course he became afebrile and his chest pressure and headache improved, however his cough and insomnia continued. Three days later, his fever, HA and chest pressure recurred. He was begun on the NMN cocktail and experienced a prompt response:
  • FIG. 11 lists Patient 2’s medical history over the course the study.
  • Patient 3 A 72-year-old woman complained of fever, fatigue, sore throat, cough, HA, anosmia and diarrhea approximately 5 days after her personal assistant came down with a similar constellation of symptoms. She was clinically diagnosed as SARS-COV-2 infected. On symptom day 3, she was seen at her home and begun on HCQ, AZ and Zn. However, despite the “triple therapy” course, her 02 sat dropped from 96 to 94% and her symptoms intensified. She was then treated with the NMN cocktail. She experienced a prompt response: Her 15-day fever resolved within 2 days. Her clinical condition improved in 3 days (resolution of cough, fatigue, and headache).
  • FIG. 12 lists Patient 3’s medical history over the course the study.
  • Patient 4 A 79-year-old businessman was admitted to the intensive care unit (ICU) on symptom day 22 with ARDS, renal failure (Cr 4.6), diabetes, liver failure (AST/ALT 2878/1598) with possible pulmonary embolism and myocarditis. His chest x-ray on day 22 showed bilateral infiltrates consistent with ARDS (FIG. 13)
  • the family requested a second opinion consultation.
  • a nasal PCR test was conducted which revealed no virus, making cytokine storm the likely cause of his week- long post convalescent plasma deterioration and rendering the Remdesivir recommendation moot.
  • FIG. 17 lists Patient 4’s medical history over the course the study.
  • Patient 5 A 52-year female chef (known SARS-CoV-2 NAA positive) was first seen on symptom day 10 complaining of persistent fever, shortness of breath, headache and loss of smell and taste. Her presenting chest x-ray revealed bilateral pneumonia (FIG. 18, showing irregular marginated parenchymal opacities in the R mid and lower lobes and possibly in the left retrocardiac region).
  • FIG. 20 lists Patient 5’s medical history over the course the study.
  • Patient 6 A 78-year-old Latino man, regularly employed in a physically demanding job, presented after prolonged contact with known SARS-COV-2 NAA positive family members and 5 days after the onset of suspicious symptoms (new fever, cough, sore throat and diarrhea). He was a past smoker on medication for hypertension, coronary heart disease and diabetes type 2. His CXR was normal (FIG. 21).
  • Patient 7 A 61 -year-old female first presented to a local ER on symptom day 5 for fever, shortness of breath (SOB), muscle cramps, cough, nausea and diarrhea. Chest x-ray (FIG. 24) was normal but a CT chest revealed several patchy peripheral regions of ground glass opacification bilaterally suspicious for viral pneumonia. She tested positive for SARS- COV-2 RT-PCR and was discharged home with no treatment.
  • Patient 8 A 60-year-old cab driver was first seen on symptom day 12 complaining of 10 days of fever, fatigue, and cough and chest pressure. A chest x-ray revealed irregular marginated bilateral parenchymal opacities L>R consistent with bilateral viral pneumonia (FIG. 29). His nasopharynx SARS-COV-2 NAA test returned positive the following day (FIG. 30).
  • Patient 10 A 62-year-old SARS-CoV-2 RT-PCR positive businessman was admitted to an outlying hospital on symptom day 14 for spiking fever to 104° F, dropping O2 sats and bilateral pneumonia. His admission chest x-ray (FIG. 32) showed scattered infiltrates predominately within the periphery of bilateral lung fields. On the second day of his hospitalization, he was told there was no treatment for his condition. His interactions with hospital staff doctor and nursing staff was less than a collective 5-10 minutes per day and his wife was not allowed in the hospital or able to speak with the assigned doctor. He requested admission to the hospital but the “lateral” Covid-19 positive patient transfer was denied based on hospital protocol. He then left the hospital against medical advice.
  • FIG. 36 lists Patient 10’s medical history over the course the study.
  • Example 2 Illustrative formulations for treating at least “Cytokine Storm Syndrome” associated with a viral infection, including COVID-19
  • compositions for treating a viral infection are disclosed.
  • NMN cocktail examples include Nicotinamide mononucleotide (NMN), Betaine, and Zinc Sulfate in a ratio of from about 7 and 20: to from about 4 and 10; to about 1. Certain formulations further comprise about a ratio of NaCl (to the other components) of from about 0.25 and about 1.25. Sodium helps absorption of components of the compositions.
  • NMN cocktail have a unit dose of the composition comprises from about 0.8 grams and about 2.0 grams of NMN, from about 0.4 grams and 0.8 grams of Betaine, and from about 0.09 and 0.25 grams of Zinc Sulfate.
  • a unit dose of the composition comprises from about 0.9 grams and about 1.1 grams of NMN, from about 0.45 grams and 0.55 grams of Betaine, and from about 0.1 and 0.12 grams of Zinc Sulfate.
  • the unit dose of the composition comprises about 1 gram of NMN, 0.5 grams of Betaine, and about 0.11 grams of Zinc Sulfate.
  • the unit dose further may further comprise from about 25 mg to about 100 mg of NaCl. In embodiments, the unit dose further comprises about 50 mg of NaCl.
  • a formulation may further comprise additional components that contribute to color, stability, flavor, sweetness, and/or stability.
  • At least one unit of compositions of these formulations are administered to a subject at each dosing.
  • the subject thus administered may have a viral infection, e.g., caused by the SARS-CoV-2.
  • at least two units of the composition, at least three units of the composition, at least four units of the composition, or at least five units of the composition is administered to the subject at each dosing.
  • the number of units of the composition per dosing may relate in part to the weight of the subject. For example, when a subject weighs 100 lbs or less, the subject is administered at least one unit of the composition per dosing. When a subject weighs over 100 lbs, the subject is administered at least one unit, at least two units, at least three units, or at least four units or at least five units of the composition per dosing.
  • the subject receives at least one dosing per day, at least two dosings per day, at least three dosings per day, or at least four dosings per day.
  • compositions may be obtained by a subject or by a healthcare provider in powdered form.
  • the powder can be mixed with water or another suitable liquid.
  • a unit dose of the composition may be sufficiently soluble in at least about 100 ml of water. If solubility or preference is otherwise, more water/liquid may be mixed. Or less water if at the subject’s preference.
  • compositions may be obtained by the subject or the healthcare provider in a sealed air proof, waterproof package, i.e., sachet.
  • the sachet may have an inner lining to help protect the composition.
  • the sachet may have a tear line, so composition does not spill when the sachet’s top is opened.
  • the sachet may have printed instructions on one surface. Illustrative instructions may include: “Take as directed by a physician Dissolve the contents of each sachet completely in a minimum of 100 ml of pure water. Dose in proportion to your body weight. Take on an empty stomach in the morning and/or evening 12 hours apart. Store any unused liquid portion in refrigerator if possible. Freeze unused sachets for long term storage.” Multiple (10 or more) sachets may come in a kit.
  • a 61 -year-old Caucasian male weighing 88 kg at the beginning of the treatment was treated with a regimen of an NMN cocktail comprising category 1, category 2, and category 3 molecules as noted below.
  • Solutions of various compounds were produced for administering to the subject by mixing a set number of grams with 500 mL of water.
  • Typical final concentrations of NMN taken by subject were 3.5 grams in 500 mL H2O, betaine were 3 grams in 500 mL H2O, H2O2 were (2 drops of 35% concentration in 500 mL H2O), and NaSH were (drops of 2 at 66uM per drop concentration in 500 mL H2O).
  • each composition was set so that by the subject drinking the full 500 mL a final dosage approximately 1.19 x 10 4 moles NMN/ kg body weight per dose, 2.91 x 10 4 moles betaine / kg body weight per dose, 1.17 x 10 5 moles of H2O2 / kg of body weight per dose, and 1.51 x 10 6 moles of NaSH / kg of body weight per dose was given to the subject through drinking the 500 mL solution.
  • Nicotinamide Mononucleotide (NMN) dosage 2.38 x 10 4 moles / Kg body weight / day
  • the subject was weighed each day.
  • the subject self-administered the formulations orally through drinking the solution at approximately 7AM and 7 PM each day. These times were chosen because they approximated the subjects’ biological clock peaks of NAD+ as determined by Ramsey K 2009. This had the effect of pulsing the ingredients into the body twice a day, approximately timed with the biological clock of the subject.
  • LabCor Inc. performed the marker testing using standard protocols on a monthly basis. Blood draw times ranged between 8:19 am and 8:54 am. Inflammatory measurements are correlated to the biological clock. LabCor tested levels of CMV IgG, C-Reactive Protein, Tumor Necrosis Factor-Alpha, and Interleukin-6 in Serum.
  • the subject also had the following data collected monthly at LabCorp, including Serum Glucose, Serum Uric Acid, BUN, Serum Creatinine, eGRF if non-African American, BUN/Creatinine Ratio, Serum Sodium, Serum Potassium, Serum Chloride, Total Carbon Dioxide, Serum Calcium, Serum Phosphorus, Serum Total Protein, Serum Albumin, Serum, Total Globulin, A/G Ratio, Total Bilirubin, Serum Alkaline Phosphatase, LDH, AST (SGOT), ALT (SGPT), Serum Iron, Total Cholesterol, Triglycerides, HDL Cholesterol, Calculation VLDL cholesterol Calculation LDL Cholesterol, Total Cholesterol/ HDL ratio, Estimated CHD risk, White Blood Cells, Red Blood Cells, Hemoglobin, Hematocrit, MCV, MCH, MCHC, RDW, Platelets, Neutrophils, Lymph
  • Spectral 3 tesla MRI of right calf leg muscle before, during, and after exercise b. Spectral 3 tesla MRI of Liver c. Structural 3 tesla MRI of Liver d. Spectral 3 tesla MRI of Brain (front and back) e. A structural 3 tesla MRI of Brain f. A structural 3 tesla MRI of the right knee (showing Arthritis) g. 3-Nitrotyrosine (a marker for oxidative / nitrative stress) h. Coagulation Tests (a marker for oxidative stress) i.
  • F2-isoprostanes (a marker for oxidative / nitrative stress,) j .
  • GSH GSSH (a marker for and protection from oxidative / nitrative stress)
  • k Urine Organic Acids
  • 8-OHDG 8-hydroxy deooxyguanosine
  • m Malondialdehyde (a marker for oxidative / nitrative stress)
  • hsCRP a marker that can be adversely affected by oxidative stress
  • Proteomic profile (a marker for oxidative / nitrative stress)
  • a list of medical history questions were answered.
  • Body fat and mineral testing was performed at private MD’s office.
  • Treadmill testing was performed at private MD’s office.
  • 4 tissue biopsy types liver (needle biopsy), skin; adipose, muscle) were obtained (stored at -80 C at UCLA).
  • a log of daily exercise and weight was obtained. Also weekly glucose monitoring before and after NMN and BP monitoring before and after NMN was obtained.
  • Table 1 The results of the monthly administration schedule and testing for the subject are presented in Table 1.
  • Table 1 shows that the subject was provided a formulation on a monthly basis, where the formulation included NMN alone for 3 months, NMN+ betaine for one month, NMN+ betaine + H2O2 for one month and NMN+ betaine +NaSH for one month.
  • the age of 61 correlates to the age of unrelated and offspring families in the Arai Y 2015 study detailed herein.
  • the markers of the 61 -year-old subject were brought to levels better than the “offspring” group of Arai (CRP, 0.43 mg/1 and IL-6, less than 0.7 pg/mL). While both of these markers do rise slightly in month one, the overall effect of the NMN treatment is to reduce the levels of these markers.
  • the lower or approximately similar levels to the “offspring” group of Arai continued to be produced by administration of NMN through months 3, but the effect seemingly plateaus in the 61-year- old male.
  • Example 4 Fifty patients have been administered NMN cocktails To date fifty patients have been administered NMN cocktails. In each case, improvements in the patient’s conditions and/or symptoms were observed. A list of the patients treated is included in Table 2, below.
  • Example 5 Additional viral infections treated by NMN cocktails
  • Illustrative viral infections may be caused by one or more of enteroviruses A-J; rhinoviruses A-C; rotaviruses A-C; norovirus; influenza virus A-C and their several types like H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H7N9, and their other relatives; human papillomaviruses (HPV); polyomaviruses like John Cunningham virus (JCV) and Merkel cell virus (MCV); poxviruses; herpesviruses such as human simplex virus 1 (HSV-1), human simplex virus 2 (HSV-2), varicella zoster virus, Epstein-Barr vims (human herpesvirus 4; EBV/HHV-4), human cytomegalovirus (HHV-5), and Herpesvirus 6 (A&B), herpesvirus 7, Kaposi's sarcoma-associated herpes
  • Non-cancer diseases include (i) non-cancer diseases: enteritis (enteroviruses A-J); common cold (rhinoviruses A-C); gastroenteritis, diarrhoea (rotaviruses A-E, norovirus); gastroenteritis (norovirus); influenza (influenza virus A-C); progressive multifocal leukoencephalopathy (JCV), nephrophathy, Merkel cell cancer (MCV), smallpox (variola) (poxvirus); herpes (HSV-1, HSV-2); chicken-pox, herpes zoster (shingles) (varicella zoster virus); infectious mononucleosis (HHV-4); hepatitis A (hepatitis A virus); hepatitis B (hepatitis B virus); hepatitis C (hepatitis C virus); acquired immunodeficiency syndrome (HIV-1, HIV-2, and their subtypes); severe acute respiratory infections
  • a subject having or suspected of having a viral infection - other than caused by SARS-CoV-2 - is administered a compound, composition, or formulation as disclosed herein and according to the methods disclosed here; thereby treating or reducing a symptom of the viral infection.

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Abstract

Sont divulgués ici des procédés et des compositions de réduction de l'inflammation, d'inversion du vieillissement et des dégâts cellulaires cumulés, et de traitement, de prévention ou de réduction des effets pathologiques d'une infection virale en particulier celle du SARS-CoV-2, les compositions comprenant un activateur du système de réparation comprenant un nicotinamide mononucléotide, un nicotinamide adénine dinucléotide, un nicotinamide riboside, du 1-méthylnicotinamide et/ou de l'adénosine monophosphate cyclique, un donneur de méthyle comprenant de la bétaïne, du S-5'-adénosyl-L-méthionine, de la méthionine, de la choline, de la séine, du folate et/ou de la vitamine B12, et un activateur de défense antioxydant comprenant du zinc, H2O2, H2S, NaSH, Na2S, du ptérostilbène et/ou du resvératrol.
PCT/US2021/024207 2020-04-02 2021-03-25 Régimes de traitement antiviral WO2021202245A1 (fr)

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CN114452271A (zh) * 2022-01-29 2022-05-10 中国医学科学院药用植物研究所 一种二芳基丁烷类化合物在制备抑制新冠病毒的药物中的应用
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