RESETTING BIOLOGICAL PATHWAYS FOR DEFENDING AGAINST AND REPAIRING DETERIORATION FROM HUMAN AGING

Abstract

Compositions for addressing one or more of the effects of aging are described. The compositions comprise a first component comprising repair system activator(s) such as nicotinamide adenine dinucleotide (NAD+), nicotinamide mononucleotide (NMN); 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 combinations thereof; a second component comprising methyl donor(s) such as S-5′-adenosyl-L-methionine (SAM), methionine, betaine, choline, folate, vitamin B12, or combinations thereof; and a third component comprising antioxidant defense activators such as H.sub.2O.sub.2, N.sub.2S, NaSH, N.sub.a2S, and several others, including combinations thereof. Methods of administering the disclosed compositions or separate formulations of repair system activator, methyl donors, and antioxidant defense activators are also disclosed.

Claims

1. A nutritional composition for administering to a subject, composition, comprising: a repair system activator chosen from, nicotinamide adenine dinucleotide (NAD+), nicotinamide mononucleotide (NMN), 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, S-5′-adenosyl-L-methionine (SAM), methionine, betaine, choline, folate, vitamin B12, and any combination thereof; and an antioxidant defense activator chosen from H.sub.2O.sub.2, H.sub.2S, NaSH, Na.sub.2S, metformin, curcumin, sulforaphane, quercetin, isoquercetin, apigenin, luteolin, ginseng, carnosic acid, 4-methylalkylcatechol, 4 vinylcatechol, 4-ethlycatechol, xanthohumol, β-lapachone, pterostilbene, resveratrol, zinc, and any combination thereof.

2. The composition of claim 1, wherein the repair system activator, the methyl donor, and the antioxidant defense activator are at least 5 wt. % of the composition.

3. The composition of claim 1, wherein the repair system activator is nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), or both.

4. The composition of claim 1, wherein the methyl donor is methionine, betaine, or both.

5. The composition of claim 1, wherein the antioxidant defense activator is H.sub.2O.sub.2, H.sub.2S, or NaSH.

6. The composition of claim 1, wherein the repair system activator, the 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.

7. The composition of claim 6 wherein the change in the level of the surrogate marker is a lowered.

8. The composition of claim 7, wherein the surrogate marker is CMV IgG, C-Reactive Protein, Tumor Necrosis Factor-Alpha, or Interleukin-6.

9. The composition of claim 6, wherein the change in the level of the surrogate marker is increased.

10. The composition of claim 9, wherein the surrogate marker is DNA methylation.

11. The composition of claim 1, where the composition further comprises water.

12. The composition of claim 1, wherein the composition comprises at least 1×10.sup.−8 moles of the repair system activator, at least 1×10.sup.−8 moles of the methyl donor, and at least 1×10.sup.−9 moles of the antioxidant defense activator.

13. The composition of claim 1, wherein the composition comprises nicotinamide mononucleotide (NMN), Betaine, and H.sub.2O.sub.2 .

14. An injectable formulation, comprising the composition of claim 1.

15. A tablet comprising the composition of claim 1.

16. A method of reducing inflammation in a subject, comprising: administering to the subject the composition of claim 1.

17-25. (canceled)

26. A method of reducing inflammation in a subject, comprising: administering to the subject a repair system activator chosen from nicotinamide adenine dinucleotide (NAD+), nicotinamide mononucleotide (NMN), 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, S-5′-adenosyl-L-methionine (SAM), methionine, betaine, choline, folate, vitamin B12, and any combination thereof; and an antioxidant defense activator chosen from H.sub.2O.sub.2, H.sub.2S, NaSH, Na.sub.2S, metformin, curcumin, sulforaphane, quercetin, isoquercetin, apigenin, luteolin, ginseng, carnosic acid, 4-methylalkylcatechol, 4 vinylcatechol, 4-ethlycatechol, xanthohumol, β-lapachone, pterostilbene, resveratrol, zinc, and any combination thereof.

27. The method of claim 26, wherein the repair system activator, the methyl donor, and the antioxidant defense activator are administered at approximately the same time.

28. The method of claim 26, wherein the repair system activator is administered within 15, 30, 60, 90, or 120 minutes of the subject's biological clock NAD+ peak.

29. The method of claim 26, wherein the repair system activator, the methyl donor, and the antioxidant defense activator are administered at different times.

30-33. (canceled)

Description

DETAILED DESCRIPTION

[0106] The materials, compounds, compositions, and methods described herein may be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples included therein.

[0107] Before the present materials, compounds, compositions, and methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific synthetic methods or specific reagents, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0108] Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.

[0109] The study of caloric restriction led to the discovery of Sirtuins, which are activated by the “depleted energy” version of NADH, which is called NAD+. 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 (Pollak N 2007). 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 e cAMP and NAD+.

[0110] NAD+ activates a set of enzymes called 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. However, also disclosed herein, 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.

[0111] Therefore, what has been additionally shown by the disclosed methods and compositions is that by adding additional molecules along with NAD+ or similar acting molecules, the beneficial effects can be extended by, for example, a continued, enhanced, and maintained reduction in inflammation markers, which has been linked to anti-aging. This information has led to 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.

[0112] Increasing life-span and health-span by repairing cellular damage and preventing the age-related changes that can occur are disclosed. The data provided herein show that to reduce markers for inflammation three broad goals to defend against and repair deterioration from aging should be sought: [0113] I. NAD+ should be available to turn on and be used by Sirtuins, [0114] II. 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 [0115] III. 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.

[0116] Disclosed herein are compositions, formulations, and methods that reduce markers of inflammation related to aging, and are consistent with enhancing these three goals.

[0117] Meeting these three goals is possible if oxidation, in the form pulsed low level H.sub.2O.sub.2, is available to turn on pre-conditioning of the anti-oxidant defense and repair system. By turning this system on, the system is protected against the down regulation of the anti-oxidant defense and repair system, which is an energy saving mechanism. In this way, when the antioxidant defense system is challenged with an oxidative assault from a larger oxidative burst, it is able to defend against this oxidation that would lead to cell damage and destruction.

[0118] In one embodiment, one provides enough oxidation from H.sub.2O.sub.2 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 H.sub.2O.sub.2. This can be kept active. It is theorize that the same or a similar process is needed for the nicotinamide-N-methyltransferase (NNMT) enzyme to make 1-methylnicotinamide from nicotinamide and thus to stop this feedback loop from shutting off the Sirtuin enzyme by cutting off the supply of nicotinamide that can fit into the Sirtuin enzyme and stop it's activity.

[0119] Disclosed is a usable solution for reversal of human aging by resetting the human endogenous defense and repair pathways and mechanisms. These mechanisms are normally set to preserve energy due to molecular settings set by and for evolutionary energy insufficiency, evolutionary sexual selection, and pathogen defense by diverting more usable energy and resources from defense and repair mechanisms. Through administration of the disclosed compounds, compositions, and formulations these pathways can be reset for increased repair and defense.

[0120] It is demonstrated herein that dietary NMN drunk by itself in water does turn into NAD+ and turns on Sirtuins in humans, but these effects are ephemeral. It is also demonstrated herein that Hormesis/feedback loops effected benefits in humans until these benefits are plateaued or reversed and even overshoot the initial beneficial effects within a three month time frame. This discovery solves this deterioration of beneficial effect problem by turning on the beneficial effects of Sirtuin enzymes, optimizing their beneficial effects, and keeping these beneficial effects turned on.

[0121] Disclosed herein are compounds, 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.

[0122] When administered, the disclosed compounds, compositions, and formulations, can perform at least one of the following activities: [0123] A) Protect against further cellular damage from the aging process [0124] B) Repair cellular damage from the aging process [0125] C) Delay the onset of the diseases of aging where aging is a causal factor.

[0126] 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. [0127] D) Promote weight loss/reduce hunger [0128] E) Promote more productive sleep, waking more rested

Compounds, Compositions, and Formulations

[0129] Also disclosed are compounds, compositions, and formulations falling into, or containing, one or more of the following three general categories:

[0130] Category 1 which are Repair System Activators

[0131] Category 2 which are Methyl Donors, and

[0132] Category 3 which are Antioxidant Defense Activators

[0133] Disclosed are compositions comprising a first compound, a second compound, and a third compound, wherein 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) wherein the second compound comprises S-5′-adenosyl-L-methionine (SAM), SAM precursor such as methionine, betaine, choline, folate, vitamin B12, and wherein the third compound comprises antioxidant defense activator such as Nuclear factor erythroid 2 (Nrf2) activator, including activators that increase nuclear translocation of Nrf2, increase Nrf2 mRNA transcription, increase Nrf2 protein expression, and increase Nrf2 downstream target genes, reduce Nrf2 inhibitors (such as Bach 1, caveolae, TGF-beta)] such as H.sub.2O.sub.2, H.sub.2O.sub.2 generator, hydrogen sulfide (H.sub.2S), H.sub.2S Donor such as, sodium hydrosulfide (NaHS), sodium sulfide (Na.sub.2S) and optionally, a carrier.

[0134] Also disclosed are 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, or metabolizes to NMN. Also disclosed are compositions wherein the composition lowers a Surrogate Marker for Aging. Also disclosed are compositions wherein the surrogate marker is CMV IgG, C-Reactive Protein, Tumor Necrosis Factor-alpha, or Interleukin-6 Serum. Also disclosed are compositions, where the composition comprises water. Also, disclosed are compositions wherein the composition is formulated for injection. Also disclosed are compositions wherein the composition is concentrate form for dissolving in a liquid. Also disclosed are compositions wherein the composition is in tablet form or aerosol. Also disclosed are compositions wherein the composition comprises at least 1×10.sup.−8 moles of the first compound, at least 1×10.sup.−8 moles of the second compound, and at least 1×10.sup.−9 moles of the third compound.

Category 1, Repair System Activators

[0135] The turning on and maintaining of Sirtuin activity provides the beneficial effects disclosed herein. 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 NADi+ 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). In humans, 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. In certain aspect, preferably one wants the two daily doses 12 hours apart so as not to disrupt the natural cycle of the biological clock. Typical formulations provide greater or equal to 1.19×10.sup.−4 moles/kg-of-subject NMN, NAD+, or NAD+ precursor when administered (NMN is 334.22 grams/mole).

[0136] One can also administer, typically through injection, NAD+ or use nicotinamide riboside (NR) which can be made into NMN in some cells of the body. Typically administering of 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.

[0137] In a specific aspect, disclosed is the administration of NMN (nicotinamide mononucleotide) to humans in preferred dosages of approximately 0.08 grams/kg total body weight per day divided into two equal doses taken approximately 12 hours apart. In certain embodiments, the dosage can be adjusted for 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.

[0138] In certain embodiments, repair system activators are administered for reducing inflammation markers related to aging. As used herein, 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.

[0139] Compounds and compositions that will activate production of NMN are disclosed. For example, Wang et al., discuss the P7C3 class of aminopropyl carbazole chemicals, compounds, and compositions which act by increasing NAD levels through its NAMPT-mediated salvage. (Wang et al. 2014)

Category 2, Methyl Donors

[0140] When adding a methyl donor for methylation, adding betaine is preferred. Betaine can bypass the need (with the use of choline) for extra NAD+ if used to make S-5′-adenosyl-L-methionine (SAM). 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-methylation 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. Typically the timing for giving would be with the Repair System Activator, such as NAD+ or NAD+ precursor.

[0141] 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 (Ulanovskaya O A 2013) of DNA found especially in older people.

[0142] Methyl Donors in addition to betaine, which can be used include SAM, methionine, choline, Folate, and B12. Typically these alternatives are less preferred because only about 2% of SAM get into the body when ingested (McMillan J M 2005); choline needs extra NAD+ to be made into betaine, which is in short supply in the body.

[0143] Dosages of betaine (trimethyl glycine) can be at least 0.03 grams/kg (3×10.sup.−4 mole/kg) of total body weight of the subject (calculated by 0.08 grams (from above NMN calculation) times 0.35 (for molecular weight ratio of betaine/NMN)=0.03 grams/kg total body weight). 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.

[0144] In certain embodiments, 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. Typically methyl donors prefer a Redox balance to be near reduction for optimal activity. S-5′Adenosyl methionine (SAM) precursors include methionine, betaine, choline (a precursor of betaine), folate, Vitamin B12 alone or in combination.

Category-3 Antioxidant Defense Activators

[0145] 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.

[0146] Hydrogen Peroxide (H.sub.2O.sub.2)

[0147] One way to create a generally reducing environment is to “shock” the organism by a pulsed burst of oxidants, such as H.sub.2O.sub.2. To keep the antioxidant enzymes being made and keeping them working one uses 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. In doing the pulse of oxidants for the preconditioning one uses a sufficient level of oxidants to turn on and keep on the antioxidant enzymes. The preferred choice for an oxidant to do the preconditioning is hydrogen peroxide (H.sub.2O.sub.2) due to its centrality in the redox signaling pathways and its relative stability for an oxidant and its low level of potential harmful effects compared to other oxidants that the cell deals with in its life cycle. H.sub.2O.sub.2 can oxidize thiol groups on proteins/enzymes thereby changing their enzymatic properties.

[0148] This pre-conditioning low level oxidation by H.sub.2O.sub.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) anti-oxidants 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.sub.2O.sub.2) Oxidation and Redox Signaling

[0149] Hydrogen peroxide (H.sub.2O.sub.2) is a ubiquitous oxidant present in all aerobic organisms (Marino H S 2014). H.sub.2O.sub.2 is now appreciated as a messenger molecule and it provides sensitivity to redox signaling. H.sub.2O.sub.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.sub.2O.sub.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-κB and AP-1. The functional consequences of H.sub.2O.sub.2 signaling concern fundamental biological processes. 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 (Helmut Sies 2014). Transcriptional factors effected by H.sub.2O.sub.2 include: AP-1, Nrf2, CREB, HSF1, HIF-1, TPSS, NF-κB, NOTCH, SP1, and SCREB-1 most involved in regulation of cell damage response, cell proliferation (cell cycle regulation) differentiation and apoptosis (Albrecht S C 2011).

[0150] Protein acetylation is regulated by H.sub.2O.sub.2 (Jung S-B 2013). Protein deacetylation is regulated by Sirtuins (Imai, S. 2000). H.sub.2O.sub.2 increase acetylation and Sirtuins decrease acetylation, so H.sub.2O.sub.2 and Sirtuins effects are in pushing acetylation reaction pathways in the opposite directions. Sirt1 is very sensitive to H.sub.2O.sub.2 inhibition of 1 μmol of extracellular H.sub.2O.sub.2 (Jung S-B 2013). Sirt1 is protected by thiol oxidation from (APE1/Ref-1). It governs the redox state and activity of Sirt1. It reduces the thiol groups in the active site of Sirt1, H.sub.2O.sub.2 oxidizes the thiols in Sirt1's active site. Sirt1 is also regulated by redox-dependent phosphorylation (Cain, S. 2010).

[0151] Need for Pulsing of Signaling Oxidants

[0152] Low levels of H.sub.2O.sub.2 increase defenses by preconditioning and thus can ultimately protect against increase of oxidized thiols in Sirtuin's active site and Sirt1's decrease in activity by an oxidative challenge. Adaptation to H.sub.2O.sub.2 decrease H.sub.2O.sub.2 permeability of plasma membranes. Different cell membranes have a full range of permeability to H.sub.2O.sub.2. Aquaporins also regulate H.sub.2O.sub.2 transport across bio-membranes (Marinho H S 2014).

[0153] Common Drugs that Change H.sub.2O.sub.2 Levels

[0154] Metformin, the most widely prescribed antidiabetic drug in the world, increases hydrogen peroxide (H.sub.2O.sub.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 anti-oxidants, abolished the positive effect of metformin on lifespan (De Haes W 2014). Pharmaceuticals that increase hydrogen peroxide in the body can also be used for this category either in addition to H.sub.2O.sub.2 or as a substitute for adding hydrogen peroxide itself. Pharmaceuticals that increase H.sub.2O.sub.2 in the body include metformin (De Haes W 2014) and acetaminophen (Hinson J 2010).

[0155] Pharmaceuticals that increase H.sub.2O.sub.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.sub.2O.sub.2 in the body (Hinson J 2010). N-acetyl-1cysteine (NAC) is a compound that is known to counter many effects of H.sub.2O.sub.2 in the body.

[0156] Timing, Duration, and Levels of H.sub.2O.sub.2

[0157] Enough oxidation to provide pre-conditioning to signal to the turn on the anti-oxidant defense and repair systems is desired; but not enough to create oxidized damage like oxidizing the thiol groups in the Sirtuin active site that turns the enzymes activities off This level has been referred to as the “Goldilocks zone”. 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.

[0158] In certain embodiments, one can add pulsed low levels of hydrogen peroxide (H.sub.2O.sub.2) transiently to humans to pre-condition the anti-oxidant defense and repair systems to turn on and stay on. In certain preferred embodiments, approximately 100 μM concentration of food grade (commercial grade has acetanilide in it as a stabilizer) H.sub.2O.sub.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. 1 mole of H.sub.2O.sub.2=1+1+16+16=approximately 34 grams. 50% of H.sub.2O.sub.2 is estimated to be absorbed by the gut so a more preferred concentration to take is approximately 200 μM (in the 500 mL). For example, in certain embodiments, one drop of H.sub.2O.sub.2 is 0.05 mL. Food grade H.sub.2O.sub.2 comes in 35% concentrations. Taking 2 drops of 35% H.sub.2O.sub.2 in 500 mL distilled water (with each dose/day), gives approximately 200 μM. H.sub.2O.sub.2 degrades at about 10%/year if no light and no contaminants in deionized/distilled H.sub.2O. H.sub.2O.sub.2 freezes at −11° C. So in certain embodiments, taking 4 drops/day or 0.2 mL of 35% H.sub.2O.sub.2/day in 1 liter of water. 35 grams/100 mL=0.07 grams/0.2 mL. In certain embodiments, a quantity of approximately 0.0008 grams of H.sub.2O.sub.2/kg total body weight dosages can be used.

[0159] A preferred method of administration is to ingest H.sub.2O.sub.2 by dissolving H.sub.2O.sub.2 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. In certain embodiments, if H.sub.2O.sub.2 is partially enhanced from endurance exercise do exercise directly before or after.

[0160] Administration of metformin (De Macs W 2014), can come in liquid form, Riomet, as well as tablets. In 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.

[0161] Hydrogen Sulfide (H.sub.2O.sub.2)

[0162] Another way to change the redox potential of oxidation-sensitive protein thiols besides using hydrogen peroxide (H.sub.2O.sub.2 ) to pre-condition the antioxidant defense system as discussed previously, is by directly augmenting the antioxidant defense system with hydrogen sulfide (H.sub.2S). NaSH (a H.sub.2S donor) (0.025-0.1 millimolar/liter) treatment dose dependently countered H.sub.2O.sub.2 treatment. Plasma H.sub.2S levels decrease in humans over 50 to 80 years of age (Chen Y 2005) and plasma levels of H.sub.2S in patients with cardiovascular disease (CHD) show a significant inverse correlation with severity of CHD and changes in the coronary artery (Jiang H 2005). NaSH decreases ROS and enhances SOD, GPx and GST expression. Lipid and protein oxidation products decrease significantly in plasma samples of healthy volunteers with H.sub.2S rich water (500 mL/day for 2 weeks) (Benedetti S 2009). A 0.1 mM NaSH/Liter can increase Sirt1 in a time dependent manner (Wu D 2015). Exogenous H.sub.2S has a protective effect on maintaining the circadian rhythm of clock genes by changing the NAD+/NADH ratio and enhancing the Sirt1 protein (Shang Z 2012). H.sub.2S is also an important endogenous inhibitor of key elements of acute inflammatory reactions (Zanardo R 2006) by down regulating NF-kB or upregulating home oxygenase 1 expression (Jin H 2008, Kim K 2008, Oh G 2006, Pan L 2011). H.sub.2S can activate ATP-sensitive, intermediate-conductance and small-conductance potassium channels through cysteine S-sulfhydration (Mustafa A 2011, Yang G 2008) causing endothelial and smooth muscle cell hyperpolarization which intern causes vasorelaxation of vascular endothelium and lowering of blood pressure. H.sub.2S has a direct inhibitory effect on angiotensin-converting enzyme (ACE) activity (Laggner H 2007). NaSH increases the expression of eNOS and PGC-1Alpha (Wu D 2015), which both play a role in mitochondria biogenesis and function (Wu, C C 2013, Lagouge H 2006). H.sub.2S upregulates the MAPK pathway (Barr L A 2014, Papapetropoulos A 2009, Yong Q C 2008). It has been inferred that calorie restriction may help maintain H.sub.2S signaling (Predmore B 2010). GYY4237 a slow releasing H.sub.2S donor can kill seven different human cancer cell lines in a concentration-dependent manner (Lee Z 2011). Sulforaphane, also a H.sub.2S donor, has dose-dependent antiprostate cancer (PC-3) properties (Pei Y 2011).

[0163] H.sub.2S is a gasotransmitter. Gasotransmitters are endogenously produced at low levels and are able to freely diffuse through cell membranes to invoke cellular signaling (Calvert J W 2010). The three gasotransmitters are nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H.sub.2S).

[0164] Hydrogen sulfide is synthesized from L-cysteine. Cystathionine gama-lyase (CSE), cystathionine beta-synthase (CBS), cysteine aminotransferase (CAT), and 3-mercaptopyruvate sulfurtransferase (MST) are endogenous enzymatic sources of hydrogen sulfide (H.sub.2S). Liver production of H.sub.2S to different extents has been shown by these enzymes and showed H.sub.2S regulates lipid peroxidation and antioxidant enzyme (GPx, T-SOD, Cu/Zn-SOD, and Mn-SOD) activities in the liver, by administration of H.sub.2S 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 (Wu D 2015). Mitochondria are able to use H.sub.1S under hypoxia and stress conditions to produce ATP (Fu M 2012).

[0165] Initial reports of H.sub.2S's antioxidant ability were that H.sub.2S can scavenge superoxide (Gong B 2004) and H.sub.2S can upregulate glutathione (Kimura Y 2004). Later came more detailed reports of its activation of antioxidant enzymes. H.sub.2S has been shown to activate Nuclear factor-erythroid 2-related factor 2 (Nfr2) (Peake B F 2013), which turns on antioxidant genes. Daily administration of Na.sub.2S for 7 days increased Nrf2 expression in both cytosolic and nuclear fractions (Calvert J W 2010). Nrf2, which up regulates expression of antioxidant response element-regulated genes, is upregulated by H.sub.2S (Islam K N 2015). H.sub.2S activation causes Nrf2 to separate itself from its adherent inhibitor, Kelch-like ECH-associated protein 1 in the cytosol (Wakabayashi N 2004) 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 (Calvert J W 2009). H.sub.2S exhibits effects on mitochondria function (Helmy N 2014, Wang C N 2014) antioxidant stress (Bos E M 2013, Du J T 2013) apoptosis (Yao L L 2010), inflammation (Lo Faro M L 2014) angiogenesis (Szabo C 2013, Coletta C 2012, Wang M J 2010), sepsis and shock (Kida, F. 2015) and blood pressure (Polhemus D J 2014, Ge S N 2014, Yang G 2008).

[0166] H.sub.2S protects against NO.sub.3.sup.−, as does glutathione. H.sub.2S also significantly reduces the toxic effects of HOCl. H.sub.2S enhances the anti-oxidant effects of N-acethyl-1-cysteine (NAC).

[0167] H.sub.2S's therapeutic effects have been most studied to date in regards to heart disease. H.sub.2S effects on heart disease include: macrophages are able to produce H.sub.2S endogenously (Zhu X Y 2010). NaHS (a H.sub.2S donor) inhibited pro-atherogenic oxidized low-density lipoproteins induced foam cell formation in macrophages (Wang Y 2009). H.sub.2S is able to down regulate ROS at the mitochondria, providing protection through reduced respiration (Chen Q 2006). H.sub.2S production (10-100 nM) enhanced mitochondrial electron transport and cellular bioenergetics (Modis K 2013) however at high concentrations H.sub.2S is toxic (Hill B C 1984, Nicholls P 1982). H.sub.2S in the diet decreased adverse left ventricle (LV) remodeling during heart failure (Kondo K 2013). H.sub.2S can upregulate endothelial nitric oxide synthase which makes NO (Kondo K 2013) and NO can upregulate the H.sub.2S synthesis enzyme CSE (Zhao, W. 2001). Mice treated with a H.sub.2S donor significantly increase phosphorylation effecting eNOS suggesting active cross talk between H.sub.2S and NO (Kondo K 2013). There also appears to be cross talk between CO and H.sub.2S (Zhange Q Y 2004, Majid. A S 2013). H.sub.2S induces vasodilation, leading to reduced blood pressure (Cheng Y 2004). H.sub.2S in the form of Na.sub.2S (10 minutes prior) prevents reperfusion injury (Sodha N R 2008). Exogenous H.sub.2S also led to improved renal function (Xu Z 2009).

[0168] H.sub.2S under in vivo conditions has an extremely short half-life which is estimated to be between seconds and minutes (Wang R 2002, Insko M A 2009). Plasma concentrations of H.sub.2S is in the range of 0.034 to 0.065 mM (Whiteman M 2009), in the brain it is three fold higher than the plasma (Hogg P 2009, Zhao W 2001). H.sub.2S concentration are inversely related to O.sub.2concentration and H.sub.2S decrease cellular O.sub.2consumption (Olson K 2015). H.sub.2S concentrations of between 0.030 and 0.300 have also been reported in the blood and plasma (Olson K 2009). H.sub.2S donors NaHS and Na.sub.2S increase H.sub.2S concentration within seconds to minutes.

[0169] The physiological range of H.sub.2S is widely variable from 0.005 to 0.300 mM (Predmore B L 2012). Endogenous levels of H.sub.2S in the brains of humans have been detected at from 0.05 to 0.16 mM (Whiteman M 2004); in the brains of Alzheimer's patients, the H.sub.2S concentration is lower (Seshadri S 2002, Tang X 2010). Diallyl trisulfide (DATS) is a stable H.sub.2S donor and shows effects 30 minutes after injection and is longer lasting. NaHS can be taken in drinking water (Givvimani S 2011). NaHS (H.sub.2S donor), in aqueous solution releases H.sub.2S, in drinking water for 6 weeks. There was an increase in plasma H.sub.2S concentration with exogenous supplementation (Peale B F 2013. Kondo K 2013). There was no difference in the consumption of water among the groups of mice treated with NaHS and untreated groups. Other H.sub.2S donors include GYY 4137 (CAS#106740-09-4) a water soluble H.sub.2S donor that slowly releases H.sub.2S over the course of hours (Li L 2008) and SG 1002 from Sulfagenix, Inc. AP97, AP39, AP67, and AP105 are also H.sub.2S donors with slower release (Whiteman M 2015, Wallace J 2015, Hancock J 2014). H.sub.2S can be ingested with foods containing organosulfides, who's polysulfides can be H.sub.2S donors.

[0170] In addition to ingesting H.sub.2S dissolved in water, H.sub.2S can be inhaled and inhalation increases blood H.sub.2S levels (40 ppm for 8 hours for 7 days was used with mice). Inhalation can also be combined with ingestible H.sub.2S donors such as Na.sub.2S and NaHS (Kida K 2011 and 2015). Measurement of H.sub.2S in blood and tissue has been done with a sensitive and reliable means (Wintner E 2010).

[0171] H.sub.2S can also be stored in cells in the form of sulfane sulfur and transported and released in response to physiological stimulus (Ishigami M. 2009).

[0172] NRF2 Activators

[0173] 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 Hrd1. Keap-1 is also a sensor far a wide array of small-molecule activators also called inducers. 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. (Dinkova-Kostova A T 2015). Over 50 genes are regulated by Nrf2 in humans (Pall M L 2015. Choi B-H 2014). 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.

[0174] Nrf2 signaling is regulated by transcriptional, translational, posttransiational, and epigenetic mechanisms as well as by other protein partners including p62, p21 and IQ motif-containing GTPase activating protein 1 (Huand Y 2015), 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) (Gegotek A 2015). The Keap1-Nrf2 pathway acts in concert with autophagy to combat proteotoxicity (Dodson M 2015).

[0175] 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 (Suzuki T 2013).

[0176] 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 (Kasper J W 2011). Keap-1 is exported out of the nucleus in 0.5 hours. Nrf2 activations enhances Sirt1 activity in mice fibroblasts cell culture (Jodar L 2010).

[0177] When Nrf2 releases Keap-1 it is available to capture IKKBeta thus inhibiting NF-κB target genes. This interaction correlates the expression of antioxidant enzymes by NrF2 and the turning on and off of the immune system by NF-κB. Nrf2 and NF-kB compete for CREB-binding protein (CBP) (Liu G H 2008). There are many phytochemicals that have Nrf2 activation abilities by interacting with Keap-1 in different ways. Immediate alkylators are fast activating. “Michael acceptors”, which are acetylene compounds conjugated to an electron-withdrawing group, form reversible alkylating reactions with Keap-1 sensor thiols.

[0178] Phenolics that appear to act most directly on Nrf2 are ortho- or para-dihydroxyphenols which can be oxidized to quinones (Kumar H 2014). 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.

[0179] H.sub.2O.sub.2 and H.sub.2S are Nrf2 activators (listed separately above). Everything mentioned that is a Nrf2 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. Sirt1 and PARP1 as discussed before can also be reversibly phosphorylated.

[0180] Nrf2 activation and the turning on of the antioxidant defense system needs to be correlated in tinting 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.

[0181] Category 3 Compounds

[0182] 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), H.sub.2O.sub.2, ROS, RNS, RCS, RSOH, O.sub.2.sup.1, O.sub.2, H.sub.2S, O.sub.3, HOCl, HOBr, HOI, ROOH, where R is alkyl, cycloalkyl, heteralkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, or hetercycloalkenyl, H.sub.2O.sub.2 generator, such as metformin or acetaminophen, ortho hydroxyphenols which can be oxidized to quinones (Kumar H 2014), para dihydroxyphenols which can be oxidized to quinones (Kumar H 2014), quinones (are oxidized derivatives of aromatic compounds), hydrogen sulfide (H.sub.2S), H.sub.2S Donor (such as), sodium hydrosulfide (NaHS), sodium sulfide (Na.sub.2S), diallyl trisulfide (DATS), GYY4137 (a water soluble H.sub.2S donor (patent WO2014018569 A1) (Li L 2008)), SG-1002 (a H.sub.2S synthetic donor from SulfaGENEX) (Kondo K 2013), penicillamine-based H.sub.2S donors (Zhao Y 2013), polyorganosulfides (Tocmo R 2015), 2-mercaptothanol, dithiothreitol, isothiocyanates, sulforaphane (in broccoli) (Nallasamy P 2014), glucoraphanin (broccoli) (Armah C N 2013), curcumin (in turmeric) (Pae H-O 2007, He H J 2012, Balogun E 2003, Goel A 2007, Pyrrolidone (water soluble), Theracumin (nanoparticle), Zerumbone (Stefanson A L 2014), Cinnamate analogs that have thioketone-conjugated-Alpha-Beta-unsaturated moiety (Kumar S 2013) like, cinamic aldehyde, quercetin (in onions, apples, tea) (Magesh S 2012, Kimura S 2009), isoquercetin (2 to 6 fold better absorption), kaempferol (Kang B Y 2008), ginseng (Panax ginseng and Panax quinquefolius), carnosic acid, xanthohumol, Dh404, (R)-alpha-lipoic acid (Flier J 2002, Suh J H 2004, Cao Z 2003), Isothiocyanate, benzyl isothiocyanate (Sahu R P 2009). Neoglucobrasssicin (Stefanson A L 2014). Glucosinolates (Stefanson A L 2014), Hydrophilic oxidized derivatives of Lycopene (Stefanson A L 2014), (HNE) 4-hydroxynonenal (Forman H J 2008), (15-dPGJ2) 15-deoxydelta prostaglandin J2 (Mochizuki M 2005), Falcarindiol (Stefanson A L 2014), Hydroxytyrosol (Stefanson A L 2014), Barley beta-glucan, Spermidine (Kwak M K 2003), Spermine (Kwak M K 2003), luteolin (Paredes-Gonzalez X 2015), 4-methylalkylcatechol, 4 vinylcatechol, 4-ethlycatechol, pyrroloquinoline quinone (Zhang Q 2012, Liang C 2015), Mangafodipir trisodium (MnDPDP) (a contrast agent currently used in magnetic resonance imaging) (Mosbah I B 2012), N-Acetylcysteine (Wallace J 2015), ATB-346 from Antibe Therapeutics (Wallace J 2015), NBS-1120 from City College of New York (Wallace J 2015), GIC-101 from GI care Pharma (Wallace J 2015), AP39 patent number WO2013045951A1 University of Exeter, Alos AP67, AP 97 and AP105, WO2014018569A1, Sialor (Wallace J 2015), Sulfarlem (Wallace J 2015), and Anethole trithione (Wallace J 2015), DHEA (Jeon S 2015), coal tar (Van den Bogaurd E H 2013), garlic (via H.sub.2S), β-lapachone (from tree bark of a South American tree: it produces oxidation by cycling cellular NADH into NAD+), pterostilbene (McCormack D 2013, resveratrol (Cheng L 2015, Mokni M 2007, Kitada M 2011, apigenin (in parsley) (Paredes-Gonzalez X 2015 and 2014, Escande C 2013), zinc (Wang F 2015, Sternberg P 2007, Magesh S 2012) and optionally, a carrier.

Specific Compositions

[0183] In specific examples, the disclosed nutritional composition can comprise nicotinamide adenine dinucleotide (NAD+), Betaine, and H.sub.2O.sub.2. In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), folate+Vitamin B12, and H.sub.2O.sub.2. In specific examples, the disclosed nutritional composition can comprise nicotinamide adenine dinucleotide (NAD+), Methionine, and H.sub.2O.sub.2. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and H.sub.2O.sub.2. In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Choline, and H.sub.2O.sub.2.

[0184] In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Betaine, and NaHS. In specific examples, the disclosed composition can comprise nicotinainide adenine dinucleotide (NAD+), Folate+Vitamin B12, and NaHS. In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Methionine, and NaHS. In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Choline, and NaHS.

[0185] In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Betaine, and Na.sub.2S. In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Folate+Vitamin B12, and Na.sub.2S. In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Methionine, and Na.sub.2S. In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Choline, and Na.sub.2S.

[0186] In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Betaine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Folate+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Methionine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In specific examples, the disclosed composition can comprise nicotinamide adenine dinucleotide (NAD+), Choline, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0187] In specific examples, the disclosed nutritional composition can comprise nicotinamide mononucleotide (NMN) Of a precursor or prodrug of NMN, Betaine, and H.sub.2O.sub.2. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Betaine, and H.sub.2O.sub.2. In other examples, 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 H.sub.2O.sub.2. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and H.sub.2O.sub.2.

[0188] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, folate+Vitamin B12, and H.sub.2O.sub.2. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), folate+Vitamin B12, and H.sub.2O.sub.2. In other examples, 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.sub.2O.sub.2. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate, (cAMP), folate+Vitamin B12, and H.sub.2O.sub.2.

[0189] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine+Vitamin B12, and H.sub.2O.sub.2. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Betaine+Vitamin B12, and H.sub.2O.sub.2. In other examples, 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.sub.2O.sub.2. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine+Vitamin B12, and H.sub.2O.sub.2.

[0190] In specific examples, the disclosed nutritional composition can comprise nicotinamide mononucleotide, (NMN) or a precursor or prodrug of NMN, Methionine, and H.sub.2O.sub.2. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and H.sub.2O.sub.2. In other examples, 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.sub.2O.sub.2. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and H.sub.2O.sub.2.

[0191] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and H.sub.2O.sub.2. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Choline, and H.sub.2O.sub.2. In other examples, 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.sub.2O.sub.2. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and H.sub.2O.sub.2.

[0192] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl-methionine (SAM), and H.sub.2O.sub.2. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and H.sub.2O.sub.2. In other examples, 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 H.sub.2O.sub.2. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and H.sub.2O.sub.2.

[0193] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and NaHS. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Betaine, and NaHS. In other examples, 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. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and NaHS.

[0194] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Folate+Vitamin B12, and NaHS. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Folate+Vitamin B12, and NaHS. In other examples, 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. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate+Vitamin B12, and NaHS.

[0195] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine+Vitamin B12, and NaHS. In other examples, the disclosed composition can comprise nicotinamide, riboside (NR), Betaine+Vitamin B12, and NaHS. In other examples, 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. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine+Vitamin B12, and NaHS.

[0196] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and NaHS. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and NaHS. In other examples, 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. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and NaHS.

[0197] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and NaHS. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Choline, and NaHS. In other examples, 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. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and NaHS.

[0198] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl-methionine (SAM), and NaHS. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and NaHS. In other examples, 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. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and NaHS.

[0199] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and Na.sub.2S. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Betaine, and Na.sub.2S. In other examples, 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.sub.2S. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and Na.sub.2S.

[0200] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Folate+Vitamin B12, and Na.sub.2S. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Folate+Vitamin B12, and Na.sub.2S. In other examples, 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 Na.sub.2S. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate+Vitamin B12, and Na.sub.2S.

[0201] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine+Vitamin B12, and Na.sub.2S. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Betaine+Vitamin B12, and Na.sub.2S. In other examples, 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 Na.sub.2S. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine+Vitamin B12, and Na.sub.2S.

[0202] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and Na.sub.2S. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and Na.sub.2S. In other examples, 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 Na.sub.2S. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and Na.sub.2S.

[0203] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and Na.sub.2S. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Choline, and Na.sub.2S. In other examples, 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 Na.sub.2S. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and Na.sub.2S.

[0204] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl-methionine (SAM), and Na.sub.2S. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and Na.sub.2S. In other examples, 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.sub.2S. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and Na.sub.2S.

[0205] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Betaine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise one or more or nicotinic acid adenine mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0206] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN), Folate+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Folate+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0207] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN), Betaine+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Betaine+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0208] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN), Methionine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Methionine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0209] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN), Choline, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), Choline, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0210] In specific examples, the disclosed composition can comprise nicotinamide mononucleotide (NMN), S-Adenosyl-methionine (SAM), and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed composition can comprise 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0211] In the disclosed compositions, the combined amount of compounds of category 1, 2, and 3 in the composition can be at least 5 wt. % of the composition. For example, the repair system activator, the methyl donor, and the antioxidant defense activator can be at least 5 wt. % of the composition. In other example, the combined amount of compounds or 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.

Delivery System for Ingredients of Category 1, 2, and 3

[0212] 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. For example, 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. By “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).

[0213] Microbiome Interaction with Delivery Via Digestive Tract or Skin

[0214] 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 (Jones R 2014). 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 H.sub.2O.sub.2 in the gut. H.sub.2S protects the mucosal lining of the gastrointestinal tract against oxidative stress as well as regulates various functions including fluid transport, inflammation, acid induced HCO.sub.3.sup.− secretion (Yonezawa D 2007, Ise F 2011, Wallace J 2009+2010, Fiorucci S 2006, Kasparek M 2008, Takeuchi K 2011+2015). Gut microbiota composition in the elderly has been correlated to plasma Il-6 levels (Claesson M J 2012).

[0215] 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 Sirt1 and its ability to deacetylate CREB (Paz J C 2014). This links the level of NAD+ and the feeling of hunger. The glucose-regulated antagonism between (yet coordinated with) CREB and Sirt1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis, this is important since a decline in neurogenesis accompanies brain aging (Bondolfi L 2004) and CREB transcription factor is activated by nutrient deprivation which is correlated to Sirtuin enzyme activity.

[0216] 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.

[0217] 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 at a later date.

Pharmaceutically Acceptable Carriers

[0218] The compositions disclosed herein can be used therapeutically in combination with a pharmaceutically acceptable carrier.

[0219] 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 Mich. USA 2012. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of 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.

[0220] Pharmaceutical carriers are known to those skilled in the art. These most typically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. The compositions can be administered intramuscularly or subcutaneously. Other compounds will be administered according to standard procedures used by those skilled in the art.

[0221] Pharmaceutical 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.

[0222] The pharmaceutical composition can be administered in a number of was 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.

[0223] Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of 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.

[0224] 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.

[0225] 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.

[0226] Some of the 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.

[0227] The various compounds and compositions of categories 1, 2and 3, can be taken at the same time or in proximity, such as within 1, 5, 10, 30, 60, 90, or 120 minutes.

[0228] Dosages of each item or items from category 1, 2, and 3 that is sufficient but not in excess (described in molar terms to body weight) and the ingredients are such that the interrelationship of these doses is balanced.

[0229] 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 liming of these three categories of ingredients.

[0230] Disclosed are methods of reducing inflammation in a subject comprising administering to the subject compounds, compositions, or formulations, and optionally, a carrier as described herein.

[0231] Also disclosed are methods, wherein the first compound, the second compound, and the third compound are administered at approximately the same time.

[0232] Also disclosed are methods, wherein the first compound is administered within 15, 30, 60, 90, or 120 minutes of the subject's biological clock NAD+ peak.

[0233] Also disclosed are methods, wherein the compositions are administered to a subject a dosage of at least 1×10.sup.−8 moles of the first compound to the subject, b 1×10.sup.−8 moles of the second compound to the subject, and 1×10.sup.−9 moles of the third compound to the subject.

[0234] Also disclosed are methods, wherein the composition is injected over 8-12 days.

[0235] Also disclosed are methods, wherein the composition is an aerosol, lyophilization, powder, or emulsion.

[0236] Also disclosed are methods, wherein the subject is a human.

[0237] Also disclosed are methods, wherein the human is treated for at least two months.

[0238] Also disclosed are methods, wherein the composition is a tablet that is administered orally at least once daily.

[0239] Also disclosed are methods, wherein the composition is administered once daily.

[0240] The disclosed compositions can be administered at a variety of dosages. For example category 1 compounds like Nicotinamide Mononucleotide (NMN), can be at dosages per day of 1×10.sup.−6 moles/kg to 1×10.sup.−2 moles/kg or 1×10.sup.−5 moles/kg to 1×10.sup.−3 moles/kg or 1×10.sup.−4 moles/kg to 1×10.sup.−3 moles/kg or 2×10.sup.−4 moles/kg to 7×10.sup.4 moles/kg. In certain embodiments, the dosages per day of the category 1 molecule can be at least 1×10.sup.−6 moles/kg, 1×10.sup.−5 moles/kg, 1×10.sup.−4 moles/kg, 1×10.sup.−3 moles/kg or 1×10.sup.−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, NAM, NaAD, NAR, MNM, and cAMP.

[0241] The dosage of category 2 compounds, such as betaine, can be at dosages per day of 1×10.sup.−6 moles/kg to 1×10.sup.−2 moles/kg or 1×10.sup.−5 moles/kg to 1×10.sup.−3 moles/kg or 1×10.sup.−4 moles/kg to 1×10.sup.−3 moles/kg or 2×10.sup.−4 moles/kg to 7×10.sup.−4 moles/kg. In certain embodiments, the dosages per day of the category 2 compound can be at least 1×10.sup.−6 moles/kg, 1×10.sup.−5 moles/kg, 1×10.sup.−4 moles/kg, 1×10.sup.−3 moles/kg or 1×10.sup.−2 moles/kg. The dosages can also be at least 5.82×10.sup.−4 moles/kg body weight/day.

[0242] The dosages of category 3 compounds, such as H.sub.2O.sub.2, can be at dosages per day of 1×10.sup.−7 moles/kg to 1×10.sup.−2 moles/kg or 1×10.sup.−6 moles/kg to 1×10.sup.−3 moles/kg or 1×10.sup.−5 moles/kg to 1×10.sup.−4 moles/kg or 1×10.sup.−5 moles/kg to 7×10.sup.−5 moles/kg. In certain embodiments, the dosages per day of the category 3 compound can be at least 1×10.sup.−7 moles/kg, 1×10.sup.−6 moles/kg, 1×10.sup.−5 moles/kg, 1×10.sup.−4 moles/kg or 1×10.sup.−3 moles/kg. The dosages can also be at least dosage 2.34×10.sup.−5 moles/kg body weight/day.

[0243] The dosages of category 3 compounds, such as NaSH, can be at dosages per day of 1×10.sup.−8 moles/kg to 1×10.sup.−3 moles/kg or 1×10.sup.−7 moles/kg to 1×10.sup.−4 moles/kg, or 1×10.sup.−6 moles/kg to 1×10.sup.−5 moles/kg or 1×10.sup.−6 moles/kg to 7×10.sup.−6 moles/kg. In certain embodiments, the dosages per day of the category 3 compound can be at least 1×10.sup.−8 moles/kg, 1×10.sup.−7 moles/kg, 1×10.sup.−6 moles/kg, 1×10.sup.−4 moles/kg or 1×10.sup.−3 moles/kg. In certain embodiments, the dosages can also be at least 3.02×10.sup.−6 moles/Kg body weight/day.

Specific Methods

[0244] Disclosed are methods of resetting biological pathways for defending against and repairing deterioration from human aging. These methods can reduce inflammation in a subject. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), S-Adenosyl-methionine (SAM), and H.sub.2O.sub.2. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), S-Adenosyl-methionine (SAM), and NaSH. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), S-Adenosyl-methionine (SAM), and Na.sub.2S. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), S-Adenosyl-methionine (SAM), and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0245] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Betaine, and H.sub.2O.sub.2. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), folate+Vitamin B12, and H.sub.2O.sub.2. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Methionine, and H.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering, to a subject nicotinamide riboside (NR), Methionine, and H.sub.2O.sub.2. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Choline, and H.sub.2O.sub.2.

[0246] In specific examples, 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 B12, 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.

[0247] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Betaine, and Na.sub.2S. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Folate+Vitamin B12, and Na.sub.2S. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Methionine, and Na.sub.2S. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Choline, and Na.sub.2S.

[0248] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Betaine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Folate+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Methionine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin and zinc. In specific examples, the disclosed methods can comprise administering to a subject nicotinamide adenine dinucleotide (NAD+), Choline, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0249] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and H.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine, and H.sub.2O.sub.2. In other examples, 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.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and H.sub.2O.sub.2.

[0250] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, folate+Vitamin B12, and H.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), folate+Vitamin B12, and H.sub.2O.sub.2. In other examples, 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.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), folate+Vitamin B12, and H.sub.2O.sub.2.

[0251] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine+Vitamin B12, and H.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine+Vitamin B12, and H.sub.2O.sub.2. In other examples, 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.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNN) and/or cyclic adenosine monophosphate (cAMP), Betaine+Vitamin B12, and H.sub.2O.sub.2.

[0252] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and H.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Methionine, and H.sub.2O.sub.2. In other examples, 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.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and H.sub.2O.sub.2.

[0253] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and H.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Choline, and H.sub.2O.sub.2. In other examples, 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.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and H.sub.2O.sub.2.

[0254] In specific examples, 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.sub.2O.sub.2. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and H.sub.2O.sub.2. In other examples, 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.sub.2O.sub.2, in other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and H.sub.2O.sub.2.

[0255] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and NaHS. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine, and NaHS. In other examples, the disclosed methods can comprise administering to a subject one or more of nicotinic acid adenine mononucleotide (NAM), nicotinic acid adenine dinucleotide (NaAD), and nicotinic acid riboside (NAR), Betaine, and NaHS. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and NaHS.

[0256] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Folate+Vitamin B12, and NaHS. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Folate+Vitamin B12, and NaHS. In other examples, 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. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate+Vitamin B12, and NaHS.

[0257] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine+Vitamin B12, and NaHS. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine+Vitamin B12, and NaHS. In other examples, 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. In other examples, the disclosed methods cart comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine+Vitamin B12, and NaHS.

[0258] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and NaHS. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Methionine, and NaHS. In other examples, 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. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and NaHS.

[0259] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and NaHS. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Choline, and NaHS. In other examples, 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. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and NaHS.

[0260] In specific examples, 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. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and NaHS. In other examples, 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. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and NaHS.

[0261] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine, and Na.sub.2S. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine, and Na.sub.2S. In other examples, 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.sub.2S. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and Na.sub.2S.

[0262] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Folate+Vitamin B12, and Na.sub.2S. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Folate+Vitamin B12, and Na.sub.2S. In other examples, 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.sub.2S. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate+Vitamin B12, and Na.sub.2S.

[0263] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Betaine+Vitamin B12, and Na.sub.2S. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine+Vitamin B12, and Na.sub.2S. In other examples, 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.sub.2S. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine+Vitamin B12, and Na.sub.2S.

[0264] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Methionine, and Na.sub.2S. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Methionine, and Na.sub.2S. In other examples, 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.sub.2S. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Methionine, and Na.sub.2S.

[0265] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, Choline, and Na.sub.2S. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Choline, and Na.sub.2S. In other examples, 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 Na.sub.2S. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Choline, and Na.sub.2S.

[0266] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) or a precursor or prodrug of NMN, S-Adenosyl-methionine (SAM), and Na.sub.2S. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and Na.sub.2S. In other examples, 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 Na.sub.2S. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), S-Adenosyl-methionine (SAM), and Na.sub.2S.

[0267] In specific examples, 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.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed methods can comprise administering to a subject methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Betaine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0268] In specific examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene resveratrol, apigenin, and zinc. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Folate+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed methods can comprise administering to a subject methylnicotinamide (MNM) and/or cyclic adenosine monophosphate (cAMP), Folate+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, α-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0269] In specific examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Betaine+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed methods can comprise administering to a subject 1-methylnicotinamide (NMM) and/or cyclic adenosine monophosphate (cAMP), Betaine+Vitamin B12, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0270] In specific examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Methionine, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0271] In specific examples, the disclosed methods can comprise administering to a subject nicotinamide mononucleotide (NMN) Of a precursor or prodrug of NMN, Choline, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), Choline, and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

[0272] In specific examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, the disclosed methods can comprise administering to a subject nicotinamide riboside (NR), S-Adenosyl-methionine (SAM), and any one or more of H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc. In other examples, 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 H.sub.2S, O.sub.3, metformin, acetaminophen, sulforaphane, glucoraphanin, curcumin, quercetin, isoquercetin, ginseng, (R)-alpha-lipoic acid, Hydrophilic oxidized derivatives of Lycopene, N-Acetylcysteine, DHEA, garlic, β-lapachone, pterostilbene, resveratrol, apigenin, and zinc.

Surrogate Markers for Aging

[0273] A variety of markers can be used as surrogates for monitoring aging.

[0274] DNA Methylation Levels

[0275] DNA methylation levels change with age. Studies have identified biomarkers of chronological age based on DNA methylation levels called an “epigenetic clock” (Horvath S 2013 based on 353 dinucleotide CpG markers). Differences between DNA methylation age and chronological age led to the conclusion that DNA methylation-derived measures of biological aging are traits that predict mortality independently of health status, lifestyle factors, and known genetic factors (Marioni R E 2015). This epigenetic clock is tissue specific since some tissues age faster than others. The cerebellum ages more slowly than other parts of the body (Horvath S 2015). HIV-1-infected individuals show accelerated aging with this epigenetic clock (Rickabaugh T M 2015). Methylation data can be collected from circulating T cells and monocytes and was done so in a population cohort of 1264 participants (Reynolds L M 2014).

[0276] DNA Breakage

[0277] Single stranded and double stranded DNA breakage has not been used as methylation has for a biological clock but it is correlated to aging (Yu Q 2015) with older age having more breakage on average. Companies such as Exogen Biotechnology are able to test for single stranded and double stranded DNA breakage, NAD+ is used in DNA repair by PARP and Sirtuin enzymes, thus seeing less DNA breakage is an indication that these enzyme systems are working.

[0278] Inflammation Markers

[0279] Inflammation markers can be analyzed for aging including those markers found in the study by Arai in 2015. Aria found inflammation markers that were predictive of who would continue to live (life-span) and who would be physically and cognitively healthy (health-span). The markers used were CMV IgG, IL-6, TNF-alpha and CRP.

[0280] Other Markers Associated with Aging

[0281] Global loss of H3K9me3 or the resulting heterochromatin architecture changes correlate to biological aging as was shown in the human aging caused by Werner syndrome's premature aging and this can also be analyzed (Zhang W 2015).

[0282] A variety of compounds in blood correlate to age, as well as effect one and can be measure. An example is TGIF-beta, which is lower in younger individuals than older individuals.

[0283] Metabalomic measurements have been correlated to aging using a nonlinear regression technique and a 13 year follow up.

[0284] Peripheral blood leukocyte telomere length can be measured and compared to 64,637 individuals of known age (Rode L 2015), although telomere length is only modestly correlated to age (r=0.5) and cellular aging continues regardless of telomere length.

Definitions

[0285] In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings:

[0286] Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.

[0287] As used in the description and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “the compound” includes mixtures of two or more such compounds, reference to “an agent” includes mixture of two or more such agents, and the like.

[0288] “Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0289] As used herein, by a “subject” is meant an individual. Thus, 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.

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EXAMPLES

[0558] The following examples are set forth below to illustrate the methods, compositions, and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art.

[0559] A 61 year old Caucasian male weighing 88 kg at the beginning of the treatment was treated with a regimine of category 1, category 2, and category 3 molecules as noted below.

[0560] Nicotinamide mononucleotide (NMN) (MW=334.22)

[0561] Betaine (trimethyl glycine) (MW =117.14)

[0562] H.sub.2O.sub.2 (MW=34.01)

[0563] NaSH (MW=56.06)

[0564] Solutions of various compounds were produced for administering to the subject by mixing a set number of grains with 500 mL of water.

[0565] Typical final concentrations of NMN taken by subject were 3.5 grams in 500 mL H.sub.2O, betaine were 3 grams in 500 mL H.sub.2O, H.sub.2O.sub.2 were (2 drops of 35% concentration in 500 mL H.sub.2O), and NaSH were (drops of 2 at 66 uM per drop concentration in 500 mL H.sub.2O).

[0566] The amounts of each composition were set so that by the subject drinking the full 500 mL a final dosage approximately 1.19×10.sup.−4 moles NMN/kg body weight per dose, 2.91×10.sup.−4 moles betaine/kg body weight per dose, 1.17×10.sup.−5 moles of H.sub.2O.sub.2/kg of body weight per dose, and 1.51×10.sup.−6 moles cf NaSH/kg of body weight per dose was given to the subject through drinking the 500 mL solution.

[0567] By taking two similar dosages per day, the sum of the two daily equal allotments was [0568] Nicotinamide Mononucleotide (NMN) dosage−2.38×10.sup.−4 moles/Kg body weight/day [0569] The betaine dosage−5.82×10.sup.−4 moles/Kg body weight/day [0570] The Hydrogen Peroxide (H.sub.2O.sub.2) dosage−2.34×10.sup.−5 moles/Kg body weight/day [0571] The Sodium Hydrogen Sulfide (NaSH) dosage−3.02×10.sup.−6 moles/Kg body weight/day

[0572] The subject was weighed each day.

[0573] 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.

[0574] 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.

[0575] 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, Lymphs, Monocytes, Los, Basos, Immature Cells, Neutrophils (Absolute). Lymphs (Absolute), Monocytes (Absolute), Los (Absolute), Baso (Absolute), Immature Granulocytes, Immature Grans (Absolute), NRBC, VAP Cholesterol Profile, LDL Cholesterol, HDL Cholesterol, VLDL Cholesterol, Cholesterol total, Triglycerides, Non HDL, Cholesterol (LDL+VLDL), ApoB100=Calculation, LDL-R (Real)-C, Lp(a) Cholesterol, IDL Cholesterol, Remnant Lipo (IDL+VLDL3) Probable Metabolic Syndrome, HDL-2 (most Protective), HDL-3 (Less Protective), VLDL-3 (Small Remnant), LDL1 Pattern A, LDL2 Pattern A, LDL3 Pattern B, LDL4 Pattern B, LDL Density Pattern, Glucose Tolerance (4 Sp Blood), Glucose Fasting, Glucose 1 hour, Glucose 2 hours, Glucose 3 hours, Insulin Fasting, Insulin 1 hour, Insulin 2 hours, insulin 3 hours, Cortisol AM, Cortisol PM, IL-1b (Serum), Hemoglobin A1c, Rheumatoid Arthritis Factor, IGF-1, Cardiac, Tumor Interleukin-8 (Serum), Homocyst(e)ine (plasma), Antinuclear Antibodies direct, Sedimentation Rate-Westergren Cortisol. (Urinary Free). Cortisol, F, ug, L, U, Cortisol, Fug, 24 hr, U, Serum Immunoglobulin G, Qn, Serum Immunoglobulin A, Qn, Serum Immunoglobulin M, On, oxLDL, CMV IgM, Ferritin, and H. pylori IgG.

[0576] University of California, San Diego measured: [0577] a. Spectral 3 tesla MRI of right calf leg muscle before, during, and after exercise [0578] b. Spectral 3 tesla MRI of Liver [0579] c. Structural 3 tesla MRI of Liver [0580] d. Spectral 3 tesla MRI of Brain (front and back) [0581] e. A structural 3 tesla MRI of Brain [0582] f. A structural 3 tesla MRI of the right knee (showing Arthritis) [0583] g. 3-Nitrotyrosine (a marker for oxidative/nitrative stress) [0584] h. Coagulation Tests (a marker for oxidative stress) [0585] i. F2-isoprostanes (a marker for oxidative/nitrative stress,) [0586] j. GSH:GSSH (a marker for and protection from oxidative/nitrative stress,) [0587] k. Urine Organic Acids [0588] l. 8-hydroxydeooxyguanosine (8-OHDG) (a marker for oxidative/nitrative stress) [0589] m. Malondialdehyde (a marker for oxidative/nitrative stress) [0590] n. hsCRP (a marker that can be adversely affected by oxidative stress) [0591] o. Proteomic profile (a marker for oxidative/nitrative stress)

[0592] A list of medical history questions (UCSD) 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.

Results

[0593]

TABLE-US-00001 TABLE 1 61 year old Male Caucasian With the additions of NMN X X X X X X Betaine X X X H.sub.2O.sub.2 X NaSH X Normal Normal Range Range Low High Baseline CMV IgH 0 0 0 0 0 0 0 0 0 C-Reactive mg/L 0 3 2.77 3.25 0.43 0.53 0.85 0.21 0.40 Protein Tumor pg/mL 0 8.1 1.1 0.9 1.1 1.1 1 0.5 0.3 Necrosis Factor-Alpha Interleukin-6 pg/mL 0 15.5 1.3 4.4 <0.7 0.9 3.1 <0.7 <0.7 Serum Inflammation 0 26.6 5.17 8.55 2.23 2.53 4.95 1.41 1.40 Score

[0594] 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+H.sub.2O.sub.2 for one month and NMN+ betaine+NaSH for one month.

[0595] Other observations of interest during study are that the subject was healthy during the full duration of the study. Photos depicted that aged skin cells on hand became youthful in appearance. The subject's complexion of facial skin improved during study. The subject had significant weight loss and apatite was lowered during study. The subject had an elimination of pain from arthritis in right knee during study. The subject had more restful sleep during study. The subject had increased energy during study. The subject had better vision at eye exam.

Discussion

[0596] The age of 61 correlates to the age of unrelated and offspring families in the Arai Y 2015 study detailed herein. The results of this study, in light of the Arai Y 2015 study, show that the triple therapy with the three categories of compounds change the predicted outcome, as identified by Arai 2015, of this 61 year old 88 kg Caucasian male from unsuccessful aging to a prediction of successful aging. In the baseline condition for the subject, both C-reactive Protein (2.77 mg/L) and Interleukin-6 (1.3 pg/m14 measurements were above the “unrelated family” level (0.7 mg/l and 1.13 pg/mL) (Arai Y 2015, Table 1) as well as the “offspring” level (0.7 mg/l and 1.03 pg/mL) (Arai Y. 2015, Table 1) respectively. The 61 male subject of this study has a similar age to the “offspring” group and the “unrelated family” group of Arai. These two inflammation test scores effect the prediction algorithm to predict a worse aging outcome for the 61 year old subject than the “offspring” or “unrelated family” groups of Arai at baseline.

[0597] After two months of treatment with NMN, however, the markers of the 61 year old subject were brought to levels better than the “offspring” group of Arai (CRP, 043 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.

[0598] All three inflammatory markers drop to their lowest level with the addition of all three categories of ingredients. IL-6 drops to undetectable levels, TNF-alpha drops by over 50%, and CRP drops to about a tenth of the original value. When H.sub.2O.sub.2 is used for the category 3 ingredient in this example CRP drops more than when NaSH is used and when NaSH is used as the category 3 ingredient TNF-alpha dropped more than when H.sub.2O.sub.2 is used. In both cases of triple therapy the results are far below the necessary levels to predict very successful aging. CMV titers were not discussed here since this 61 year old male had no or undetectable levels of CMV IgG and this is as good as the measured value of this variable can get.

[0599] When the interventional therapy for this 61 year old male in this experiment is compared to the results gained by one or two years of calorie restriction one can see that the results are far greater with this triple category therapy and they are far easier to obtain (Di Francesco A 2015, Ravussin E 2015).

Correlations by Other Authors to Human Health Improvements from the Lowering TNF-Alpha and IL-6 Which were Lowered in this Example;

[0600] Other Studies (Similar to Arai Y 2015)

[0601] Immune markers (a simple index of serum interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) two of the Arai 4 markers) were found to be the best predictor of mortality in 1,155 older adults in a 10 year all-cause mortality study after adjusting for variables already known to cause death (Varadhan R 2014). A single immune marker (Serum IL-6) predicted all-cause mortality, cancer, cardiovascular disease and liver disease in a 1843 person prospective cohort study (Lee J K 2012). These studies confirmed results in smaller prior studies (Derhovanessian E 2010, Reuben D B 2002, Taaffe D R 2000).

[0602] Possible Mechanism of Action:

[0603] In December 2013, A. Gomes et al, published a study demonstrating that raising the levels of NAD+ with precursor NMN in old mice restores mitochondrial function to that of a young mouse. C. Correia-Melo showed with age mitochondria drive a cellular pro-inflammatory phenotype including IL-6 secretion.

[0604] Immune Dysfunction:

[0605] In July 2014, I. V. Astrakhantseva et al, issued a report showing the benefits of reducing the levels of TNF and IL-6 as effective ways to control inflammation symptoms such as joint destruction and autoimmune diseases. A. Puchta et al, hypothesized a molecular mechanism using these two inflammation variables (TNF and IL-6) for predictive effects on life span and health span. The study showed how TNF increasingly drives immune dysfunction with age and that lowering the levels of TNF decrease this impairment.

[0606] Brain Disease:

[0607] In September 2014 Brianne Bettcher et al, published a study indicating that at older ages, there is a positive correlation between increased levels of IL-6 and lowered white matter function in the brain. In February 2015, Brianne Bettcher et al, published a study showing that reducing systemic inflammation had a positive effects on cognition and brain structure which may reverse neurodegenerative disease processes.

[0608] Heart Disease:

[0609] In 2000, Paul Ridker et al, published 2 studies concluding that in apparently healthy men, elevated levels of IL-6 is associated in increased risk of future Myocardial Infarction and TNF increases the risk of recurrent coronary events after Myocardial Infarction. In August 2005, N J Goodson et al, published a study linking increased levels of C-Reactive Protein with a prediction of death from cardiovascular disease.

[0610] Kidney Disease:

[0611] In 2015, Belinda Lee et al, published a study demonstrating the association between elevated levels of CRP, TNF and IL-6 with chronic kidney disease.

[0612] Alzheimer's Disease:

[0613] Lowering TNF-alpha and IL-6 lowers the chance of getting Alzheimer's disease and lowers the negative effects of Alzheimer's disease (Butchart J 2015, Holmes C 2011). Adding NMN in a mouse Alzheimer's disease model was beneficial (Long A N 2015).

[0614] Research into the Potential Benefits of Lowering TNF-Alpha and IL-6 for a More Effective Immune Response to Viruses and Bacteria:

[0615] McElroy A K, after analyzing the kinetics of inflammatory signaling in life threatening human Ebola Virus disease, proposed the possible therapeutic benefit of lowering the proinflammatory signaling of IL-6 for clinical intervention of these patients. A. Puchta proposed the possible therapeutic benefit of lowering IL-6 and TNF alpha to increase the ability to fight Streptococcus pneumoniae.

[0616] Research Correlation of the Potential Benefits of Lowering, TNF-Alpha and IL-6 to Better Physical Performance.

[0617] Cesari M in 2004 concluded higher levels of IL-6 was correlated to lower physical performance in older adults and a target for intervention. Puzianowska-Kuznicka M showed IL-6 and CRP were good predictors of physical and cognitive performance and the risk of mortality in 3496 individuals.

[0618] Sleep:

[0619] Irwin M R correlated sleep disturbances to increased CRP and IL-6 but not TNF in a meta-analysis of 72 previous sleep studies.