Compositions for increasing NAD levels and methods and uses thereof

Abstract

Provided herein are compositions and methods of using the same for effectively increasing NAD levels in a subject in need thereof and improving body function associated with low NAD levels. The compositions comprise an NAD precursor and additional components that increase NAD levels and improve mitochondrial and cellular function. The additional components include NAD +, NADH, D-ribose and creatine monohydrate, nicotinamide and / or nicotinic acid (NA), and can be added to a formulation to further enhance the efficacy of the composition.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 385,327, filed on November 29, 2022, which is incorporated by reference in its entirety. Technical Field

[0003] The present invention generally relates to compositions and methods of use for increasing NAD levels in a subject in need thereof. Background Art

[0004] Nicotinamide adenine dinucleotide (NAD) is a coenzyme present in all living cells. It is essential for life because it catalyzes reactions in over 500 enzymes, including those involved in the production of cellular energy (ATP). NAD plays a crucial role in the six hallmarks of aging: DNA repair, epigenetic alterations, loss of proteostasis (proper protein regulation), mitochondrial dysfunction, cellular senescence, and dysregulated nutrient sensing.

[0005] NAD optimization has many benefits. Common and important benefits include increased energy, better sleep, improved performance, reduced muscle and joint pain, enhanced immunity against infection, reduced inflammation, reduced insulin resistance, clearer thinking, and improved liver function, to name a few. Actual benefits may vary from person to person and may depend on the underlying health condition.

[0006] NAD levels decline with age, and low NAD levels are associated with loss of function and vitality, as well as many age-related diseases. The vast majority of adults and a small percentage of young children have suboptimal or insufficient NAD and can benefit from NAD optimization. Who needs NAD supplementation and how much someone needs can be determined through laboratory testing.

[0007] There are many options that could potentially increase a person's NAD levels. These options fall into four different categories. One way to increase NAD in cells is by supplementing with NAD precursors, the building blocks that cells use to make NAD molecules. Nicotinamide mononucleotide (NMN) is a one-step precursor for making NAD, and nicotinamide riboside (NR) is a two-step NAD precursor. Nicotinamide (NAM) and nicotinic acid (NA) can also be converted to NAD, but with much lower efficiency for most people. Several studies in human subjects have evaluated the efficacy of NMN or NR in raising NAD levels; however, these studies included only very small numbers of subjects. How effective these products are remains unknown and may depend on the individual. Other ways to increase NAD levels that have been explored include NAD molecules (delivered orally, by injection, patch, or via IV), inhibiting enzymes that degrade NAD, and increasing enzymes that make NAD. The efficacy of these methods is largely unknown. Therefore, it is important to develop new products to efficiently raise NAD levels in as many people as possible.

[0008] Because NAD plays a critical role in many biological functions and because NAD levels decline in an age- and health-dependent manner, optimizing NAD levels is important for maintaining health, performance, and longevity. The key task is to formulate a product that can effectively elevate NAD levels and provide benefits in terms of improved physical, physiological, sexual, and / or mental function.

[0009] A common method for increasing NAD levels is intravenous (iv) infusion of the NAD molecule. NAD iv infusion has been widely used in clinical medicine for decades and has shown promising results for a variety of health conditions and diseases, including addiction, neurological diseases such as dementia, and infectious diseases including Lyme disease, COVID-19, and long-term COVID. However, NAD iv does not increase intracellular NAD levels and is therefore not a good method for increasing the cellular function of NAD.

[0010] NAD precursors such as NMN and NR have recently been used as supplements to increase NAD levels. In clinical trials with a small number of subjects, both precursors have been shown to increase NAD levels. However, these studies did not show the percentage of subjects who experienced a significant increase in NAD levels. Data from consumers indicate that NAD levels remain suboptimal for many users of these precursors, suggesting that these products may not be optimal.

[0011] Several products attempt to improve the effectiveness of NMN by adding other supplemental ingredients, such as resveratrol and trimethylglycine (TMG). It is unclear whether these formulations are more effective than pure NMN.

[0012] Therefore, there is a need for an NAD formulation that can: 1) effectively elevate NAD levels and 2) provide benefits in terms of improved biochemical, physical, physiological, sexual and / or psychological health. It is an object of the present invention to provide a composition that can achieve these goals. Summary of the Invention

[0013] It should be understood that this summary is not a comprehensive overview of the present disclosure. This summary is illustrative and non-restrictive and is neither intended to identify key or important elements of the present disclosure nor to limit the scope of the present disclosure. The sole purpose of this summary is to explain and exemplify certain concepts of the present disclosure as a preface to the complete and comprehensive detailed description that follows.

[0014] In accordance with one or more objects of the present invention, as embodied and broadly described herein, the present invention relates in one aspect to a composition for increasing nicotinamide adenine dinucleotide (NAD) levels in a subject in need thereof, the composition comprising an effective amount of an NAD precursor, an NAD compound, or a combination thereof. In one embodiment, the NAD precursor is selected from nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), or a combination thereof. In another embodiment, the NAD compound is selected from NAD+ or NADH, or a combination thereof.

[0015] In one embodiment, an NAD precursor, NAD compound, or combination thereof is further combined with D-ribose or creatine monohydrate. In another embodiment, the combination of an NAD precursor or NAD compound and D-ribose or creatine monohydrate is further combined with NAM or NA, or a combination thereof. In yet another embodiment, the combination of D-ribose or creatine monohydrate with an NAD precursor promotes NAD production and supports cellular function.

[0016] In another aspect, the present invention relates to a method of increasing nicotinamide adenine dinucleotide (NAD) levels in a subject in need thereof, the method comprising administering an effective amount of an NAD precursor, an NAD compound, or a combination thereof to optimize NAD and improve health conditions affected by NAD levels. In one embodiment, the NAD precursor is selected from nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), or a combination thereof. In another embodiment, the NAD compound is selected from NAD+ or NADH, or a combination thereof.

[0017] In one embodiment, an NAD precursor, an NAD compound, or a combination thereof is combined with D-ribose or creatine monohydrate. In another embodiment, the combination of an NAD precursor or an NAD compound with D-ribose or creatine monohydrate is further combined with NAM or NA, or a combination thereof.

[0018] In another embodiment, the subject has suboptimal or insufficient NAD levels. In another embodiment, suboptimal or insufficient NAD levels are associated with diseases and conditions caused by or associated with low NAD levels. In another embodiment, the diseases and conditions caused by or associated with low NAD levels are selected from the group consisting of: addiction; neurological diseases, such as dementia; infectious diseases, including Lyme disease and COVID-19, long COVID; lipid disorders (e.g., dyslipidemia, hypercholesterolemia, or hyperlipidemia); stroke; type I and type II diabetes; cardiovascular disease; kidney disease; liver disease; chronic fatigue syndrome; lung disease; autoimmune disease; obesity; and other physical, physiological, sexual, or mental problems.

[0019] Additional advantages of the present invention will be set forth in part in the following description and in part will become apparent from the description or may be learned by practice of the present invention. The advantages of the present invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that the foregoing summary and the following detailed description are merely exemplary and explanatory and do not limit the invention as claimed. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and, together with the description, serve to explain the principles of the invention.

[0021] Figure 1 The longitudinal changes in NAD levels in a 58-year-old male user are shown. Baseline NAD levels were determined on and before January 19, 2021, and were found to be very low (below 24 μM). Supplementation with a competitor NAD precursor increased intracellular NAD levels to 31.9 μM on February 12, 2021, but did not reach the optimal level of 40 μM. Supplementation with 1000 mg of VitalityBoost (which contains 500 mg NMN) increased NAD levels to 46.2 μM on March 4, 2021, reaching the optimal (green) zone. Four weeks after stopping supplementation (April 7, 2021), NAD levels fell to 31.9 μM. After increasing the dose to 1500 mg of Vitality powder (750 mg NMN) for approximately four weeks, NAD levels reached 55 μM on May 5, 2021. A subsequent washout period reduced NAD levels to 37.4 μM on June 7, 2021. Dose escalation to 2000 mg of Vitality powder (1000 mg NMN) increased NAD levels to 62.3 μM on June 14, 2021. Continuing daily supplementation with 2000 mg of Vitality powder until September 2022 maintained NAD levels around 60 μM.

[0022] Figure 2A NAD optimization is shown for a 68-year-old female user. On February 15, 2021, baseline NAD levels were determined and found to be 20.9 μM, well below the optimal range. Various NAD precursors from other companies were used in the hope of raising her NAD levels, but with no efficacy or minimal efficacy. She began supplementing with 2000mg of Vitality Boost (1000mg NMN) daily for four weeks, and on July 7, 2021, her NAD levels rose to over 115 μM, an increase of over 500%. She then reduced her dose to 1000mg of Vitality Boost powder per day and dropped her NAD levels to around 55-70uM, which is the ideal level for most people.

[0023] Figure 2B It showed that her aging-associated beta-galactosidase decreased as her NAD levels increased.

[0024] Figure 3A Shown are NAD levels for a 43-year-old male subject at baseline (#1 and #2) and two weeks (#3) and four weeks (#4) after supplementing with VitalityBoost, as well as alanine aminotransferase (ALT) levels at the same time points. As NAD levels increased, ALT levels decreased.

[0025] Figure 3B A decrease in triglycerides (TRIG) following supplementation was shown in the same subjects.

[0026] Figure 4 Shown are NAD levels for a 37-year-old male subject at baseline (#1 and #2) and two weeks (#3) and four weeks (#4) after supplementing with VitalityBoost, as well as alanine aminotransferase (ALT) levels at the same time points. Increasing NAD levels through VitalityBoost supplementation reduced ALT levels.

[0027] Figure 5 Shown are NAD levels for a 32-year-old female subject at baseline (#1 and #2) and two weeks (#3) and four weeks (#4) after supplementing with VitalityBoost, as well as alanine aminotransferase (ALT) levels at the same time points. Increasing NAD levels through VitalityBoost supplementation reduced ALT levels.

[0028] Figure 6A summary of the subjects' NAD increases is shown. Baseline NAD levels were measured twice, approximately one week apart, for all 25 users. The users took 2000mg of Vitality Boost for four weeks, and their post-supplement NAD levels were measured two and four weeks after supplementation. Shown are box plots of NAD levels.

[0029] Figure 7 Vitality Boost was shown to outperform pure NMN and increase intracellular NAD levels better than NMN alone.

[0030] Figure 8 Vitality Boost (NMN, creatine, D-ribose, and niacinamide) was shown to elevate NAD much more than pure NMN.

[0031] Figure 9 Vitality Boost was shown to optimize NAD in all 5 SubQ NAD+ users. DETAILED DESCRIPTION

[0032] The present invention may be understood more readily by reference to the following detailed description of the preferred embodiments of the invention and the examples included therein, and by reference to the drawings and their previous and following descriptions.

[0033] I. Definition

[0034] It should be understood that the present disclosure is not limited to the compositions and methods described herein and the experimental conditions described, as they may vary. It should also be understood that the terminology used herein is for the purpose of describing certain embodiments only and is not intended to be limiting, as the scope of the present disclosure will be limited only by the appended claims.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any compositions, methods, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, all publications mentioned are incorporated herein by reference in their entirety.

[0036] The use of the terms "a," "an," and "the" and similar referents in the context of describing the presently claimed invention (especially in the context of the claims) are to be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context.

[0037] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

[0038] The use of the term "about" is intended to describe values within a range of approximately + / - 10% above or below the stated value; in other embodiments, the range of values may be values within a range of approximately + / - 5% above or below the stated value; in other embodiments, the range of values may be values within a range of approximately + / - 2% above or below the stated value; in other embodiments, the range of values may be values within a range of approximately + / - 1% above or below the stated value. The foregoing ranges are intended to be clearly expressed by the context and do not imply further limitations. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended solely to better illustrate the present invention and does not impose limitations on the scope of the present invention unless otherwise required. The language in this specification should not be interpreted as indicating any non-required element as necessary to practice the present invention.

[0039] As used herein, the phrase "nutritional composition" or variations thereof refers to a composition containing a compound disclosed herein and further containing a food or liquid, a portion of a food or liquid, or as an additive to a food or liquid, wherein such composition provides a medical or health benefit, including the prevention and treatment of disease, or the induction of a beneficial physiological response, alone or in combination with a primary therapy.

[0040] Nutritional compositions as disclosed herein provide a source of nutrition, and therefore, nutritional compositions can be food products, raw materials of food, functional foods, or supplementary compositions of food products or raw materials of food. As used herein, the term food product refers to any food that provides a source of nutrition and is suitable for oral consumption by humans or animals. The food product can be a prefabricated and packaged food or animal feed. As used herein, the term raw materials of food refers to a source of nutrition for human or animal consumption. Functional foods are foods consumed as part of a diet that have been shown to have physiological benefits beyond basic nutritional functions. Food products, raw materials of food, or functional foods include, but are not limited to, beverages, such as non-alcoholic beverages and alcoholic beverages, and liquid preparations added to drinking water and liquid foods, as well as solid or semi-solid foods. Non-alcoholic beverages include, but are not limited to, nutritional shakes, soft drinks, sports drinks, fruit juices; and milk and other dairy beverages, such as yogurt drinks and protein shakes. Examples of solid or semi-solid foods include, but are not limited to, baked goods; puddings; dairy products; confectionery; snacks; or frozen confectionery or novelties; prepared frozen meals; candy; liquid foods such as soups; spreads; sauces; salad dressings; prepared meat products; cheese; yogurt and any other food containing fat or oil; and food ingredients.

[0041] As used herein, the term "consisting essentially of" (and grammatical variations thereof), when applied to the compositions and methods of the present invention, means that the composition / method may contain additional components, so long as the additional components do not substantially alter the composition / method. The term "substantially alters," when applied to the compositions / methods of the present invention, means that the effectiveness of the composition / method is increased or decreased by at least about 20% or more. For example, a component added to a composition of the present invention would "substantially alter" the composition if the component increased or decreased the composition's ability to inhibit tumor growth by at least 20%.

[0042] As used herein, "pharmaceutically acceptable" means that the material is suitable for administration to a subject and will allow the desired treatment to proceed without undue deleterious adverse effects. In determining whether any particular side effect is unduly deleterious, the severity of the disease and the necessity of the treatment will generally be considered.

[0043] As used herein, the term "purified" or "isolated" refers to a compound after separation from a synthetic process (e.g., from a reaction mixture) or from a natural source, or some combination thereof. Thus, the term "purified" or its alternatives (including "in purified form" or "in isolated and purified form") refers to the physical state of a compound after being obtained by one or more purification methods (e.g., chromatography, recrystallization, etc.) as described herein or well known to those skilled in the art, with a purity sufficient to be characterized by standard analytical techniques described herein or well known to those skilled in the art. The purification techniques disclosed herein produce isolated and purified forms of the subject metabolites. It is expected that such separation and purification techniques will result in a product purity of 95 wt% or higher, including enantiomers of the same molecule.

[0044] As used herein, the terms "prevent," "preventing," and "prevention" (and grammatical variations thereof) refer to avoiding, preventing, and / or delaying the onset of, and / or reducing the severity of, one or more diseases, disorders, and / or clinical symptoms in a subject relative to what would occur in the absence of the compositions and / or methods of the present invention. In some embodiments, prevention is complete, resulting in the complete absence of one or more diseases, disorders, and / or clinical symptoms. In some embodiments, prevention is partial, resulting in a reduction in severity and / or a delay in the onset of one or more diseases, disorders, and / or clinical symptoms.

[0045] As used herein, the term "prophylactically effective amount" (and grammatical variations thereof) refers to an amount sufficient to prevent and / or delay the onset of one or more diseases, disorders, and / or clinical symptoms in a subject, and / or reduce the severity of the onset of one or more diseases, disorders, and / or clinical symptoms in a subject, and / or delay the onset of one or more diseases, disorders, and / or clinical symptoms in a subject, relative to what would occur in the absence of the methods of the present invention. It will be understood by those skilled in the art that the level of prevention need not be complete, as long as some benefit is provided to the subject.

[0046] As used herein, the term "subject" (and grammatical variants thereof) refers to mammals, birds, reptiles, amphibians, or fish. Mammalian subjects may include, but are not limited to, humans, non-human primates (e.g., monkeys, chimpanzees, baboons, etc.), dogs, cats, mice, hamsters, rats, horses, cattle, pigs, rabbits, sheep, and goats. Avian subjects may include, but are not limited to, chickens, turkeys, ducks, geese, quail, and pheasants, as well as birds raised as pets (e.g., parakeets, parrots, macaws, cockatoos, etc.). In a specific embodiment, the subject is from endangered species. In a specific embodiment, the subject is a laboratory animal. Human subjects may include neonates, infants, teenagers, adults, and elderly subjects. In a specific embodiment, the subject is male. In a specific embodiment, the subject is female.

[0047] As used herein, the term "therapeutically effective" means providing some improvement or benefit to the subject. Alternatively stated, a "therapeutically effective amount" is an amount that will provide some relief, alleviation, or reduction in at least one clinical symptom of the subject (e.g., in the case of cancer, reduction in tumor size, reduction in the incidence of metastasis, etc.). One skilled in the art will understand that the therapeutic effect need not be complete or curative, as long as some benefit is provided to the subject.

[0048] As used herein, the terms "therapeutically effective amount" and "therapeutically acceptable amount" (and grammatical variations thereof) refer to an amount that will elicit a therapeutically useful response in a subject. A therapeutically useful response can provide some relief, alleviation, or reduction in at least one clinical symptom of the subject. The terms also include an amount that will prevent or delay at least one clinical symptom of the subject and / or reduce the severity of the occurrence of a clinical symptom of the subject and / or delay the onset of a clinical symptom of the subject relative to what would occur in the absence of the methods of the present invention. It will be understood by those skilled in the art that a therapeutically useful response need not be complete or curative or permanently preventive, as long as some benefit is provided to the subject.

[0049] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of a disease or disorder, inhibiting the progression of a disease or disorder, or preventing a disease or disorder. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other predisposing factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0050] As used herein, the term "therapeutically effective amount" (and grammatical variations thereof) refers to an amount sufficient to provide some improvement or benefit to a subject. Stated alternatively, a "therapeutically effective amount" is an amount that will provide some relief, alleviation, reduction, or stabilization of at least one clinical symptom of a subject. One skilled in the art will understand that the therapeutic effect need not be complete or curative, as long as some benefit is provided to the subject.

[0051] In one aspect of the invention, the compositions disclosed herein are "nutritional compositions" that help control the symptoms of a disease; alleviate undesirable side effects of an underlying disease or a therapy for such an underlying disease; prevent future disease, or help treat a disease. In some embodiments, the nutritional composition is administered concurrently with the drug treatment; in other embodiments, the nutritional composition is administered before or after the drug treatment. When the nutritional composition is administered before or after the drug treatment, such administration occurs hours, days, or months before the drug treatment. In some embodiments, the nutritional composition is administered after one or more symptoms have appeared. In other embodiments, the nutritional composition can be administered in the absence of symptoms. For example, the nutritional composition is administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Administration of the nutritional composition can also be continued after the symptoms have subsided, for example to prevent or delay their recurrence.

[0052] II. Composition

[0053] The compositions provided herein comprise three components consisting of: 1) one or two NAD precursors (NMN and NR) and / or NAD molecules (NAD+ and / or NADH); 2) D-ribose and / or creatine; 3) with or without additional ingredients consisting of NAM, NA and / or other ingredients. In one embodiment, the disclosed composition comprises a combination of NAD precursors and D-ribose, which provides cellular support and can be used to produce NMN together with endogenous nicotinamide (NAM) or exogenously supplied NAM. The disclosed composition may also include creatine monohydrate, which is important for muscle mass and function and other cellular functions. The disclosed composition may also use NAD molecules together with NAD precursors (NMN and / or NR), or use them in place of NAD precursors together with D-ribose and / or creatine monohydrate. The disclosed composition may also include NAM and / or niacin, which have important cellular functions and make NAD production more efficient. The disclosed composition works synergistically to promote endogenous production of NAD and promote mitochondrial and cellular function.

[0054] A. NAD precursors

[0055] Provided herein are compositions comprising an effective amount of an NAD precursor to increase NAD levels in vivo. In one embodiment, the NAD precursor can be nicotinamide mononucleotide (NMN) and / or nicotinamide riboside (NR). In a preferred embodiment, the NAD precursor is NMN, which is a one-step precursor used by cells to make NAD.

[0056] In certain embodiments, the compositions provided herein may contain between about 30% and about 70% (w / w) of NAD precursor NMN or NR. In some embodiments, the composition may contain between about 30% and 40%, 30% and 50%, 30% and 60%, or 30% and 70% NMN or NR. In other embodiments, the composition may contain between about 40% and 50%, 40% and 60%, or 40% and 70% NMN or NR. In further embodiments, the composition may contain between about 50% and 60%, or 50% and 70% NMN or NR. In some embodiments, the composition may contain between about 60% and about 70% NMN or NR.

[0057] In some embodiments, the compositions provided herein may contain between about 30% and about 70% of a combination of NAD precursors NMN and NR. In some embodiments, the composition may contain between about 30% and 40%, 30% and 50%, 30% and 60%, or 30% and 70% NMN and NR. In other embodiments, the composition may contain between about 40% and 50%, 40% and 60%, or 40% and 70% NMN and NR. In further embodiments, the composition may contain between about 50% and 60%, or 50% and 70% NMN and NR. In some embodiments, the composition may contain between about 60% and about 70% NMN and NR.

[0058] i. Nicotinamide mononucleotide (NMN)

[0059] NMN is the first and most efficient precursor to NAD. NMN can be converted to NAD by the enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT). In cells, NMN is primarily synthesized from phosphoribosyl pyrophosphate (PRPP) and nicotinamide by the enzyme nicotinamide phosphoribosyltransferase (NAMPT). NMN can also be made from nicotinamide ribonucleoside (NR) by the enzyme nicotinamide ribonucleoside kinase (NRK). NMN, NR, and NAD can all be degraded, resulting in the production of nicotinamide (NAM), which can be converted back to NAD via the NAD salvage pathway.

[0060] Therefore, diseases, disorders, and conditions that are affected by increased NAD levels are also affected by the amount of NMN precursors available for NAD biosynthesis and can therefore be treated by administering the NMN compounds and compositions disclosed herein.

[0061] NMN acts through the nicotinamide mononucleotide adenylyltransferase (NMNAT) pathway or other pathways of NAD+ biosynthesis, and has nutritional and / or therapeutic value in improving plasma lipid profiles, preventing stroke, and / or extending lifespan and health. Other embodiments relate to methods for preventing or treating diseases or conditions associated with the nicotinamide mononucleotide adenylyltransferase (NMNAT) pathway or other pathways of NAD+ biosynthesis by administering a composition comprising NMN. Diseases or conditions that typically have altered levels of NAD or its precursors that can be prevented or treated by supplementing NMN and / or NAD in a diet or treatment regimen include, but are not limited to, lipid disorders (e.g., dyslipidemia, hypercholesterolemia, or hyperlipidemia), stroke, type I and type II diabetes, cardiovascular disease, and other physical problems associated with obesity.

[0062] ii. Nicotinamide riboside (NR)

[0063] Nicotinamide riboside can be used as a precursor to synthesize NMN via nicotinamide riboside kinase (NRK), and is therefore a two-step precursor to NAD.

[0064] NR is found in certain natural products, such as milk, and can also be synthesized in the laboratory. NR has been used as a dietary supplement to increase NAD levels in animals and humans, thereby improving certain physiological and bodily functions.

[0065] B. Ribose

[0066] Ribose exists as L and D enantiomers. The L-ribose enantiomer is unstable, so D-ribose is the primary functional isoform of ribose. D-ribose is highly water-soluble and is found in various RNA molecules and adenosine triphosphate (ATP). D-ribose is also present in the NAD molecule and its metabolites, including NMN and NR. Therefore, D-ribose is an essential component for the production of NAD precursors and NAD.

[0067] A combination of D-ribose and nicotinamide has been used as a supplement to increase NAD levels. However, the supplement only slightly increases NAD levels and not in all individuals.

[0068] D-ribose itself may also have an important physiological function in certain diseases and health conditions such as congestive heart failure (CHF). D-ribose can be supplemented intravenously or orally and has been used by patients and athletes to supplement energy through ATP synthesis.

[0069] In certain embodiments, the compositions provided herein can include D-ribose between about 5% and about 40%. In some embodiments, the compositions can include D-ribose between about 5% and 10%, 5% and 20%, or 5% and 40%. In other embodiments, the compositions can include D-ribose between about 10% and 20%, or 10% and 30%. In additional embodiments, the compositions can include D-ribose between about 20% and 30%.

[0070] C. Creatine Monohydrate

[0071] Creatine is a natural energy source for muscle contraction. Approximately 50% of the body's creatine supply comes from a carnivorous diet, including red meat, dairy, and seafood. The other half is produced in the liver and kidneys and then delivered to skeletal muscle, where 95% of creatine is stored and used for physical activity. Small amounts of creatine are also located in the heart, brain, and other tissues.

[0072] In certain embodiments, the compositions provided herein may comprise between about 10% and about 50% creatine. In some embodiments, the compositions may comprise between about 10% and 20%, 10% and 30%, 10% and 40%, or 10% and 50% creatine. In other embodiments, the compositions may comprise between about 20% and 30%, 20% and 40%, or 20% and 50% creatine. In yet other embodiments, the compositions may comprise between about 30% and 40%, or 30% and 50% creatine. In additional embodiments, the compositions may comprise between about 40% and 50% creatine.

[0073] The most common form of creatine is creatine monohydrate. It is used as a dietary supplement to improve athletic performance, aid recovery after intense exercise, prevent or reduce the severity of injuries, and help athletes tolerate heavy training loads. Multiple studies have shown that users experience consistently lower rates of cramps, muscle tightness, muscle strains / pulses, non-contact injuries, systemic injuries, and dehydration compared to those who do not take creatine.

[0074] Additionally, creatine supplementation may be helpful for patients with diabetes, cardiac ischemia, osteoarthritis, fibromyalgia, disorders of creatine metabolism or transport, aging, brain health, and neurodegenerative diseases including muscular dystrophy, Parkinson's disease, and Huntington's disease.

[0075] D. Niacinamide (NAM)

[0076] Nicotinamide (NAM, also known as niacinamide) is a form of vitamin B3. It is water-soluble. Nicotinamide and its related molecule, niacin (NA), are also known as niacin. NAM is found in foods rich in niacin, such as fish, poultry, nuts, beans, eggs, and grains. Nicotinamide is widely used as a supplement.

[0077] NAM is also used to treat niacin deficiency (such as pellagra) and skin conditions (such as acne and rosacea). Niacinamide helps prevent the development of skin cancer and reduces the risk of melanoma.

[0078] NAM is an important building block of NAD and its precursors NMN and NR. It is used in combination with D-ribose to increase NAD levels in the body and achieve moderate results.

[0079] In certain embodiments, the compositions provided herein may include NAM between 0.1% and about 30%. In some embodiments, the compositions may include NAM between about 0.1% and 5%, 0.1% and 10%, 0.1% and 15%, 0.1% and 20%, or 0.1% and 30%. In other embodiments, the compositions may include NAM between about 5% and 10%, 5% and 15%, or 5% and 30%. In yet other embodiments, the compositions may include NAM between about 10% and 20%, or 10% and 30%. In additional embodiments, the compositions may include NAM between about 15% and 30%. In certain embodiments, the compositions may include NAM between 0% and about 30%, indicating that in some embodiments, the compositions may not contain NAM.

[0080] E. Niacin (NA)

[0081] Niacin (NA), commonly known as nicotinic acid, is a water-soluble vitamin B3. Although both NA and NAM are referred to by many as niacin, they are not interchangeable and have very different functions and risks. NA supplements are widely available.

[0082] NA is used to prevent and treat niacin deficiency disorders such as pellagra. It is also available as a supplement and an FDA-approved medication to lower LDL and raise HDL.

[0083] NA can be converted into either nicotinamide or NAD, making it another NAD building block. Both processes require three distinct steps to convert NA into NAD. NA is generally not a very effective component in raising NAD levels, and levels vary widely between people.

[0084] In certain embodiments, the compositions provided herein may comprise between 0.1% and about 20% NA. In some embodiments, the composition may comprise between about 0.1% and 5%, 0.1% and 10%, or 0.1% and 15% niacinamide. In other embodiments, the composition may comprise between about 5% and 10%, 5% and 15%, or 5% and 20% NA. In yet other embodiments, the composition may comprise between about 10% and 20% NA. In certain embodiments, the composition may comprise between 0% and about 20%, indicating that in some embodiments, the composition may not contain NA.

[0085] III. Method of Administration

[0086] In some in vivo methods, the compositions disclosed herein are administered to a subject in a therapeutically effective amount. As used herein, the term "effective amount" or "therapeutically effective amount" means a dose sufficient to treat, inhibit or alleviate one or more symptoms of the disease being treated or otherwise provide the desired pharmacological and / or physiological effect. The exact dose will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, disease, etc.).

[0087] In this regard, the selected dosage depends on the desired therapeutic effect, the route of administration, and the desired duration of treatment. However, for the disclosed compositions, a typical dosage level is about 2000 mg of formulation or 1000 mg of NMN. However, the desired dosage may be as low as 250 mg of NMN per day and as high as 2000 mg of NMN. The desired dosage of NR is similar to that of NMN.

[0088] In some embodiments, the disclosed compositions are formulated for enteral administration, including oral, sublingual, cream and rectal delivery, subcutaneous injection, intravenous infusion, preferably oral. In one embodiment, the disclosed compositions are administered in a solid dosage form. Suitable solid dosage forms include tablets, capsules, pills, lozenges, cachets, pellets, powders or granules, or by incorporating the substance into water, juice or other beverages.

[0089] A. Formulations for Oral Administration

[0090] In some embodiments, the composition is formulated for oral delivery. Oral solid dosage forms are generally described in Remington's Pharmaceutical Sciences, 18th edition 1990 (Mack Publishing Co. Easton Pa. 18042), Chapter 89. Solid dosage forms include tablets, capsules, pills, lozenges or pastilles, cachets, pills, powders or granules, or the substance is incorporated into a granular formulation of a polymer compound (such as polylactic acid, polyglycolic acid, etc.) or into a liposome. Such compositions may affect the disclosed physical state, stability, in vivo release rate, and in vivo clearance rate. See, for example, Remington's Pharmaceutical Sciences, 18th edition (1990, Mack Publishing Co., Easton, Pa. 18042), pages 1435-1712, which are incorporated herein by reference. The composition can be prepared into a liquid form, or can be in the form of a dry powder (e.g., lyophilized powder). Liposomes or protein-like encapsulation can be used to prepare the composition. Liposome encapsulation can be used and liposomes can be derivatized with various polymers (e.g., U.S. Pat. No. 5,013,556). See also Marshall, K., Modern Pharmaceutics, ed. by G.S. Banker and C.T. Rhodes, Chapter 10, 1979. Generally, the formulation will include the peptide (or a chemically modified form thereof) and an inert ingredient that protects the peptide in the gastric environment and releases the biologically active substance in the intestine.

[0091] Another embodiment provides liquid dosage forms for oral administration, including pharmaceutically acceptable emulsions, solutions, suspensions, and syrups, which may contain other components including inert diluents; adjuvants such as wetting agents, emulsifying agents, and suspending agents; and sweetening, flavoring, and perfuming agents.

[0092] Controlled-release oral formulations may be ideal. The agent can be incorporated into an inert matrix (e.g., a gum) that allows release by diffusion or leaching mechanisms. Slowly degradable matrices can also be incorporated into the formulation. Another form of controlled-release is based on the Oros Therapeutic System (Alza Corp.), which encapsulates the drug in a semipermeable membrane that allows water to enter and, due to osmosis, pushes the agent out through a single small opening.

[0093] For oral formulations, the release site can be the stomach, small intestine (duodenum, jejunum or ileum) or large intestine. In some embodiments, the release will avoid the harmful effects of the gastric environment, by protecting the medicament (or derivative) or by releasing the medicament (or derivative) outside the gastric environment (as in the intestinal tract). In order to ensure complete gastric fluid tolerance, it is crucial to coat impermeable to at least pH 5.0. Examples of the more common inert ingredients used as enteric coatings are: cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D TM 、Aquateric TM , Cellulose acetate phthalate (CAP), Eudragit L TM 、Eudragit S TM and Shellac TM These coatings can be used as hybrid films.

[0094] Example

[0095] The disclosed compositions can be used, for example, to increase NAD levels, improve health, increase energy, enhance physical, physiological, sexual and / or mental performance, reduce inflammation, increase insulin sensitivity, improve sleep, enhance immunity, and reduce the likelihood of age-related diseases.

[0096] Example 1: 58-year-old male user

[0097] This individual is generally healthy and physically active with a mild form of asthma that requires occasional treatment, joint and back pain from playing tennis, and very severe sciatica pain. He started taking 1000 mg of the formulation daily, quickly increased to 2000 mg of the powder, and has remained on the formulation for 18 months to date.

[0098] His intracellular NAD level steadily increased to and remained at around 60 μM ( Figure 1 After taking the supplement for about three months, the joint and back pain, as well as the sciatica pain, completely disappeared. His tennis level returned to what it was when he was in his mid-40s. He recovers much faster from tennis and has much more energy and sleep has improved. He no longer requires any asthma medication. His biological age, as determined by telomere length and methylation, is now much younger than his chronological age (7-9 years). His chronic inflammation (hs-CRP), oxidative stress (reactive oxygen metabolites), and cellular senescence burden have all been greatly reduced.

[0099] Example 2: 68-year-old female user

[0100] The individual was generally healthy and physically active. She started taking the 2000 mg formulation and after six weeks the dose was reduced to 1000 mg.

[0101] After four weeks of supplementation, her intracellular NAD levels increased dramatically from approximately 20 μM to over 115 μM, and then dropped to 60-75 μM after reducing her dose to 1000 mg of powder ( Figure 2A ). Her energy levels, sleep, and mental clarity improved significantly, and she grew new hair. Coincident with the increase in her icNAD, her aging-related beta-galactosidase activity also decreased ( Figure 2B ), indicating that her aging burden has been reduced, which has good benefits for her health.

[0102] Example 3: 43-year-old male user

[0103] The individual was generally healthy and not very physically active. He began taking the formulation at a dose of 2000 mg of powder for four weeks. He stopped the supplement three days before the final laboratory test because he ran out of product.

[0104] His intracellular NAD levels rapidly increased to 84.9 μM two weeks after supplementation and decreased to 66.5 μM at the four-week time point, three days after stopping supplementation (Figure 3). He reported more energy and better sleep. His triglyceride levels also decreased significantly (Figure 3).

[0105] Example 4: 37-year-old male user

[0106] The individual was in good health but had some liver issues. His NAD levels were measured before supplementation and after two and four weeks of supplementation.

[0107] His baseline NAD level was 28.7 μM, and after two weeks of taking 2000 mg of the formulation daily his NAD level increased to 72.1 μM, and after four weeks further increased to 76.7 μM ( Figure 4 Meanwhile, his liver enzyme ALT decreased from 63 to 45 two weeks after supplementation and to 42 four weeks after supplementation ( Figure 4 ). He reports having more energy and sleeping better after taking the supplement.

[0108] Example 5: 32-year-old female user

[0109] The individual was in good health but had poor sleep. Her NAD levels were measured before and after four weeks of supplementation.

[0110] Her baseline NAD levels at two different time points were 21.8 μM and 24.4 μM, respectively. Her NAD levels increased to 45 μM after two weeks of supplementation with 2000 mg of the formulation daily, and to 46.7 μM ( Figure 5 Her sleep improved, and she had more energy. As her NAD levels went up, her liver enzyme ALT also went down ( Figure 4 ).

[0111] Example 6: Comparison of Vitality Boost Performance.

[0112] In an experiment comparing the performance of Vitality Boost to pure NMN, intracellular NAD levels were measured at baseline in 14 subjects who took a pure NMN product and then switched to Vitality Boost for four weeks. Figure 7 Vitality Boost (NMN, creatine, D-ribose, and niacinamide) was shown to elevate NAD much more significantly than pure NMN. Figure 8 Intravenous infusions of NAD+ (750 mg, five times) did not increase intracellular NAD levels. In contrast, oral supplementation with 2000 mg of Vitality Boost for four weeks improved NAD levels in seven of eight subjects, with NAD levels also significantly increasing in one other individual. Figure 9 Vitality Boost optimizes all 5 SubQ NADs + The NAD levels of users were slightly higher on average than those who had never received NAD treatment.

[0113] Example 7: 50-year-old male user

[0114] The individual was a very active professional athlete in good health. He was tired and often took naps in the afternoon. His NAD levels were measured before and after four weeks of supplementation.

[0115] His baseline NAD level was 18.4 μM, and after taking 2000 mg of the daily formulation, his NAD level increased to 55.5 μM. He reports that after optimizing his NAD with the supplement, he has much more energy and does not need to take naps in the afternoon.

[0116] Example 8: Increased mean NAD levels

[0117] Figure 6A summary of changes in NAD levels in a group of 25 individuals whose NAD levels were measured at two different baseline time points, two weeks after supplementation, and four weeks after supplementation is presented. Each individual supplemented with 2000 mg of powder for at least four weeks. The mean NAD level was 27.5 μM at the first baseline time point without supplementation and 27.9 μM at the second baseline time point ( Figure 6 Two weeks after supplementation, average NAD levels increased to 55.5 μM, an average increase of approximately 100%. Four weeks after supplementation, average NAD levels increased further to 59.5 μM.

[0118] Example 9: 39-year-old woman using NR formulation

[0119] This 39-year-old female individual was in good health. Her NAD level at baseline was 20.9 μM, and after taking 2000 mg of a NR formulation consisting of NR, creatine monohydrate, D-ribose, and niacinamide, her NAD level increased to 51.7 μM. She reported having much more energy, clearer thinking, and improved overall performance.

[0120] Example 10: 55-year-old woman using NR formulation

[0121] The 58-year-old female individual was in good health. Her NAD level at baseline was 31.9.4 μM, and after taking 2000 mg of the NR formulation, her NAD level increased to 58.5 μM. Her abnormal liver enzyme ALT decreased from 30 to 18, and her triglycerides also decreased.

[0122] Example 11: 28-year-old female using NR formulation

[0123] This 28-year-old female individual had multiple health issues. Her NAD level at baseline was 33.5 μM, and after taking 2000 mg of the NR formulation, her NAD level increased to 43.6 μM. Her liver enzyme ALT decreased from a high of 73 to 34, a significant improvement.

[0124] Example 12: 56-year-old male using NR formulation

[0125] This 56-year-old female individual had multiple health issues, including type 2 diabetes and hypertension. Her NAD level at baseline was 42.1 μM, and after taking 2000 mg of the NR formulation, her NAD level increased to 50.76 μM. Her liver enzyme ALT decreased from 64 to 53, a significant improvement. Her triglycerides decreased from 430 to 328.

[0126] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention belongs.Publications cited herein and the materials in which they are cited are specifically incorporated by reference.

[0127] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A composition for increasing nicotinamide adenine dinucleotide (NAD) levels in a subject in need thereof, the composition comprising an effective amount of an NAD precursor, an NAD compound, or a combination thereof.

2. The composition of claim 1, wherein the NAD precursor is selected from nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), or a combination thereof.

3. The composition of claim 1, wherein the NAD precursor comprises 30%-70% of the composition.

4. The composition of claim 1, wherein the NAD precursor comprises 50% of the composition.

5. The composition of claim 1, wherein the NAD compound is selected from NAD+ or NADH or a combination thereof.

6. The composition of claim 1, further comprising D-ribose or creatine monohydrate.

7. The composition of claim 6, wherein the D-ribose comprises 5% to 40% of the composition.

8. The composition of claim 6, wherein the creatine monohydrate comprises 10% to 50% of the composition.

9. The composition of claim 1, further comprising NAM or NA or a combination thereof.

10. The composition of claim 9, wherein the NAM comprises 0.1% to 30% of the composition.

11. The composition of claim 9, wherein NA comprises 0.1% to 20% of the composition.

12. The composition of claim 6, wherein the combination of D-ribose or creatine monohydrate and the NAD precursor promotes NAD production and supports cellular function.

13. A method of increasing nicotinamide adenine dinucleotide (NAD) levels in a subject in need thereof, the method comprising administering an effective amount of the composition of claim 1 to optimize NAD and improve health conditions affected by NAD levels.

14. The method of claim 13, wherein the subject has suboptimal or insufficient NAD levels.

15. The method of claim 14, wherein the suboptimal or insufficient NAD levels are associated with diseases and conditions caused by or associated with low NAD levels.

16. The method of claim 15, wherein the diseases and conditions caused by or associated with low NAD levels are selected from the group consisting of: addiction; neurological diseases such as dementia; infectious diseases, including Lyme disease and COVID-19, long COVID; lipid disorders (e.g., dyslipidemia, hypercholesterolemia, or hyperlipidemia); stroke; type I and type II diabetes; cardiovascular disease; kidney disease; liver disease; chronic fatigue syndrome; lung disease; autoimmune disease; obesity; infertility; coma; and other physical, physiological, sexual, or psychiatric problems.

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