Nadp+-precursor as antiaging supplement

Abstract

The invention pertains to an oral anti-ageing formulation comprising the active ingredients Niacinamide mononucleotide (NMN), Hydroxycobalamin or Adenosylcobalamin, 5-MTHF, Methionine, and Vitamin B6. Further, a method of promoting overall health and mitigating aging effects in a subject, where the subject may have MTHFR, MTR, MTRR, AHCY, and / or COMT gene mutations, is disclosed. Also, a food product or dietary supplement comprising the composition.

Description

[0001] ANTIAGING SUPPLEMENT

[0002] Field of the Invention

[0003] This invention pertains in general to the field of antiaging supplements. More particularly the invention relates to a supplement comprising an NAD+precursor, such as Nicotinamide Mononucleotide (NMN), and that addresses the complexities of methylation issues and supports cellular integrity. Furthermore, the supplement comprises a combination of supplements especially beneficial for individuals with MTHFR, MTR, MTRR, AHCY, and COMT gene mutations.

[0004] Background of the Invention

[0005] Aging is a complex and multifactorial process characterized by various interconnected biological mechanisms, including oxidative stress, chronic inflammation, and cellular senescence. These processes contribute to the gradual decline in physiological function, leading to age-related diseases and the general deterioration of health. Each of these mechanisms plays a critical role in the aging process, and their interdependence makes it difficult to develop a single therapeutic intervention capable of targeting all of them simultaneously. Oxidative stress damages cells and tissues, inflammation accelerates tissue degradation, and cellular senescence leads to the accumulation of non-functional cells, all of which contribute to the aging process.

[0006] Consequently, addressing these diverse and interconnected mechanisms with a single drug or supplement remains an unresolved challenge.

[0007] Another significant limitation in the field of longevity research is the lack of comprehensive long-term studies. Although a variety of longevity drugs and supplements have been proposed, few have undergone rigorous testing over extended periods, making it difficult to evaluate their long-term safety and efficacy in humans. The aging process itself spans decades, and current clinical studies are often too short to provide conclusive evidence on the potential benefits or risks of such interventions. Without robust longitudinal data, it remains challenging to determine whether these therapies genuinely promote healthy aging or merely offer short-term benefits.

[0008] In addition to the biological complexity and limited long-term data, individual variability presents a further challenge in developing effective longevity treatments. Genetic differences, lifestyle factors, and pre-existing health conditions cause individuals to respond differently to the same drug or supplement. This variability complicates efforts to develop universally effective therapies, as a treatment that proves beneficial for one person may be ineffective or even harmful for another. The diversity of individual responses underscores the need for personalized approaches to longevity interventions, further complicating the development of one-size-fits-all solutions.

[0009] Given the multifaceted nature of aging and the challenges inherent in developing treatments that address all underlying mechanisms, there is a clear need for novel strategies aimed at promoting healthy aging and longevity. Such strategies must not only target the broad spectrum of biological processes involved in aging but also account for the variability in individual responses. Moreover, these interventions must be designed with long-term safety and efficacy in mind, given their intended use over extended periods. The development of new drugs or supplements that can meet these criteria is essential for advancing the field of healthy aging and addressing the limitations of current approaches.

[0010] Summary of the Invention

[0011] Accordingly, the present invention preferably seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves at least the above mentioned problems by providing an oral anti-ageing formulation comprising the active ingredients an NAD+precursor, Hydroxycobalamin or Adenosylcobalamin, 5-MTHF, Methionine, and Vitamin B6, wherein the NAD+precursor is selected from nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide (NAM), nicotinic acid (NA), nicotinic acid riboside (NAR), nicotinic acid mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NAAD), reduced nicotinamide riboside (NRH), reduced nicotinamide mononucleotide (NMNH), and nicotinamide adenine dinucleotide (NADH), and pharmaceutically acceptable salts, esters, solvates, hydrates, stereoisomers and functional analogues thereof.

[0012] In one aspect, the the NAD+precursor is Niacinamide mononucleotide (NMN). In one aspect, the composition comprises: NAD+precursor, such as nicotinamide mononucleotide (NMN), in the amount from about 500 mg to 1000 mg, such as 650 mg to 850 mg; Hydroxy cobalamin or Adenosylcobalamin in the amount from about 500 pg to 1000 pg, such as 700 pg to 900 pg; 5-MTHF in the amount from about 500 pg to 1000 pg, such as 700 pg to 900 pg; Methionine in the amount ranges from about 500 mg to 1000 mg, such as 700 mg to 900 mg; and Vitamin B6 (pyridoxine) in the amount from about 15 mg to 55 mg, such as 25 mg to 45 mg.

[0013] In one further aspect, the composition comprises TMG, and Spermidine. In one further aspect, the composition comprises: TMG in the amount from about 250 mg to 750 mg, such as 400 mg to 600 mg; and Spermidine in the amount from about 1 mg to 10 mg, such as 0.8 to 6 mg.

[0014] According to one further aspect, the composition comprises: NAD+precursor, such as nicotinamide mononucleotide (NMN), in the amount of about 750 mg;

[0015] Hydroxycobalamin or Adenosylcobalamin in the amount of about 800 pg; 5-MTHF in the amount of about 800 pg; Methionine in the amount of about 800 mg; Vitamin B6 in the amount of about 35 mg; TMG in the amount of about 500 mg; and Spermidine in the amount of about 1 mg to 10 mg, such as 0.8 to 6 mg.

[0016] In one aspect, the formulation is for use in targeting key areas of cellular health, DNA repair, and methylation processes in a subject having MTHFR (methylenetetrahydrofolate reductase), MTR (methionine synthase), MTRR (methionine synthase reductase), AHCY (adenosylhomocysteinase), and / or COMT (catechol-O-methyltransferase) mutations.

[0017] In one aspect, the formulation is for use in promoting overall health and mitigating aging effects in a subject having MTHFR, MTR, MTRR, AHCY, and / or COMT gene mutations.

[0018] According to one aspect, the formulation further comprises antioxidants, such as ascorbic acid (vitamin C), tocopherols (vitamin E), or polyphenols like resveratrol and quercetin.

[0019] According to one aspect, the formulation further comprises excipients, such as silica, cellulose derivatives, or maltodextrin, for improving stability, solubility, or bioavailability.

[0020] In one further aspect, the formulation is provided in at least any one or more forms include capsules, microcapsules, tablets, wax prills, liquid, liposomal, micelles, phospholipid or topical form, softgels, drinks, powder, medical food, intravenous and an oral composition, preferably in the form of capsules or microcapsules.

[0021] Further is provided a food product or dietary supplement comprising the composition.

[0022] In one aspect is provided a method of promoting overall health and mitigating aging effects in a subject or treating or preventing a disease or condition characterized by problems concerning cellular health, DNA repair, and methylation processes in a subject, comprising administering to the subject a therapeutically effective amount of the composition, or the food product or dietary supplement. In one further aspect, the subject has MTHFR, MTR, MTRR, AHCY, and / or COMT gene mutations.

[0023] Further is provided the formulation for use in the treatment of a disease or condition characterized by problems concerning cellular health, DNA repair, and / or methylation processes in a subject, wherein the subject has one or several of MTHFR, MTR, MTRR, AHCY, and / or COMT gene mutations.

[0024] In one aspect, the ratio of methionine to trimethylglycine (TMG) is from 3 : 2 to 3 : 2.5, preferably 3 : 2, and the formulation maintains a SAM:SAH ratio ( ) of > 5 under NAD+precursor administration.

[0025] In one further aspect, the formulation is for use in a subject having one or more of MTR A2756G, MTRR A66G, or COMT Vall58Met variants, wherein the TMG : NAD+precursor ratio is adjusted to 1 : 2.5-3.0.

[0026] In one further aspect, plasma homocysteine is maintained between 5 and 12 pM under NAD+precursor administration.

[0027] In one further aspect, the SAM:SAH ratio is maintained at > 5 during daily administration of > 500 mg NAD+precursor.

[0028] Description of embodiments

[0029] The following description focuses on an embodiment of the present invention applicable to a supplement with antiaging effect. More particularly, a formulation comprising the active ingredients NAD+precursor (such as Niacinamide mononucleotide (NMN)), Hydroxycobalamin or Adenosylcobalamin, 5-MTHF, Methionine, and Vitamin B6, wherein the NAD+precursor selected from nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide (NAM), nicotinic acid (NA), nicotinic acid riboside (NAR), nicotinic acid mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NAAD), reduced nicotinamide riboside (NRH), reduced nicotinamide mononucleotide (NMNH), and nicotinamide adenine dinucleotide (NADH), and pharmaceutically acceptable salts, esters, solvates, hydrates, stereoisomers and functional analogues thereof.

[0030] In the invention, it was realized that several of the general problems with antiaging supplements can be overcome by providing tailored supplements. For instance, older adults may have specific nutrient deficiencies due to changes in metabolism, absorption, and dietary habits. Individuals with chronic health conditions such as diabetes, cardiovascular disease, or neurodegenerative disorders may benefit from supplements tailored to address their specific needs and mitigate disease progression. Finally, patients have genetic variations, which influence nutrient metabolism and susceptibility to age-related diseases.

[0031] The supplements must promote healthy aging by addressing key biological mechanisms that contribute to the aging process. Healthy aging refers to the maintenance of optimal physiological function and the prevention of age-related diseases, allowing individuals to live longer, healthier lives. The aging process is driven by several interconnected factors, including oxidative stress, chronic inflammation, mitochondrial dysfunction, and cellular senescence. Over time, these processes lead to the gradual decline in tissue function, increased vulnerability to diseases such as cardiovascular disorders, neurodegenerative conditions, and metabolic imbalances, as well as a reduction in overall vitality.

[0032] The formulation of the invention focuses on aspects of the methylation cycle and homocysteine metabolism. The methylation cycle and homocysteine metabolism is targeted based on their crucial roles in maintaining cellular health and function, such as their role in epigenetic regulation, DNA repair and stability, neuroprotection, cardiovascular health and mitochondrial function. Also, dysregulation of the methylation cycle and homocysteine metabolism can lead to increased inflammation and oxidative stress, which are hallmarks of aging and contribute to age-related diseases. Overall, targeting the methylation cycle and homocysteine metabolism for anti-aging interventions offers a multifaceted approach to promoting healthy aging and extending lifespan by addressing key molecular mechanisms underlying aging and age-related diseases.

[0033] By targeting these fundamental drivers of aging, this supplement enhances the body's capacity for self-repair and regeneration, ultimately promoting healthy aging. The formulation is designed not only to slow the visible signs of aging but also to maintain internal physiological resilience, helping individuals preserve their physical and cognitive health as they grow older. This holistic approach to healthy aging makes the supplement particularly beneficial for individuals who are genetically predisposed to accelerated aging or age-related conditions, offering both preventive and restorative benefits.

[0034] Each component in the formulation is strategically selected to address different aspects of the methylation cycle and homocysteine metabolism, ensuring comprehensive support for cellular health and potentially aiding in managing genetic mutations related to methylation. Mechanistic framework of the +5 cofactors: During sustained NAD+upregulation, activation of NAD-dependent enzymes (sirtuins, PARPs) increases cellular demand for methyl groups through enhanced nicotinamide clearance via nicotinamide N-methyltransferase (NNMT). This drains the cellular methyl-donor pool and elevates homocysteine (Hey), reducing the methylation potential, defined as = [S-adenosyl-methionine (SAM)] / [S-adenosyl-homocysteine (SAH)].

[0035] The five auxiliary cofactors act in defined biochemical analogies across the one-carbon and sulfur amino-acid networks to maintain within physiological limits (<D> 5):

[0036] 1. MTR Pathway (5-MTHF + Cobalamin): 5-Methyltetrahydrofolate (5-MTHF) donates a methyl group to homocysteine via the methionine-synthase (MTR) reaction, with cobalamin (hydroxy- or adenosyl-B ) as cofactor. This step regenerates methionine and replenishes SAM. The pair functions as a catalytic recycling module, continuously returning methyl equivalents to the SAM pool.

[0037] 2. BHMT Pathway (Trimethylglycine): Trimethylglycine (betaine) operates in hepatocytes and renal cells as a parallel remethylation route through betainehomocysteine methyltransferase (BHMT). Functionally, the BHMT reaction is analogous to the MTR reaction, but it bypasses folate dependence, directly converting homocysteine — methionine using betaine-derived methyl groups. This redundancy ensures remethylation even under impaired folate cycling (e.g., MTHFR variants).

[0038] 3. Transsulfuration Valve (Pyridoxal-5 '-phosphate): Vitamin Be, in its active form pyridoxal-5 '-phosphate (P5P), serves as an obligate cofactor for cystathionine P-synthase (CBS) and cystathionine y-lyase (CGL). These enzymes channel excess homocysteine away from the remethylation pool into the transsulfuration pathway, forming cysteine and glutathione. This process is analogous to a metabolic safety-valve, preventing accumulation of homocysteine when remethylation capacity is saturated.

[0039] 4. Methionine Supply Loop: Exogenous methionine replenishes the substrate pool for SAM synthesis via methionine adenosyl-transferase (MAT). In functional analogy to TMG, methionine contributes direct methyl equivalents to sustain the SAM cycle under NAD+-driven consumption.

[0040] 5. Polyamine Coupling (Spermidine): Spermidine consumes and regenerates decarboxylated SAM (dcSAM) during polyamine biosynthesis. Through this linkage, it couples methyl-donor utilization to cellular growth and autophagy pathways. The spermidine module is analogous to a dynamic buffer, modulating SAM turnover and preventing uncontrolled methyl depletion. Collectively, these reactions act as an integrated methylation-buffering system. The MTR and BHMT modules restore methionine, the CBS / CGL pathway removes excess Hey, and the polyamine pathway recycles dcSAM — all stabilizing = [SAM] / [SAH] during heightened NAD+flux. Maintaining this ratio preserves DNA and histone methylation, redox balance, and overall epigenetic stability.

[0041] Preferred embodiments include specific ratios and biomarker endpoints to optimize efficacy, particularly in subjects with genetic polymorphisms affecting methylation pathways.

[0042] Table 1: Preferred Component Ratios and Biomarker Targets Component Dose Range Preferred Ratio Biomarker Target < >

[0043]

[0044] 5-MTHF 500-1000 pg 800 pg — —

[0045] B12 (active) 500-1000 pg 800 pg — —

[0046] B6 15-55 mg 35 mg — —

[0047] The methionine : TMG ratio of 3 : 2 is particularly effective in maintaining > 5 under NNMT flux, as higher TMG compensates for BHMT impairment in MTHFR variants. In subjects with MTR A2756G, MTRR A66G, or COMT Vall58Met variants, the TMG : NAD+precursor ratio may be increased to 1 : 2.5-3.0 to sustain methylation homeostasis.

[0048] Subsequent literature has confirmed that NAD-precursor use perturbs one- carbon metabolism, depletes methyl donors, and elevates homocysteine, supporting the mechanistic rationale herein (see Cell Metabolism 2025, PMID 40215896).

[0049] Nicotinamide mononucleotide (NMN) is a nucleotide derived from ribose, nicotinamide, nicotinamide riboside and niacin. In humans, several enzymes use NMN to generate nicotinamide adenine dinucleotide (NADH). NADH is a cofactor for processes inside mitochondria, for sirtuins and PARP, thus NMN has been studied as a neuroprotective and anti-aging agent for the reversal of aging at the cellular level by inhibiting mitochondrial decay in presence of increased levels of NAD+. In Example 1 is summarized how long-term oral administration of NMN in mice enhanced NAD+ levels, improved mitochondrial function. Together with NMN, Vitamin B 12 Variants Hydroxy cobalamin or Adenosylcobalamin, enhances NAD+ synthesis and supports methionine regeneration, pivotal for DNA repair and energy metabolism.

[0050] The composition comprises nicotinamide mononucleotide (NMN) in the amount from about 500 mg to 1000 mg, such as 650 mg to 850 mg and Hydroxycobalamin or Adenosylcobalamin in the amount from about 500 pg to 1000 pg, such as 700 pg to 900 pg, preferably 750 pg.

[0051] Further, the formulation comprises 5-MTHF (activated form of Vitamin B9) with Methionine and Vitamin B6: This trio works collectively in methylation pathways.

[0052] 5-MTHF aids in the methylation process; Methionine serves as a key methyl donor; Vitamin B6 supports the conversion of homocysteine, moderated by Methionine, into cysteine, thus helping to regulate homocysteine levels and contribute to glutathione production.

[0053] The composition comprises 5-MTHF in the amount from about 500 pg to 1000 pg, such as 700 pg to 900 pg, Methionine in the amount ranges from about 500 mg to 1000 mg, such as 700 to 900 mg, preferably 800 mg, and Vitamin B6 (pyridoxine) in the amount from about 15 mg to 55 mg, such as 25 to 45 mg.

[0054] The synergy of the components is pivotal in addressing various aspects of the methylation cycle and homocysteine metabolism. Since the ingredients support and enhance each other’s actions, this creates a more potent overall effect in combating aging.

[0055] The composition may further comprise Trimethylglycine (TMG) and Spermidine.

[0056] These compounds add further layers of synergy. TMG acts as an alternative methyl donor in the methylation process, particularly useful for lowering homocysteine levels. Its presence complements Methionine and 5-MTHF, enhancing overall methylation efficiency and supporting cardiovascular health. As for Spermidine, it is known for its role in autophagy and cellular rejuvenation, which may enhance the benefits related to DNA repair and cellular health.

[0057] The composition may comprise TMG in the amount from about 250 mg to 750 mg, such as 400 mg to 600 mg, preferably 500 mg; and Spermidine in the amount from about 1 mg to 10 mg, such as 0.8 to 6 mg.

[0058] The amounts of each constituent of the formulation is important, since the effect is synergistic. In one specific example, NAD+precursor, such as nicotinamide mononucleotide (NMN), is in the amount of about 750 mg, Hydroxycobalamin or Adenosylcobalamin is in the amount of about 800 jug, 5-MTHF is in the amount of about 800 pg, Methionine is in the amount of about 800 mg, Vitamin B6 is in the amount of about 35 mg, TMG is in the amount of about 500 mg and Spermidine is in the amount of about 1 mg to 10 mg.

[0059] The constituents could also be specified by their ratio, such as NAD+precursor (such as NMN) : Hydroxycobalamin or Adenosylcobalamin : 5-MTHF : Methionine : Vitamin B6 being in the ratio of about 1 : 0.009-0.012 : 0.009-0,012 : 0.9-1.2 : 0.03- 0.07, such as about 1 : 1.07 : 1.07 : 1.07 : 0.047.

[0060] Similarly, NAD+precursor (such as NMN) : Hydroxycobalamin or Adenosylcobalamin : 5-MTHF : Methionine : Vitamin B6 : TMG : Spermidine may be in the ratio of about 1 : 0.009-0.012 : 0.009-0.012 : 0.9-1.2 : 0.03-0.07 : 0.5 - 08 : 0.001 - 0.01, such as about 1 : 1.07 : 1.07 : 1.07 : 0.047 : 0.67 : 0.0013-0.013.

[0061] Preferred quantitative relationships along with the biological rationale is summarized in table 2.

[0062] Table 2. Preferred quantitative relationships

[0063] Ratio to NAD+Example (600 mg

[0064] Component Biological rationale Booster NAD+)

[0065]

[0066] Met 200-400 mg :

[0067] Methionine : TMG 1 : 1 - 1 : 3 excess; strong Hey TMG 600-1200 mg

[0068] reduction.

[0069] NAD+: Total methyl

[0070]

[0071] Covers » 90-140 % methyl 1 : 1.2 - 1 : 2.8 720-1680 mg donors

[0072] donors demand under NAD+flux.

[0073]

[0074] Folate bypass; stabilizes NAD+ : 5-MTHF

[0075] 600 : 0.4 - 1.0 0.4-1 mg remethylation in MTHFR (mg:mg)

[0076] variants.

[0077] NAD+: Active B12

[0078]

[0079] Maintains MTR cycling;

[0080] 600 : 0.5 - 2.0 0.5-2 mg

[0081] (mg:mg) supports methyl recycling.

[0082] Enhances transsulfuration NAD+: P5P (mg:mg) 600 : 25 - 75 25-75 mg

[0083] (CBS / CGL).

[0084]

[0085] Modulates SAM economy NAD+: Spermidine

[0086] 600 : 0.8 - 6 0.8-6 mg and autophagy within (mg:mg)

[0087] EFSA safety limit. These ratios maintain plasma Hey 5-12 pM and SAM:SAH > 5 during NAD-precursor administration, confirming sustained methylation and epigenetic stability relative to precursor-only controls.

[0088] Since the synergistic effect of the formulation depends on the combination of the active constituents, it is important that an individual using the supplement can absorb and assimilate all active ingredients. However, it was found that for individuals with genetic mutations in genes like MTHFR, MTR, MTRR, AHCY, and COMT, these genetic variations impair the body’s ability to methylate (activate) standard forms of B9 and B 12, rendering them ineffective for a significant portion of the population.

[0089] This is made worse by that individuals with mutations in genes such as MTHFR (methylenetetrahydrofolate reductase), MTR (methionine synthase), MTRR (methionine synthase reductase), AHCY (adenosylhomocysteinase), and COMT (catechol-O-methyltransferase) may experience various health challenges due to disruptions in key metabolic pathways.

[0090] MTHFR mutations can impair the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, leading to reduced methylation capacity. This can affect processes such as DNA synthesis, neurotransmitter metabolism, and detoxification. Also, impaired MTHFR function can result in elevated levels of homocysteine, which is associated with an increased risk of cardiovascular disease, neurological disorders, and pregnancy complications. The most common MTHFR mutations are the C677T and A1298C variant. C677T mutation occurs in approximately 10-15% of the Caucasian population, and the A1298C mutation is typically found in around 5-10% of the Caucasian population.

[0091] MTR and MTRR Gene Mutations can disrupt the conversion of homocysteine to methionine, a process essential for the synthesis of S-adenosylmethionine (SAMe), a critical methyl donor in numerous biochemical reactions. Defects in MTR or MTRR can also lead to elevated homocysteine levels, contributing to cardiovascular disease and other health issues.

[0092] AHCY encodes the enzyme adenosylhomocysteinase, which plays a key role in the methylation cycle by catalyzing the breakdown of S-adenosylhomocysteine (SAH). Mutations in AHCY can disrupt this process, leading to dysregulated methylation and impaired cellular function. It may also lead to elevated levels of SAH, which can inhibit methyltransferase enzymes and interfere with methylation reactions, contributing to various health issues. Mutations in COMT can affect the efficiency of catecholamine metabolism (the breakdown of catecholamines such as dopamine, epinephrine, and norepinephrine), leading to altered neurotransmitter levels and neurotransmission. COMT mutations have been associated with neurological and psychological disorders, including Parkinson's disease, schizophrenia, depression, anxiety, and cognitive dysfunction. Variants in the COMT gene are relatively common, and several single nucleotide polymorphisms (SNPs) have been identified. The most studied COMT SNP is rs4680 (Vall58Met), which results in functional differences in COMT enzyme activity.

[0093] Overall, while specific prevalence percentages may vary, mutations in genes related to methylation and homocysteine metabolism, such as MTHFR, MTR, MTRR, AHCY, and COMT, are relatively common in the general population and can contribute to a range of health issues when present in certain combinations or in conjunction with other genetic or environmental factors. However, it is important to note that while these mutations may be relatively common in the general population, not all of them result in significant clinical effects. Many individuals with these mutations may remain asymptomatic or may only experience mild symptoms. Additionally, the impact of these mutations can be influenced by various factors, including genetic background, environmental factors, and lifestyle choices. Therefore, many of the carriers of these mutations get any targeted treatment or supplements. This helps to explain why treatment or supplements targeting disruptions in key metabolic pathways may give varied results, since it may not take individual mutations into account.

[0094] In the invention, it was realized that NMN supplementation for counteracting age-related decline in NAD+ levels, and improving improve metabolic health, has to take disruption of key metabolic pathways by genetic predispositions into account.

[0095] Thus, bioavailable forms of vitamins B9 and B 12, such as hydroxycobalamin and adenosylcobalamin and adenosylcobalamin, for individuals with absorption issues or genetic mutations affecting B12 metabolism. Similar, 5-MTHF, the active form of folate, is more effective than folic acid, especially in individuals with MTHFR mutations. These forms bypass potential metabolic blockages, ensuring effective participation in methylation processes are provided and the synergistic effects described above are also present for this patient group. If other (non-active forms) of B9 or B12 are used, this synergistic effect will not be achieved (since the B9 and B12 forms will not be bio-available for this patient group).

[0096] Thus, the formulation can be used in targeting key areas of cellular health, DNA repair, and methylation processes in a subject having MTHFR (methylenetetrahydrofolate reductase), MTR (methionine synthase), MTRR (methionine synthase reductase), AHCY (adenosylhomocysteinase), and / or COMT (catechol-O-methyltransferase) mutations.

[0097] Similarly, the formulation can be used to promote overall health and mitigating aging effects in a subject having MTHFR, MTR, MTRR, AHCY, and / or COMT gene mutations.

[0098] Thus, the formulation may be used in a method of promoting overall health and mitigating aging effects in a subject or treating or preventing a disease or condition characterized by problems concerning cellular health, DNA repair, and methylation processes in a subject, comprising administering to the subject a therapeutically effective amount of the composition (or a food product or dietary supplement comprising the composition). The subject may have MTHFR, MTR, MTRR, AHCY, and / or COMT gene mutations.

[0099] As such, the formulation may be used as a medicament.

[0100] Thus, the formulation may be for use in the treatment of a disease or condition characterized by problems concerning cellular health, DNA repair, and / or methylation processes in a subject, wherein the subjecthas one or several of MTHFR, MTR, MTRR, AHCY, and / or COMT gene mutations.

[0101] A daily dose of the formulation for a grown (adult) individual thus comprises nicotinamide mononucleotide (NMN) in the amount from about 500 mg to 1000 mg, such as 650 to 850 mg or about 750 mg, Hydroxycobalamin or Adenosylcobalamin in the amount from about 500 pg to 1000 pg, such as 700 pg to 900 pg, such as 800 pg, 5-MTHF in the amount from about 500 pg to 1000 pg, such as 700 pg to 900 pg, such as 800 pg, Methionine in the amount ranges from about 500 mg to 1000 mg, such as 700 to 900 mg, such as 800 mg and Vitamin B6 (pyridoxine) in the amount from about 15 mg to 55 mg, such as 25 to 45 mg, such as 35 mg. It may also comprise TMG in the amount from about 250 mg to 750 mg, such as 400 mg to 600 mg, such as 500 mg and Spermidine in the amount from about 1 mg to 10 mg.

[0102] As described above, during sustained NAD+up-regulation, activation of NAD-dependent enzymes (sirtuins, PARPs) increases cellular demand for methyl groups through enhanced nicotinamide clearance via nicotinamide N-methyltransferase (NNMT). This drains the cellular methyl-donor pool and elevates homocysteine (Hey), reducing the methylation potential, defined as = [S-adenosyl-methionine (SAM)] / [S-adenosyl-homocysteine (SAH)]. The five auxiliary cofactors act in defined biochemical analogies across the one-carbon and sulfur amino-acid networks to maintain within physiological limits ( > 5).

[0103] Thus, in a method, the ratio of methyl-donor components may also be adjusted according to genomic variants in MTHFR, NNMT, or BHMT; for example, in MTHFR 677TT or NNMT rsl941404 carriers, increase the TMG:NAD+ratio to 1 : 2.5-3.0 to maintain > 5.

[0104] NMN is relatively unstable and can degrade rapidly when exposed to light, heat, or moisture. Therefore, supplements containing NMN may require special formulation techniques to enhance stability and preserve its efficacy. Further, antioxidants like ascorbic acid can help stabilize and prevent oxidation the active forms of vitamins B9 and B 12 in the formulation, which are sensitive compounds, especially in environments exposed to air or light.

[0105] Thus, the formulation may further comprise antioxidants, such as ascorbic acid (vitamin C), alpha-lipoic acid, tocopherols (vitamin E), or polyphenols like resveratrol and quercetin to help prevent the oxidation of NMN (or other NAD+precursor).

[0106] Similarly, chelating agents, such as magnesium stearate or calcium phosphate may be used as stabilizers, particularly in capsule forms, by preventing moisture buildup, which can cause the degradation of NMN, 5-MTHF and hydroxy cobalamin.

[0107] Cellulose and other fibers, may be used as fillers and binders, helping to stabilize the active ingredients, for instance by absorbing any residual moisture, extending shelflife. Dicalcium phosphate may also be used (especially in tablets) as a stabilizing agent, which also improves the overall consistency of the formulation without affecting the bioavailability.

[0108] Thus, the formulation may further comprise excipients, such as silica, cellulose derivatives, or maltodextrin to improve stability, solubility, or bioavailability.

[0109] Finally, buffering agents, such as calcium or magnesium salts, may be used to maintain a stable pH and enhance stability for compounds sensitive to pH changes, such as 5-MTHF and active B 12 forms.

[0110] In order for an individual to take a daily dose of the supplement, the formulation is provided a forms suitable for oral ingestion. Such as capsules, microcapsules, tablets, wax prills, liquid, liposomal, micelles, phospholipid or topical form, softgels, drinks, powder, medical food, intravenous and an oral composition, preferably in the form of capsules or microcapsules. It was found that capsulation or microencapsulation enhanced stability and preserved efficacy, especially when stored under proper storage conditions, such as cool and dry environments to maintain the stability of the NMN.

[0111] However, a food product or dietary supplement comprising the composition may also be used.

[0112] Examples

[0113] In the Example below, it is summarized how NMN enhances NAD+ levels, improving mitochondrial function and DNA repair (Example 1). Also, how supplementation supporting methylation processes improves methylation and reducing associated health risks, influence aging and longevity (Example 2).

[0114] Example 1. Nicotinamide Mononucleotide (NMN)

[0115] A. NMN Enhances NAD+ Levels and Mitochondrial Function

[0116] Study. Mills KF, Yoshida S, Stein LR, et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metabolism 2016;24(6):795-806.

[0117] Findings'. This study demonstrated that long-term oral administration of NMN in mice enhanced NAD+ levels, improved mitochondrial function, and ameliorated age-associated physiological decline. The results suggest that NMN can be an effective antiaging intervention by restoring NAD+ levels and improving cellular energy metabolism.

[0118] B. NMN and DNA Repair

[0119] Study. Yoshino J, Baur JA, Imai S-I. NAD+ intermediates: The biology and therapeutic potential of NMN and NR. Cell Metabolism. 2018;27(3):513-528.

[0120] Findings'. This review highlights the role of NMN in boosting NAD+ biosynthesis, which is essential for the activity of sirtuins and PARPs involved in DNA repair and genomic stability. The paper underscores NMN's potential in enhancing DNA repair mechanisms and promoting cellular health.

[0121] Example 2, Methylation Cycle and Epigenetic Aging

[0122] Impact of Methylation on Aging

[0123] Study. Wilson VL, Jones PA. DNA methylation decreases in aging but not in immortal cells. Science. 1983;220(4601): 1055-1057. Findings'. This early study indicates that DNA methylation patterns change with aging, suggesting that interventions supporting methylation processes could influence aging and longevity.

[0124] Although the present invention has been described above with reference to (a) specific embodiment(s), it is not intended to be limited to the specific form set forth herein. Rather, the invention is limited only by the accompanying claims and, other embodiments than the specific above are equally possible within the scope of these appended claims, e.g. different than those described above.

[0125] In the claims, the term "comprises / comprising" does not exclude the presence of other elements or steps. Furthermore, although individually listed, a plurality of means, elements or method steps may be implemented by e.g. a single unit or processor. Additionally, although individual features may be included in different claims, these may possibly advantageously be combined, and the inclusion in different claims does not imply that a combination of features is not feasible and / or advantageous. In addition, singular references do not exclude a plurality. The terms "a", "an", “first”, “second” etc do not preclude a plurality. Reference signs in the claims are provided merely as a clarifying example and shall not be construed as limiting the scope of the claims in any way.

Claims

CLAIMS1. An oral anti-ageing formulation comprising the active ingredients NAD+precursor, Hydroxycobalamin or Adenosylcobalamin, 5-MTHF, Methionine, and Vitamin B6,wherein the NAD+precursor is selected from nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide (NAM), nicotinic acid (NA), nicotinic acid riboside (NAR), nicotinic acid mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NAAD), reduced nicotinamide riboside (NRH), reduced nicotinamide mononucleotide (NMNH), and nicotinamide adenine dinucleotide (NADH), and pharmaceutically acceptable salts, esters, solvates, hydrates, stereoisomers and functional analogues thereof.

2. The formulation of claim 1, wherein the NAD+precursor is Niacinamide mononucleotide (NMN).

3. The formulation of claim 1 or 2, wherein the composition comprises:NAD+precursor, such as nicotinamide mononucleotide (NMN), in the amount from about 500 mg to 1000 mg, such as 650 mg to 850 mg; Hydroxycobalamin or Adenosylcobalamin in the amount from about 500 pg to 1000 pg, such as 700 pg to 900 pg;5-MTHF in the amount from about 500 pg to 1000 pg, such as 700 pg to 900 pg;Methionine in the amount ranges from about 500 mg to 1000 mg, such as 700 mg to 900 mg; andVitamin B6 (pyridoxine) in the amount from about 15 mg to 55 mg, such as 25 mg to 45 mg.

4. The formulation according to any one of claims 1 to 3, wherein the composition further comprises TMG, and Spermidine.

5. The formulation according to any one of claims 1 to 4, wherein the composition comprises:TMG in the amount from about 250 mg to 750 mg, such as 400 mg to 600 mg; and Spermidine in the amount from about 1 mg to 10 mg, such as 0.8.

6. The formulation according to any one of claims 1 to 5, wherein the composition comprises:NAD+precursor, such as nicotinamide mononucleotide (NMN), in the amount of about 750 mg; Hydroxycobalamin or Adenosylcobalamin in the amount of about 800 pg; 5-MTHF in the amount of about 800 pg; Methionine in the amount of about 800 mg; Vitamin B6 in the amount of about 35 mg; TMG in the amount of about 500 mg; and Spermidine in the amount of about 1 mg to 10 mg, such as 0.8 to 6 mg.

7. The formulation according to any one of claims 1 to 6, for use in targeting key areas of cellular health, DNA repair, and methylation processes in a subject having MTHFR (methylenetetrahydrofolate reductase), MTR (methionine synthase), MTRR (methionine synthase reductase), AHCY (adenosylhomocysteinase), and / or COMT (catechol- O-methyltransferase) mutations.

8. The formulation according to any one of claims 1 to 7, for use in promoting overall health and mitigating aging effects in a subject having MTHFR, MTR, MTRR, AHCY, and / or COMT gene mutations.

9. The formulation according to any one of claims 1 to 8, further comprising antioxidants, such as ascorbic acid (vitamin C), Alpha-Lipoic Acid, tocopherols (vitamin E), or polyphenols like resveratrol and quercetin.

10. The formulation according to any one of claims 1 to 9, further comprising excipients, such as silica, cellulose derivatives, or maltodextrin, for improving stability, solubility, or bioavailability.

11. The formulation according to any one of claims 1 to 10, wherein the formulation is provided in at least any one or more forms include capsules, microcapsules, tablets, wax prills, liquid, liposomal, micelles,phospholipid or topical form, softgels, drinks, powder, medical food, intravenous and an oral composition, preferably in the form of capsules or microcapsules.

12. A food product or dietary supplement comprising the composition of any one of claims 1 to 11.

13. A method of promoting overall health and mitigating aging effects in a subject or treating or preventing a disease or condition characterized by problems concerning cellular health, DNA repair, and methylation processes in a subject, comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1-11, or the food product or dietary supplement of claim 12.

14. The method of claim 13, wherein the subject has MTHFR, MTR, MTRR, AHCY, and / or COMT gene mutations.

15. The formulation according to any one of claims 1 to 11, for use in the treatment of a disease or condition characterized by problems concerning cellular health, DNA repair, and / or methylation processes in a subject, wherein the subject has one or several of MTHFR, MTR, MTRR, AHCY, and / or COMT gene mutations.

16. The formulation according to any one of claims 1 to 11, wherein the ratio of methionine to trimethylglycine (TMG) is from 3 : 2 to 3 : 2.5, preferably 3 : 2, and the formulation maintains a SAM:SAH ratio (<b) of > 5 under NAD+precursor administration.

17. The formulation according to any one of claims 1 to 11, for use in a subject having one or more of MTR A2756G, MTRR A66G, or COMT Vall58Met variants, wherein the TMG : NAD+precursor ratio is adjusted to 1 : 2.5-3.0.

18. The formulation according to any one of claims 1 to 11, wherein plasma homocysteine is maintained between 5 and 12 pM under NAD+precursor administration.

19. The formulation according to any one of claims 1 to 11, wherein the SAM:SAH ratio is maintained at > 5 during daily administration of > 500 mg NAD+precursor.

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