Coenzyme Q production promoter and method for promoting coenzyme Q production

Abstract

Provided is a coenzyme Q production promoter that can increase the intracellular coenzyme Q level. The present invention relates to a coenzyme Q production promoter containing nicotinamide mononucleotide as an active ingredient.

Description

[Technical Field]

[0001] The present invention relates to a coenzyme Q production promoter and a method for promoting coenzyme Q production. [Background technology]

[0002] Coenzyme Q is a lipid-soluble biological substance synthesized in almost all living organisms, including humans. In eukaryotes, it is found most abundantly in the inner membrane of mitochondria and is an essential component of the electron transport chain, acting as a carrier for electron transport in the production of energy (ATP) through oxidative phosphorylation. Its structure consists of a benzoquinone ring and an isoprenoid side chain, and various types of coenzyme Q with different chain lengths exist in nature. For example, the predominant coenzyme Q in humans and cattle is coenzyme Q10, which has a 10-unit isoprenoid side chain; in mice and rats, it is coenzyme Q9; and in lower organisms, it is coenzyme Q6-9. Coenzyme Q10 exists in three forms: "oxidized" (ubiquinone), "radical intermediate" (semiquinone radical), and "reduced" (ubiquinol). Ubiquinone undergoes two-electron reduction to become ubiquinol. It is estimated that 60-80% of coenzyme Q10 in the human body is in the reduced form. The structure of coenzyme Q10 is shown below.

[0003] [ka]

[0004] The physiological effects of coenzyme Q (especially the reduced form) have been reported to be its ability to enhance cellular energy production and reduce physical fatigue (energy metabolism improvement). Therefore, in the human body, coenzyme Q10 is found at high levels in organs with high energy demands and active energy metabolism. Typically, the heart, brain, kidneys, liver, spleen, and pancreas contain relatively high concentrations of coenzyme Q10.

[0005] In addition to its energy metabolism-improving effect, coenzyme Q is also known to possess antioxidant properties. Modern life exposes us to various stressors, making our bodies prone to the generation of reactive oxygen species. Coenzyme Q, as an endogenously produced antioxidant, is part of the body's system for scavenging reactive oxygen species. Coenzyme Q exerts its antioxidant function by repeatedly undergoing redox reactions, providing a strong defense against various types of oxidative stress in the body, which are thought to be the cause of aging and various diseases. In particular, in humans, ubiquinol, the reduced form of coenzyme Q10, exhibits strong antioxidant properties and is believed to be effective in preventing lifestyle-related diseases and strengthening the immune system by preventing cell damage caused by reactive oxygen species. As described above, coenzyme Q is an important molecule in the body involved in vital physiological functions, such as improving energy metabolism and acting as an antioxidant.

[0006] The coenzyme Q10 required by the human body is produced internally and supplied through diet, but the amount of coenzyme Q10 synthesized in the body decreases with age, starting around the age of 20. This decrease is associated with various functional declines associated with aging. As we age, the content of coenzyme Q10 decreases in almost all organs. For example, in mice, the organs in which coenzyme Q10 decreases significantly are the heart, kidneys, and spleen, which are active in energy metabolism. The heart, which is constantly in motion and requires a large amount of energy, is particularly affected by this decrease.

[0007] Furthermore, the decrease in coenzyme Q10 is caused not only by aging but also by medication and disease. For example, it is known that the intake of statins (HMG-Co reductase inhibitors), which are used to treat dyslipidemia (hyperlipidemia) and have the effect of lowering LDL-C (LDL cholesterol), reduces the body's coenzyme Q10 levels. For example, it has been reported that taking 20 mg of pravastatin or simvastatin per day for 12 weeks reduced the amount of coenzyme Q10 in the blood by approximately 50%.

[0008] In addition, as an example of the disease, in mitochondrial diseases caused by mitochondrial dysfunction, coenzyme Q10 biosynthesis disorders occur, resulting in various symptoms. Conversely, mutations in genes involved in coenzyme Q10 biosynthesis can cause fatal multiple organ failure, central nervous system disorders, etc. The decrease in coenzyme Q10 amount caused by mitochondrial dysfunction is associated with various diseases, and for example, it has been suggested that some subtypes of heart disease may be caused by a decrease in the amount of coenzyme Q10 in myocardial mitochondria. In fact, it has been pointed out that plasma coenzyme Q10 levels tend to decrease in patients with heart failure.

[0009] Healthy humans can obtain enough coenzyme Q10 from their daily diet and internal synthesis to prevent coenzyme Q10 deficiency, but as mentioned above, when coenzyme Q10 production levels decline due to aging, medication, etc., it becomes difficult to obtain sufficient amounts of coenzyme Q10. Therefore, to compensate for the deficiency, exogenous coenzyme Q10 is often supplemented as medicine, food, or supplement.

[0010] In Japan, oxidized coenzyme Q10 is listed in the Japanese Pharmacopoeia under the generic name ubidecarenone. It is used as a myocardial metabolic improver and is approved at a daily dose of 30 mg for the treatment of mild to moderate congestive heart failure symptoms during basic therapy. Oral administration of ubidecarenone has been shown to be absorbed via lymphatics, transported to intracellular mitochondria, and stimulate ATP production in the intracellular electron transport system. Pharmacologically, ubidecarenone has been shown to mildly reduce myocardial oxygen deprivation caused by isoprenaline. Furthermore, it has been shown to improve heart failure due to hypertension and other causes. Clinically, double-blind controlled trials have demonstrated that adding this drug to conventional treatments (e.g., digitalis and diuretics) improves congestive heart failure symptoms in patients with underlying heart disease, such as ischemic heart disease, valvular disease, or cardiomyopathy. To improve these types of heart diseases, coenzyme Q10 replacement therapy (oral supplements and intravenous injections) has been carried out worldwide, and some degree of effectiveness has been observed.

[0011] Coenzyme Q10, which has been used as a pharmaceutical ingredient, was approved for use as a food ingredient in 2001, and since then, various health foods (supplements) have been sold. The most commonly available health food products contain a recommended daily amount of 60 mg, with over 80% exceeding 30 mg, and 300 mg products are also available.

[0012] Attempts have been made to treat and prevent various diseases caused by a deficiency of coenzyme Q10 by externally supplying exogenous coenzyme Q10 in this way. For example, Patent Document 1 reports a food composition for lowering blood LDL cholesterol levels, for lowering blood LDL cholesterol levels and improving fatigue, or for improving fatigue, which contains coenzyme Q10 in an amount 1.8 times or more the standard intake amount of coenzyme Q10 as an alternative to pharmaceuticals for preventing the progression of lifestyle-related diseases.

[0013] As another example, Patent Document 2 reports an antioxidant supplement that contains reduced coenzyme Q10, which works more effectively in the body, rather than the oxidized coenzyme Q10 that has been widely used in the past, and that is characterized by containing vitamin E, vitamin C, reduced coenzyme Q10, α-lipoic acid, anthocyanidin, β-carotene, selenium, S-adenosylmethionine, vitamin B6, vitamin B12, and folic acid. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] Japanese Patent Application Publication No. 2018-14912 [Patent Document 2] Japanese Patent Application Laid-Open No. 2015-218140 Summary of the Invention [Problem to be solved by the invention]

[0015] However, conventional techniques for externally supplying exogenous coenzyme Q10 as supplements, etc., are thought to have an improving effect due to the antioxidant properties of coenzyme Q10, rather than directly taking up coenzyme Q10 into organs and promoting energy metabolism within cells.

[0016] Furthermore, exogenously administered coenzyme Q10 is highly lipophilic, mostly insoluble in water, and has a relatively large molecular weight, resulting in low absorption efficiency of orally administered coenzyme Q10. Therefore, it is questionable whether the full effects of coenzyme Q10 can be expected from exogenously administered coenzyme Q10.

[0017] Furthermore, when coenzyme Q10 is ingested, the absorption rate varies from organ to organ, and it is hardly absorbed by organs such as the heart and kidneys, which need it the most. Therefore, simply ingesting exogenous coenzyme Q10 makes it difficult to replenish the required amount for organs with the highest energy demands, such as the heart and kidneys.

[0018] Therefore, an objective of the present invention is to provide a coenzyme Q production promoter that can increase the endogenous (biosynthetically derived) coenzyme Q level in cells. [Means for solving the problem]

[0019] As a result of intensive research to solve the above-mentioned problems, the present inventors discovered, for the first time in the world, that nicotinamide mononucleotide, an intermediate metabolite involved in the biosynthesis of the coenzyme NAD (nicotinamide adenine dinucleotide), promotes the production of coenzyme Q. Based on this groundbreaking research result, they believed that nicotinamide mononucleotide could be applied to the prevention or treatment of diseases resulting from coenzyme Q deficiency, and thus completed the present invention.

[0020] Thus, the present invention is as follows. [1] A coenzyme Q production promoter characterized by containing nicotinamide mononucleotide as an active ingredient. [2] The coenzyme Q production promoter according to [1] above, wherein the coenzyme Q is coenzyme Q10 or coenzyme Q9. [3] The agent according to [1] or [2] above, wherein the coenzyme Q is coenzyme Q present in the heart, brain, kidney, liver, spleen, or pancreas. [4] A food or drink for promoting coenzyme Q production, characterized by containing the coenzyme Q production promoter described in [1] above. [5] A pharmaceutical for treating or preventing a disease caused by a deficiency of coenzyme Q, characterized by containing the coenzyme Q production promoter described in [1] above. [6] A method for promoting coenzyme Q production, comprising having a subject ingest an effective amount of the compound according to [1] above for promoting coenzyme Q production. [Effects of the Invention]

[0021] The present invention activates the biosynthesis of coenzyme Q in mitochondria in organs and can increase the endogenous coenzyme Q level in cells, so that it can directly increase the coenzyme Q level even in organs such as the heart and kidneys where exogenous coenzyme Q is poorly absorbed. It can also increase the level of reduced coenzyme Q, which was difficult to supply with conventional exogenous coenzyme Q. Therefore, it is very effective in preventing or treating diseases caused by a deficiency of coenzyme Q. Furthermore, it can increase the level of NAD in vivo. + It is safe and can be taken over a long period of time because its active ingredient is nicotinamide mononucleotide, an intermediate metabolite involved in the biosynthesis of nicotinamide. [Brief explanation of the drawings]

[0022] [Figure 1a] FIG. 1 is a graph showing the results of Example 1. [Figure 1b] FIG. 1 is a graph showing the results of Example 1. [Figure 2] FIG. 1 is an explanatory diagram showing the metabolic pathway involved in niacin (a collective term for nicotinamide and nicotinic acid). DETAILED DESCRIPTION OF THE INVENTION

[0023] The coenzyme Q production promoter of the present invention (hereinafter sometimes referred to as "the agent") contains nicotinamide mononucleotide as an active ingredient and activates the biosynthesis of coenzyme Q in mitochondria to promote coenzyme Q production. Although the mechanism of action of the agent has not been fully elucidated, it is presumed that nicotinamide mononucleotide increases the amount of nicotinamide adenine dinucleotide (NAD) to promote the reaction catalyzed by sirtuins, and activates mitochondria to increase ATP production, thereby promoting coenzyme Q production. Therefore, the agent is thought to be effective in preventing or treating diseases caused by coenzyme Q deficiency by increasing coenzyme Q levels through the active ingredient nicotinamide mononucleotide.

[0024] This product uses its active ingredient, nicotinamide mononucleotide, to activate coenzyme Q production and increase endogenous coenzyme Q10 levels, thereby enabling the physiological effects of coenzyme Q10 to be exerted more efficiently and effectively than exogenous coenzyme Q10. Therefore, for diseases caused by decreased coenzyme Q10 levels (most notably heart disease), nicotinamide mononucleotide, instead of exogenous coenzyme Q10, can be expected to provide short-term symptomatic relief, or to prevent disease by taking it as a supplement. For example, for patients with heart disease caused by decreased coenzyme Q10 levels, administration of this product can be expected to have the same effect as directly replenishing coenzyme Q10 into cardiac mitochondria.

[0025] This drug uses its active ingredient, nicotinamide mononucleotide, to activate coenzyme Q production in various organs, particularly the heart, brain (especially the cerebellum), kidneys, liver, spleen, and pancreas, thereby increasing endogenous coenzyme Q10 levels.

[0026] Nicotinamide mononucleotide (chemical formula: C11 H 15 N2O8P) is a compound represented by the following structural formula [Chemical Formula 2], which is produced in the bodies of many living organisms, including humans. It is commonly called NMN (nicotinamide mononucleotide) and is a coenzyme NAD + It is known as an intermediate metabolite involved in the biosynthesis of

[0027] [ka]

[0028] Nicotinamide mononucleotide is produced in vivo through the NAD metabolic pathway in liver tissue, i.e., the pathway involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from quinolinic acid via the kynurenine pathway. This point will be explained in detail with reference to Figure 2. Figure 2 is an explanatory diagram showing the metabolic pathway involved in niacin (a collective term for nicotinamide and nicotinic acid), also known as vitamin B3. Nicotinic acid ingested through diet is taken up by the liver and converted to nicotinamide, which is then distributed throughout the body via the bloodstream. Each cell takes up nicotinamide from the blood and converts it to NAD and NADP for use. Nicotinamide can also be biosynthesized from tryptophan.

[0029] As shown in Figure 2, in vivo, when tryptophan is used as a starting material, tryptophan is converted to quinolinic acid (QA) via the kynurenine pathway, which is the tryptophan metabolic pathway, and then to nicotinic acid mononucleotide (NaMN). On the other hand, when nicotinic acid (Na) is used as a starting material, nicotinic acid is directly converted to NaMN. NaMN then passes through nicotinic acid adenine dinucleotide (NaAD) and is interconverted to NAD, nicotinamide (NaM), and nicotinamide mononucleotide via the NAD cycle. Nicotinamide (NaM) is converted to nicotinamide mononucleotide by nicotinamide phosphoribosyltransferase (NAMPT), and nicotinamide mononucleotide is then converted to NAD by nicotinamide mononucleotide adenyltransferase (NMNAT). Nicotinamide mononucleotide can also be produced from nicotinamide riboside (NR), an NAD intermediate.

[0030] Nicotinamide mononucleotide exists as two optical isomers, α- and β-, and the β-isomer is used in the present invention. Nicotinamide mononucleotide can be obtained, for example, by synthesizing nicotinamide riboside from nicotinamide and ribose (see Bioorg. Med. Chem. Lett., 12, 1135-1137 (2002)), followed by phosphorylating the 5-hydroxyl group of the ribose moiety (see Chem. Comm., 1999, 729-730). Specifically, for example, nicotinamide and L-ribose tetraacetate are first dissolved in anhydrous acetonitrile, and an excess amount of trimethylsilyltrifluorosulfonic acid is added under a nitrogen stream. The mixture is stirred at room temperature, and the reaction is terminated by adding methanol. The reaction solution is then loaded onto a column packed with activated carbon, washed with distilled water, and eluted with methanol to recover the product. Next, to phosphorylate the 5-hydroxyl group of the L-ribose moiety of this product, the product is dissolved in trimethoxyphosphate, and phosphorus oxychloride is added dropwise under ice cooling. The mixture is stirred under a nitrogen stream, and aqueous sodium hydroxide is added to neutralize the reaction. To the reaction solution, which has been stopped, a cold acetonitrile-ether solution is added. The lower layer (aqueous phase) is then passed through an anion exchange resin to recover the reaction product, which is then further purified with a cation exchange resin to recover highly pure nicotinamide mononucleotide. Nicotinamide mononucleotide is also commercially available, and these commercially available products can be purchased and used.

[0031] The nicotinamide mononucleotide is a purified product with a low content of impurities, and its purity is preferably 90% or more, and more preferably 95% or more. If the purity is less than 90%, an unpleasant odor may be generated or the effect of nicotinamide mononucleotide may be weakened, making it difficult to fully obtain the effects of the present invention.

[0032] The present preparation can be easily produced by using nicotinamide mononucleotide alone or by mixing it with other ingredients, which are not particularly limited as long as the present preparation exhibits the effects of the present invention.

[0033] As mentioned above, examples of other ingredients include carotenoids (lycopene, lutein, vitamin A, etc.), astaxanthin, polyphenols (flavonoids, catechins, isoflavones, sesamin, curcumin, etc.), vitamin E, and vitamin C, which are known as food ingredients that remove reactive oxygen; vitamin A, vitamin E, vitamin C, and zinc, which are known as food ingredients that enhance immunity; and docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), lecithin, tryptophan, etc., which are known as food ingredients that prevent aging. Other ingredients may also be included, such as supplementary ingredients commonly used in the food industry, such as various vitamins, trace elements, citric acid, malic acid, flavorings, and inorganic salts.

[0034] To achieve the effects of the present invention, the active ingredient, nicotinamide mononucleotide, is administered in a dose sufficient to activate mitochondria and promote the production of coenzyme Q. The specific amount varies depending on the age, sex, weight, expected effects, symptoms, etc., of the subject taking the drug, but the daily intake of nicotinamide mononucleotide for adults is typically 1 mg to 500 mg, preferably 5 mg to 350 mg, more preferably 50 mg to 300 mg, and even more preferably 150 mg to 300 mg. If the dose is less than 1 mg, the effects of the present invention may not be achieved, while if the dose is more than 500 mg, the effects obtained will not change significantly and it will be economically disadvantageous.

[0035] This agent can be used for the purposes of promoting coenzyme Q production and treating or preventing diseases caused by coenzyme Q deficiency. Examples of diseases caused by coenzyme Q deficiency include mitochondrial diseases (e.g., mitochondrial encephalomyopathies), lifestyle-related diseases, cardiovascular diseases (e.g., congestive heart failure, myocardial infarction, angina pectoris, vascular endothelial dysfunction), diabetes, and neurodegenerative diseases (e.g., Parkinson's disease, Huntington's disease, Friedreich's ataxia). In the present invention, "treatment of diseases caused by coenzyme Q deficiency" refers to curing the disease or alleviating its symptoms. This includes halting the progression of the disease, downstaging, and inhibiting metastasis. Furthermore, "prevention of diseases caused by coenzyme Q deficiency" broadly encompasses not only preventing the onset of the disease but also preventing recurrence and worsening of the disease after it has been cured or improved.

[0036] The method for producing the present agent is not particularly limited, and a general production method used for producing the agent may be appropriately selected depending on the form. For example, if the agent is in the form of a powder, it can be produced by uniformly kneading nicotinamide mononucleotide and other ingredients to be added as needed. Note that the active ingredient, nicotinamide mononucleotide, is distributed on the market and can be commercially obtained. In particular, with regard to nicotinamide mononucleotide, a quality control system and a mass production system for nicotinamide mononucleotide have been established in recent years.

[0037] This agent can be used as a food or beverage or a pharmaceutical. When used as a food or beverage, this agent can be provided in the food industry as a food or beverage for promoting coenzyme Q production. When taken daily in the form of a food, the effects of the present invention are continuously exerted, making it particularly effective in enjoying even greater effects. The types of foods that are the subject of the present invention are not particularly limited, and include general foods, as well as functional foods, foods for specified health uses, nutritional supplements, food additives, feed, nursing care foods, dietary foods, therapeutic foods, dietary foods, and diet foods. Specific examples include confectioneries (gum, candy, cookies, gummies, biscuits, cakes, chocolates, Japanese sweets, jellies, etc.), bread, noodles, processed rice and grain products (cereals, etc.), processed meat products, processed seafood products, processed vegetables, prepared dishes, fermented foods, seasonings (sauces, dressings, ketchup, etc.), spices, dairy products (yogurt, cheese, milk, etc.), ice cream, frozen foods, retort pouch foods, beverages (carbonated drinks, soft drinks, dairy drinks, alcoholic drinks, sports drinks, fruit juice drinks, teas, nutritional drinks, concentrated drinks, etc.), powdered beverages (powdered juice, powdered soup, etc.), etc. The form of the food is not limited, and in the case of functional foods and foods for specified health uses, for example, the food can be processed and provided as a powder, tablet, pill, granule, hard capsule, soft capsule, jelly, liquid, paste, etc.

[0038] The intake amount of the food varies depending on the type of food, the age, sex, and weight of the person taking it, the expected effects, symptoms, etc., but the daily intake amount of nicotinamide mononucleotide contained in the food per adult is usually 1 mg to 500 mg, preferably 5 mg to 350 mg, more preferably 50 mg to 300 mg, and even more preferably 150 mg to 300 mg. If the intake amount is less than 1 mg, the effects of the present invention may not be obtained, while if the intake amount is more than 500 mg, the obtained effects will not change significantly and it will be economically disadvantageous. The blending ratio of nicotinamide mononucleotide in the food can be appropriately set within a range of 100% or less of the total weight of the food.

[0039] The food product is safe and has no particular side effects, so it can be taken over a long period of time and is applicable to both the elderly and young people.

[0040] On the other hand, in the pharmaceutical field, this agent can be administered orally or parenterally as a drug (including quasi-drugs) for the treatment or prevention of diseases caused by coenzyme Q deficiency. The dosage form of the drug is not particularly limited, and examples include oral administration preparations such as powders, tablets, sustained-release tablets, chewable tablets, effervescent tablets, troches, buccal tablets, sublingual tablets, capsules, fine granules, granules, pills, dry syrups, liquids, suspensions, syrups, and elixirs, as well as injections, infusions, suppositories, and topical preparations. Among these, oral administration preparations such as powders, tablets, and capsules are preferred in terms of ease of administration and stability of the active ingredient. The diseases caused by coenzyme Q deficiency are the same as those already described in the section on this agent.

[0041] The pharmaceutical may be appropriately blended with known pharmaceutically acceptable additives suitable for the dosage form, taking into consideration physicochemical properties, biological properties, etc. Examples of such additives include excipients (lactose, starch, crystalline cellulose, sodium phosphate, etc.), solvents (water, soybean oil, saline, non-aqueous solvents for injection, etc.), binders (starch, gelatin, gum arabic, sodium alginate, carmellose sodium, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), disintegrants (starch, carmellose sodium, etc.), lubricants (talc, magnesium stearate, calcium stearate, macrogol, sucrose fatty acid esters, etc.), coating agents (sucrose, HPC, shellac, gelatin, glycerin, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, etc.), stabilizers (sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutylhydroxybenzoate, etc.), and the like. Preservatives (methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, thimerosal, etc.), thickeners (methylcellulose, carmellose sodium, chondroitin sulfate, sodium alginate, etc.), suspending agents (various nonionic surfactants, methylcellulose, carmellose sodium, etc.), Examples of such additives include emulsifiers (gum arabic, cholesterol, sorbitan sesquioleate, polysorbate 80, sodium lauryl sulfate, etc.), buffers (citric acid, acetic acid, sodium phosphate, boric acid), surfactants (hydrogenated castor oil, polysorbate 80, etc.), colorants (water-soluble food dyes, lake dyes, etc.), flavoring agents (lactose, sucrose, glucose, mannitol, etc.), flavoring agents (aromatic essential oils, etc.), plasticizers (phthalate esters, vegetable oils, polyethylene glycol, etc.), etc.

[0042] The dosage of the pharmaceutical varies depending on the age, weight, symptoms, and frequency of administration of the patient and cannot be uniformly defined. However, the dosage of the pharmaceutical is typically 1 mg to 500 mg, preferably 5 mg to 350 mg, more preferably 50 mg to 300 mg, and even more preferably 150 mg to 300 mg, of nicotinamide mononucleotide administered to an adult per day. If the dosage is less than 1 mg, the effects of the present invention may not be achieved. On the other hand, if the dosage is more than 500 mg, the effects obtained will not change significantly and it will be economically disadvantageous. The proportion of nicotinamide mononucleotide in the pharmaceutical can be appropriately determined depending on the dosage form and dosage of the pharmaceutical.

[0043] The number of times the pharmaceutical is administered can be determined appropriately depending on the age, weight, symptoms, and single dose of the pharmaceutical of the subject, etc. One example of the number of times the pharmaceutical is administered per day is 1 to 3 times.

[0044] As described above, nicotinamide mononucleotide, when administered at a dose sufficient to promote coenzyme Q production, has the effect of treating or preventing diseases caused by coenzyme Q deficiency. Therefore, the present invention further provides a method for treating or preventing diseases caused by coenzyme Q deficiency by administering an effective amount (i.e., the above-mentioned dose) of the agent to a subject in need thereof, thereby activating mitochondria and promoting coenzyme Q production. Preferred subjects for administration include mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys, with humans being particularly preferred. In the method, the amount of nicotinamide mononucleotide to be administered, the number of times per day, and other factors are as described for the agent. Furthermore, the agent can be administered to a subject at any time and in any circumstances, and can be administered over a long period of time. [Example]

[0045] The present invention will be described in more detail below based on examples, but the present invention is not limited to the following examples.

[0046] Example 1 To investigate the effect of nicotinamide mononucleotide on coenzyme Q10 production, HEK293 cells (human embryonic kidney-derived cells) were cultured for 3 days at 37°C and 5% CO2 in DMEM medium containing β-nicotinamide mononucleotide at the indicated concentrations (0 mM (control), 1 mM, and 2.5 mM, added daily). After the first 3 days of culture, mitochondria were isolated from the HEK293 cells, and the contents of the reduced (ubiquinol) and oxidized (ubiquinone) forms of coenzyme Q10 in the mitochondria were analyzed by LC-MS (LC column: KINETEX C18 column (Phenomenex)), MS: Shimadzu LCMS-8060 (Shimadzu), eluent: 10 mM ammonium formate in methanol, flow rate: 0.5 mL / min, detection: MS / MS analysis by multiple reaction monitoring (MRM) method; Q10H2 883.6 -> 197.15 m / z, Q10 881.4 -> 197.15 m / z, Q9H2 815.6 -> 197.15 m / z, Q9 813.6 -> 197.15 m / z, Q8H2 747.6 -> 197.15 m / z, Q8 745.6 -> 197.15 The m / z values ​​were quantified using an ODS column (column: ODS, column temperature: 40°C, eluent: 70% acetonitrile / methanol (1:1) and 30% 0.05 M ammonium formate (adjusted to pH 7.2 with 10% aqueous ammonium), flow rate: 1.0 mL / min, detection: UV 276 nm). The results are shown in Figure 1a and b. Figure 1a shows the changes in the Q10H2 and Q10 contents, and Figure 1b shows the changes in the combined amounts of Q10H2 and Q10. In Figures 1a and 1b, Q10H2 represents reduced coenzyme Q10 (ubiquinol), and Q10 represents oxidized coenzyme Q10 (ubiquinone). An asterisk (*) indicates a p-value of less than 0.05 in the Student's two-tailed t-test. As a result, it was found that in the nicotinamide mononucleotide-containing medium, the content of both reduced and oxidized forms of coenzyme Q10 increased by approximately 1.5 to 2 times for both forms. Furthermore, the total amount of reduced and oxidized forms increased by approximately 2 times. These results confirm that in cells fed with nicotinamide mononucleotide, the production of coenzyme Q10 (both reduced and oxidized forms) in mitochondria is activated, resulting in a dramatic increase in coenzyme Q10 concentration.

Claims

[Claim 1] A method for promoting coenzyme Q production, characterized in that a subject ingests an effective amount of a coenzyme Q production promoter containing nicotinamide mononucleotide as an active ingredient, thereby promoting the production of coenzyme Q, wherein the coenzyme Q is reduced coenzyme Q10 (however, this method does not apply to medical procedures performed on humans).

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