Low nutritional state improving agent, composition, low nutritional state improving food product and method for producing improving low nutritional state

Abstract

To provide a low nutritional state improving agent capable of improving a symptom caused by a low nutritional state, a composition containing the low nutritional state improving agent, a low nutritional state improving food product containing the low nutritional state improving agent, and a method for improving a low nutritional state using the low nutritional state improving agent.SOLUTION: There are provided: a low nutritional state improving agent which contains pyrroloquinoline quinone and / or its salt as an active ingredient, and improves one or more symptoms among symptoms of a low nutrition state; a composition and a low nutritional state improving food product which contain the low nutritional state improving agent; and a method for improving a low nutritional state using the low nutritional state improving agent.SELECTED DRAWING: Figure 3

Description

Technical Field

[0001] The present invention relates to a hypo-nutrition improving agent, a composition containing the hypo-nutrition improving agent, a hypo-nutrition improving food containing the hypo-nutrition improving agent, and a method for improving hypo-nutrition using the hypo-nutrition improving agent.

Background Art

[0002] Hypo-nutrition refers to a state in which energy, protein, vitamins, etc. necessary for daily life are insufficient. Hypo-nutrition leads to sarcopenia.

[0003] Sarcopenia refers to a state in which muscle strength decreases with aging or muscle mass decreases with aging. Sarcopenia causes a decrease in vitality, muscle strength, and walking speed. As a result, daily activity level decreases, leading to a decrease in energy consumption. Consequently, it leads to a decrease in appetite and promotes further malnutrition. This vicious cycle is called the frailty cycle (also called the frailty cycle), and in order to break this vicious cycle, it is necessary to improve hypo-nutrition (see Non-Patent Document 1). Measures for this improvement are also important as a prevention so that the elderly do not require nursing care or support.

[0004] In hypo-nutrition, which is a state in which nutrients necessary to maintain body functions are lacking, risks such as the occurrence of pressure ulcers due to subcutaneous fat reduction, anemia, osteoporosis, muscle atrophy, fatigue, and weakness increase (see Non-Patent Document 2). This state is caused by aging or diseases (cancer or COPD) (see Non-Patent Document 3). The definition of hypo-nutrition is a state in which unintentional weight loss occurs. More specifically defined, it is a state in which two of the items of weight loss, decreased energy intake, decreased muscle mass, decreased body fat, increased water volume, and decreased grip strength are observed (see Non-Patent Document 4). Also, in experimental animals, it has been reported that body fat reduction and muscle reduction occur (see Non-Patent Document 5).

[0005] In the case of sarcopenia, it is characterized by not only atrophy of muscle fibers but also a decrease in the number of muscle fibers. Generally, a decrease in physical activity associated with aging is considered to be the main factor contributing to sarcopenia. In histological examinations, selective atrophy of type II fibers (fast muscle fibers) is observed in the elderly (see Non-Patent Document 6).

[0006] The intestinal tract is the longest conduit among the digestive organs, including the duodenum, jejunum, ileum, cecum, colon, and rectum, with a total length of approximately 7 m. The jejunum and ileum are located in the center of the abdomen and are surrounded by the colon. In the intestinal tract, nutrients such as sugars and amino acids can be absorbed into the body by transporting them through solute transporters expressed in intestinal epithelial cells. Nutrient transport in the intestinal tract is closely related to the nutritional status of the entire organism, and the function of solute transporters is very important for maintaining the body functions of the organism.

[0007] The digestive system that ingests nutrients is also affected by aging. The stomach mucosa atrophies with aging, resulting in a decrease in gastric acid secretion. In addition, the elasticity of the stomach decreases with aging, so it becomes impossible to store a large amount of food in the stomach at once. Furthermore, since peristaltic movements weaken, the ability to transport food to the small intestine also decreases. Although the small intestine is considered to be an organ that is less affected by aging, its ability to secrete digestive juices still decreases, leading to poor digestion and absorption. As a result, it becomes difficult to eat fatty foods, and the ability to digest and absorb dairy products declines.

[0008] Efforts have been made to overcome the frailty cycle by providing energy through lipids and carbohydrates, and nutritional supplements such as vitamins and minerals, but for elderly people with reduced digestive and metabolic functions, these are merely symptomatic measures and do not lead to overcoming the frailty cycle. In addition, excessive intake of lipids and carbohydrates may exacerbate diseases such as hyperlipidemia and diabetes. As a method for promoting nutrient transport, inventions using polyphenol absorption promoters (see Patent Document 1) and calcium absorption promoters (see Patent Document 2) are known. However, these inventions are related to the transport of only specific nutrients, and are insufficient as a method for supporting the transport of nutrients obtained from daily meals.

[0009] Pyrroloquinoline quinone and its salts are present in mitochondria and are known as functional food ingredients with antioxidant and brain function improving effects. Pyrroloquinoline quinone and its salts are widely contained in foods in trace amounts, but not at concentrations that can be detected by a general absorbance detector.

[0010] In addition, pyrroloquinoline quinone and its salts are known to have a lipid reduction promoting effect (see Patent Document 3). Furthermore, a hair graying prevention agent using pyrroloquinoline quinone as an external preparation is known (see Patent Document 4). [Prior art documents] [Patent documents]

[0011] [Patent Document 1] JP 2016-193845 A [Patent Document 2] JP 2017-171594 A [Patent Document 3] Patent Publication No. 2021-78397 [Patent Document 4] Japanese Patent Application Publication No. 63-301810 [Non-patent literature]

[0012]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Summary of the Invention

Problems to be Solved by the Invention

[0013] However, regarding pyrroloquinoline quinone and its salts, the effect of suppressing fat loss caused by malnutrition due to aging, etc. is not known. Also, regarding pyrroloquinoline quinone and its salts, there have been no studies on improving malnutrition or on nutritional intake efficiency. Furthermore, there have been no reports that pyrroloquinoline quinone and its salts can improve hair deterioration caused by malnutrition through oral intake.

[0014] As a result of intensive research, the present inventors have found that pyrroloquinoline quinone and its salts have an effect of improving symptoms caused by malnutrition. Based on such findings, the present inventors have completed the present invention through further repeated research.

[0015] An object of the present invention is to provide a malnutrition improver capable of improving symptoms caused by malnutrition, a composition containing the malnutrition improver, a malnutrition-improving food containing the malnutrition improver, and a method for improving malnutrition using the malnutrition improver. In the present invention, "improvement of malnutrition" means "improvement of symptoms caused by malnutrition".

Means for Solving the Problems

[0016] In order to achieve the above object, the present invention provides the following malnutrition improver, composition, malnutrition-improving food, and method for improving malnutrition.

[0017] [1] A malnutrition improver that contains pyrroloquinoline quinone and / or a salt thereof as an active ingredient and improves one or more of the symptoms of malnutrition. [2] The malnutrition improver according to [1] above, wherein the one or more symptoms are symptoms selected from muscle mass reduction, body fat reduction, hair deterioration, and increase in water content. [3] The malnutrition improver according to [1] above, wherein the one or more symptoms include muscle mass reduction. [4] The malnutrition improver according to [1] above, wherein the one or more symptoms include body fat reduction. [5] The malnutrition improver according to [1] above, wherein the one or more symptoms include hair deterioration. [6] The malnutrition improver according to any one of [1] to [5] above, wherein the malnutrition is malnutrition caused by aging. [7] The malnutrition improver according to any one of [1] to [6] above, which improves two or more of the symptoms of the malnutrition. [8] The malnutrition improver according to any one of [1] to [7] above, wherein the salt is a disodium salt. [9] The malnutrition improver according to any one of [1] to [8] above, wherein the pyrroloquinoline quinone and / or its salt is a hydrate.

[10] A composition comprising the malnutrition-improving agent according to any one of [1] to [9].

[11] A malnutrition-improving food comprising the malnutrition-improving agent according to any one of [1] to [9].

[12] A method for improving malnutrition, which uses the malnutrition-improving agent according to any one of [1] to [9]. [Effect of the Invention]

[0018] According to the present invention, it is possible to provide a malnutrition-improving agent capable of improving symptoms caused by malnutrition, a composition comprising the malnutrition-improving agent, a malnutrition-improving food comprising the malnutrition-improving agent, and a method for improving malnutrition using the malnutrition-improving agent. [Brief Description of the Drawings]

[0019]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

[0020] Hereinafter, the modes for carrying out the present invention will be described in detail, but the present invention is not limited thereto, and various modifications are possible without departing from the gist thereof.

[0021] [Nutritional status improver] The nutritional status improver according to an embodiment of the present invention (hereinafter referred to as "the present embodiment") improves one or more symptoms among the symptoms of nutritional status, and contains pyrroloquinoline quinone (PQQ) and / or a salt thereof as an active ingredient.

[0022] The PQQ used in the present embodiment is a compound having a chemical structure represented by the following formula (Chemical formula 1). [Chemical formula]

[0023] In the present embodiment, the PQQ used may be a reduced PQQ having a chemical structure represented by the following formula (Chemical formula 2) in addition to the oxidized PQQ represented by the above formula. The reduced PQQ is produced by reducing the oxidized PQQ in an aqueous solution. [Chemical formula]

[0024] PQQ may be used in the form of a salt. The salt of PQQ is one in which 1 to 3 of the carboxyl groups in the above formula form a salt with an alkali metal ion or the like. The salt of PQQ is not particularly limited, and examples thereof include alkali metal salts such as sodium and potassium (specifically, sodium PQQ, potassium PQQ, etc.), alkaline earth metal salts such as calcium and magnesium (specifically, calcium PQQ, magnesium PQQ, etc.), PQQ aluminum, PQQ zinc, PQQ manganese, and PQQ iron. Among these, the salt of PQQ is preferably sodium PQQ or calcium PQQ. In particular, for the sodium salt, monosodium, disodium, and trisodium can be used, and disodium pyrroloquinoline quinone is easily available and easy to use.

[0025] PQQ and its salt may be used in the form of a solvate. Examples of the solvate include hydrates, and preferably 1 to 3 hydrates.

[0026] PQQ and its salts may be used individually or in combination of two or more.

[0027] There are no particular limitations on the methods for obtaining PQQ and its salts, and they may be either natural ones derived from animals or plants or those obtained by chemical synthesis methods, fermentation methods, etc. Based on the purity of the obtained PQQ and its salts, manufacturing costs, etc., a suitable manufacturing method for PQQ and its salts can be appropriately selected. Also, as PQQ and its salts, commercially available PQQ and its salts can be used. Examples of such commercially available products include those manufactured or sold by Mitsubishi Gas Chemical Company, Inc. Further, in the present embodiment, PQQ obtained by culturing bacteria (such as PQQ bacteria) using a fermentation method or a composition containing PQQ can be used as it is or after granulation processing.

[0028] Since PQQ and its salts are designated as foods in Japan and can be used as food and drink, it can be said that the malnutrition improver according to the present embodiment has sufficient safety for animals such as humans.

[0029] The malnutrition improver according to the present embodiment improves one or more of the symptoms of malnutrition, preferably two or more symptoms, more preferably three or more symptoms, and even more preferably four or more symptoms.

[0030] In the present embodiment, the symptoms of malnutrition refer to the symptoms caused by malnutrition, and examples thereof include weight loss, reduced energy intake, reduced muscle mass, reduced body fat, increased water content, decreased grip strength, deterioration of hair, and deterioration of skin. The malnutrition improver according to the present embodiment has particularly high effects on the symptoms of reduced muscle mass, reduced body fat, deterioration of hair, and / or increased water content. Also, as factors leading to malnutrition, aging, nutritional deficiency due to illness, nutritional deficiency in infancy, nutritional deficiency due to poverty, etc. can be mentioned, and particularly, the effect is high in the case of malnutrition caused by aging.

[0031] When in a state of malnutrition, symptoms of weight loss appear, but according to the malnutrition-improving agent of the present embodiment, the reduction rate of weight loss can be reduced. That is, weight loss can be suppressed.

[0032] When in a state of malnutrition, symptoms of reduced energy intake appear, but according to the malnutrition-improving agent of the present embodiment, the reduction rate of reduced energy intake can be reduced. That is, reduced energy intake can be suppressed.

[0033] When in a state of malnutrition, symptoms of muscle mass loss appear, but according to the malnutrition-improving agent of the present embodiment, the reduction rate of muscle mass loss can be reduced. That is, muscle mass loss can be suppressed.

[0034] When in a state of malnutrition, symptoms of body fat loss appear, but according to the malnutrition-improving agent of the present embodiment, the reduction rate of body fat loss can be reduced. That is, body fat loss can be suppressed. Body fat (which can also be referred to as lipid here) is a general term for water-insoluble substances present in the living body. Also, the lipid may be solid or liquid at normal temperature, but is preferably solid. Note that normal temperature indicates 15 to 25°C according to the general rules of the sixteenth revised Japanese Pharmacopoeia. Lipids include, for example, simple lipids (such as neutral fat), compound lipids (such as phospholipids, glycolipids), and derived lipids (such as fatty acids, cholesterol). Among these, simple lipids are preferred, among which neutral fat is more preferred, and most preferably triacylglycerol (triglyceride). The amount of body lipids can be measured as subcutaneous fat and visceral fat by a body composition analyzer, CT, MRI, etc.

[0035] When in a state of malnutrition, symptoms of increased water content appear, but according to the malnutrition-improving agent of the present embodiment, the increase rate of increased water content can be reduced. That is, the increase in water content can be suppressed.

[0036] When a state of malnutrition occurs, symptoms of decreased grip strength appear. However, according to the malnutrition improver of the present embodiment, the degree of decrease in grip strength can be reduced. That is, the decrease in grip strength can be suppressed.

[0037] When a state of malnutrition occurs, symptoms of hair deterioration appear. However, according to the malnutrition improver of the present embodiment, the degree of hair deterioration (such as an increase in the number of hairs lost and deterioration of hair quality) can be reduced. That is, hair deterioration can be suppressed.

[0038] When a state of malnutrition occurs, symptoms of skin deterioration appear. However, according to the malnutrition improver of the present embodiment, the degree of skin deterioration (such as deterioration of skin condition) can be reduced. That is, skin deterioration can be suppressed.

[0039] The malnutrition improver of the present embodiment is not particularly limited as long as it is a method used for improving the state of malnutrition. For example, it can be used as a food, functional food, pharmaceutical, or quasi-drug for humans or animals. Here, the functional food means a food such as a health food, dietary supplement, nutrient-functional food, or nutritional insurance food, which is ingested for the purpose of maintaining health or supplementing nutrition instead of a meal. Note that food includes beverages. Specific forms include, but are not limited to, capsules, tablets, chewables, pills, drinkable agents, etc.

[0040] As a pharmaceutical use, the malnutrition improver of the present embodiment can be used by methods such as oral administration, injection, drip infusion, and transdermal absorption. In the case of oral administration, the malnutrition improver of the present embodiment can be used in the form of hard capsules, soft capsules, or tablets, mixed with other substances. In addition, the malnutrition improver of the present embodiment can also be used as a beverage, drip solution, or injection solution.

[0041] The malnutrition improver of the present embodiment is preferably orally ingested in the form of a beverage, soft capsule, or tablet.

[0042] The malnutrition improver of the present embodiment is useful as a medicine, food, etc., and its application target can be a mammal. Such mammals include, for example, primates (e.g., humans, monkeys, chimpanzees), rodents (e.g., mice, rats, guinea pigs), pets (e.g., dogs, cats, rabbits), draft animals or livestock (e.g., cows, horses, pigs, sheep, goats), but humans are preferred in the present embodiment. When applying to mammals other than humans, the dosage (intake amount) of the malnutrition improver of the present embodiment may be appropriately adjusted according to the weight or size of the animal.

[0043] 〔Composition〕 The composition according to the present embodiment includes the malnutrition improver according to the present embodiment.

[0044] The malnutrition improver of the present embodiment can be formulated into a composition by a conventional method using a pharmaceutically acceptable and / or food-use carrier as appropriate according to the requirements of the formulation, and can be made into a composition (hereinafter referred to as "the composition of the present embodiment"). Since the composition of the present embodiment includes the malnutrition improver of the present embodiment, it can have all of the above-described effects exhibited by the malnutrition improver of the present embodiment.

[0045] The above carrier can be appropriately selected according to the dosage form of the preparation (composition) and is not particularly limited. For example, excipients, binders, lubricants, disintegrants, solvents, stabilizers, solubilizers, antioxidants, colorants, flavoring agents, sweeteners and other additives can be mentioned.

[0046] The excipient is not particularly limited, and examples thereof include saccharides (sucrose, lactose, glucose, mannitol, etc.), starches (corn starch, etc.), crystalline cellulose, calcium phosphate, calcium sulfate, magnesium sulfate, and the like.

[0047] The binder is not particularly limited, and examples thereof include pregelatinized starch, gelatin, tragacanth gum, gum arabic, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and the like.

[0048] The lubricant is not particularly limited, and examples thereof include magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, and the like.

[0049] The disintegrant is not particularly limited, and examples thereof include starch, crystalline cellulose, carboxymethyl cellulose, agar, calcium citrate, calcium carbonate, sodium hydrogen carbonate, dextrin, and the like.

[0050] The solvent is not particularly limited, and examples thereof include water, ethanol, glycerol, physiological saline, soybean oil, and the like.

[0051] The stabilizer is not particularly limited, and examples thereof include benzoic acid, sodium benzoate, ethyl paraoxybenzoate, propylene glycol, and the like.

[0052] The solubilizing agent is not particularly limited, and examples thereof include fumaric acid, succinic acid, malic acid, and the like.

[0053] The antioxidant is not particularly limited, and examples thereof include ascorbic acid, tocopherol, sodium bisulfite, sodium thiosulfate, sodium pyrosulfite, citric acid, and the like.

[0054] Examples of the coloring agent, flavoring agent, and sweetening agent include those that are usually permitted to be added in the pharmaceutical field and / or food field.

[0055] The content of PQQ and / or its salt in the composition of this embodiment is preferably 0.10 to 99.99% by mass, more preferably 0.60 to 99.90% by mass, and still more preferably 1.00 to 99.90% by mass, based on the total mass of the composition of this embodiment. The content of PQQ and / or its salt in the agent of this embodiment is handled as the mass of that substance. Therefore, it is not necessary to convert the salt of PQQ into the free form of PQQ, and when the salt of PQQ forms a hydrate, the mass is calculated in a form including water molecules.

[0056] The composition of this embodiment can be used as a medicine (i.e., a pharmaceutical composition). In this case, the pharmaceutical composition of this embodiment can be treated as a medicine for improving malnutrition, that is, a preventive or therapeutic medicine for symptoms caused by malnutrition, and such symptoms are as described above.

[0057] The administration method of the pharmaceutical composition of this embodiment is not particularly limited, and generally includes an oral administration method. However, depending on the condition, severity, etc. of the target patient, parenteral administration (intravascular (intravenous, intra-arterial) administration, subcutaneous administration, transdermal administration, rectal administration, etc.) may be appropriately selected. Since PQQ and / or its salt, which are active ingredients, are all edible, it is preferable to adopt oral administration in this embodiment.

[0058] The dosage form of the pharmaceutical composition of this embodiment is not particularly limited and can be made into a form suitable for the administration method. Forms suitable for oral administration include, for example, tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs, etc. Forms suitable for parenteral administration include, for example, forms suitable for parenteral injection, such as sterile solutions, suspensions, emulsions, etc. for intravenous, subcutaneous, intramuscular, intravascular or infusion administration, and forms suitable for transdermal administration, such as creams, ointments, gels, aqueous or oily liquids (including suspensions), etc.

[0059] The composition of this embodiment can also be used as a food (i.e., a food composition). Note that foods include beverages. In this case, the food composition of this embodiment can be treated as a food for improving malnutrition, that is, a prophylactic food or therapeutic food for symptoms caused by malnutrition, and such symptoms are as described above.

[0060] The food in this embodiment means all foods in general, and includes general foods including so-called health foods, as well as special-purpose foods (foods for specified health uses, foods for patients, foods for those with difficulty in swallowing, etc.) and foods with nutritional functions defined by the Consumer Affairs Agency. Furthermore, supplements, feeds, etc. are also included in the foods of this embodiment.

[0061] The dosage form of the food composition of this embodiment is not particularly limited, and can be in the form of fine granules, granules, pills, tablets (including coated tablets and sugar-coated tablets), capsules (including hard capsules, soft capsules, and microcapsules), beverages, drink agents, liquid agents (including syrups, emulsions, and suspensions), powdered foods, jellies, candies, etc.

[0062] The dosage (intake) of the malnutrition improver and composition of this embodiment is not particularly limited, and may be within the range of an effective amount that can exhibit a malnutrition improving effect in the body, and can be appropriately set according to individual differences, symptoms, administration methods, etc. of the subject. Also, the dosage (intake) per day can be administered (intaken) once or divided into several times (for example, 2 or 3 times). The administration (intake) of the malnutrition improver and composition of this embodiment can be carried out regardless of before meals, after meals, or between meals, and the period is not particularly limited as long as the effects of this embodiment are achieved. Hereinafter, when the term "administration" is used in this specification, it means that the concept of "intake" is also included.

[0063] In this embodiment, when two or more of PQQ and / or its salts are used, they can be formulated into separate preparations, and in that case, each preparation can be used in combination.

[0064] When using the malnutrition improver and composition of the present embodiment, it is also possible to use them in combination with existing components having a malnutrition improving effect. In such a case, the order of administering the malnutrition improver and composition of the present embodiment and the above-mentioned existing components may be simultaneous or separate. In the case of separate administration, the malnutrition improver and composition of the present embodiment may be administered either before or after the above-mentioned existing components.

[0065] 〔Method for improving malnutrition〕 The method for improving malnutrition according to the present embodiment is characterized by using the malnutrition improver according to the present embodiment. When using, the malnutrition improver of the present embodiment may be used as it is, or may be used as the composition of the present embodiment described above. The composition of the present embodiment can be used as a pharmaceutical composition or a food composition. The amount used, that is, the dosage, is as described above.

Examples

[0066] The present invention will be described more specifically with reference to the following examples, which are illustrative and do not limit the scope of the present invention in any way.

[0067] <Experimental materials> For the pyrroloquinoline quinone disodium salt used in this example, BioPQQ manufactured by Mitsubishi Gas Chemical Company (hereinafter also referred to as "PQQ") was used. For other compounds, reagents manufactured by Wako Pure Chemical Industries, Ltd. were used unless otherwise specified.

[0068] <Animals> Six 8-week-old male C57BL / 6J mice and twelve 83-week-old male C57BL / 6J mice were purchased from Jackson Laboratory Japan Co., Ltd. After about one week, the 9-week-old and 84-week-old mice were used as the young group and the old group, respectively.

[0069] <Breeding conditions> After arrival, the animals were housed in a breeding room with the room temperature set at 20 - 26°C, humidity at 40 - 70%, lighting on for 12 hours (7:00 - 19:00) and off for 12 hours (19:00 - 7:00) until the end of the test. The animals were housed in polycarbonate flat-bottom cages Clean S-TPX (213×324×131 (mm), CLEA Japan, Inc.) with bedding (Parsolft, Oriental Yeast Co., Ltd.) placed inside. Each cage accommodated 1 - 3 animals and they were bred on a mouse cage stand (Japan Cage Co., Ltd.). During the acclimation and test periods, the animals were allowed to freely consume solid feed AIN-93M (Oriental Yeast Co., Ltd.) (hereinafter sometimes referred to as the control feed). Also, tap water was placed in a water supply bottle (CK-200S, CLEA Japan, Inc.) for the animals to freely consume. The tap water was changed more than twice a week. After acclimation, the old-age group of mice was divided into two groups, designated as the Old group (Comparative Example 1) and the Old+PQQ group (Example 1) respectively. Thereafter, the Old+PQQ group was allowed to consume AIN-93M containing 0.02% BioPQQ (hereinafter referred to as the 0.02% BioPQQ-containing feed).

[0070] <Feed composition> AIN-93M: Cited from "Feeds for Laboratory Animals, Oriental Yeast Co., Ltd." 〔Calories〕3582 kcal / kg, 〔Components〕Total protein (12.6%), total fat (4.0%), total carbohydrates (72.7%), moisture (6.8%), 〔Raw materials used〕Casein (14.0%), L-cystine (0.18%), corn starch (46.6%), gelatinized corn starch (15.5%), sucrose (10.0%), soybean oil (4.0%), cellulose powder (5.0%), AIN-93M mineral blend (3.5%), AIN-93 vitamin mixture (1.0%), choline bitartrate (0.25%), tertiary butylhydroquinone (0.0008%)

[0071] <Grouping> After acclimation, body weight and body composition were measured, and the old-age group of mice was divided into two groups of 6 each so that their averages were approximately the same. As a control, 6 young-group mice were prepared. The number of animals bred per cage was 3 or less. (Comparative Example 1) Old group: Total of 6 animals, 2 animals / cage (Example 1) Old + PQQ group: Total of 6 animals, 1 - 2 animals / cage (Comparative Example 2) Young group: Total of 6 animals, 3 animals / cage

[0072] Administration of 0.02% BioPQQ - containing feed and control feed was started after acclimation. Feed and drinking water (filtered water) were provided for free intake. Bedding (chips) and replacement of drinking water and its bottle were carried out more than twice a week.

[0073] <Body weight and food intake (changes over time)> The body weight and food intake of the Young group, Old group, and Old + PQQ group were continuously measured weekly. As a result, an increase in body weight was observed in the Young group (Comparative Example 2), while no change in body weight was found in the Old group (Comparative Example 1) and the Old + PQQ group (Example 1). Regarding food intake, in the Young group, it increased in the first 3 weeks, then slightly decreased and remained unchanged until 8 weeks. In the Old group, food intake increased in the first 2 weeks and then remained unchanged. In the Old + PQQ group, there was no change in food intake during the experimental period. The average food intake differed among the groups, and the Old + PQQ group had a significantly lower food intake compared to the Old group. Figure 1 shows the change in body weight over time as a graph. The data represent the mean ± standard deviation. Also, Figure 2 shows the change in food intake over time as a graph. The data represent the mean value.

[0074] Table 1 shows the average food intake of each group throughout the entire experimental period and the average PQQ intake of the Old + PQQ group throughout the entire experimental period. The data represent the mean ± standard deviation. Roman letters (a, b) indicate the results of statistical analysis, and different Roman letters among groups indicate statistically significant differences. There was no significant difference between the Young group and the Old group. In contrast, the Old + PQQ group had a significant difference from these two groups. The average PQQ intake of the Old + PQQ group throughout the entire experimental period was approximately 20 mg / kg body weight / day.

[0075]

Table 1

[0076] <Body weight and body composition (changes over time)> The body weights and body compositions of the Young group, Old group, and Old+PQQ group were measured at the start of the experiment (0M) and 2 months later (2M). Body composition was measured under isoflurane anesthesia using a body composition analyzer (ImpediVET). The body composition analyzer is a device that measures the bioimpedance scanned by passing 256 frequencies from 4 kHz to 1000 kHz within 1 second. The following values were calculated from this value. Total body water (TBW), extracellular fluid volume (ECF), intracellular fluid volume (ICF), fat-free mass, and fat mass were measured and analyzed from the impedance data. The results of the body weights and body compositions of the mice are shown in Table 2. The data are presented as mean ± standard deviation. Roman letters (a, b) indicate the results of statistical analysis, and different Roman letters among groups indicate statistically significant differences.

[0077]

Table 2

[0078] Along with the progress of the test, the Young group (Comparative Example 2) grew and their body weight increased. On the other hand, the Old group (Comparative Example 1) and the Old + PQQ group (Example 1) had no change in body weight but a change in body composition. At the start of the test (0M), the body fat mass of each group was almost the same. While the body fat ratio was the highest in the Young group at 44.9%, there was no difference between the Old group and the Old + PQQ group at 35.7% and 35.1% respectively. Two months after the test (2M), the body fat mass of the Young group increased, while the body fat mass of the Old group and the Old + PQQ group decreased. The decrease in the body fat mass of the Old + PQQ group was small compared to the Old group, and the change in body fat mass was small. In terms of the body fat ratio (%), the body fat ratio decreased in each group, but the change in the body fat ratio was the smallest in the Old + PQQ group. Also, the amount of water in the body was 46%, 55% and 52% in the Young group, Old group and Old + PQQ group respectively, and the Old group had the most. Body fat functions not only as an energy storage but also plays important roles such as body temperature regulation and internal organ protection. The rapid decrease in body fat mass in the Old group of mice is considered to be due to the effects of aging and a state of malnutrition.

[0079] From the body composition data, the decrease in body fat in the Old + PQQ group (Example 1) was suppressed compared to the Old group (Comparative Example 1). The Old group (Comparative Example 1) was in a state of malnutrition with almost no body fat. In contrast, the Old + PQQ group that ingested PQQ suppressed the change to a state of malnutrition.

[0080] <CT imaging> After anesthetizing mice in each group (6 mice per group) with 3% isoflurane, CT images were taken using an industrial X-ray CT device (NAOMi-CT(3D), RF). The tube voltage was set at 70 kV and the tube current at 5 mA, and an X-ray filter was used. Analysis was performed using CTviewer software (RF). To always obtain cross-sectional images at the same position of the mice, a 90° cross-section was taken with respect to the mouse spine. A cross-sectional image of the second vertebra from the sacrum was obtained. The cross-sectional images were saved, and the body fat portion was determined using CTImageAnalyzer software. The CT image of one randomly selected individual from each group is shown in Figure 3. In Figure 3 (gray-scale conversion diagram), the areas that appear white are the body fat portions.

[0081] In the Young group, body fat accumulated as subcutaneous fat and visceral fat. On the other hand, in the Old group, there was little body fat accumulation and a decrease in body fat was observed. In the Old+PQQ group, it was confirmed that the age-related decrease in body fat could be suppressed. This is consistent with the body fat ratio data shown in Table 2 above.

[0082] <Hanging Test (Muscle Strength Measurement)> The hanging test is a test for measuring muscle strength. A wire-hanging experimental device (O'HARA & CO., LTD.) (Figure 4) was used. The mouse was made to grip the wire mesh and then the wire mesh was turned over (Figure 5). Thereafter, the time until the mouse fell from the wire mesh was measured. For mice in each group (6 mice per group), this was repeated 3 times for each mouse at intervals of 30 to 60 minutes. Measurements were taken at the start of the test (0M) and 2 months later (2M). Figure 4 shows the wire-hanging experimental device, and Figure 5 shows the state of the mouse hanging from the turned-over wire mesh. Table 3 shows the time from hanging to falling. The data represent the mean ± standard deviation. The Roman letters indicate the results of the statistical analysis, and different Roman letters for different groups indicate statistically significant differences.

[0083]

Table 3

[0084] In the hanging test results, in all groups, muscle strength decreased with aging (2 months). At the start of the test, there was a significant difference in the average hanging time between the Young group (Comparative Example 2) and the Old group (Comparative Example 1). There was also a significant difference between the Young group and the Old+PQQ group (Example 1), but there was no significant difference between the Old group and the Old+PQQ group. After 2 months of the test, there was a significant difference between the Young group and the Old group. The Old+PQQ group had no significant difference from either the Young group or the Old group, but the time until dropping was longer in the Old+PQQ group than in the Old group. The results of the hanging test showed that there was a significant difference between the Young group and the Old+PQQ group in the initial state, but the significant difference between the Young group and the Old+PQQ group disappeared after 2 months. This indicates that muscle strength is improved by PQQ intake.

[0085] <Histological examination of flounder muscle> The muscle fibers of the flounder muscle of mice were stained, and fast and slow muscle fibers were evaluated. The flounder muscles of each mouse in the Young group, Old group, and Old+PQQ group were fixed with ice-cold 4% paraformaldehyde, and paraffin sections were prepared according to the conventional method. The fast muscle fibers and slow muscle fibers in the sections were immunostained using Anti-Fast Myosin Skeletal Heavy chain antibody (abcam, ab91506), Anti-Slow Myosin Skeletal Heavy chain antibody (abcam, ab234431), and DAB chromogen, respectively. The tissue specimens subjected to various immunostainings were photographed for tissue images using an optical microscope (Nikon Eclipse TC2000-S) and a digital camera for microscopes (Nikon DS-Ri2), and saved as JPEG files (the darker parts in Fig. 6 (gray-scale conversion diagram) are the immunostaining positive parts). Using the said files, the immunostaining positive muscle fiber area and number in the tissue section were measured with ImageJ software. The results are shown in Table 4 and Fig. 7.

[0086] As a result, when comparing the Young group and the Old group, aging led to a decrease in the number and cross-sectional area of both fast and slow muscle fibers. When comparing the mice in the Old+PQQ group with those in the Old group, there was no change in the number of muscle fibers in either the fast or slow muscle, but the cross-sectional area was significantly larger in the fast muscle and all fibers. Additionally, the cross-sectional area per muscle fiber in the Old+PQQ group became the same as that in the Young group. In the flounder muscle, atrophy of muscle fibers due to aging was observed, but ingestion of PQQ significantly suppressed atrophy of the fast muscle, and although there was no significant difference, a tendency to suppress atrophy of the slow muscle was observed. Therefore, it was considered that ingestion of PQQ contributes to improvement of muscle function and muscle strength.

[0087]

Table 4

[0088] <Appearance (evaluation of mouse skin)> The skin condition of the mice was observed and evaluated at the start of the test (0M), 1 month after the test (1M), and 2 months after the test (2M). The evaluation method was based on the scores described in Table 5 below, which scored the skin condition (hair loss, dermatitis, hair quality) due to aging as evaluation items, referring to the clinical frailty index in aging mice in the following paper (1). The score was either 0, 0.5, or 1 point, with 1 point being severe. The obtained data are shown in Table 6. The data represent the score average value ± standard deviation. Roman letters indicate the results of statistical analysis, and different Roman letters for different groups indicate statistically significant differences. (1) Whitehead, J. et. al., 2014. “A Clinical Frailty Index in Aging Mice: Comparisons With Frailty Index Data in Humans.” The Journals of Gerontology. 621-32. https: / / doi.org / 10.1093 / gerona / glt136.

[0089]

Table 5

[0090]

Table 6

[0091] The skin conditions due to aging (hair loss, dermatitis, hair quality) were scored to evaluate the anti-aging effect of PQQ. As a result, the effect of suppressing the deterioration of the skin condition due to aging was observed by PQQ intake. The scores after 2 months were 0.11, 0.67, and 0.44 in the Young group (Comparative Example 2), Old group (Comparative Example 1), and Old + PQQ group (Example 1), respectively (score 1 being severe). Among the 6 mice in the Old group, 3 were severe (score ≥ 0.7) and 3 were mild (score ≥ 0.3, < 0.7). On the other hand, in the Old + PQQ group, 2 out of 6 were severe and 1 was mild.

[0092] <Serum test> The biochemical test of the mice was entrusted to Oriental Yeast. Albumin (ALB), total cholesterol (T-CHO), triglyceride (TG), creatine kinase (CK), and cholinesterase (ChE) in the serum were measured from the blood samples.

[0093] (Serum collection method) Under isoflurane anesthesia, a 1 ml syringe (Terumo) and a 25G injection needle (Terumo) were used to collect blood from the posterior vena cava of the mice. The collected venous blood was dispensed into a blood collection tube (Capject II Plain (Terumo)) and allowed to stand at room temperature within 2 - 2.5 hours. After detaching the blood clot from the wall, it was centrifuged at 1500G and 18°C for 15 minutes. The supernatant was dispensed into one cryogenic vial (1.2 ml capacity, outer lid, Iwaki) and stored frozen at -80°C until analysis.

[0094] Biochemical parameters serving as indicators of malnutrition include serum albumin (ALB) and total cholesterol (T-CHO). Compared with the Young group, the ABL and T-CHO values were lower in the Old group, which was considered the cause of nutritional deficiency. This result is consistent with the fat ratio of body composition. There was no difference in the ABL value between the Old group and the Old+PQQ group, and there was a tendency for the T-CHO value to be improved by PQQ. Regarding serum triglyceride, the Old+PQQ group had the lowest TG value among the three groups.

[0095] Choline esterase (ChE) is an enzyme synthesized in hepatocytes and secreted into the blood, and it is one of the tests for examining liver cirrhosis. Compared with the Young group, the Old group and the Old+PQQ group had higher ChE test values, and when the test value is high, it is a disease suspected of fatty liver and diabetes.

[0096] Creatine kinase (CK) plays an important role in muscle energy metabolism, and by performing a blood test, the value of CK dissolved in the blood can be known. When the CK value is high, it indicates that tissues such as muscle have been damaged and the CK contained therein has flowed into the blood. Compared with the Young group, the CK value was higher in the Old group, and the CK value was the lowest in the Old+PQQ group, showing a tendency to improve muscle damage by PQQ intake.

[0097] The results of the mouse serum test are shown in Table 7. The data represent the score mean value ± standard deviation. The Roman letters indicate the results of the statistical analysis, and different Roman letters for different groups indicate statistically significant differences.

[0098]

Table 7

Claims

1. A hypo-nutrition improving agent that contains pyrroloquinoline quinone and / or a salt thereof as an active ingredient and improves one or more symptoms among the symptoms of hypo-nutrition.

2. The hypo-nutrition improving agent according to Claim 1, wherein the one or more symptoms are symptoms selected from muscle mass reduction, body fat reduction, hair deterioration, and increase in water content.

3. The hypo-nutrition improving agent according to Claim 1, wherein the one or more symptoms include muscle mass reduction.

4. The hypo-nutrition improving agent according to Claim 1, wherein the one or more symptoms include body fat reduction.

5. The hypo-nutrition improving agent according to Claim 1, wherein the one or more symptoms include hair deterioration.

6. The hypo-nutrition improving agent according to Claim 1, wherein the hypo-nutrition is hypo-nutrition caused by aging.

7. The hypo-nutrition improving agent according to Claim 1, which improves two or more symptoms among the symptoms of hypo-nutrition.

8. The hypo-nutrition improving agent according to Claim 1, wherein the salt is a disodium salt.

9. The hypo-nutrition improving agent according to Claim 1, wherein the pyrroloquinoline quinone and / or the salt thereof is a hydrate.

10. A composition containing the hypo-nutrition improving agent according to any one of Claims 1 to 9.

11. A hypo-nutrition improving food containing the hypo-nutrition improving agent according to any one of Claims 1 to 9.

12. A method for improving hypo-nutrition, which uses the hypo-nutrition improving agent according to any one of Claims 1 to 9.

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