Use of at least one imidazole dipeptide in the manufacture of an oral nutritional composition for the improvement of logical memory

Abstract

The present invention relates to the use of at least one of the imidazole dipeptides, any one of camosine, anserine, balenine and homoanserine, in the manufacture of an oral nutritional composition for the improvement of logical memory.

Description

[0001] This application is a divisional application. The original application's international application number is PCT / JP2015 / 056412, its Chinese national application number is 201580017212.3, its application date is March 4, 2015, and its invention title is "Reagent Containing Imidazole Dipeptide". Technical Field

[0002] This invention relates to the use of at least one imidazole dipeptide in the manufacture of an oral nutritional composition for improving logical memory. It also relates to a reagent having at least one selected from the group consisting of imidazole dipeptides and their metabolites as an active ingredient. The reagent of this invention can be used for improving cognitive function, improving psychological function, anti-aging, and maintaining health. This invention is useful in the fields of general food, health food, pharmaceuticals, cosmetics, health, and medical care. Background Technology

[0003] Carnosine is a dipeptide composed of β-alanine and histidine, while anserine is a dipeptide composed of β-alanine and methylated histidine. Both are known to be found in chicken meat and other similar foods. Studies have been conducted on the effects of carnosine and anserine on promoting skin metabolism (Patent Document 1), regulating autonomic nervous system function (Patent Document 2), relieving stress (Patent Document 3), and improving learning ability and reducing anxiety (Patent Document 4).

[0004] In recent years, the prevention of aging-related diseases and the enhancement of immunity have gradually gained attention in terms of maintaining health and longevity. Aging is often accompanied by some degree of cognitive decline. Furthermore, the onset and progression of Alzheimer's disease also lead to cognitive decline.

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: Japanese Patent Application Publication No. 2000-201649

[0008] Patent Document 2: WO2002 / 076455

[0009] Patent Document 3: Japanese Patent Application Publication No. 2007-70316

[0010] Patent Document 4: Japanese Patent Application Publication No. 2000-116987 Summary of the Invention

[0011] The problem that the invention aims to solve

[0012] The hope is that through proper diet, exercise, and psychotherapy, the aging process can be slowed down in daily life, and that diseases associated with aging can be addressed as early as possible.

[0013] Besides serving as a source of energy and essential nutrients (nutritional value), food also provides the pleasure of tasting (palmatism) and contributes to a healthy lifestyle (functional value). Foods, or products containing functional ingredients derived from food, are expected to play a role in health and beauty, and are widely accepted as health foods. From a safety and peace of mind perspective, it is also considered preferable to utilize natural products with proven edibility.

[0014] Methods for solving problems

[0015] The inventors of this invention effectively utilize natural resources and are dedicated to the research and development of foods and materials beneficial to health. In this invention, they discovered that carnosine and anserine derived from chicken have effects such as improving psychological function, thus completing this invention. The present invention provides the following technical solution.

[0016] [1] An agent for improving neuropsychological function, comprising at least one selected from the group consisting of imidazole dipeptide and its metabolites.

[0017] [2] The reagents described in [1], wherein neuropsychological function is associated with Alzheimer’s disease or aging.

[0018] [3] An anti-aging agent based on the improvement of neuropsychological function, comprising at least one selected from the group consisting of imidazole dipeptide and its metabolites.

[0019] [4] An agent for altering the expression of the following genes, comprising at least one selected from the group consisting of imidazole dipeptides and their metabolites. The gene is selected from at least one of the following groups of genes: The genes that act as transport proteins are SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12, and SLC6A13; CXCL12 and CCL17 are chemokine genes; TSPO and P2RY1 are aging-related genes; CAMK1 is a gene for the nervous system; Genes that form the mitochondrial system include ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA, and TAP2; and SMARCD1 and SIRT6 are anti-aging genes.

[0020] [5] The reagent described in [1] has anti-inflammatory effects.

[0021] [6] A reagent for regulating the blood concentration of the following cytokines, comprising at least one selected from the group consisting of imidazole dipeptides and their metabolites, wherein the cytokines are at least one selected from the group consisting of IP-10 (CXCL10), IL-2, IL-5, IL-7, IL-8 (CXCL8), IL-13, G-CSF and MCP-1 (CCL2).

[0022] [7] The reagent described in [1] has an inhibitory effect on blood glucose levels or a lowering effect on blood glucose levels.

[0023] [8] The reagent described in [1] has an inhibitory effect on the increase or decrease of insulin concentration in the blood.

[0024] [9] The reagent according to any one of claims [1] to [8] is used to administer to a subject an intake of at least one of the group consisting of imidazole dipeptide and its metabolites in a daily amount of 200 mg or more.

[0025]

[10] A nutritional composition comprising at least one of imidazole dipeptides derived from animal meat in a daily amount of 200 mg or more.

[0026]

[11] The nutritional composition as described in

[10] , wherein at least one of the imidazole dipeptides is derived from chicken.

[0027]

[12] The reagent or nutritional composition as described in any one of [1] to

[11] , wherein it further comprises creatine and nucleic acid.

[0028]

[13] The reagent or nutritional composition as described in any one of [1] to

[12] is intended for elderly people or people with mild mood disorders.

[0029]

[14] An agent for the treatment of diabetes and / or Alzheimer's disease, comprising at least one selected from the group consisting of imidazole dipeptides and their metabolites.

[0030]

[15] A dietary method comprising the step of ingesting a nutritional composition comprising at least one selected from the group consisting of imidazole dipeptides and their metabolites by an individual wishing to improve neuropsychological function.

[0031]

[16] A method for determining the neuropsychological function of an object, the method being based on the carnosine hydrolase (CNDP1) activity possessed by the object.

[0032]

[17] A method for predicting the improvement of neuropsychological function produced by subjecting a subject to ingest any of the reagents or nutritional compositions described in any of [1] to

[14] , the method being based on CNDP1 activity in the subject.

[0033]

[18] A method for detecting improvement or deterioration of neuropsychological function based on the expression analysis of the following genes, The gene is selected from at least one of the following groups of genes: The genes that act as transport proteins are SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12, and SLC6A13; CXCL12 and CCL17 are chemokine genes; TSPO and P2RY1 are aging-related genes; CAMK1 is a gene for the nervous system; Genes that form the mitochondrial system include ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA, and TAP2; and SMARCD1 and SIRT6 are anti-aging genes.

[0034]

[19] A kit for detecting improvement or deterioration of neuropsychological function, comprising a nucleic acid consisting of a base sequence selected from at least one base sequence selected from the group consisting of all or part of any base sequence from sequence numbers 1 to 20 and all or part of a base sequence complementary to any base sequence from sequence numbers 1 to 20.

[0035]

[20] A pharmaceutical composition for the treatment of functional aging of the brain and / or dementia, comprising a compound represented by formula I or II.

[0036]

Chemistry 1

Chemistry 2

[21] A method for exploring effective ingredients for the treatment of functional aging of the brain and / or dementia, using compounds represented by formula I or formula II as defined in

[20] as lead compounds. Attached Figure Description

[0037] Figure 1 It is the result of a psychological function test (BDI test).

[0038] Figure 2 This is the result of a psychological function test (ADAScog test, which evaluates brain aging). It shows the proportions of improvement, no change, and deterioration.

[0039] Figure 3-1 These are brain regions (gray matter) where atrophy is improved through the uptake of imidazole dipeptide. Regions with p < 0.005 are indicated by color.

[0040] Figure 3-2 It is the brain region (white matter) whose atrophy is improved through the uptake of imidazole dipeptide.

[0041] Figure 4 The improvement in neural circuit function was induced by the uptake of imidazole dipeptide. With aging, the function of neural circuits in the hippocampus and postcingulate gyrus decreases (left figure), but in the experimental dietary intake group, this functional decline was improved after intake (right figure).

[0042] Figure 5 These are genes whose expression changes are mediated by the uptake of imidazole dipeptides. Among the six genes belonging to the SLC (transporter protein) group, the expression levels of these genes changed significantly with the experimental diet compared to a placebo diet. In addition, changes were observed in the expression levels of genes such as chemokines, as shown in the figure.

[0043] Figure 6 These are blood cytokines and chemokines that change through the uptake of imidazole dipeptide. Mean ± SE, experimental diet: solid line, placebo: dashed line, paired t-test. p < 0.05 p < 0.01

[0044] Figure 7 The decrease in blood glucose levels is caused by the intake of imidazole dipeptide.

[0045] Figure 8-1 This indicates a decrease in blood cytokines in dementia model mice. The decrease in cytokines in the carnosine-containing diet group suggests suppressed inflammation. wt: wild-type, tg: transgenic. p < 0.05 : P < 0.01 (Dunnett's test for tgHFD), #: p < 0.05, ##: P < 0.01 (Student's t-test)

[0046] Figure 8-2It inhibits the inflammatory response in the brain of mice with dementia (mouse MRI images). Inflammation suppression was observed through the uptake of imidazole dipeptide.

[0047] Figure 8-3 This is due to the inhibition of GABA transporter gene expression in glial cells caused by high-functioning dipeptide uptake. Slc6A13: GABA transporter 2 (GAT-2) expressed in astrocytes; Slc6A12: betaine / GABA transporter 1 (BGT-1) expressed in astrocytes.

[0048] Figure 8-4 This refers to the blood insulin concentration in mice. A significant difference was identified between the values ​​in the Alzheimer's disease (AD) high-fat diet group and the AD high-fat diet + carnosine group (Student's t-test, P < 0.05).

[0049] Figure 9 It is an ASL analysis.

[0050] Figure 10 The site of difference observed between the two groups was the posterior cingulate cortex (ACG) through ASL analysis.

[0051] Figure 11 This is the score of Logical Memory II (results of subgroup analysis in individuals aged 60 and older). There was no significant difference between the two groups (P < 0.01). It should be noted that post-intake testing is far more challenging than pre-intake testing.

[0052] Figure 12 This is the score of Logical Memory II (results of subgroup analysis in individuals aged 60 and older). In the experimental diet group, function did not decline across all ages, whereas in the placebo diet group, there was a tendency for age-related functional decline to become significant. Detailed Implementation

[0053] [Active Ingredients]

[0054] This invention relates to a reagent in which at least one of the groups selected from imidazole dipeptides and their metabolites is used as the active ingredient. In this specification, when referring to imidazole dipeptides, unless otherwise specified, it means a dipeptide formed by the combination of an amino acid having an imidazole ring with other amino acids.

[0055] The imidazole dipeptide mentioned in this invention can be represented by the following formula I or formula II.

[0056]

Transformation 3

Chemistry 4

[0057] In formula I, R 1 R 2 C is preferred. 1-6 Alkyl group, the other being H. In formula II, R 2 R 3 C is preferred. 1-6 Alkyl group, the other being H. C 1-6 One preferred example of an alkyl group is methyl.

[0058] As X is -COR 4 Specific examples include formyl, acetyl, propionyl, benzoyl, and acrylyl groups.

[0059] For methods of manufacturing compounds represented by Formula I or Formula II, please refer to Japanese Patent Application Publication Nos. 2003-520221, 2006-232686, 2006-504701, 2008-517911, 2009-512459, 2010-31004, 2011-37891, 2011-37892, 2013-165728, and 2014-12735.

[0060] Imidazole dipeptides include carnosine, anserine, cetacean carnosine, and homocarnosine. Carnosine is a dipeptide composed of β-alanine and histidine. Depending on the stereostructure of the histidine residues that constitute carnosine, it exists in L-forms and D-forms. In this invention and its description, when referred to simply as "carnosine," unless specifically stated otherwise, it refers to L-carnosine, D-carnosine, or mixtures thereof. L-carnosine is known to exist in relatively high concentrations in muscle and nerve tissue in mammals such as humans.

[0061] The structure of L-carnosine (IUPAC name: (2S)-2-[(3-amino-1-oxopropyl)amino]-3-(3H-imidazol-4-yl)propionic acid) is shown below.

[0062]

Transformation 5

[0063] In some animals, L-aneserin, composed of β-alanine and methylated histidine, is commonly found. In this invention and its description, when referred to simply as "aneserin," unless specifically stated otherwise, it refers to L-aneserin, D-aneserin, or mixtures thereof. The structure of L-aneserin (IUPAC name: (2S)-2-[(3-amino-1-oxopropyl)amino]-3-(3-methyl-4-imidazolyl)propionic acid) is shown below.

[0064]

Transformation 6

[0065] Both carnosine and anserine are water-soluble (carnosine is 1g / 3.1ml at 25℃).

[0066] In this specification, unless otherwise specified, references to the metabolites of imidazole dipeptides refer to a metabolite of one imidazole dipeptide selected from the group consisting of carnosine, anserine, cetirine, and homocarnosine. The metabolites of imidazole dipeptides include β-alanine, histidine, methylated histidine, and γ-aminobutyric acid (GABA).

[0067] When this invention refers to "at least one selected from the group consisting of imidazole dipeptides and their metabolites," unless specifically stated otherwise, it refers to one or more imidazole dipeptides. For example, when referring to "containing at least one selected from the group consisting of imidazole dipeptides and their metabolites as an active ingredient," it includes cases where carnosine is the active ingredient and no other imidazole dipeptides are included, and cases where carnosine and anserine are the active ingredients. Furthermore, regarding "at least one selected from the group consisting of imidazole dipeptides and their metabolites," when referring to amount or concentration, unless specifically stated otherwise, when two or more imidazole dipeptides and their metabolites are present, it refers to the total amount or concentration of all imidazole dipeptides and their metabolites. It should be noted that in this specification, the use of imidazole peptides, carnosine, or anserine as examples of imidazole dipeptides and their metabolites is sometimes used, but this description is also applicable to cases where other imidazole dipeptides and their metabolites are used.

[0068] In this invention, the imidazole dipeptide and its metabolites used as the active ingredient can be synthetic substances, fermented substances, or substances obtained from natural sources. Alternatively, they can be isolated or purified substances. More specifically, the imidazole dipeptide and its metabolites can be derived from various animals, such as cattle, horses, pigs, chickens, whales, and fish (e.g., skipjack tuna, tuna, eel; a preferred example is from chicken). The imidazole dipeptide and its metabolites can also be contained in reagents as extracts, concentrates, or crude / refined products of natural substances.

[0069] [Purpose, Function]

[0070] The reagents of this invention can be used to improve neuropsychological function. Improvements in neuropsychological function include antidepressant effects (improvement of psychological function) and cognitive function improvement. Additionally, improvements in neuropsychological function include inhibition of brain atrophy, inhibition of decreased brain function (enhanced functional connections with the hippocampus), and improvement of neuronal damage caused by inflammation. Neuropsychological function may also be associated with Alzheimer's disease or aging. Furthermore, improvements in neuropsychological function include the management of functional aging of the brain and / or dementia.

[0071] The antidepressant (improvement of psychological function) effect produced by the reagent of the present invention can be evaluated using the BDI questionnaire (http: / / www.chibatc.co.jp / catalogue / 04 / 1 / 67.html). A high score on the BDI questionnaire indicates a tendency towards depression; therefore, the degree of improvement in psychological function can be compared, for example, by conducting a survey before and after the period of ingestion of the reagent of the present invention and comparing the scores before and after ingestion. The reagent of the present invention is particularly expected to improve psychological function in individuals with mild mood disorders.

[0072] The cognitive function improvement effect produced by the reagent of the present invention can be evaluated using the ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) method. The cognitive function improvement effect produced by the present invention includes: improvement in the degree of age-related memory decline and improvement in pathological cognitive decline (dementia). The reagent of the present invention is particularly expected to improve cognitive function decline associated with Alzheimer's disease or aging.

[0073] The reagents of this invention can be used to inhibit brain atrophy, suppress brain function decline (enhanced functional connectivity with the hippocampus), or improve neuronal damage caused by inflammation. The effects on these impairments can be evaluated using methods well-known to those skilled in the art, such as imaging diagnostics. According to the inventors' research, in a group including elderly subjects, sites of inhibited atrophy progression were observed in both the gray and white matter of the brain. This effect was not observed in the group receiving a placebo that did not contain chemoresine or carnosine.

[0074] The reagents of this invention can be used to treat functional aging of the brain and the onset of dementia, and more specifically, can be used to prevent, delay, or inhibit functional aging of the brain and the onset of dementia, or to prevent its progression to severe illness. This effect can be confirmed by evaluating changes in blood flow in the postcingulate gyrus of subjects, or by assessing logical memory (delayed recall task) in subjects aged 60 and older. According to the inventors' research, in subjects including those aged 60 and older, blood flow in the postcingulate gyrus remained significantly different compared to the placebo diet group in the experimental diet containing imidazole dipeptide. Furthermore, in subjects aged 60 and older, logical memory scores showed a significant difference compared to the placebo diet group in the 3-month experimental diet group.

[0075] The reagents of this invention can be used to alter the expression of transport proteins. Transport proteins are membrane proteins that coexist with channels and receptors in the cell membrane. However, unlike channels, transport proteins recognize not only endogenous substances as transport substrates but also many exogenous substances, including drugs and environmental chemicals. Transport proteins are currently classified into two families: the ABC (ATP-binding cassette) family, which utilizes the hydrolysis energy of ATP for transport, and the SLC (solute carrier) family, which does not utilize ATP energy for transport. In humans, 48 ​​ABC transport protein genes and 319 SLC transport protein genes have been identified. Diseases caused by abnormalities in transport proteins are increasing with aging; it is believed that approximately 10% of age-related diseases after age 50 are related to transport proteins.

[0076] The reagents of the present invention are particularly useful for altering the expression of at least one, preferably at least three, more preferably five, and even more preferably all transport proteins selected from the group consisting of SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12, and SLC6A13. Changes in expression include increasing and decreasing expression.

[0077] The reagents of this invention can be used to alter the expression of chemokines. Chemokines are basic proteins that exert their effects through G protein-coupled receptors and are a class of cytokines. They induce the migration of leukocytes and other cells, participating in the formation of inflammation. Numerous chemokines have been discovered to date. Based on structural differences, they are classified into CC chemokines, CXC chemokines, CC chemokines, and CX3 C chemokines. More than 50 chemokines have been identified to date.

[0078] The reagents of the present invention can be used in particular to alter the expression of at least one, preferably two, chemokines selected from the group consisting of CXCL12 and CCL17. Changes in expression include increasing and decreasing expression.

[0079] The reagents of this invention can be used to alter the expression of aging-related genes. Aging-related genes, which are associated with individual aging and cellular aging, have been identified, and a large number of aging-related genes have been identified to date.

[0080] The reagents of this invention are particularly useful for altering the expression of at least one, preferably two, aging-related genes selected from the group consisting of TSPO and P2RY1. Changes in expression include both increasing and decreasing expression.

[0081] The reagents of this invention can be used to alter the expression of nervous system genes. Nervous system genes are those related to neurogenesis, neural differentiation, etc., and a large number of nervous system genes have been identified to date.

[0082] The reagents of this invention can be used in particular to alter the expression of the nervous system gene CAMK1. Changes in expression include both increasing and decreasing expression.

[0083] The reagents of this invention can be used to alter the expression of mitochondrial system genes. Mitochondrial system genes are those involved in mitochondrial biosynthesis, fusion, the TCA cycle, and respiration, and a large number of these genes have been identified to date.

[0084] The reagents of the present invention are particularly useful for altering the expression of at least one, preferably at least three, more preferably five, and even more preferably all mitochondrial system genes selected from the group consisting of ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA, and TAP2. Changes in expression include increasing and decreasing expression.

[0085] The reagents of this invention can be used to alter the expression of anti-aging genes. Anti-aging genes are genes that inhibit cellular aging and combat aging; to date, a large number of these genes have been identified.

[0086] The reagents of this invention are particularly useful for altering the expression of at least one, preferably two, chemokines selected from the group consisting of SMARCD1 and SIRT6. Changes in expression include both increasing and decreasing expression.

[0087] Furthermore, the reagents of the present invention can be used to regulate at least one cytokine selected from the group consisting of IP-10 (CXCL10), IL-2, IL-5, IL-7, IL-8 (CXCL8), IL-13, G-CSF, and MCP-1 (CCL2). Regulation includes increasing and decreasing levels.

[0088] In addition, the reagents of the present invention can also be used as anti-inflammatory agents or to inhibit or reduce the rise in blood glucose levels.

[0089] In this invention, when referring to a disease or condition, the terms "improvement" or "treatment" include reducing the risk of disease onset, delaying the onset of disease, prevention, treatment, and stopping or delaying its deterioration. Actions for improvement or treatment include: medical actions performed by physicians for the purpose of treating the disease; and non-medical actions performed by persons other than physicians, such as nutritionists (managed nutritionists, health care workers, midwives, nurses, clinical laboratory technicians, beauty professionals, beauticians, food manufacturers, food sellers, etc.). Furthermore, treatment includes: recommendations for the administration or intake of specific foods, dietary guidance, health guidance, nutritional guidance (including nutritional guidance needed for the recuperation of the injured and sick, and nutritional guidance for maintaining and improving health), dietary management, and guidance needed for nutritional improvements related to dietary management. The object of treatment in this invention includes persons (individuals), preferably persons who wish to implement any of the above-described treatments or who need to implement any of the above-described treatments.

[0090] It should be noted that, in order to verify the individual differences arising from the effectiveness of imidazole dipeptide, the inventors measured the serum carnosine-degrading enzyme (hereinafter referred to as CNDP1) activity in the serum of the test subjects. The results of the activity measurement confirmed that there were significant individual differences among the test subjects. CNDP1 is present in the blood and breaks down imidazole dipeptide. Therefore, CNDP1 can affect the concentration of imidazole dipeptide in the blood after imidazole dipeptide ingestion, and thus may affect the effectiveness of imidazole dipeptide. Therefore, it is considered that information on the CNDP1 activity in the subject is useful for pre-determining whether treatment based on imidazole dipeptide ingestion is effective. Therefore, the present invention provides a method for determining the neuropsychological function of a subject based on the carnosine-degrading enzyme (CNDP1) activity of the subject; and provides a method for predicting the improvement effect of neuropsychological function produced by subject ingestion of the reagent or nutritional composition of the present invention based on the CNDP1 activity of the subject. Among these methods, it may be a method of pre-determining a benchmark value for judgment and mechanically predicting based on that benchmark.

[0091] [Reagents]

[0092] In this invention, when referring to "reagent", unless otherwise specified, it includes the case of the active ingredient itself and the case of containing the active ingredient and other ingredients, but does not include existing foods containing at least one of the group consisting of imidazole dipeptides and their metabolites, such as chicken itself.

[0093] As long as the desired effect can be achieved, the reagents of this invention can be mixed with other components besides the active ingredient. These other components can be various additives permitted as food or pharmaceuticals. Examples include excipients, antioxidants, flavorings, seasonings, sweeteners, colorants, thickeners and stabilizers, color-developing agents, bleaching agents, antifungal agents, gum bases, bittering agents, enzymes, gloss agents, acidulants, emulsifiers, reinforcing agents, manufacturing agents, binders, isotonic agents, buffers, solubilizers, preservatives, stabilizers, coagulants, etc.

[0094] Other ingredients can also be functional ingredients other than the active ingredients. Examples of other functional ingredients include amino acids (such as branched-chain amino acids, ornithine), unsaturated fatty acids (such as EPA, DHA), vitamins, trace metals, glucosamine, chondroitin, etc.

[0095] When the reagent of the present invention is composed of an active ingredient and other components besides the active ingredient, the content of the active ingredient can be appropriately designed by those skilled in the art from the perspectives of ease of manufacture and ease of use. For example, it can be 0.1% to 99.9%, 1% to 95%, 10% to 90%, or even 51% to 90% or more. Furthermore, the content of carnosine can be 21% or more, and the content of anserine can be 31% or more.

[0096] As described above, in addition to existing food products, the reagents of the present invention can be in various forms. For example, they can be pharmaceutical compositions such as oral medicines or nutritional compositions. Furthermore, the reagents of the present invention can be added to pharmaceutical compositions such as oral medicines or nutritional compositions for use. When referring to "nutritional composition" in the present invention, unless specifically stated otherwise, it includes not only solid substances but also liquid substances, such as beverages. Furthermore, when referring to "nutritional composition" in the present invention, unless specifically stated otherwise, it includes health foods, nutritional supplements, health functional foods (including nutritional functional foods and foods for specific health purposes), and includes therapeutic foods (foods intended for therapeutic purposes; foods prepared according to recipes prepared by nutritionists or the like based on dietary prescriptions issued by doctors), dietary therapy foods, ingredient-adjusted foods, low-sodium foods, care foods, low-calorie foods, and weight-loss foods, as well as materials used in these foods.

[0097] Examples of the forms of reagents, pharmaceutical compositions, or nutritional compositions of the present invention include powders, granules, pellets, tablets, capsules, liquid preparations (including elixirs, lemonades, syrups, emulsions, suspensions, solutions, and beverages), gel preparations, therapeutic foods, beverages, snacks, processed meat products, processed fish and shellfish products, processed vegetable products, side dishes, seasoning compositions, and food additives.

[0098] Regarding the intake of the active ingredient of this invention, those skilled in the art can appropriately design it according to the age, weight, sex, applicable disease or condition of the person taking it. The intake of the active ingredient can be, for example, 200 mg / day, preferably 400 mg / day, more preferably 500 mg / day or more, and even more preferably 750 mg / day or more. Alternatively, it can be 1,000 mg / day or more, 2,000 mg / day or more, 5,000 mg / day or more, or 7,500 mg / day or more. In any case, it can be 10,000 mg / day or less. Furthermore, in any case, the lower limit can be 50,000 mg / day or less, preferably 30,000 mg / day or less, more preferably 20,000 mg / day or less, and even more preferably 10,000 mg / day or less. As the active ingredient, the above-mentioned daily intake can be taken all at once, or it can be taken in two or more doses.

[0099] Regarding the amount of the active ingredient in the reagent, pharmaceutical composition, or nutritional composition of the present invention, those skilled in the art can appropriately design it, for example, it can be 1,000 mg / 100 g or more, preferably 1,500 mg / 100 g or more, more preferably 2,000 mg / 100 g or more, more preferably 2,500 mg / 100 g or more, more preferably 3,000 mg / 100 g or more, and even more preferably 3,500 mg / 100 g or more. In any case, it can be 50,000 mg / 100 g or less, preferably 40,000 mg / 100 g or less, more preferably 30,000 mg / 100 g or less, and even more preferably 20,000 mg / 100 g or less.

[0100] Furthermore, the reagents, pharmaceutical compositions, or nutritional compositions of the present invention may also contain components other than the active ingredient. Components other than the active ingredient include, for example, creatine and nucleic acids. Regarding the creatine content, for example, the daily dose may be 10 mg or more, preferably 20 mg or more, more preferably 30 mg or more, more preferably 60 mg or more, more preferably 100 mg or more, and even more preferably 200 mg or more. In any case, it may be 2,000 mg or less, preferably 1,000 mg or less, more preferably 750 mg or less, and even more preferably 500 mg or less. Regarding the nucleic acid content, for example, the daily dose may be 0.15 mg or more, preferably 0.30 mg or more, more preferably 0.50 mg or more, more preferably 1.0 mg or more, more preferably 2.0 mg or more, and even more preferably 3.0 mg or more. In any case, it may be 50 mg or less, preferably 40 mg or less, more preferably 20 mg or less, and even more preferably 10 mg or less.

[0101] When the reagents, pharmaceutical compositions, or nutritional compositions of the present invention are formulated into therapeutic foods (foods intended for therapeutic purposes; foods prepared according to recipes prepared by nutritionists or the like based on dietary prescriptions written by doctors), dietary therapy foods, ingredient-adjusted foods, low-sodium foods, care foods, low-calorie foods, weight-loss foods, or sports foods (including foods intended to enhance capacity during aerobic exercise, foods intended to enhance endurance during aerobic exercise, foods intended to accumulate nutrients in the body up to the day of the competition, foods used to replenish nutrients during the competition, and foods intended to recover from fatigue after the competition), the content of the active ingredient can be designed as an intake for one meal.

[0102] The reagents, pharmaceutical compositions, or nutritional compositions of the present invention can be repeatedly ingested by the subject and can be ingested by the subject for extended periods. Particularly when the purpose is to enhance exercise-related capabilities, it is preferable to ingest them before exercise, and more preferably daily.

[0103] The reagents, pharmaceutical compositions, or nutritional compositions of the present invention may be labeled with indications of their applicability to neuropsychological function, brain atrophy or functional decline, and neuronal damage caused by inflammation, and may be recommended for specific groups, such as the elderly over 65 years of age or people with mild mood disorders. These indications may be direct or indirect. Examples of direct indications include descriptions on tangible objects such as the product itself, packaging, containers, labels, and tags. Examples of indirect indications include advertising and promotional activities conducted through websites, shops, exhibitions, billboards, bulletin boards, newspapers, magazines, television sets, radios, mail, emails, and other similar venues or means.

[0104] [Manufacturing Method]

[0105] The reagents, pharmaceutical compositions, or nutritional compositions of the present invention can be manufactured using various known techniques. The step of adjusting the active ingredient to a specified concentration can be applied at various stages of the manufacturing process. Those skilled in the art can appropriately design the manufacturing steps for the reagents used in the present invention, taking into account the solubility, stability, volatility, etc., of the active ingredient. Based on the inventors' research, it has been confirmed that anserine and carnosine are sufficiently stable at room temperature and sufficiently stable under cooking conditions below 180°C. Furthermore, it has been confirmed that they can be stably stored in solution for at least 2 years and 9 months.

[0106] In the case where chicken extract constitutes the active ingredient of the present invention, an example of a method for manufacturing the chicken extract will be specifically described. Chicken meat is chopped, added to warm water, the pH is adjusted as needed, and heating is performed as needed, followed by extraction over several minutes to several days. An example of extraction conditions is treatment at 50°C to 100°C for 1 to 10 hours. The obtained extract can be purified and graded as needed using diatomaceous earth filtration, ultrafiltration, etc. Desalting and protease treatment can be performed as needed. The part of the chicken used as raw material is not particularly limited, but breast meat is preferred due to its high content of carnosine and / or anserine. The obtained extract can be dried by hot air drying, spray drying, freeze drying, etc., to produce a dried product. It can also be granulated to produce granules.

[0107] [Expression Analysis]

[0108] In addition, the present invention provides a method for detecting improvement or deterioration of neuropsychological function based on the expression analysis of the following genes, which are at least one selected from the group consisting of: SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12 and SLC6A13 as transporter genes; CXCL12 and CCL17 as chemokine genes; TSPO and P2RY1 as aging-related genes; CAMK1 as a nervous system gene; ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA and TAP2 as mitochondrial system genes; and SMARCD1 and SIRT6 as anti-aging genes. Furthermore, a kit for detecting improvement or deterioration of neuropsychological function is provided, comprising a nucleic acid consisting of at least one base sequence selected from all or part of any base sequence selected from sequence numbers 1 to 20, and all or part of a base sequence complementary to any base sequence selected from sequence numbers 1 to 20.

[0109] Expression analysis preferably focuses on the expression of the following genes: at least one transporter gene selected from the group consisting of SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12, and SLC6A13; at least one chemokine gene selected from the group consisting of CXCL12 and CCL17; at least one aging-related gene selected from the group consisting of TSPO and P2RY1; a nervous system gene selected from CAMK1; at least one mitochondrial system gene selected from the group consisting of ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA, and TAP2; and at least one anti-aging gene selected from the group consisting of SMARCD1 and SIRT6. More preferably, the expression of all of the above genes is analyzed.

[0110] In the development of new drugs and functional food ingredients, the following methods have attracted attention: monitoring the effects of candidate drugs and ingredients at the cellular level, evaluating their efficacy and safety, capturing genes expressed in cells before and after drug administration across the entire genome, and quantitatively capturing the effects of drugs or ingredients by changes in gene expression levels. In this method, by analyzing the expression of combinations of genes provided by this invention, the effects of candidate drugs on neuropsychological functions can be analyzed.

[0111] In this invention relating to expression analysis, the nucleic acid, consisting of at least one base sequence selected from all or part of any base sequence chosen from Serial Numbers 1 to 20, and all or part of a base sequence complementary to any base sequence chosen from Serial Numbers 1 to 20, can be a probe capable of specifically hybridizing with the transcript in the sample being detected, or a primer pair capable of amplifying all or part of the transcript. The nucleic acid can be DNA or RNA.

[0112] In this invention related to expression analysis, the length of the nucleic acid composed of at least one base sequence selected from the group consisting of all or part of any base sequence selected from sequence numbers 1 to 20 and all or part of a base sequence complementary to any base sequence selected from sequence numbers 1 to 20, when used as a probe, is, for example, 15 bases or more, preferably 20 bases or more, and more preferably 25 bases or more. For the probe nucleic acid, in order to enable the detection and quantification of the target nucleic acid, it can be labeled using, for example, radioisotopes, enzymes, fluorescent substances, or luminescent substances. The nucleic acid used as a probe can be immobilized on a solid phase.

[0113] The length of the nucleic acid used as a primer is, for example, 15 to about 100 bases, preferably 15 to 50 bases, and preferably a primer pair designed to amplify DNA fragments of 100 bp to several kbp.

[0114] The nucleic acids used can be chemically synthesized using commercially available automated DNA / RNA synthesizers. Alternatively, nucleic acids can be directly synthesized on a solid phase such as silicon or glass to create a chip (array) with immobilized nucleic acids. DNA microarrays are a preferred method of providing nucleic acid probes immobilized on a substrate.

[0115] To quantitatively analyze the expression of specified gene clusters using minute amounts of sample, competitive RT-PCR or real-time RT-PCR can be used. The sample to be analyzed can be blood collected from a human.

[0116] [Use as a lead compound]

[0117] According to the present invention, a method (screening method) is provided for exploring effective components for improving neuropsychological function, particularly for treating functional aging of the brain and / or dementia, using the aforementioned imidazole dipeptide and its metabolites as lead compounds. Lead compounds are generally defined as compounds with well-defined pharmacological activities, whose activity can be increased and toxicity reduced by chemical modification. The imidazole dipeptide and its metabolites, as described above, possess pharmacological activities such as improving neuropsychological function, particularly for treating functional aging of the brain and / or dementia; further chemical modification can be expected to increase activity and reduce toxicity.

[0118] Chemical modification refers, for example, to the optimization of the lead compound through chemical modification. Chemical modification can include, for example, the substitution or removal of some amino acids, or the addition or insertion of at least one amino acid. Additionally, the addition, substitution, or removal of functional groups of each amino acid can be considered; as well as the substitution of each amino acid for a D-form amino acid or an artificial amino acid.

[0119] According to the present invention, by using imidazole dipeptide and its metabolites as lead compounds for optimization, it is possible to explore effective components with superior physical properties, pharmacokinetics and toxicity.

[0120] The present invention will now be described using examples, but the scope of the present invention is not limited to the scope described in the examples.

[0121] Example

[0122] [Evaluation using healthy volunteers 1]

[0123] The participants (28 healthy male and female volunteers aged 40 and above were divided into an experimental diet group and a placebo diet group) consumed an experimental diet containing chicken-derived imidazole dipeptides (calculated as carnosine and anserine, 1000 mg per day) for 3 months. Changes in brain function were evaluated before, during, and after the experimental diet. The ratio of the experimental diet to the placebo diet (in daily amounts) is shown in the table below.

[0124] Table 1

[0125] 1. Antidepressant effect (evaluated using the BDI questionnaire)

[0126] Depressive tendencies were assessed before and after the intake period using the BDI questionnaire (http: / / www.chibatc.co.jp / catalogue / 04 / 1 / 67.html). It should be noted that a high score on the BDI questionnaire indicates a predisposition to depression.

[0127] The results are shown in Figure 1 The degree of improvement was compared by the change in BDI score, i.e., the score before intake (Test 1) versus the score after intake (Test 2). The results showed almost no improvement in the placebo group, while a tendency for improvement was observed in the experimental diet group. Furthermore, the changes before and after intake were displayed in ranking (the higher the number, the greater the improvement), and the experimental diet group showed a tendency for greater changes. Healthy individuals sometimes exhibit a tendency towards mild depression, and it is believed that imidazole dipeptide may improve this depressive tendency by modulating the function of the GABA nervous system.

[0128] 2. Improvement in cognitive function (based on ADAS-cog evaluation)

[0129] Cognitive function was assessed before and after the intake period using the ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale).

[0130] The results are shown in Figure 2 The study showed the proportion of people whose scores improved by more than 3 points and whose scores worsened by more than 3 points before and after the intake. As a result, the proportion of people who improved was greater in the experimental diet group than in the placebo group.

[0131] 3. Effects on brain atrophy, etc.

[0132] Brain structural analysis based on three-dimensional T1-weighted images and functional connectivity analysis based on resting-state functional MRI were performed. Longitudinal cross-sectional analysis of baseline and 3-month-long structural changes in 15 participants in the experimental diet group and 13 participants in the placebo diet group revealed that in gray matter, the right inferior frontal gyrus and left inferior temporal gyrus (…) Figure 3-1 In the white matter, specifically in the right posterior cingulate cortex, the experimental diet group, compared to the placebo diet group, inhibited the progression of atrophy. Figure 3-2 ).

[0133] Furthermore, in functional connectivity analysis based on resting-state functional MRI, at baseline, functional connectivity with the hippocampus decreased at the postcingulate gyrus with age. Figure 4 The postcingulate gyrus is associated with memory retrieval and is known to be among the first areas to decline in Alzheimer's disease. In the experimental diet group, compared to the placebo diet group, functional connectivity between this region and the hippocampus was enhanced after 3 months. Furthermore, this region correlated with white matter regions where atrophy inhibition was observed in the experimental diet group (…). Figure 3-2 ) are consistent.

[0134] 4. Gene expression analysis

[0135] The diet group used blood samples from 13 participants (2 of whom could not be prepared) (samples from the initial and intermediate examinations), while the placebo group used blood samples from all 13 participants (samples from the initial and intermediate examinations). Blood was collected using PAXgene RNA blood collection tubes (Becton Dickinson, Tokyo, Japan), and high-quality RNA was prepared using the PAXgene Blood RNA Kit (Qiagen). Changes in gene expression were analyzed using microarrays.

[0136] method

[0137] The microarray was performed using Agilent Technologies' (CA, USA) whole human genome oligoDNA microarray (4×44K) v2.

[0138] (1) Mark

[0139] First, total RNA was extracted from blood samples using the PAXgene Blood RNA Kit (Qiagen). 200 ng of each RNA was labeled using the Agilent Low-Input QuickAmp Labeling Kit and a single-color labeling agent. First, 2.5 μL of 200 ng of total RNA was added to 2 μL of a pre-prepared one-color spiked mix stock solution. Next, 0.8 μL of the T7 promoter primer was added, and the mixture was incubated at 65°C for 10 minutes using a micro-incubator, followed by quenching on ice for 5 minutes. Then, 4.7 μL of a pre-prepared cDNA stock solution was added, and the mixture was incubated at 40°C for 2 hours using a micro-incubator, followed by incubation at 70°C for 15 minutes. Finally, the mixture was quenched on ice for 5 minutes, and 6 μL of a pre-prepared transcription stock solution was added. After incubating in a micro-incubator at 40°C in the dark for 2 hours, 84 μL of RNase-free water was added to bring the total volume to 100 μL. Then, 350 μL of RLT buffer and 250 μL of ethanol were added. The entire volume was then added to an RNeasy column, centrifuged at 13000 rpm at 4°C for 30 seconds, washed twice with 500 μL of RPE buffer, and finally eluted with 30 μL of RNase-free water.

[0140] (2) Hybridization

[0141] Next, hybridization was performed according to the procedures recommended by Agilent Technologies. First, the previously eluted RNA was fragmented by mixing it with the fragmentation mix and incubated at 60°C for 30 minutes using a microincubator, followed immediately by 1 minute of freezing. Then, 2x GEx hybridization buffer HI-RPM was mixed into the cRNA from the fragmentation mix to prepare the hybridization mixture. The hybridization mixture was then loaded onto a microarray slide, placed in a hybridization chamber, and incubated in a molecular hybridization instrument at 65°C at 10 rpm for 17 hours.

[0142] (3) Cleaning and scanning of microarray slides

[0143] The microarray slides were cleaned using pre-prepared gene expression washing buffer. First, before hybridization, two of the three cleaning glass containers were filled with gene expression washing buffer 1, and the remaining container was filled with gene expression washing buffer 2 at 37°C. After hybridization, the hybridization chamber was disassembled in the first cleaning glass container, and the microarray slides were removed and cleaned in the second cleaning glass container. After further cleaning the microarray slides in the third cleaning glass container, the slides were slowly lifted from the water surface to dry them. Finally, they were placed in a dedicated scanner for scanning.

[0144] (4) Data Analysis

[0145] The data were numerically represented using Agilent's feature extraction software. Standardization was performed using the statistical analysis software R, employing the quantile method. Furthermore, Z-scores and proportions were calculated from the standardized signal values. Only genes exhibiting variations greater than ±2 were extracted. The obtained data were analyzed using the DAVID annotation database (http: / / david.abcc.ncifcrf.gov / ).

[0146] First, the GenBank accession numbers of the genes whose changes were confirmed were entered into the database. Then, functional annotation and clustering were performed, with each function that had undergone gene changes being clustered separately. Additionally, pathway analysis using the KEGG (Kyoto Encyclopedia of Genes and Genomes) database was conducted using DAVID.

[0147] result

[0148] Based on a p<0.05 significance level, genes that showed significant changes in the intake of the experimental diet compared to the placebo diet group were listed. Figure 5 The gene expression analysis revealed significant changes in the expression of various transporter proteins present on blood cells. In particular, it was found that the expression of vitamin C transporters located on the lymphocyte membrane surface was altered through the uptake of imidazole dipeptides. Figure 5 In this study, the expression level of SLC23A2 was significantly increased. Furthermore, the expression of several genes related to mitochondrial energy metabolism was also increased (ACO2 (cis-aconitase), an enzyme involved in the TCA cycle, and IDH3G (isocitrate dehydrogenase)). Through this mechanism, imidazole dipeptides may potentially exert health-enhancing effects.

[0149] Among the chemokines, decreased expression of CXC and CC chemokines was observed, suggesting that the experimental diet has a tendency to suppress inflammation.

[0150] Furthermore, enhanced expression of aging-related genes was confirmed, suggesting aging regulation induced by the experimental diet.

[0151] Furthermore, enhanced expression of anti-aging genes was confirmed, suggesting that the experimental diet induced anti-aging effects.

[0152] Carnosine is known to improve muscle fatigue, and fatigue recovery is thought to be due to its effect of neutralizing the pH in muscles. However, in this study, enhanced gene expression in the mitochondrial system was observed through dietary intake, suggesting a new function for muscles: enhanced mitochondrial function via the glycolytic system. Furthermore, enhanced expression of SIRT6, a known longevity gene, was observed. High expression of this gene in mice is known to extend lifespan. Therefore, it may be possible to extend lifespan through imidazole dipeptides. Moreover, given that imidazole dipeptide intake alters gene expression in various SLCs, combining it with carnosine may lead to a so-called "combination effect," where responses to various physiologically active substances and food components change.

[0153] 5. Changes in serum cytokine concentrations

[0154] During the 3-month intake period, biochemical tests, blood cell counts, blood glucose tests, and coagulation tests were performed on blood samples from participants before, during (6 weeks after) intake, and immediately after the period. A tendency to decrease blood glucose levels was observed with the intake of the test diet. No changes were observed in other indicators before and after intake, thus further confirming the safety of the test diet and placebo diet.

[0155] In addition, quantitative analysis of 27 cytokines and chemokines was performed on the same blood samples. Serum cytokine concentrations in peripheral blood of the subjects were quantitatively analyzed using bead-based multiplex analysis with xMAP technology (Luminex). This method uses specific antibodies bound to microbeads labeled with different fluorescent dyes, and utilizes flow cytometry to simultaneously quantify each cytokine. The following shows the use of Bio-Plex Pro... TMSummary of the analytical method for the Human Cytokine Grp I panel 27-pLex kit (Bio-Rad). Antibody beads were aliquoted into 96-well analytical plates, washed twice with Bio-Plex washing buffer, then serum and standard solutions were added, and the plates were incubated in the dark at room temperature on a shaker for 1 hour. After washing three times with washing buffer, detection antibody solution was added, and the plates were incubated in the dark at room temperature on a shaker for 30 minutes. After washing three times with washing buffer, PE-labeled streptavidin solution was added, and the plates were incubated in the dark at room temperature on a shaker for 10 minutes. After washing three times with washing buffer, detection buffer was added, and the plates were shaken in the dark for 10 seconds. The PE fluorescence intensity of each bead was measured using a Bio-Plex 200 system (Bio-Rad), and the concentrations of each cytokine in serum were calculated from a standard curve derived using known samples. For each subject, a paired t-test was used for statistical analysis before and after intake. Cytokines that showed changes in the experimental diet group were listed below. Figure 6 .

[0156] It was found that the blood levels of many cytokines and chemokines, including IL-8 (CXCL8), IL-5, IL-7, granulocyte colony-stimulating factor (G-CSF), and MCP-1 (CCL2), were significantly reduced after consuming the experimental diet. Conversely, the blood level of IP-10 (CXCL10) was significantly increased after consuming the experimental diet. It should be noted that, to ensure the essential amino acid levels matched those of the experimental diet, the placebo diet included histidine, which is known to have anti-inflammatory effects. Therefore, the blood levels of IL-5, IL-7, and MCP-1 (CCL2) were also significantly reduced after consuming the placebo diet.

[0157] Blood glucose levels were measured. The results are shown below. Figure 7 The placebo group showed an upward trend, while the experimental diet group showed a downward trend. Compared to the placebo group, the experimental diet group showed a tendency for improved blood glucose levels. On the other hand, this pilot trial targeted healthy middle-aged and elderly individuals; therefore, HbA1c (glycated hemoglobin), considered a marker of diabetes, was within the normal range in many participants, and its value did not change with the intake of the experimental diet.

[0158] [Evaluation using diseased mice]

[0159] Providing transgenic mice (Alzheimer's disease model mice) with a high-fat diet (HFD) induced a decline in brain function. The effects of carnosine (L-histidine-β-alanine) were evaluated by administering it to the mice.

[0160] The results are shown in Figure 8-1 , Figure 8-2 , Figure 8-3 and Figure 8-4 In the carnosine-containing diet group, cytokine levels were reduced, suggesting that inflammation was suppressed. Figure 8-1 Furthermore, MRI scans showed that brain inflammation was suppressed in the carnosine administration group. Figure 8-2 (Red portion). Microarray analysis showed that the increased expression of GABA transporters such as 7Slc6a12 and slc6a13 observed in the Alzheimer's model was suppressed in the carnosine administration group. Figure 8-3 This suggests the possibility that, in Alzheimer's disease model mice, the amount of GABA that can function as a neurotransmitter is reduced due to increased expression of transport proteins, while carnosine inhibits the reduction of GABA.

[0161] In addition, after fasting mice for one night, blood was collected, and serum insulin concentration was measured using a reagent kit (morinaga). The blood test results showed that the increase in serum insulin concentration observed in Alzheimer's disease induced by a high-fat diet was suppressed in the carnosine administration group. Figure 8-4 ).

[0162] [Evaluation using healthy volunteers 2]

[0163] Similarly, participants (healthy volunteers aged 40 and above were divided into an experimental diet group and a placebo diet group) consumed an experimental diet containing chicken-derived imidazole dipeptides for 3 months. Changes in brain function were evaluated before, during, and after the experimental diet. The ratio of the experimental diet to the placebo diet (in daily amounts) is shown in Table 1. Two pilot trials were conducted.

[0164] The total number of participants in the first and second trials combined was 30 in the experimental diet group and 30 in the normal diet group (placebo diet group) (see table below).

[0165] Table 2

[0166] Research participants in the first pilot trial

[0167] Table 3

[0168] Research participants in the second pilot trial

[0169] 1. Analysis based on MRI imaging

[0170] In the second pilot trial, MRI imaging was used to directly measure changes in cerebral blood flow accompanying the progression of dementia.

[0171] Changes in cerebral blood flow can be measured using MRI devices through methods that use magnetism to detect changes in blood flow without the use of markers—such as arterial spin labeling.

[0172] The results are shown in Figure 9 and 10 It can be seen that in the experimental diet group, the decrease in blood flow in the postcingulate gyrus, which changes with the progression from the pre-dementia stage and the onset of the disease, was significantly different from that in the placebo diet group (P<0.005).

[0173] 2. Subgroup analysis

[0174] A subgroup analysis of participants (aged 60 and older) from the first and second pilot trials was conducted to evaluate the decline in logical memory (delayed recall task) as dementia progressed from the pre-dementia stage and onset.

[0175] The results are shown in Figure 11 and 12 It can be seen that, in this experiment, since the second experiment was more difficult than the first, there was a tendency for the score in the second experiment to be worse than that in the first. However, in the experimental diet intake group, the score variation was suppressed with strong statistical significance (P<0.01) compared with the placebo diet group.

[0176] These two results suggest that reagents containing chicken-derived imidazole dipeptides may have a role in preventing functional aging of the brain and the onset of dementia.

[0177] [Manufacturing Example]

[0178] (1) Manufacturing of chicken extract

[0179] An experimental diet containing chicken-derived imidazole dipeptides was prepared using the following steps.

[0180] Chicken breast was minced using a meat grinder. Warm water, which was 1.5 times the weight of the meat, was added to the minced chicken breast. The mixture was heated at 90°C for 4 hours and concentrated until the Brix concentration was above 20%. Then, the mixture was filtered through diatomaceous earth and ultrafiltration to finally prepare a carnosine + anserine concentration of about 10% (w / v%).

[0181] (2) Capsules

[0182] 1.0 part by weight of carnosine, 0.2 part by weight of placental extract (powder) and 1.3 part by weight of lactose were mixed and homogenized, and then filled into hard capsules according to conventional methods to produce capsules with a content of 250 mg (carnosine 100 mg / capsule).

[0183] (3) Tablets

[0184] The tablets are manufactured such that each tablet (300 mg) contains 60 mg of a mixture of carnosine and anserine, along with maltose, dextrin, starch, vegetable oil containing vitamin E, isomaltooligosaccharide, indigestible dextrin, calcium saccharide, trehalose, sucrose ester, vitamin C, citric acid, calcium phosphate, flavoring, shellac, niacin, vitamin K, sweetener, potassium chloride, vitamin A, calcium pantothenate, biotin, ferric pyrophosphate, B vitamins, vitamin D, magnesium carbonate, and folic acid.

[0185] Sequence List Free Text

[0186] Serial Number 1: SLC23A2, NM_203327

[0187] Serial Number 2: SLC43A2, NM_152346

[0188] Serial Number 3: SLC29A3, NM_018344

[0189] Serial Number 4: SLC35C1, NM_018389

[0190] Serial Number 5: SLC25A33, NM_032315

[0191] Serial Number 6: SLC22A23, NM_015482

[0192] Serial Number 7: CXCL12, NM_199168

[0193] Serial Number 8: CCL17, NM_002987

[0194] Serial Number 9: TSPO, NM_000714

[0195] Serial number 10: P2RY1, NM_002563

[0196] Serial number 11: CAMK1, NM_003656

[0197] Serial number 12: ACO2, NM_001098

[0198] Serial number 13: ATP7A, NM_000052

[0199] Serial Number 14: POLG, NM_002693

[0200] Serial Number 15: IDH3G, NM_004135

[0201] Serial Number 16: UCP2, NM_003355

[0202] Serial Number 17: BCKDHA, NM_000709

[0203] Serial Number 18: TAP2, NM_018833

[0204] Serial Number 19: SMARCD1, NM_139071

[0205] Serial number 20: SIRT6, NM_016539

Claims

1. Use of at least one of imidazole dipeptides in the manufacture of an oral nutritional composition for improving logical memory, said imidazole dipeptide being any one of carnosine, anserine, cetirine, and homocarnosine.

2. The use as described in claim 1, wherein the nutritional composition comprises at least one of imidazole dipeptides in a daily dose of 200 mg or more.

3. The use as described in claim 1, wherein, At least one of the imidazole dipeptides is derived from animal meat.

4. The use as described in claim 1, wherein, At least one of the imidazole dipeptides is derived from cattle, horses, pigs, chickens, whales, or fish.

5. The use as described in claim 4, wherein, At least one of the imidazole dipeptides is derived from chicken.

6. The use as described in claim 1, wherein, Imidazole dipeptide is carnosine or anserine.

7. The use as described in claim 1, wherein, The nutritional composition further comprises creatine and nucleic acids.

8. The use as described in claim 1, wherein, The nutritional composition contains, as an active ingredient, at least one of imidazole dipeptides in a daily dose of 200 mg or more.

9. The use as described in any one of claims 1 to 8, wherein, The nutritional composition was designed for healthy individuals aged 40 and over.

10. The use as described in any one of claims 1 to 8, wherein, The nutritional composition is used to improve age-related cognitive decline, inhibit brain atrophy, maintain cerebral blood flow, or enhance functional connectivity between the postcingulate gyrus and the hippocampus.

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