Agents containing imidazole dipeptide

Abstract

To provide an anti-aging agent derived from a natural product. [Solution] The present invention uses an imidazole dipeptide as an active ingredient. The present invention also provides an agent for improving neuropsychological function, which contains an imidazole dipeptide as an active ingredient. The present invention also provides an agent for modulating the expression of transporters such as SLC23A2, which contains an imidazole dipeptide, an agent for regulating the blood concentration of cytokines such as IP-10, which contains an imidazole dipeptide, as well as an expression analysis method for detecting improvement or deterioration of neuropsychological function, and a kit for detecting improvement or deterioration of neuropsychological function.

Description

[Technical Field]

[0001] The present invention relates to an agent comprising at least one selected from the group consisting of imidazole dipeptides and their metabolites as an active ingredient. The agent of the present invention can be used for improving cognitive function, improving psychological function, anti-aging, and maintaining health. The present invention is useful in fields related to general foods, health foods, pharmaceuticals, cosmetics, health, and medicine. [Background technology]

[0002] Carnosine is a dipeptide composed of β-alanine and histidine, and anserine is a dipeptide composed of β-alanine and methylated histidine. Both are known to be found in chicken and other meats. Carnosine and anserine have been studied for their effects on promoting skin metabolism (Patent Document 1), regulating the autonomic nervous system (Patent Document 2), reducing stress (Patent Document 3), and improving learning function and reducing anxiety (Patent Document 4).

[0003] In recent years, there has been growing interest in maintaining health and living a long life, including preventing age-related diseases and strengthening the immune system. Aging often involves a certain degree of cognitive decline. Cognitive decline can also result from the onset and progression of Alzheimer's disease. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2000-201649 [Patent Document 2] WO2002 / 076455 publication [Patent Document 3] Japanese Patent Publication No. 2007-70316 [Patent Document 4] Japanese Patent Publication No. 2000-116987 [Overview of the project] [Problems that the invention aims to solve]

[0005] It is desirable to slow down the aging process in daily life through appropriate diet, exercise, and psychotherapy, and to be able to address age-related diseases early.

[0006] Food is not only a source of energy and essential nutrients (nutritional value), but also provides enjoyment through eating (palatability) and contributes to a healthy lifestyle (functionality). Foods or products containing functional ingredients derived from food are expected to be beneficial for health and beauty, and have become widely accepted as health foods, etc. The use of natural products with a history of consumption is considered preferable from the standpoint of safety and security. [Means for solving the problem]

[0007] The inventors have been engaged in the research and development of foods and materials that are beneficial to health by utilizing natural products. In this research, they have now discovered that carnosine and anserine derived from chicken meat have psychological function-improving effects, and have completed the present invention. The present invention provides the following:

[0008] [1] An agent for improving neuropsychological function, comprising at least one selected from the group consisting of imidazole dipeptides and their metabolites. [2] The agent described in [1], wherein the neuropsychological function is related to Alzheimer's disease or aging. [3] An anti-aging agent comprising at least one selected from the group consisting of imidazole dipeptides and their metabolites, which improves neuropsychological function. [4] Contains at least one selected from the group consisting of imidazole dipeptides and their metabolites, The transporter genes are SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12, and SLC6A13; The chemokine genes CXCL12 and CCL17; TSPO and P2RY1 are aging-related genes; CAMK1, a gene in the nervous system; Mitochondrial genes, including ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA and TAP2; and The anti-aging genes SMARCD1 and SIRT6 An agent for altering the expression of at least one gene selected from the group consisting of the following. [5] The agent described in [1] having an anti-inflammatory effect. [6] An agent for controlling the blood concentration of 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), comprising at least one selected from the group consisting of imidazole dipeptides and their metabolites. [7] The agent described in [1] that has an effect of suppressing or reducing the rise in blood glucose levels. [8] The agent according to [1] that has an effect of suppressing or reducing the increase in blood insulin concentration. [9] The agent described in any one of items [1] to 8, for administering at least one selected from the group consisting of imidazole dipeptides and their metabolites in an amount of 200 mg or more per day.

[10] A nutritional composition comprising at least 200 mg or more of an imidazole dipeptide derived from animal meat as a daily dose.

[11] The nutritional composition according to

[10] , wherein at least one imidazole dipeptide is derived from chicken.

[12] The agent or nutritional composition according to any one of [1] to

[11] , further comprising creatine and nucleic acid.

[13] The agent or nutritional composition described in any one of paragraphs [1] to

[12] , for use by elderly persons or persons with mild mood disorders.

[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. A dietary method comprising the step of administering to a subject in whom improvement of neuropsychological function is desired a nutritional composition comprising at least one selected from the group consisting of imidazole dipeptides and their metabolites. A method for determining the neuropsychological function of a subject based on the activity of carnosine-degrading enzyme (CNDP1) possessed by the subject. A method for predicting the effect of improving neuropsychological function by administering to a subject the agent or nutritional composition according to any one of [1] to

[14] based on the CNDP1 activity possessed by the subject.

[18] For detecting improvement or deterioration of neuropsychological function (8) Transporter genes: SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12 and SLC6A13; (9) Chemokine genes: CXCL12 and CCL17; (10) Aging-related genes: TSPO and P2RY1; (11) Nervous system gene: CAMK1; (12) Mitochondrial genes: ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA and TAP2; and (13) Anti-aging genes: SMARCD1 and SIRT6 A method by analyzing the expression of at least one gene selected from the group consisting of above.

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

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

[0009] [Chemical formula] [ka]

[0010] (In formula I, formula II, R 1 , R 2 and R 3 These are, independently, H or C 1-6 It is alkyl, X is H or -COR 4 And at this time R 4 is H or C 1-6 It is alkyl.

[21] A method for searching for active ingredients for the treatment of functional aging of the brain and / or dementia, using a compound represented by formula I or formula II as defined in claim 20 as a lead compound. [Brief explanation of the drawing]

[0011] [Figure 1] Results of the psychological function test (BDI test). [Figure 2] Results of a psychological function test (ADAScog test, which assesses brain aging). The percentages for improvement, no change, and deterioration are shown. [Figure 3-1] Brain regions (gray matter) where atrophy improved with imidazole dipeptide intake. Regions with p<0.005 are shown in color. [Figure 3-2] Brain region (white matter) where atrophy improved after intake of imidazole dipeptide. [Figure 4] Improvement of neural circuit function by intake of imidazole dipeptide. Neural circuit function between the hippocampus and posterior cingulate cortex declines with age (left figure), but in the group that consumed the test diet, this decline improved after intake (right figure). [Figure 5] Genes affected by imidazole dipeptide intake. In six genes belonging to the SLC (transporter) group, gene expression levels were significantly altered by the intake of the test diet compared to the placebo diet. Furthermore, altered expression levels were observed in various genes, including those related to chemokines, as shown in the figure. [Figure 6]Changes in blood cytokine and chemokine levels following imidazole dipeptide intake. Mean ± SE, test food: solid line, placebo: dashed line, paired t-test, *: p < 0.05, **: p < 0.01 [Figure 7] Lowering of blood glucose levels due to imidazole dipeptide intake. [Figure 8-1] Reduced blood cytokine levels in dementia model mice. The carnosine-containing diet group showed reduced cytokine levels, suggesting suppressed inflammation. wt: wild-type, tg: transgenic, *: p < 0.05, **: P < 0.01 (Dunnett's test vs tgHFD), #: p < 0.05, ##: P < 0.01 (Student ttest) [Figure 8-2] Suppression of brain inflammatory response in dementia model mice (mouse MRI images). Inflammation suppression was observed after administration of imidazole dipeptide. [Figure 8-3] Suppression of GABA transporter gene expression in glial cells by intake of high-performance dipeptides. Slc6A13: GABA Transporter 2 (GAT-2) expressed in astrocytes, Slc6A12: Betaine / GABA Transporter 1 (BGT-1) expressed in astrocytes. [Figure 8-4] Blood insulin levels in mice. A significant difference (student's t-test, P<0.05) was observed between the Alzheimer's disease (AD) high-fat diet group and the AD high-fat diet + carnosine group. [Figure 9] ASL analysis [Figure 10] Areas where differences were observed between the two groups based on ASL analysis (posterior cingulate cortex) [Figure 11] Logical Memory II scores (results from a sub-analysis of participants aged 60 and over). Significant difference between the two groups (P<0.01). Note that the post-intake test was significantly more difficult than the pre-intake test. [Figure 12]Score of logical memory II (results of sub-analysis of those aged 60 and above). In the test diet group, the function did not decline at any age, whereas in the placebo diet group, there was a marked tendency for the function to decline with age.

Mode for carrying out the invention

[0012] 〔Active ingredient〕 The present invention relates to an agent comprising at least one selected from the group consisting of imidazole dipeptides and their metabolites as an active ingredient. When the term "imidazole dipeptide" is used in the present specification, it refers to a dipeptide formed by the binding of an amino acid having an imidazole ring and another amino acid, unless otherwise specified.

[0013] The imidazole dipeptide referred to in the present invention can be represented by the following formula I or formula II.

[0014]

Chemical formula

[0015]

Chemical formula

[0016] In formula I and formula II, R 1 , R 2 and R 3 are each independently H or C 1-6 alkyl, X is H or -COR 4 , and at this time R 4 is H, C 1-6 alkyl, optionally substituted benzyl, or H2C=CH-.

[0017] In formula I, it is preferable that either R 1 , R 2 is C 1-6 alkyl and the other is H. In formula II, it is preferable that either R 2 , R 3 is C 1-6It is preferable that the other component is alkyl and the other component is H. 1-6 One preferred example of an alkyl group is methyl.

[0018] -COR 4 Specific examples of X include formyl, acetyl, propionyl, benzoyl, and acryloyl.

[0019] Regarding methods for producing compounds represented by formula I or formula II, you can refer to JP 2003-520221, JP 2006-232686, JP 2006-504701, JP 2008-517911, JP 2009-512459, JP 2010-31004, JP 2011-37891, JP 2011-37892, JP 2013-165728, JP 2014-12735, etc.

[0020] Imidazole dipeptides include carnosine, anserine, balenine, and homocarnosine. Carnosine is a dipeptide composed of β-alanine and histidine. Due to the three-dimensional structure of the constituent histidine, carnosine exists in L- and D-forms. In this invention and its description, when simply referred to as "carnosine," it refers to L-carnosine, D-carnosine, or mixtures thereof, unless otherwise specified. L-carnosine is known to be present in relatively high concentrations in muscle and nerve tissue in mammals such as humans.

[0021] The structure of L-carnosine (IUPAC name: (2S)-2-[(3-Amino-1-oxopropyl)amino]-3-(3H-imidazol-4-yl)propanoic acid) is shown below.

[0022] [ka]

[0023] In some animals, L-anserine, composed of β-alanine and methylated histidine, is frequently found. In this invention and its description, when "anserine" is used, it refers to L-anserine, D-anserine, or mixtures thereof, unless otherwise specified. The structure of L-anserine (IUPAC name: (2S)-2-[(3-amino-1-oxopropyl)amino]-3-(3-methyl-4-imidazolyl)propanoic acid) is shown below.

[0024] [ka]

[0025] Both carnosine and anserine are water-soluble (carnosine 1g / 3.1ml at 25℃).

[0026] In this specification, when referring to a metabolite of an imidazole dipeptide, unless otherwise specified, it means one metabolite selected from the group consisting of carnosine, anserine, balenine, and homocarnosine. Metabolites of imidazole dipeptides include β-alanine, histidine, methylated histidine, and γ-aminobutyric acid (GABA).

[0027] In this invention, when we refer to "at least one selected from the group consisting of imidazole dipeptides and their metabolites," unless otherwise specified, we mean one or more imidazole dipeptides. For example, when we refer to "containing at least one selected from the group consisting of imidazole dipeptides and their metabolites as an active ingredient," this includes cases where carnosine is the active ingredient and other imidazole dipeptides are not included, as well as cases where carnosine and anserine are the active ingredients. Furthermore, when we refer to "at least one selected from the group consisting of imidazole dipeptides and their metabolites" in terms of quantity or concentration, unless otherwise specified, if two or more imidazole dipeptides and their metabolites are present, it refers to the total quantity or concentration of all imidazole dipeptides and their metabolites. In this specification, we may describe embodiments using imidazole peptides, carnosine, or anserine as examples, but these descriptions also apply to cases using other imidazole dipeptides and their metabolites.

[0028] In the present invention, the imidazole dipeptide and its metabolites used as active ingredients may be synthesized, fermented, or obtained from natural products. They may also be isolated or purified. More specifically, the imidazole dipeptide and its metabolites may be derived from various animals, such as cattle, horses, pigs, chickens, whales, or fish (e.g., skipjack tuna, tuna, eels). One preferred example is chicken meat. The imidazole dipeptide and its metabolites may be included in the formulation as extracts, concentrates, crude products, etc., of natural products.

[0029] [Applications, functions] The agents of the present invention can be used to improve neuropsychological function. Improvement of neuropsychological function includes antidepressant effects (improvement of psychological function) and improvement of cognitive function. Improvement of neuropsychological function also includes suppression of brain atrophy, suppression of brain functional decline (strengthening of functional connections with the hippocampus), and improvement of neuronal damage due to inflammation, which are related to neuropsychological function. Neuropsychological function may be related to Alzheimer's disease or aging. Improvement of neuropsychological function also includes treatment of brain functional aging and / or dementia.

[0030] The antidepressant (improvement of psychological function) effect of the agent of the present invention can be evaluated using the BDI questionnaire (http: / / www.chibatc.co.jp / catalogue / 04 / 1 / 67.html). Since a higher score on the BDI questionnaire indicates a tendency towards depression, for example, by conducting a survey before and after the period of taking the agent of the present invention and comparing the score before and after taking the agent, the degree of improvement in psychological function can be compared. The agent of the present invention is particularly expected to have an effect of improving psychological function in subjects with mild mood disorders.

[0031] The cognitive function-improving effect of the agent of the present invention can be evaluated using the ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) method. The cognitive function-improving effect of the present invention includes improving age-related memory loss and improving pathological cognitive decline (dementia). The agent of the present invention is particularly expected to have an improving effect on cognitive decline associated with Alzheimer's disease or aging.

[0032] The agent of the present invention can be used to suppress brain atrophy, suppress brain functional decline (strengthen functional connections with the hippocampus), or improve neuronal damage caused by inflammation. These effects can be evaluated by methods well known to those skilled in the art, such as diagnostic imaging. According to our studies, in a control group including elderly individuals, areas of suppressed atrophy progression were observed in both the gray and white matter of the brain. Such effects were not observed in the group administered a placebo without anserine and carnosine.

[0033] The agent of the present invention can be used to treat functional aging of the brain and the onset of dementia, more specifically, to prevent, delay, or inhibit the onset of functional aging of the brain and dementia, or to prevent its progression. Such effects can be confirmed by evaluating changes in blood flow in the posterior cingulate cortex region in subjects, or by evaluating logical memory (delayed recall task) in subjects aged 60 years or older. According to the inventors' studies, in subjects including those aged 60 years or older, blood flow in the posterior cingulate cortex region was found to be significantly preserved in the group that consumed the test diet containing imidazole dipeptide compared to the placebo group. Furthermore, in subjects aged 60 years or older, logical memory scores were found to be significantly preserved in the group that consumed the test diet for three months compared to the placebo group.

[0034] The agent of the present invention can be used to alter the expression of transporters. Transporters are membrane proteins that exist in the cell membrane along with channels and receptors. Unlike channels, transporters recognize not only endogenous substances but also many exogenous substances, including drugs and environmental chemicals, as transport substrates. Transporters are currently divided into two families: the ABC (ATP binding cassette) family, which transports using the energy of ATP hydrolysis, and the SLC (Solute carrier) family, which transports without using ATP energy. In humans, 48 ​​types of ABC transporter genes and 319 types of SLC transporter genes have been identified. Diseases caused by abnormalities in transporters increase with age, and it is estimated that transporters are associated with approximately 10% of age-related disease-associated genes after the age of 50.

[0035] The agents of the present invention can be used to alter the expression of at least one, preferably at least three, more preferably five, and even more preferably all, transporters selected from the group consisting of SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12, and SLC6A13. Alteration of expression includes increasing expression and decreasing expression.

[0036] The agent of the present invention can be used to alter the expression of chemokines. Chemokines are basic proteins that exert their effects via G protein-coupled receptors and are a group of cytokines. They induce migration of leukocytes and other cells and are involved in the formation of inflammation. Numerous chemokines have been discovered to date. Based on structural differences, they are classified into CC chemokines, CXC chemokines, C chemokines, and CX3C chemokines. More than 50 types of chemokines have been identified to date.

[0037] The agents of the present invention can be used in particular to alter the expression of at least one, preferably both, chemokines selected from the group consisting of CXCL12 and CCL17. Alteration of expression includes increasing expression and decreasing expression.

[0038] The agent of the present invention can be used to alter the expression of aging-related genes. Aging-related genes have been identified as genes involved in individual aging and cellular aging, and numerous aging-related genes have been identified to date.

[0039] The agents of the present invention can be used in particular to alter the expression of at least one, preferably both, aging-related genes selected from the group consisting of TSPO and P2RY1. Alteration of expression includes increasing expression and decreasing expression.

[0040] The agent of the present invention can be used to alter the expression of nervous system genes. Nervous system genes are genes involved in neurogenesis, neurogenic differentiation, and so on, and a large number of nervous system genes have been identified to date.

[0041] The agents of the present invention can be used, in particular, to alter the expression of the nervous system gene CAMK1. Alteration of expression includes increasing expression and decreasing expression.

[0042] The agent of the present invention can be used to alter the expression of mitochondrial genes. Mitochondrial genes are genes involved in mitochondrial biosynthesis, fusion, the TCA cycle, and respiration, and numerous such genes have been identified to date.

[0043] The agents of the present invention can be used to alter the expression of at least one, preferably at least three, more preferably five, and even more preferably all, mitochondrial genes selected from the group consisting of ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA, and TAP2. Alteration of expression includes increasing expression and decreasing expression.

[0044] The agent of the present invention can be used to alter the expression of anti-aging genes. Anti-aging genes are genes that suppress cellular senescence and achieve anti-aging, and numerous such genes have been identified to date. The agents of the present invention can be used in particular to alter the expression of at least one, preferably both, chemokines selected from the group consisting of SMARCD1 and SIRT6. Alteration of expression includes increasing expression and decreasing expression.

[0045] The agents of the present invention can also be used to control 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). Control includes increasing and decreasing levels.

[0046] The agent of the present invention can also be used as an anti-inflammatory agent or for suppressing or reducing the rise in blood glucose levels.

[0047] In this invention, when we refer to "improvement" or "treatment" in relation to a disease or condition, it includes reducing the risk of onset, delaying onset, prevention, treatment, cessation or delay of progression. Actions for improvement or treatment include medical actions performed by physicians for the purpose of treating diseases, and non-medical actions performed by persons other than physicians, such as dietitians (registered dietitians, public health nurses, midwives, nurses, clinical laboratory technicians, beauty consultants, estheticians, food manufacturers, food distributors, etc.). Treatment also includes the administration or recommendation of specific foods, guidance on dietary methods, health guidance, nutritional guidance (including guidance on nutrition necessary for the treatment of sick or injured persons, and guidance on nutrition for maintaining and promoting health), food service management, and guidance necessary for nutritional improvement related to food service. The target of treatment in this invention includes humans (individuals), and preferably humans for whom it is desirable to administer any of the above-mentioned treatments, or for whom it is necessary to administer any of the above-mentioned treatments.

[0048] Furthermore, the inventors measured serum carnosine-degrading enzyme (hereinafter referred to as CNDP1) activity in the serum of subjects in order to verify the individual differences in the effectiveness of imidazole dipeptides. The results of the activity measurement confirmed that there are significant individual differences among subjects. CNDP1 is present in the blood and degrades imidazole dipeptides. Therefore, CNDP1 may affect the blood concentration of imidazole dipeptides after ingestion, and thus may affect the effectiveness of imidazole dipeptides. Thus, information on CNDP1 activity in subjects is considered useful for determining in advance whether treatment by ingestion of imidazole dipeptides will be effective. Accordingly, 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 a method for predicting the effect of administering the agent or nutritional composition of the present invention to a subject based on the CNDP1 activity of the subject. In these methods, a reference value for judgment may be predetermined, and the prediction may be made mechanically according to that reference value.

[0049] [Agent] In this invention, the term "agent" refers to either the active ingredient itself or an active ingredient and other components, unless otherwise specified. However, it does not include existing foods containing at least one selected from the group consisting of imidazole dipeptides and their metabolites, such as chicken itself.

[0050] The agent of the present invention may contain other components besides the active ingredient, as long as they can exert the desired effect. These other components may be various additives that are acceptable as food or as pharmaceuticals. Examples include excipients, antioxidants (oxidizing agents), flavorings, seasonings, sweeteners, colorants, thickeners and stabilizers, color fixatives, bleaching agents, antifungal agents, gum bases, bittering agents, enzymes, glazing agents, acidulants, emulsifiers, fortifiers, processing agents, binders, tensioning agents (isotonic agents), buffering agents, solubilizers, preservatives, stabilizers, coagulants, etc.

[0051] Other ingredients may be functional ingredients other than the active ingredient. Examples of other functional ingredients include amino acids (e.g., branched-chain amino acids, ornithine), unsaturated fatty acids (e.g., EPA, DHA), vitamins, trace metals, glucosamine, chondroitins, etc.

[0052] When the agent of the present invention consists of an active ingredient and other components, the content of the active ingredient can be appropriately designed by a person skilled in the art from the standpoint of ease of manufacture, ease of use, etc. For example, it can be 0.1 to 99.9%, 1 to 95%, 10 to 90%, or even 51 to 90% or more. In addition, it can be 21% or more as carnosine and 31% or more as anserine.

[0053] As described above, the form of the agent of the present invention can be in various forms, excluding existing foods. For example, it may be a pharmaceutical composition such as an oral drug or a nutritional composition. Furthermore, the agent of the present invention can be used by adding it to a pharmaceutical composition such as an oral drug or a nutritional composition. In the present invention, when "nutritional composition" refers to a solid, it includes not only solids but also liquids, such as beverages, unless otherwise specified. Furthermore, when "nutritional composition" refers to a nutritional composition in the present invention, it includes health foods, supplements, functional foods (including functional foods and foods for specified health uses), therapeutic foods (those that serve a therapeutic purpose; prepared based on a menu created by a dietitian or the like based on a diet prescription issued by a doctor), therapeutic diets, diets with adjusted components, low-salt diets, care foods, low-calorie diets, and diet foods, as well as ingredients for these.

[0054] Examples of the forms of the agent, pharmaceutical composition, or nutritional composition of the present invention include powders, granules, tablets, capsules, liquid formulations (including elixirs, lemonades, syrups, emulsions, suspensions, solutions, and drinks), gel formulations, therapeutic foods, beverages, confectionery, processed meat products, processed seafood products, processed vegetable products, prepared foods, seasoning compositions, and food additives.

[0055] The amount of active ingredient to be taken according to the present invention can be appropriately designed by a person skilled in the art depending on the age, weight, sex, disease or condition to which it is applied, etc. of the person taking the dose. The amount of active ingredient to be taken 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. It may also 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. 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. The above daily intake amount of the active ingredient may be taken all at once or divided into multiple doses.

[0056] The amount of the active ingredient in the agent, pharmaceutical composition, or nutritional composition of the present invention can be appropriately designed by a person skilled in the art, but 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.

[0057] The agent, pharmaceutical composition, or nutritional composition of the present invention may also contain components other than the active ingredient. These components other than the active ingredient are, for example, creatine and nucleic acids. The creatine content can be, for example, 10 mg or more per day, 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 can 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. The nucleic acid content can be, for example, 0.15 mg or more per day, 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, the amount can be 50 mg or less, preferably 40 mg or less, more preferably 20 mg or less, and even more preferably 10 mg or less.

[0058] When the agent, pharmaceutical composition, or nutritional composition of the present invention is used as a therapeutic diet (a diet that serves a therapeutic purpose, prepared based on a menu created by a dietitian or the like based on a diet prescription issued by a physician), a therapeutic diet, a diet with adjusted components, a low-sodium diet, a nursing care diet, a low-calorie diet, a diet for weight loss, or a sports diet (including diets aimed at enhancing performance in aerobic exercise, diets aimed at enhancing endurance in aerobic exercise, diets for storing nutrients in the body until the day of the competition, diets for supplementing nutrients during the competition, and diets aimed at recovering from fatigue after the competition), the content of the active ingredient can be designed taking into account the amount consumed in one meal.

[0059] The agent, pharmaceutical composition, or nutritional composition of the present invention can be administered to a subject repeatedly and over a long period of time. In particular, when the purpose is to enhance athletic performance, it is preferable to administer it before exercise and also to administer it on a daily basis.

[0060] The agent, pharmaceutical composition, or nutritional composition of the present invention may be labeled as being usable for neuropsychological function, brain atrophy or dysfunction, and neuronal damage due to inflammation, and may also be labeled as being recommended for consumption by specific individuals, such as elderly people aged 65 or older or those with mild mood disorders. Labeling may be direct or indirect. Examples of direct labeling include inscriptions on the product itself, packaging, containers, labels, tags, etc., while examples of indirect labeling include advertising and promotional activities by places or means such as websites, stores, exhibitions, signs, bulletin boards, newspapers, magazines, television, radio, mail, and email.

[0061] [Manufacturing method] The agent, pharmaceutical composition, or nutritional composition of the present invention can be manufactured using various known techniques. The step of adjusting the active ingredient to a predetermined concentration can be applied at various stages of the manufacturing process. Those skilled in the art can appropriately design the manufacturing process for the agent of the present invention, taking into consideration the solubility, stability, volatility, etc., of the active ingredient. The inventors' studies have confirmed that anserine and carnosine are sufficiently stable at room temperature and also sufficiently stable under cooking conditions of 180°C or below. Furthermore, it has been confirmed that they can be stored stably in solution for at least 2 years and 9 months.

[0062] When the active ingredient of the present invention is composed of chicken extract, a specific example of a method for producing the chicken extract is as follows: finely chop the chicken, add warm water, adjust the pH as needed, heat as needed, and extract over several minutes to several days. An example of extraction conditions is to treat at 50-100°C for 1-10 hours. The obtained extract can be purified and fractionated by diatomaceous earth filtration, ultrafiltration, etc., as needed. Desalting and protease treatment can be performed as needed. The part of the chicken used as the raw material is not particularly limited, but it is preferable to include breast meat as it contains a large amount of carnosine and / or anserine. The obtained extract can be dried by hot air drying, spray drying, freeze-drying, etc., to obtain a dried product. It can also be granulated to obtain granules.

[0063] [Facial Expression Analysis] The present invention also provides a method for detecting improvement or deterioration of neuropsychological function by analyzing the expression of at least one gene selected from the group consisting of transporter genes SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12 and SLC6A13; chemokine genes CXCL12 and CCL17; aging-related genes TSPO and P2RY1; nervous system gene CAMK1; mitochondrial system genes ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA and TAP2; and anti-aging genes SMARCD1 and SIRT6; as well as a kit for detecting improvement or deterioration of neuropsychological function, comprising a nucleic acid consisting of all or part of any of the nucleotide sequences of SEQ ID NOs: 1 to 20 and at least one nucleotide sequence selected from the group consisting of all or part of nucleotide sequences complementary to any of the nucleotide sequences of SEQ ID NOs: 1 to 20.

[0064] Expression analysis preferably involves analyzing the expression of 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-mentioned genes is analyzed.

[0065] In the development of new drugs and functional food ingredients, the effects of candidate drugs and ingredients are monitored at the cellular level to evaluate their efficacy and safety. However, there is growing interest in methods that capture the genes expressed in cells across the entire genome before and after drug administration, and quantitatively assess the effects of drugs and ingredients as changes in gene expression levels. By analyzing the expression of the gene combinations provided by this invention using such methods, the effects of candidate drugs on neuropsychological functions can be analyzed.

[0066] In the present invention relating to expression analysis, the nucleic acid comprising at least one nucleotide sequence selected from the group consisting of all or part of any of the nucleotide sequences of SEQ ID NOs: 1 to 20 and all or part of nucleotide sequences complementary to any of the nucleotide sequences of SEQ ID NOs: 1 to 20 may be a pair of primer sets capable of functioning as a probe that can specifically hybridize with a transcript in the sample to be detected, or as a primer that amplifies all or part of the transcript. The nucleic acid may be DNA or RNA.

[0067] In the present invention relating to expression analysis, the length of the nucleic acid, which consists of all or part of any of the base sequences of SEQ ID NOs: 1 to 20 and at least one base sequence selected from the group consisting of all or part of base sequences complementary to any of the base sequences of SEQ ID NOs: 1 to 20, is, for example, 15 bases or longer, preferably 20 bases or longer, and more preferably 25 bases or longer, when used as a probe. The probe nucleic acid may be labeled with, for example, a radioisotope, enzyme, fluorescent substance, or luminescent substance to enable the detection and quantification of the target nucleic acid. The nucleic acid to be used as a probe may be immobilized on a solid phase.

[0068] When used as primers, the nucleic acid length is, for example, 15 to about 100 nucleotides, preferably 15 to 50 nucleotides, and it is preferable that the pair is designed to amplify DNA fragments of 100 bp to several kbp.

[0069] The nucleic acids used can be manufactured by chemical synthesis using commercially available automated DNA / RNA synthesizers or the like. Alternatively, nucleic acids can be directly synthesized on a solid phase such as silicon or glass to create immobilized chips (arrays). A preferred embodiment in which nucleic acid probes are provided immobilized on a substrate is a DNA microarray.

[0070] To quantitatively analyze the expression of a specific group of genes using a small amount of sample, competitive RT-PCR or real-time RT-PCR can be used. The sample to be analyzed may be blood collected from a human.

[0071] [Use as a lead compound] The present invention provides a method (screening method) for searching for active ingredients for improving neuropsychological function, particularly for treating functional aging of the brain and / or dementia, using the above-mentioned imidazole dipeptide and its metabolites as lead compounds. A lead compound is generally a compound whose pharmacological activity profile is clear and which can be expected to have improved activity and reduced toxicity by chemical modification. As described above, the imidazole dipeptide and its metabolites have pharmacological activity for improving neuropsychological function, particularly for treating functional aging of the brain and / or dementia, and further chemical modification can be expected to improve activity and reduce toxicity.

[0072] Chemical modification refers to optimizing the lead compound by chemically modifying it, for example. 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. It can also include the addition, substitution, or removal of functional groups to each amino acid, as well as the substitution of each amino acid with a D-isomer or an artificial amino acid.

[0073] This invention enables the search for superior active ingredients in terms of physical properties, pharmacokinetics, and toxicity by optimizing imidazole dipeptides and their metabolites as lead compounds.

[0074] The present invention will be described below using examples, but the scope of the present invention is not limited to what is described in the examples. [Examples]

[0075] [Evaluation by able-bodied volunteers 1] A test diet containing chicken-derived imidazole dipeptides (1000 mg per day as carnosine and anserine) was administered to subjects (28 healthy male and female volunteers aged 40 and over, divided into two groups: a test diet group and a placebo group) for three months. Changes in brain function were evaluated before, during, and after the study. The composition of the test diet and placebo diet (as daily amounts) is shown in the table below.

[0076] [Table 1]

[0077] 1. Antidepressant effect (evaluated using the BDI questionnaire) Before and after the intake period, depressive tendencies were assessed using the BDI questionnaire (http: / / www.chibatc.co.jp / catalogue / 04 / 1 / 67.html). A higher score on the BDI questionnaire indicates a greater tendency towards depression.

[0078] The results are shown in Figure 1. When comparing the degree of improvement by the change in BDI score, i.e., the score before intake (test1) - the score after intake (test2), there was almost no improvement in the placebo group, while an improvement trend was observed in the test food group. Furthermore, when the changes before and after intake were ranked (higher rank numbers indicate greater improvement), the test food group tended to show greater changes. Even healthy individuals may have mild depressive tendencies, and it is thought that imidazole dipeptide improved these depressive tendencies by regulating the function of the GABAergic nervous system.

[0079] 2. Improvement in cognitive function (evaluated using ADAS-cog) Cognitive function was assessed using ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) before and after the intake period.

[0080] The results are shown in Figure 2. When we showed the proportion of people who improved by 3 points or more and those who worsened before and after intake, the proportion of people who improved was higher in the test food group than in the placebo group.

[0081] 3. Effects on brain atrophy, etc. Brain structure analysis was performed using 3D T1-weighted imaging, and functional connectivity analysis was performed using resting-state functional MRI. Longitudinal analysis of structural changes at baseline and 3 months in 15 subjects in the test diet group and 13 subjects in the placebo group showed that the progression of atrophy was suppressed in the test diet group compared to the placebo group in the right inferior frontal gyrus and left inferior temporal gyrus in the gray matter (Figure 3-1), and in the right posterior cingulate gyrus in the white matter (Figure 3-2).

[0082] Furthermore, functional connectivity analysis using resting-state functional MRI showed that functional connectivity with the hippocampus in the posterior cingulate cortex decreased with age at baseline (Figure 4). The posterior cingulate cortex is involved in memory retrieval and is known to be the first area of ​​function to decline in Alzheimer's disease. In this area, the test diet group showed enhanced functional connectivity with the hippocampus compared to the placebo group after 3 months. This area also coincided with the white matter region where atrophy suppression was observed in the test diet group (Figure 3-2).

[0083] 4. Gene expression analysis For the test diet group, blood samples were collected from 13 subjects (2 samples could not be prepared). For the placebo group, blood samples were collected from all 13 subjects (from the initial and intermediate examinations). Blood was collected using Paxgene RNA collection tubes (Becton Dickinson, Tokyo). High-quality RNA was then prepared using the PAXgene Blood RNA kit (Qiagen), and changes in gene expression were analyzed using microarrays.

[0084] method Microarray analysis was performed using Agilent's (CA, USA) Whole Human Genom OligoDNA Microarray (4×44K) v2. (1) Labeling First, total RNA was extracted from the subjects' blood samples using the PAXgene blood RNA Kit (Qiagen), and each sample (200 ng) was labeled using the Agilent Low-Input QuickAmp Labeling Kit, one-color. Initially, 2.5 μL of 200 ng of total RNA was added to 2 μL of pre-prepared One-Color Spike Mix stock solution. Next, 0.8 μL of T7 Promoter Primer was added, and the mixture was incubated at 65°C for 10 minutes in a heat block, followed by rapid cooling on ice for 5 minutes. Furthermore, 4.7 μL of pre-prepared cDNA Master Mix was added, and the mixture was incubated at 40°C for 2 hours, then transferred to a 70°C heat block and incubated for another 15 minutes. After that, the mixture was rapidly cooled on ice for 5 minutes, and 6 μL of pre-prepared Transcription Master Mix was added. After incubation for 2 hours in a light-shielded heat block at 40°C, 84 μL of nuclease-free water was added to bring the total volume to 100 μL. Then, 350 μL of Buffer RLT was added, followed by 250 μL of ethanol. Next, the entire volume was added to an RNeasy column and centrifuged at 13000 rpm at 4°C for 30 seconds. After washing twice with 500 μL of Buffer RPE, the mixture was finally eluted with 30 μL of RNase-free water.

[0085] (2) Hybridization Next, hybridization was performed using the protocol recommended by Agilent. First, the previously eluted RNA was mixed with the Fragmentation mix and fragmented, incubated in a 60°C heat block for 30 minutes, and then immediately cooled on ice for 1 minute. Next, 2x GEx Hybridization Buffer HI-RPM was mixed with the cRNA from the Fragmentation Mix to prepare the Hybridization mix. After applying the Hybridization mix to a microarray slide, it was placed in a hybridization chamber and then in a hybridization oven, where hybridization was performed at 65°C and 10 rpm for 17 hours.

[0086] (3) Cleaning and scanning of microarray slides The microarray slides were washed using pre-prepared Gene Expression Wash Buffer. First, before hybridization was complete, two of the three washing glass containers were filled with Gene Expression Wash Buffer 1, and the remaining one was filled with Gene Expression Wash Buffer 2 at 37°C. After hybridization was complete, the hybridization chamber was disassembled in the first washing glass container, the microarray slides were removed, and washed in the second washing glass container. After further washing the microarray slides in the third washing glass container, they were dried by slowly lifting them out of the water, and finally, they were placed in a dedicated scanner and scanned.

[0087] (4) Data analysis The data was quantified using Agilent's Feature Extraction software. Normalization was performed using the quantile method with the statistical analysis software R. Furthermore, the Z-score and Ratio were calculated from the normalized signal values, and only those with a variation of ±2 or greater were extracted. The resulting data was then analyzed using the annotation database DAVID (http: / / david.abcc.ncifcrf.gov / ). First, after inputting the GenBank Accession Numbers of the genes whose changes were confirmed into the database, Functional Annotation Clustering was performed to cluster the genes according to their respective functions. Similarly, pathway analysis using KEGG (Kyoto Encyclopedia of Genes and Genomes) was performed using DAVID.

[0088] result Based on a significance level of p<0.05, Figure 5 shows the genes that significantly changed compared to the placebo group after consuming the test diet. This gene expression analysis revealed significant changes in the expression of various transporter molecules present on blood cells. In particular, the intake of imidazole dipeptide significantly increased the expression of the vitamin C transporter (SLC23A2 in Figure 5) located on the membrane surface of lymphocytes. Furthermore, the expression of several genes related to mitochondrial energy metabolism increased (ACO2 (aconidase) and IDH3G (isocitrate dehydrogenase), enzymes in the TCA cycle). It is possible that imidazole dipeptide exerts its health-promoting effects through this mechanism.

[0089] In the chemokine group, a decrease in the expression of CXC chemokine and CC chemokine was observed. This suggests that the test diet tends to suppress inflammation. Furthermore, enhanced expression of aging-related genes was observed. This suggests that the test diet may control aging. Furthermore, enhanced expression of anti-aging genes was observed. This suggests that the test diet has anti-aging properties.

[0090] Carnosine is known to improve muscle fatigue, and this fatigue recovery has been thought to be due to its effect of neutralizing pH in muscles. However, the fact that the intake of the test diet resulted in an enhancement of mitochondrial genes suggests a new function on muscles: enhancement of mitochondrial function via glycolysis. Furthermore, it was found that the expression of SIRT6, known as a longevity gene, was enhanced. It is known that high expression of this gene in mice extends the lifespan of the mice. Therefore, life extension may also be expected with imidazole dipeptides. In addition, the fact that the intake of imidazole peptides alters the gene expression of various SLCs suggests that combining them with carnosine may alter the response to various physiologically active substances and food components, a so-called food combination effect.

[0091] 5. Changes in serum cytokine concentrations During a 3-month intake period, blood samples from subjects were examined for biochemical tests, blood cell counts, blood glucose tests, and coagulation tests before food intake, during intake (6 weeks after the start), and immediately after the end of the period. A downward trend in blood glucose levels was observed with the intake of the test food. No changes were observed in other indicators before and after intake, thus reaffirming the safety of both the test food and the placebo.

[0092] Furthermore, quantitative analysis of 27 types of cytokines and chemokines was performed on the same blood samples. The serum cytokine concentrations in the subjects' peripheral blood were quantitatively analyzed using bead-based multiplex analysis with xMAP technology (Luminex). This method utilizes the principle of flow cytometry to simultaneously quantitatively analyze each cytokine using specific antibodies bound to beads labeled with different fluorescence. Bio-Plex Pro TMThe following outlines the analysis method using the Human Cytokine Grp I panel 27-pLex kit (Bio-Rad). Each antibody bead was dispensed into a 96-well assay plate, washed twice with Bio-Plex Wash buffer, serum and standard solution were added, and the plate was incubated on a shaker at room temperature for 1 hour in the dark. After washing three times with Wash buffer, the detection antibody solution was added and the plate was incubated on a shaker at room temperature for 30 minutes in the dark. After washing three times with Wash buffer, PE-labeled streptavidin solution was added and the plate was incubated on a shaker at room temperature for 10 minutes in the dark. After washing three times with Wash buffer, Assay buffer was added and the plate was shaken for 10 seconds in the dark. The PE fluorescence intensity of each bead was measured using the Bio-Plex 200 system (Bio-Rad), and the serum cytokine concentrations were calculated from standard curves obtained using known samples. Statistical analysis was performed for each subject using paired t-tests before and after ingestion, and the cytokines that changed in the test diet group are shown in Figure 6.

[0093] Ingestion of the test diet significantly reduced the blood levels of many cytokine and chemokine molecules, including IL-8 (CXCL8), IL-5, IL-7, granulocyte colony-stimulating factor (G-CSF), and MCP-1 (CCL2). On the other hand, blood levels of IP-10 (CXCL10) significantly increased with the intake of the test diet. The placebo diet in this study contained histidine to match the amount of essential amino acids in the test diet, and histidine is known to have anti-inflammatory effects. Therefore, among the molecules mentioned above, blood levels of IL-5, IL-7, and MCP-1 (CCL2) also significantly decreased with the intake of the placebo diet.

[0094] Blood glucose levels were measured. The results are shown in Figure 7. Blood glucose levels tended to increase in the placebo group and decrease in the test food group. Compared to the placebo group, blood glucose levels tended to improve in the test food group. On the other hand, since this pilot study targeted healthy middle-aged and elderly individuals, HbA1c (glycated hemoglobin), a marker molecule for diabetes, was within the normal range in many subjects, and no change in its value was observed after consuming the test food.

[0095] [Evaluation using diseased mice] Transgenic mice (Alzheimer's disease model mice) were fed a high-fat diet (HFD) to induce a decline in brain function. The mice were then administered carnosine (L-histidine-β-alanine), and the effects of carnosine were evaluated.

[0096] The results are shown in Figures 8-1, 8-2, 8-3, and 8-4. In the carnosine-containing diet group, cytokine levels were reduced, suggesting that inflammation was suppressed (Figure 8-1). Furthermore, MRI results showed that brain inflammation was suppressed in the carnosine-administered group (Figure 8-2: red area). Microarray analysis revealed that the increased expression of GABA transporters such as 7Slc6a12 and slc6a13, which is observed in Alzheimer's models, was suppressed in the carnosine-administered group (Figure 8-3). In Alzheimer's disease model mice, the amount of GABA that can act as a neurotransmitter decreases due to increased transporter expression, and this suggests that carnosine may suppress this decrease in GABA levels.

[0097] Furthermore, after fasting mice overnight, blood samples were taken and blood insulin levels were detected using a kit (morinaga). The blood test results showed that the increase in blood insulin levels seen in Alzheimer's disease treated with a high-fat diet was suppressed in the carnosine-administered group (Figure 8-4).

[0098] [Evaluation by able-bodied volunteers 2] A test diet containing the same chicken-derived imidazole dipeptide as described above was administered to subjects (healthy volunteers aged 40 and over, divided into a test diet group and a placebo group) for three months, and changes in brain function, etc., were evaluated before, during, and after the study. The formulations of the test diet and placebo diet (as daily amounts) are shown in Table 1. A first and second pilot study were conducted.

[0099] The total number of subjects in the first and second studies combined was 30 in the test diet group and 30 in the regular diet group (placebo group) (see figure below).

[0100] [Table 2]

[0101] [Table 3]

[0102] 1. Analysis using MRI imaging In the second pilot study, MRI imaging was used to directly measure cerebral blood flow, which changes as dementia progresses.

[0103] Changes in cerebral blood flow can be measured using an MRI device and methods such as Arterial Spin Labeling, which uses magnetism to measure blood flow changes without the need for labels.

[0104] The results are shown in Figures 9 and 10. It was found that the reduction in blood flow changes in the posterior cingulate cortex, which is affected by progression from the pre-dementia stage and the onset of dementia, was maintained in the group consuming the test diet with a significant difference (P<0.005) compared to the placebo group.

[0105] 2. Subgroup Analysis We evaluated logical memory (delayed recall task), which declines with progression from the pre-dementia stage and with the onset of dementia, in subgroup analyses of subjects (aged 60 and over) from the first and second pilot studies.

[0106] The results are shown in Figures 11 and 12. In this study, the second trial was more difficult than the first trial, so scores tended to be worse in the second trial than in the first. However, it was found that the deterioration in scores was suppressed in the group that consumed the test food compared to the placebo group with statistically strong significance (P<0.01).

[0107] These two results suggest that agents containing imidazole dipeptides derived from chicken meat have a preventive effect against brain functional aging and the onset of dementia.

[0108] [Manufacturing example] (1) Production of chicken extract A test food containing chicken-derived imidazole dipeptide was prepared using the following process. Chicken breast was finely chopped using a meat grinder, and 1.5 times the weight of the chicken breast was added to the chicken breast. The mixture was heated at 90°C for 4 hours until the Brix reached 20% or more, and then filtered using diatomaceous earth filtration and ultrafiltration to prepare a final carnosine + anserine concentration of approximately 10% (w / v%).

[0109] (2) Capsules 1.0 part by weight of carnosine, 0.2 parts by weight of placenta extract (powder), and 1.3 parts by weight of lactose were mixed and homogenized, then filled into hard capsules according to conventional methods to produce capsules with a net content of 250 mg (100 mg of carnosine per capsule).

[0110] (3) Tablets Tablets containing 60 mg of a carnosine-anserine mixture per tablet (300 mg) were manufactured, along with maltose, dextrin, starch, vitamin E-containing plant oil, isomaltoligosaccharide, indigestible dextrin, shell calcium, 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. [Sequence Listing Free Text]

[0111] Sequence ID 1: SLC23A2, NM#203327 Sequence ID 2: SLC43A2, NM#152346 Sequence ID 3: SLC29A3, NM#018344 Sequence ID 4: SLC35C1, NM#018389 Sequence ID 5: SLC25A33, NM#032315 Sequence ID 6: SLC22A23, NM#015482 Sequence ID 7: CXCL12, NM#199168 Sequence ID 8: CCL17, NM#002987 Sequence ID 9: TSPO, NM#000714 Sequence ID 10: P2RY1, NM#002563 Sequence ID 11: CAMK1, NM#003656 Sequence ID 12: ACO2, NM#001098 Sequence ID 13: ATP7A, NM#000052 Sequence number 14: POLG, NM#002693 Sequence ID 15: IDH3G, NM#004135 Sequence ID 16: UCP2, NM#003355 Sequence ID 17: BCKDHA, NM#000709 Sequence ID 18: TAP2, NM#018833 Sequence ID 19: SMARCD1, NM#139071 Sequence ID 20: SIRT6, NM#016539

Claims

1. A pharmaceutical or food composition comprising a compound represented by the following formula I or II (excluding carnosine, anserine, and balenine) for at least one selected from the group consisting of improving age-related decline in cognitive function, improving age-related decline in logical memory, reducing the risk of developing dementia, improving symptoms in human patients with Alzheimer's disease, stopping or delaying the progression of predementia, suppressing brain atrophy, improving age-related decline in functional connectivity between the posterior cingulate cortex and the hippocampus, and maintaining blood flow to the posterior cingulate cortex that declines with progression from the predementia stage and with the onset of the disease. 【Chemistry 1】 【Chemistry 2】 (In formula I, formula II, R 1 , R 2 and R 3 These are, independently, H or CH 3 And, X is H or -COR 4 And at this time R 4 is H or CH 3 (That is the case.)

2. A method for searching for an active ingredient for at least one selected from the group consisting of suppressing brain atrophy, improving the decline in functional connectivity between the posterior cingulate cortex and the hippocampus associated with aging, and maintaining blood flow in the posterior cingulate cortex region that declines with progression from the pre-dementia stage and with the onset of the disease, using a compound represented by the following formula I or II as a lead compound. 【Transformation 3】 【Chemistry 4】 (In formula I, formula II, R 1 、R 2 and R 3 are each independently H or CH 3 and X is H or -COR 4 And at this time R 4 is H or CH 3 (That is the case.)

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