JP2019070048A - Agent comprising imidazole dipeptide - Google Patents

Abstract

An anti-aging agent derived from a natural product is provided. An imidazole dipeptide is used as an active ingredient. The present invention also provides an agent for improving neuropsychological function comprising imidazole dipeptide as an active ingredient. The present invention also includes an agent for varying the expression of a transporter such as SLC23A2 containing an imidazole dipeptide, an agent for controlling the blood concentration of a cytokine such as IP-10 containing an imidazole dipeptide, and An expression analysis method for detecting improvement or deterioration of neuropsychological function and a kit for detecting improvement or deterioration of neuropsychological function are also provided. [Selection figure] None

Description

  The present invention relates to an agent comprising, as an active ingredient, at least one selected from the group consisting of imidazole dipeptides and their metabolites. The agent of the present invention can be used for cognitive function improvement, psychological function improvement, anti-aging, health maintenance. The present invention is useful in the fields related to general food, health food, medicine, beauty, health and medical care.

  Carnosine is a dipeptide consisting of β-alanine and histidine, and anserine is a dipeptide consisting of β-alanine and methylated histidine. All are known to be included in chicken and the like. Carnosine and anserine have been studied for promoting skin metabolism (patent document 1), autonomic nervous control function (patent document 2), stress alleviation (patent document 3), and learning function improvement and anti-anxiety (patent document 4) actions .

  In recent years, there has been an interest in maintaining health while maintaining health, such as preventing diseases associated with aging and strengthening immunity. Aging often involves some degree of cognitive decline. Decreased cognitive function also results from the onset and progression of Alzheimer's disease.

JP, 2000-201649, A WO 2002/076455 Japanese Patent Application Publication No. 2007-70316 JP 2000-116987 A

  It is desirable to be able to delay the progress of aging in daily life and to cope early with the diseases associated with aging through proper diet, exercise, psychotherapy, etc.

  In addition to being an energy source and an essential nutrient source (nutritionality), food also provides enjoyment of eating (palatability) and contributes to a healthy life (functionality). Products containing food or food-derived functional ingredients are expected to be useful for health and beauty, and have been widely accepted as health food and the like. Use of natural products with food experience is considered to be preferable from the viewpoint of safety and security.

  The present inventors have worked on research and development of food and materials useful for health by utilizing natural products. Among them, the present inventors have found that carnosine and anserine derived from chicken meat have an effect of improving the psychological function and the like, and completed the present invention. The present invention provides the following.

[1] An agent for improving neuropsychological function, comprising at least one selected from the group consisting of an imidazole dipeptide and a metabolite thereof.
[2] The agent according to [1], wherein the neuropsychological function is associated with Alzheimer's disease or aging.
[3] An anti-aging agent, which comprises at least one member selected from the group consisting of an imidazole dipeptide and a metabolite thereof, which is improved in neuropsychological function.
[4] containing at least one selected from the group consisting of an imidazole dipeptide and a metabolite thereof,
The transporter genes SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12 and SLC6A13;
Chemokine genes, CXCL12 and CCL17;
Senescence related genes, TSPO and P2RY1;
A nervous system gene, CAMK1;
Mitochondrial genes ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA and TAP2; and anti-aging genes SMARCD1 and SIRT6
An agent for varying the expression of at least one gene selected from the group consisting of
[5] The agent according to [1], which has anti-inflammatory activity.
[6] IP-10 (CXCL10), IL-2, IL-5, IL-7, IL-8 (CXCL8), IL- containing at least one member selected from the group consisting of imidazole dipeptides and their metabolites 13. An agent for controlling the concentration in blood of at least one cytokine selected from the group consisting of G-CSF and MCP-1 (CCL2).
[7] The agent according to [1], which has a suppressive action or a suppressive action on the rise in blood glucose level.
[8] The agent according to [1], which has a suppressive action or a suppressive action on the increase of insulin concentration in blood.
[9] The agent according to any one of [1] to [8], for taking at least one selected from the group consisting of 200 mg or more of imidazole dipeptide and its metabolite as a daily dose.
[10] A nutritional composition comprising a daily dose of at least one of 200 mg or more of an animal meat-derived imidazole dipeptide.
[11] The nutritional composition according to [10], wherein at least one of the imidazole dipeptides is derived from chicken meat.
[12] The agent or nutritional composition according to any one of [1] to [11], further comprising creatine and a nucleic acid.
[13] The agent or nutritional composition according to any one of [1] to [12], intended for elderly people or those with mild mood disorders.
[14] An agent for treating diabetes and / or Alzheimer's disease, which comprises at least one member selected from the group consisting of imidazole dipeptides and their metabolites.
[15] A dietary method, comprising: feeding a nutritional composition comprising at least one selected from the group consisting of an imidazole dipeptide and a metabolite thereof to a subject whose neuropsychological function is desired to be improved.
[16] A method of judging neuropsychological function of a subject based on carnosine degrading enzyme (CNDP1) activity of the subject.
[17] A method for predicting the improvement effect of neuropsychological function by having a subject take the agent or the nutritional composition according to any one of [1] to [14] based on the CNDP1 activity of the subject.
[18] SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12 and SLC6A13, which are transporter genes for detecting improvement or deterioration of neuropsychological function;
Chemokine genes, CXCL12 and CCL17;
Senescence related genes, TSPO and P2RY1;
A nervous system gene, CAMK1;
Mitochondrial genes ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA and TAP2; and anti-aging genes SMARCD1 and SIRT6
A method by analyzing the expression of at least one gene selected from the group consisting of
[19] It is selected from the group consisting of all or part of the nucleotide sequence of any of SEQ ID NO: 1 to 20, and all or part of the nucleotide sequence complementary to any of the nucleotide sequences of SEQ ID NO: 1 to 20 A kit for detecting improvement or deterioration of neuropsychological function, which comprises a nucleic acid consisting of at least one base sequence.
[20] A pharmaceutical composition for treatment of functional ageing and / or dementia of the brain, comprising a compound represented by the formula I or II.

(In formula I, formula II,
R ¹ , R ² and R ³ are each independently H or C _1-6 alkyl,
X is H or -COR ⁴ where R ⁴ is H or C _1-6 alkyl. )
[21] A method for searching for an active ingredient for treatment of brain functional aging and / or dementia, using the compound represented by the formula I or formula II as defined in claim 20 as a lead compound.

Results of psychological function test (BDI test). Results of psychological function test (ADAS Scog test to evaluate brain aging). The improvement, no change, deterioration, and the respective rates were displayed. Brain site (gray matter) in which atrophy is improved by intake of imidazole dipeptide. The portions where p <0.005 were displayed in color. Brain site (white matter) in which atrophy is improved by the intake of imidazole dipeptide. Improvement of neural circuit function by intake of imidazole dipeptide. The hippocampus and posterior cingulate nerve circuit function declines with age (left figure), but in the test food intake group, this decline was improved after intake (right figure). Genes that fluctuate with intake of imidazole dipeptide. In 6 genes belonging to SLC (transporter), the intake of the test diet significantly changed the gene expression level compared to the placebo diet intake. In addition, it was found that the expression levels of each of the genes shown in the figure, such as chemokines, fluctuate. Blood cytokines and chemokines that fluctuate with intake of imidazole dipeptide. Mean value ± SE, test food: solid line, placebo: broken line, paired t test, *: p <0.05, **: p <0.01 Decrease in blood sugar level by intake of imidazole dipeptide. Decreased blood cytokines in dementia model mice. In the carnosine-containing group, cytokines are reduced, suggesting that inflammation is suppressed. wt: wild-type, tg: transgenic, *: p <0.05, **: P <0.01 (Dunnett's test vs tgHFD), #: p <0.05, ##: P <0.01 (Student ttest) Suppression of intracerebral inflammatory response in dementia model mice (mouse MRI image). Inflammation suppression by intake of imidazole dipeptide was seen. Suppression of GABA transporter gene expression in glial cells by high-functional dipeptide intake. Slc6A13: GABA Transporter 2 (GAT-2) expressed in astrocytes, Slc6A12: Betaine / GABA Transporter 1 (BGT-1) expressed in astrocytes Blood insulin levels in mice. There was a significant difference (student's t-test, P <0.05) between the values of the Alzheimer's disease (AD) high fat diet group and the AD high fat diet + carnosine group. ASL analysis A difference between the two groups by ASL analysis (posterior cingulate) Logical Memory II scores (results of sub-analysis over 60). Significant difference between the two groups (P <0.01). It should be noted that post-consumption testing is much more difficult than pre-consumption testing. Logical Memory II scores (results of sub-analysis over 60). While there was no decline in function at any age in the test diet group, there was a marked decline in function decline with age in the placebo diet group.

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

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

In Formula I, Formula II, R ¹ , R ² and R ³ are each independently H or C _1-6 alkyl, and X is H or -COR ⁴ , wherein R ⁴ is H, C _1-6 alkyl, optionally substituted benzyl, or H ₂ C = CH—.

In formula I, it is preferred that ^one of R ¹ and R ² is C _1-6 alkyl and the other is H. In Formula II, it is preferable that one of R ² and R ³ is C _1-6 alkyl and the other is H. One of the preferable examples of C _1-6 alkyl is methyl.

Specific examples of X which is -COR ⁴ include formyl, acetyl, propionyl, benzoyl and acryloyl.

  With regard to the method for producing the compound represented by the formula I or formula II, etc., JP-A-2003-520221, JP-A-2006-232686, JP-A-2006-504701, JP-A-2008-517911, JP-A-2009-512459, JP-A-2010- 31004, JP-A-2011-37891, JP-A-2011-37892, JP-A-2013-165728, JP-A-2014-12735, etc. can be referred to.

  Imidazole dipeptides include carnosine, anserine, varenin and homocarnosine. Carnosine is a dipeptide consisting of β-alanine and histidine. Due to the three-dimensional structure of histidine which composes, carnosine has L form and D form. In the present invention and the description thereof, when simply referred to as "carnosine", it refers to L-carnosine, D-carnosine or a mixture thereof, unless otherwise specified. L-carnosine is known to be present at relatively high concentrations in muscle and nerve tissues in mammals such as humans.

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

  In some animals, L-anthelin composed of β-alanine and methylated histidine is often found. In the present invention and the description thereof, when simply referred to as "anserine", it refers to L- anserine, D- anserine or a mixture thereof, unless otherwise specified. The structure of L-anserine (L-anserine, IUPAC name: (2S) -2-[(3-amino-1-oxopropyl) amino] -3- (3-methyl-4-imidazolyl) propanoic acid) is shown below .

  Both carnosine and anserine are water soluble (carnosine 1 g / 3.1 ml at 25 ° C.).

  The term "metabolite of imidazole dipeptide" as used herein refers to one metabolite selected from the group consisting of carnosine, anserine, varenin and homocarnosine unless otherwise specified. Metabolites of imidazole dipeptides include β-alanine, histidine, methylated histidine and γ-aminobutyric acid (GABA).

  In the present invention, the phrase "at least one selected from the group consisting of imidazole dipeptides and their metabolites" is intended to mean one or more of the imidazole dipeptides unless otherwise specified. For example, when "containing at least one member selected from the group consisting of imidazole dipeptide and its metabolite as an active ingredient", carnosine is the active ingredient and other imidazole dipeptide is not contained, and carnosine and anserine are active ingredients. And the like. In addition, when referring to "at least one selected from the group consisting of imidazole dipeptides and their metabolites", when referring to amounts or concentrations, except where otherwise noted, two or more imidazole dipeptides and their metabolites are present. Refers to the combined amount or concentration of all imidazole dipeptides and their metabolites. In the present specification, an imidazole peptide, or an embodiment using carnosine or anserine among imidazole dipeptides and their metabolites may be described as an example, but the description is based on other imidazole dipeptides and their metabolites. The same applies when used.

  In the present invention, the imidazole dipeptide and its metabolite to be used as an active ingredient may be synthesized, may be produced by fermentation, or may be obtained from a natural product. Also, it may be isolated or purified. More specifically, the imidazole dipeptide and its metabolite may be derived from various animals, for example, cattle, horses, pigs, chickens, whales, fish (eg, tuna, eel, eel). One preferred example is from chicken meat. The imidazole dipeptide and its metabolite may be contained in the agent as an extract of natural products, a concentrate, a crude product and the like.

[Use, function]
The agent of the present invention can be used to improve neuropsychological function. Improvements in neuropsychological function include antidepression (improvement of psychological function) and improvement of cognitive function. In addition, the improvement of neuropsychological function includes the suppression of brain atrophy, the suppression of cerebral hypofunction (the strengthening of the functional connection with the hippocampus), and the improvement of neuronal damage due to inflammation, which is related to the neuropsychological function . The neuropsychological function may be related to Alzheimer's disease or aging. Improving neuropsychological function also includes treatment of functional aging of the brain and / or dementia.

  The antidepressant (improvement of psychological function) effect by the agent of the present invention can be evaluated by BDI questionnaire (http://www.chibatc.co.jp/catalogue/04/1/67.html). As the score by the BDI questionnaire indicates that the higher one is depressed, for example, the survey is performed before and after the intake period of the agent of the present invention, and the score before intake is compared with the score after intake, It is possible to compare the degree of improvement of psychological function. In particular, the agent of the present invention can be expected to have an effect of improving psychological function to a subject having mild mood disorder.

  The improvement effect of the cognitive function by the agent of the present invention can be evaluated by the ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) method. The improvement effect of the cognitive function according to the present invention includes the case of improving the degree to which the memory becomes worse with aging and the case of improving the morbidly cognitive ability (dementia). In particular, the agent of the present invention can be expected to have an improving effect on cognitive function deterioration associated with Alzheimer's disease or aging.

  The agent of the present invention can be used for suppression of brain atrophy, suppression of depression of brain function (intensification of function connection with hippocampus), or improvement of neuronal damage caused by inflammation. The effects on these can be evaluated by methods well known to those skilled in the art such as diagnostic imaging. According to the study of the present inventors, in the target group including the elderly, the gray matter and the white matter of the brain each had a site where the progress of atrophy was suppressed. No such effect was seen in the group receiving placebo without anserine and carnosine.

  The agent of the present invention may be used to treat the onset of functional aging and dementia of the brain, more particularly to prevent, delay or inhibit the onset of functional aging and dementia of the brain, or to prevent the aggravation Can. Such an effect can be confirmed by evaluating the change in blood flow in the posterior cingulate region of the subject or the logical memory (delayed regeneration task) for subjects 60 years of age or older. According to the study of the present inventors, blood flow in the posterior cingulate region is significantly different from that in the placebo diet group in the test diet intake group containing the imidazole dipeptide when the test subject includes subjects aged 60 years or older. It turned out that it was kept. In addition, it was found that, when the test subject was 60 years old or more as a subject, the score of the logical memory was maintained with a significant difference in the group receiving the test food for 3 months as compared with the placebo food group.

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

  The agent of the present invention is particularly preferably at least one, preferably at least three, more preferably five or more, still more preferably all selected from the group consisting of SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12, SLC6A13. Can be used to alter the expression of the Fluctuating expression includes increasing expression and decreasing expression.

  The agents of the invention can be used to alter the expression of chemokines. Chemokines are basic proteins that express their actions via G protein coupled receptors and are a group of cytokines. It causes migration of leukocytes and the like and participates in the formation of inflammation. Many chemokines have been discovered so far. Due to structural differences, they are classified into CC chemokines, CXC chemokines, C chemokines, and CX3C chemokines. So far, more than 50 types of chemokines have been identified.

  The agent of the present invention can be used to specifically alter the expression of at least one, preferably both chemokines selected from the group consisting of CXCL12 and CCL17. Fluctuating expression includes increasing expression and decreasing expression.

  The agent of the present invention can be used to change the expression of senescence related genes. Senescence-related genes are identified as genes involved in individual aging and cellular senescence, and numerous senescence-related genes have been identified so far.

  The agent of the present invention can be used particularly to change the expression of at least one, preferably both senescence related genes selected from the group consisting of TSPO and P2RY1. Fluctuating expression includes increasing expression and decreasing expression.

  The agent of the present invention can be used to change the expression of nervous system genes. Nervous system genes are genes involved in neurogenesis, neural differentiation and the like, and numerous nervous system genes have been identified so far.

  The agent of the present invention can in particular be used to alter the expression of nervous system gene CAMK1. Fluctuating expression includes increasing expression and decreasing expression.

  The agent of the present invention can be used to change the expression of mitochondrial gene. Mitochondrial genes are genes involved in mitochondrial biogenesis, fusion, TCA cycle, and respiration, and many genes have been identified so far.

  The agent of the present invention is particularly preferably at least one, preferably at least three or more, more preferably five or more, still more preferably all mitochondria selected from the group consisting of ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA and TAP2. It can be used to change the expression of gene expression. Fluctuating expression includes increasing expression and decreasing expression.

The agent of the present invention can be used to change the expression of anti-aging gene. Anti-aging genes are genes that achieve cell aging suppression and anti-aging, and numerous genes have been identified so far.
The agent of the present invention can in particular be used to alter the expression of at least one, preferably both, chemokines selected from the group consisting of SMARCD1 and SIRT6. Fluctuating expression includes increasing expression and decreasing expression.

  The agent of the present invention is also a group consisting of IP-10 (CXCL10), IL-2, IL-5, IL-7, IL-8 (CXCL8), IL-13, G-CSF and MCP-1 (CCL2). It can be used for control of at least one cytokine selected. Control includes raising and lowering levels.

  The agent of the present invention can also be used to suppress or reduce the increase in anti-inflammatory agent or blood sugar level.

  In the present invention, the terms "improvement" or "treatment" for a disease or condition include reduction in the risk of onset, delay in onset, prevention, treatment, cessation of progression, and delay. Actions for improvement or treatment include medical practices performed by doctors, and medical acts for the treatment of diseases, and persons other than doctors, such as dietitians (administrator, nurses, midwife, nurses, clinical technologists, cosmetologists, etc. It includes non-medical activities performed by staff members, estheticians, food manufacturers, food sellers etc. Treatment also includes recommendations for the administration or intake of specific foods, dietary instruction, health guidance, nutrition guidance Including nutrition instruction necessary for medical treatment of the person and nutrition instruction for health maintenance and improvement), dietary management, and necessary instruction for nutritional improvement for feeding. An (individual), preferably a human, in whom it is desirable to receive any of the treatments described above, or in need of any of the treatments described above.

  The present inventors measured the activity of serum carnosine degrading enzyme (hereinafter referred to as CNDP1) in the serum of the subject in order to verify individual differences given to the efficacy of the imidazole dipeptide. As a result of activity measurement, it was confirmed that there were large individual differences among subjects. CNDP1 is present in the blood and degrades the imidazole dipeptide. Thus, CNDP1 may affect the concentration of imidazole dipeptide in the blood following intake of the imidazole dipeptide and thus affect the efficacy of the imidazole dipeptide. Therefore, the activity information of CNDP1 in a subject is considered to be useful for determining in advance whether the treatment by intake of imidazole dipeptide is effective. Therefore, the present invention allows a subject to ingest the agent or nutritional composition of the present invention based on the subject's method for determining the neuropsychological function of a subject based on the subject's carnosine degrading enzyme (CNDP1) activity, and the subject's CNDP1 activity. Provides a method to predict the improvement effect of neuropsychological function by In these methods, a reference value for determination may be determined in advance and mechanically predicted according to the reference.

[Agent]
The term "agent" in the present invention may be the active ingredient itself or may contain the active ingredient and the other components except when specifically described, but a group consisting of an imidazole dipeptide and its metabolite It does not include existing foods containing at least one selected from the above, such as chicken itself.

  In the agent of the present invention, components other than the active ingredient can be blended as long as the desired effects can be exhibited. The other ingredients may be various food acceptable additives or various pharmaceutically acceptable additives. In this example, an excipient, an antioxidant (antioxidant), a flavor, a seasoning, a sweetener, a coloring agent, a thickening stabilizer, a color former, a bleaching agent, a fungicide, a gum base, a bitter taste agent, etc. Enzymes, brighteners, acidulants, emulsifiers, fortifying agents, manufacturing agents, binders, tonicity agents (tonicity agents), buffers, solubilizers, preservatives, stabilizers, coagulants, etc.

  Other ingredients may be functional ingredients other than an active ingredient. Other functional components include, for example, amino acids (for example, branched chain amino acids, ornithine), unsaturated fatty acids (for example, EPA, DHA), vitamins, trace metals, glucosamine, chondroitins and the like .

  When the agent of the present invention comprises the active ingredient and other ingredients other than the active ingredient, the content of the active ingredient can be appropriately designed by those skilled in the art in terms of easiness of production, ease of use, etc. It can be 0.1 to 99.9%, can be 1 to 95%, can be 10 to 90%, and can be 51 to 90% or more. Moreover, it can be 21% or more as carnosine, and can be 31% or more as anserine.

  The forms of the agent of the present invention may be in various forms except for existing foods as described above. For example, it may be a pharmaceutical composition or a nutritional composition such as an oral medicine. In addition, the agent of the present invention can be used by being added to a pharmaceutical composition or nutritional composition such as an oral medicine. In the present invention, the term "nutritional composition" includes not only solid substances but also liquid substances, such as beverages, unless otherwise specified. Further, in the present invention, the term "nutritional composition" includes health foods, supplements, health functional foods (including nutritional function foods and food for specified health use) unless otherwise specified, and also a therapeutic diet (treatment) Fulfilling the purpose of the medical treatment, the doctor gives a meal prescription and the food is prepared based on the menu prepared by the dietitian etc.), diet food, component adjustment diet, low salt diet, care diet, reduced calorie diet, And diet foods, as well as ingredients for them.

  Examples of forms of the agent, pharmaceutical composition or nutritional composition of the present invention include powders, fine granules, granules, tablets, capsules, liquid preparations (elixirs, limonade agents, syrups, emulsions, suspensions, Examples include solutions, drinks, gel preparations, therapeutic foods, beverages, confectionery, processed meat products, processed fish products, processed vegetable products, prepared vegetables, seasoning compositions, and food additives.

  The intake amount of the active ingredient according to the present invention can be appropriately designed by those skilled in the art according to the age, weight, sex, applied disease or condition, etc. of the subject to be ingested. The intake amount of the active ingredient can be, for example, 200 mg / day, preferably 400 mg / day, more preferably 500 mg / day or more, and 750 mg / day or more. More preferable. Further, it may 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 may be 50,000 mg / day or less, preferably 30,000 mg / day or less, more preferably 20,000 mg / day or less, and 10,000 mg / day. It is more preferable to set it as day or less. As the active ingredient, the daily intake may be taken at one time, or may be divided and taken several times.

  The amount of the active ingredient in the agent, pharmaceutical composition or nutritional composition of the present invention can be appropriately designed by those skilled in the art, and can be, for example, 1,000 mg / 100 g or more, 1,500 mg / 100 g or 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, 3,500 mg / 100 g or more It is further preferred that 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, 20,000 mg / 100 g It is more preferable to set it as the following.

  The agent, pharmaceutical composition or nutritional composition of the present invention may also contain components other than the active ingredient. Ingredients other than the active ingredient are, for example, creatine and nucleic acid. The content of creatine can be, for example, 10 mg or more in a daily dose, preferably 20 mg or more, more preferably 30 mg or more, and more preferably 60 mg or more. It is more preferable to set it as 100 mg or more, and it is more preferable to set it as 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 still more preferably 500 mg or less. The content of the nucleic acid can be, for example, 0.15 mg or more in a daily dose, preferably 0.30 mg or more, more preferably 0.50 mg or more, and more preferably 1.0 mg or more. It is more preferable to set it as 2.0 mg or more, and it is more preferable to set it as 3.0 mg or more. In any case, it can be 50 mg or less, preferably 40 mg or less, more preferably 20 mg or less, and still more preferably 10 mg or less.

  The agent, the pharmaceutical composition or the nutritional composition of the present invention is used as a therapeutic diet (that fulfills the purpose of therapy; it is prepared based on a menu prepared by a physician and based on a menu prepared by a dietitian etc.), a diet Diet, component adjustment diet, low-salt diet, nursing diet, reduced-calorie diet, diet diet, or sports diet (food intended to enhance ability in aerobic exercise, diet intended to enhance endurance in aerobic exercise, The content of the active ingredient, if it is a diet to accumulate the nutrition on the day of the competition, a diet to supplement the nutrition during the competition, and a diet to recover fatigue after the competition. Can be designed taking into account the intake as a single meal.

  The agent, pharmaceutical composition or nutritional composition of the present invention can be repeatedly taken by the subject, and can be taken by the subject for a long period of time. In particular, when it is intended to enhance the ability to exercise, it is preferable to take it before exercise, and it is preferable to take it on a daily basis.

  The agent, pharmaceutical composition or nutritional composition of the present invention can indicate that it can be used for neuropsychological function, brain atrophy or hypofunction, and neuronal damage due to inflammation, and it can also be used for specific subjects. For example, it can be displayed to recommend intake for elderly people over 65 years old or persons with mild mood disorder. The indication can be direct or indirect, and an example of the direct indication is a description on the product itself, a tangible item such as a package, a container, a label, a tag or the like, and an example of the indirect indication is Including advertising and promotion activities by places or means such as websites, storefronts, exhibitions, billboards, billboards, newspapers, magazines, television, radio, mail, mail etc.

〔Production method〕
The agent, pharmaceutical composition or nutritional composition of the present invention can be manufactured using various known techniques. The process of adjusting the active ingredient to a predetermined concentration can be applied at various stages of the production process. Those skilled in the art can appropriately design the production process for the agent of the present invention in consideration of the solubility, stability, volatility and the like of the active ingredient. According to the study of the present inventor, it has been confirmed that anserine and carnosine are sufficiently stable at ordinary temperature, and sufficiently stable under cooking conditions of 180 ° C. or less. Furthermore, it has been confirmed that the solution can be stably stored for at least 2 years in September.

  When the active ingredient of the present invention is constituted as a chicken extract, to illustrate an example of a method for producing a chicken extract, chicken meat is shredded, warm water is added, pH is adjusted as necessary, and as necessary By warming and extracting over several minutes to several days. An example of the extraction conditions is treatment at 50 to 100 ° C. for 1 to 10 hours. The obtained extract can be purified / fractionated by filtration through diatomaceous earth, ultrafiltration, etc., if necessary. If necessary, desalting treatment and protease treatment can be performed. Although the site | part of the chicken which is a raw material is not specifically limited, It is preferable to include a breast, since it contains many carnosine and / or anserine. The obtained extract can be dried by hot air drying, spray drying, lyophilization and the like to give a dried product. It can also be granulated and made into granules.

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

  Expression analysis is preferably at least one chemokine selected from the group consisting of CXCL12 and CCL17, at least one transporter gene selected from the group consisting of SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12 and SLC6A13 Gene, at least one senescence related gene selected from the group consisting of TSPO and P2RY1, a nervous system gene selected from CAMK1, at least one group selected from the group consisting of ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA and TAP2 By analyzing the expression of at least one anti-aging gene selected from the group consisting of mitochondrial gene of SMARCD1 and SIRT6. More preferably, by analyzing the expression of all the above mentioned genes

  In the development of new drugs and functional food components, etc., the actions of candidate drugs and components are monitored at the cellular level to evaluate their efficacy and safety, but they are expressed in cells before and after drug administration. There is a focus on methods that capture the gene in the whole genome and quantitatively analyze the effects of drugs and components as changes in gene expression level. In such a method, the effect of the candidate drug on neuropsychological function can be analyzed by analyzing the expression of the combination of genes provided by the present invention.

  In the present invention relating to expression analysis, a group consisting of all or part of the nucleotide sequence of any of SEQ ID NO: 1 to 20 and all or part of the nucleotide sequence complementary to any of the nucleotide sequences of SEQ ID NO: 1 to 20 The nucleic acid consisting of at least one base sequence selected from among the above can be a probe capable of specifically hybridizing to the transcript in the sample to be detected, or a function as a primer for amplifying all or part of the transcript It may be a pair of primer sets. The nucleic acid may be DNA or RNA.

  In the present invention relating to expression analysis, a group consisting of all or part of the nucleotide sequence of any of SEQ ID NO: 1 to 20 and all or part of the nucleotide sequence complementary to any of the nucleotide sequences of SEQ ID NO: 1 to 20 When used as a probe, the length of a nucleic acid consisting of at least one base sequence selected from these is, for example, 15 bases or more, preferably 20 bases or more, and more preferably 25 bases or more. The probe nucleic acid may be labeled with, for example, a radioactive isotope, an enzyme, a fluorescent substance, or a luminescent substance to enable detection and quantification of the target nucleic acid. The nucleic acid to be a probe may be immobilized on a solid phase.

  The length of nucleic acid when used as a primer is, for example, 15 to about 100 bases in length, preferably 15 to 50 bases in length, and is a pair designed to amplify a 100 bp to several kbp DNA fragment. Is preferred.

  The nucleic acid to be used can be produced by chemical synthesis using a commercially available DNA / RNA automatic synthesizer or the like. Alternatively, by directly synthesizing the nucleic acid on a solid phase such as silicon or glass, a chip (array) on which the nucleic acid is immobilized can also be obtained. A preferred embodiment in which the nucleic acid probe is provided immobilized on a substrate is a DNA microarray.

 In order to quantitatively analyze the expression of a predetermined gene group 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 human.

[Use as lead compound]
The present invention provides a method (screening method) for searching for an active ingredient etc. for improvement of neuropsychological function, in particular for treatment of functional aging of the brain and / or dementia, using the above imidazole dipeptide and its metabolite as a lead compound. Do. In general, a lead compound is a compound which has a clear pharmacological activity profile and can be chemically modified to improve its activity or reduce its toxicity. As described above, the imidazole dipeptide and its metabolite have the pharmacological activity of improving neuropsychological function, in particular, treating functional aging of the brain and / or dementia, and by further chemically modifying it, the activity is improved Can be expected to reduce toxicity.

  Chemically modifying means, for example, performing optimization of the lead compound by chemically modifying the lead compound. The chemical modification can be, for example, substitution of some amino acids, deletion, addition of at least one amino acid, insertion. Also, addition, substitution, removal of a functional group to each amino acid, substitution to D amino acid of each amino acid, or substitution to an artificial amino acid are conceivable.

  According to the present invention, by optimizing an imidazole dipeptide and its metabolite as a lead compound, it is possible to search for a more superior active ingredient in terms of physical properties, pharmacokinetics and toxicity.

  Hereinafter, the present invention will be described using examples, but the scope of the present invention is not limited to those described in the examples.

[Evaluation 1 by healthy volunteers]
Test subjects containing chicken-derived imidazole dipeptide (carnosine, 1000 mg a day as anserine) were divided into test subjects (28 healthy males and females aged 40 and over, divided into 2 groups: test food group and placebo food group) for 3 months Intake, and before, during, and after that, changes in brain function etc. were evaluated. The combination of test and placebo diets (as a daily dose) is shown in the table below.

1. Antidepressant effect (Evaluation by BDI questionnaire)
The depression tendency was evaluated by BDI questionnaire (http://www.chibatc.co.jp/catalogue/04/1/67.html) before and after the intake period. In addition, the score by BDI questionnaire shows that the higher one is in depression tendency.

  The results are shown in FIG. When the degree of improvement was compared by the change in BDI score, that is, the score before intake (test 1)-the score after intake (test 2), there was almost no improvement in the placebo group, but there was a tendency for improvement in the test food group It was seen. In addition, the change before and after intake was shown by the rank (the higher the rank number, the better), and the change tended to be larger in the test food group. Even healthy individuals may have a slight depression tendency, and the imidazole dipeptide may improve this depression tendency by regulating the function of the GABA nervous system.

2. Improvement effect of cognitive function (Evaluation by ADAS-cog)]
Before and after the intake period, cognitive function was evaluated by ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale).

  The results are shown in FIG. The ratio of those who improved by 3 points or more and those who did worse before and after intake was shown in the test food group, but the percentage of people who improved was higher than that in the placebo group.

3. Effects on brain atrophy, etc. Brain structure analysis using 3D T1-weighted images and functional linkage analysis using resting-time functional MRI were performed. Longitudinal analysis of structural changes in the baseline and 3 months after the trial group of 15 and the group of 13 in the placebo group: right lower frontal and left lower temporal gyrus in the gray matter (Figure 3-1), right posterior in the white matter In the cingulate gyrus, it was found that the progress of atrophy was suppressed in the test food group compared to the placebo food group (FIG. 3-2).

  In addition, in functional linkage analysis by resting functional MRI, functional connectivity with the hippocampus was decreased in the posterior zonal gyrus with aging at baseline (FIG. 4). The posterior cingulate is involved in the regeneration of memory and in Alzheimer's disease it is known to first decline in function. At this site, the test food group had a stronger functional connection with the hippocampus than the placebo food group after 3 months. In addition, this site was in agreement with the white matter site (FIG. 3-2) in which the atrophy suppression effect was observed in the test food group.

4. Gene expression analysis Using the subject's blood samples (at the time of the initial examination and those at the intermediate examination) for 13 subjects (not for 2 subjects) for the test diet group and for all 13 subjects for the placebo group After collecting blood using an RNA blood collection tube (Nippon Becton Dickinson, Tokyo), high quality RNA was prepared using PAX gene Blood RNA kit (Qiagen), and changes in gene expression were analyzed by microarray.

Methods Microarrays were performed using Whole Human Genom oligo DNA microarray (4 × 44 K) v2 from Agilent (CA, USA).
(1) Labeling First, total RNA was extracted from a blood sample of a subject using PAXgene blood RNA Kit (Qiagen), and 200 ng of each was labeled using Agilent Low-Input QuickAmp Labeling Kit, one-color. First, 2.5 μL of 200 ng total RNA was added to 2 μL of the previously prepared One-Color Spike Mix stock solution. Next, 0.8 μL of T7 Promoter Primer was added and incubated in a heat block at 65 ° C. for 10 minutes, followed by quenching on ice for 5 minutes. Furthermore, after adding 4.7 microliters of previously prepared cDNA Master Mix and incubating by a heat block for 2 hours at 40 ° C., it was transferred to a heat block at 70 ° C. and further incubated for 15 minutes. Thereafter, it was quenched on ice for 5 minutes, and 6 μL of the previously prepared Transcription Master Mix was added. After light blocking and incubation for 2 hours with a heat block at 40 ° C., 84 μL of nuclease-free water was added to make the total volume 100 μL, 350 μL of Buffer RLT was added, and 250 μL of ethanol was further added. Next, the whole was added to an RNeasy column, centrifuged at 13000 rpm at 4 ° C. for 30 seconds, washed twice with 500 μL of buffer RPE, and finally eluted with 30 μL of RNase-free water.

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

(3) Cleaning and scanning microarray slide
The microarray slide was washed using Gene Expression Wash Buffer prepared in advance. First, before hybridization was completed, 2 of 3 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. The hybridization chamber in which the hybridization was completed was disassembled in a first washing glass container, the microarray slide was taken out, and washed in a second washing glass container. After washing the microarray slide further with a third cleaning glass container, the microarray slide was slowly pulled up from the water surface to be dried, and finally it was placed on a dedicated scanner to scan the microarray slide.

(4) Data analysis
Data were quantified using the Agilent Feature Extraction software. Normalization was performed by the quantile method using statistical analysis software R. In addition, the data obtained by calculating Z-score and Ratio from the signal value after normalization and extracting only those that have a variation of ± 2 or more can be obtained from the annotation database DAVID (http: //david.abcc. Analysis was performed using ncifcrf.gov/).
First, after entering the GenBank Accession Number of the gene whose variation was confirmed in the database, Functional Annotation Clustering was performed to perform clustering for each function in which gene variation occurred. Similarly, pathway analysis of KEGG (Kyoto Encyclopedia of Genes and Genomes) was performed using DAVID.

Results Based on the significant difference level p <0.05, genes that are significantly changed by the intake of the test food as compared to the placebo food group are shown in FIG. From the results of this gene expression analysis, it was found that the expression of various transporter molecules present on blood cells was greatly fluctuated. In particular, it was found that the amount of expression of the vitamin C transporter (SLC23A2 in FIG. 5) on the membrane surface on lymphocytes was significantly increased by the intake of the imidazole dipeptide. In addition, the expression of multiple genes related to mitochondrial energy metabolism was increased (TCA cycle enzymes ACO2 (aconidase), IDH3G (isocitrate dehydrogenase)). The imidazole dipeptide may have a health promoting effect by utilizing such a mechanism.

In chemokines, decreased expression of CXC chemokine and CC chemokine was observed. It is suggested that the test diet tends to suppress inflammation.
In addition, enhanced expression of senescence related genes was observed. Aging control by the test food is suggested.
Furthermore, expression enhancement of anti-aging gene was observed. Anti-aging by test food is suggested.

  Carnosine is known to have an effect on improving muscle fatigue, and recovery from fatigue has been considered as an effect to neutralize pH in muscle. However, since the gene of the mitochondrial system was enhanced by the intake of the test food, it is suggested that a new function for muscle, namely, the functional enhancement of the mitochondria via glycolysis, is also suggested. Also, it was found that expression of SIRT6, which is known as a longevity gene, is enhanced. This gene is known to extend the lifespan of mice when it is highly expressed in mouse individuals. Therefore, survival may be expected by the imidazole dipeptide. Furthermore, regarding intake of the imidazole peptide, the gene expression of various SLCs fluctuates, so that the response to various physiologically active substances and food components is changed by eating with carnosine, such as the so-called eating effect. It can be expected.

5. Changes in concentration of serum cytokines
Biochemical tests, blood counts, blood glucose tests, and coagulation tests were performed on blood samples from subjects immediately before and after food intake (6 weeks after initiation) and immediately after the end of the intake period of 3 months. It was observed that the blood sugar level tended to decrease due to the intake of the test food. As no other changes were observed before and after intake, the safety of the test and placebo diets was reconfirmed.

In addition, quantitative analysis of 27 types of cytokines and chemokines was performed on the same blood sample. Serum cytokine concentrations in the subject's peripheral blood were quantitatively analyzed using bead-based multiplex analysis using xMAP technology (Luminex). This method is to analyze the respective cytokines simultaneously at the same time by utilizing the principle of flow cytometry using specific antibodies bound on beads which are respectively different in fluorescent labeling. Description of ^{Bio-Plex Pro TM Human Cytokine Grp} I panel 27-pLex Kit (Bio-Rad, Inc.) analysis method using the below. Each antibody bead was aliquoted into a 96-well assay plate and washed twice with Bio-Plex Wash buffer, then serum and standard solution were added and incubated in a shaker at room temperature for 1 hour protected from light. After washing three times with Wash buffer, the detection antibody solution was added and incubated for 30 minutes at room temperature on a shaker protected from light. After washing 3 times with Wash buffer, PE-labeled streptavidin solution was added and incubated on a shaker at room temperature for 10 minutes protected from light. After washing three times with Wash buffer, Assay buffer was added and shaken for 10 seconds in the dark. The PE fluorescence intensity of each bead was measured using a Bio-Plex 200 system (Bio-Rad), and each cytokine concentration in serum was calculated from a standard curve determined using a known sample. Statistical analysis was performed by the corresponding t-test before and after intake for each subject, and the cytokines in which changes were observed in the test food group are shown in FIG.

  Ingestion of the test diet included many cytokine and chemokine molecules including IL-8 (CXCL8), IL-5, IL-7, granulocyte colony stimulating factor (G-CSF), MCP-1 (CCL2), etc. It turned out that the blood level is falling significantly. On the other hand, it was also revealed that the blood level of IP-10 (CXCL10) was significantly increased by the test food intake. The present placebo diet contains histidine for the purpose of combining the essential amino acid amount with the test diet, and it is known that histidine has an anti-inflammatory effect. Therefore, in the IL-5, IL-7, and MCP-1 (CCL2) among the above-mentioned molecular groups, their blood levels were significantly lowered by the intake of the placebo diet.

  Blood glucose levels were measured. The results are shown in FIG. The placebo group tended to rise, and the test food group tended to decline. Blood glucose levels tended to improve in the test food group compared to the placebo group. On the other hand, HbA1c (glycated hemoglobin), which is a marker molecule of diabetes, is in the range of normal values in many subjects because this pilot test targets healthy middle-aged and elderly people, and intake of test food There was no change in value.

[Evaluation with diseased mice]
Transgenic mice (Alzheimer's disease model mice) were fed with a high fat diet (HFD: High Fat Diet) to induce brain dysfunction. Mice were given carnosine (L-histidine-β-alanine) and the effects of carnosine were evaluated.

  The results are shown in FIGS. 8-1, 8-2, 8-3 and 8-4. In the carnosine-containing group, cytokines are reduced, suggesting that inflammation is suppressed (FIG. 8-1). In addition, it was shown from the result of MRI examination that brain inflammation is suppressed in the carnosine administration group (FIG. 8-2: red part). As a result of microarray analysis, elevated expression of GABA transporters such as 7Slc6a12 and slc6a13 found in the Alzheimer's model was suppressed in the carnosine-administered group (FIG. 8-3). In the Alzheimer's disease model mice, elevated transporter expression reduced the amount of GABA that can act as a transmitter, but it has been suggested that carnosine may suppress the decrease in the amount of GABA.

  In addition, after fasting the mouse overnight, blood was collected and blood insulin concentration was detected by a kit (morinaga). As a result of blood test, it was found that in the carnosine-administered group, the increase in blood insulin concentration observed in high fat diet-administered Alzheimer's disease was suppressed (FIG. 8-4).

[Evaluation 2 by healthy volunteers]
The same test food as above, containing chicken-derived imidazole dipeptide, is taken for 3 months to the subject (a healthy volunteer aged 40 years or older divided into a test food group and a placebo food group), before, during, and after And evaluated changes in brain function, etc. The combination of the test diet and the placebo diet (as a daily dose) is as described in Table 1. The first pilot test and the second pilot test were conducted.

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

1. Analysis by MRI imaging In the second pilot study, MRI imaging was performed to directly measure cerebral blood flow that changes as dementia progresses.

  Changes in blood flow in the brain can be measured using the MRI apparatus, for example, the Arterial Spin Labeling method, which is a method of changing the blood flow using magnetism without using a label body.

  The results are shown in FIGS. 9 and 10. Decreased blood flow changes in the posterior cingulate region where blood flow changes with progression and development from the pre-dementia stage have a significant difference (P <0.005) in the test food intake group compared to the placebo food group Was found to be maintained.

2. Subgroup analysis Subjective subgroup analysis (over 60 years old) of the 1st and 2nd pilot study, the logical memory that declines with progression and onset from pre-dementia stage (delayed regeneration task) Was rated.

  The results are shown in FIGS. In the case of this test, the score tends to be worse in the second test than in the first test because the second test is more difficult than the first test, but in the test food intake group compared to the placebo food group It was found that the deterioration of the score was suppressed with strong statistical significance (P <0.01).

  These two results suggest that agents containing an imidazole dipeptide derived from chicken meat have a function to prevent the onset of brain functional aging and dementia.

[Production example]
(1) Production of Chicken Extract A test meal containing a chicken-derived imidazole dipeptide was produced by the following steps.
Slice the chicken breast with a meat grinder, add 1.5 times the amount of warm water to the weight of the meat to the chicken breast, heat at 90 ° C for 4 hours, concentrate to 20% or more Brix, and then diatomaceous earth Filtration and ultrafiltration were carried out to adjust the final carnosine + anserine concentration to about 10% (w / v%).

(2) Capsules After mixing and homogenizing 1.0 part by weight of carnosine, 0.2 parts by weight of placenta extract (powder) and 1.3 parts by weight of lactose, the mixture is filled into hard capsules according to a conventional method, Carnosine (100 mg / capsule) was produced.

(3) Tablets Maltose, dextrin, starch, crude oil containing vitamin E, isomaltooligosaccharide, indigestible dextrin, shellfish calcium, trehalose, sucrose ester, vitamin C, citric acid, calcium phosphate, flavor, shellac, niacin, vitamin A tablet containing 60 mg of carnosine anserine mixture per tablet (300 mg) together with K, sweetener, potassium chloride, vitamin A, calcium pantothenate, biotin, iron pyrophosphate, vitamins B, vitamin D, magnesium carbonate, folic acid Manufactured.

Sequence number 1: SLC23A2, NM # 203327
Sequence number 2: SLC43A2, NM # 152346
SEQ ID NO: 3: SLC29A3, NM # 018344
Sequence number 4: SLC35C1, NM # 018389
Sequence number 5: SLC25A33, NM # 032315
SEQ ID NO: 6: SLC22A23, NM # 015482
Sequence number 7: CXCL12, NM # 199168
Sequence number 8: CCL17, NM # 002987
SEQ ID NO: 9: TSPO, NM # 000714
SEQ ID NO: 10: P2RY1, NM # 002563
Sequence number 11: CAMK1, NM # 003656
SEQ ID NO: 12: ACO2, NM # 001098
Sequence number 13: ATP7A, NM # 000052
Sequence number 14: POLG, NM # 002693
SEQ ID NO: 15: IDH3G, NM # 004135
Sequence number 16: UCP2, NM # 003355
SEQ ID NO: 17: BCKDHA, NM # 000709
Sequence number 18: TAP2, NM # 018833
SEQ ID NO: 19: SMARCD1, NM # 139071
Sequence number 20: SIRT6, NM # 016539

Claims (16)

Ameliorating the decline in cognitive function with age, preventing brain functional aging, and reducing the risk of developing dementia, comprising at least one imidazole dipeptide selected from the group consisting of carnosine, anserine, varenin and homocarnosine An oral agent for at least one selected from the group consisting of An oral preparation containing at least one imidazole dipeptide selected from the group consisting of carnosine, anserine, varenin and homocarnosine, for the prevention of functional aging of the brain or for the improvement of deterioration of cognitive function due to aging. Suppression of brain atrophy, enhancement of functional connection with the hippocampus in the posterior cingulate, or blood flow of the posterior cingulate region, containing at least one imidazole dipeptide selected from the group consisting of carnosine, anserine, varenin and homocarnosine An oral preparation for the maintenance of Suppression of brain atrophy, enhancement of functional connection with the hippocampus in the posterior cingulate, or blood flow of the posterior cingulate region, containing at least one imidazole dipeptide selected from the group consisting of carnosine, anserine, varenin and homocarnosine Oral agents (except for any treatment selected from the group consisting of Alzheimer's disease, Gulf War disease, autism, pervasive developmental disorder, brain injury, cerebral palsy and epilepsy) for the maintenance of ). The agent according to any one of claims 1 to 4, which comprises at least one imidazole dipeptide selected from the group consisting of carnosine, anserine, varenin and homocarnosine as a chicken extract. The agent according to any one of claims 1 to 5, which is a nutritional composition or a food composition. A pharmaceutical composition for treatment of dementia, which comprises at least one imidazole dipeptide selected from the group consisting of carnosine, anserine, varenin and homocarnosine as a chicken extract. Containing at least one imidazole dipeptide selected from the group consisting of carnosine, anserine, varenin and homocarnosine as a chicken extract, suppression of brain atrophy, enhancement of functional connection with hippocampus in posterior cingulate, or posterior cingulate Pharmaceutical composition for the maintenance of blood flow at a site. The transporter genes SLC23A2, SLC43A2, SLC29A3, SLC35C1, SLC25A33, SLC25A23, SLC6A12 and SLC6A13;
Chemokine genes, CXCL12 and CCL17;
Senescence related genes, TSPO and P2RY1;
A nervous system gene, CAMK1;
Mitochondrial genes ACO2, ATP7A, POLG, IDH3G, UCP2, BCKDHA and TAP2; and anti-aging genes SMARCD1 and SIRT6
Varying the expression of at least one gene selected from the group consisting of
The agent or pharmaceutical composition according to any one of claims 1 to 8, or having an anti-inflammatory effect;
At least one member 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 the concentration of cytokines in the blood;
Has an action of suppressing or reducing the rise of blood glucose level; or has an action of suppressing or reducing the rise of insulin concentration in blood
The agent or pharmaceutical composition according to any one of claims 1 to 8. The agent or pharmaceutical composition according to any one of claims 1 to 9, for taking 200 mg or more of an imidazole dipeptide as a daily dose. The agent or pharmaceutical composition according to any one of claims 1 to 10, which is used for taking a daily dose of 1000 mg or more of an imidazole dipeptide in one or more divided doses. The agent or pharmaceutical composition according to any one of claims 1 to 11, further comprising creatine and a nucleic acid. The agent or pharmaceutical composition according to any one of claims 1 to 12, intended for persons aged 40 and over. Improvement in deterioration of cognitive function due to aging, including the step of taking a food composition or a nutritional composition containing at least one imidazole dipeptide selected from the group consisting of carnosine, anserine, varenin and homocarnosine to a subject A method for at least one selected from the group consisting of the prevention of functional aging and the reduction of the risk of developing dementia (excluding medical practice). Suppression of brain atrophy by ingesting a nutritional composition or a food composition containing at least one imidazole dipeptide selected from the group consisting of carnosine, anserine, varenin and homocarnosine to the subject, with hippocampus in the posterior cingulate Methods for enhancing functional connectivity or maintaining blood flow in the posterior cingulate area (except for medical practices). Use of at least one imidazole dipeptide selected from the group consisting of carnosine, anserine, varenin and homocarnosine as a lead compound to improve deterioration of age-related cognitive function, to prevent brain functional aging, and to develop dementia A method of searching for an active ingredient for at least one selected from the group consisting of the reduction of the risk of