AU2019380798A1 - Composition and method for improving linguistic ability and the like - Google Patents

Abstract

The present invention provides a composition and method for improving linguistic ability, thinking ability, logical ability, insight, visual imaging ability, and/or information processing ability. The present invention provides a composition for improving linguistic ability, thinking ability, logical ability, insight, visual imaging ability, and/or information processing ability, the composition containing a peptide (LNDP) comprising the amino acid sequence NIPPLTQTPVVVPPFLQPE or a salt thereof. The present invention also provides a method.

Description

(Y J5. 2(a))

Specification Title of Invention COMPOSITIONS AND METHODS FOR IMPROVING VERBAL ABILITY AND OTHERS

Technical Field of the Invention The present invention relates to a composition and a method for improving verbal ability, reasoning, logical thinking, insight, visualization, and/or information processing.

Background Art With the progress of an aging society, there have arisen problems of deteriorations of the ability to absorb knowledge, daily alertness, visual-spatial reasoning, visual-motor coordination, ability to perceive a whole from its parts, verbal concept formation and conceptual thinking abilities, and so on. Therefore, developments of medicines, foods, and beverages for improving or enhancing these abilities have been demanded more and more strongly. Patent Document 1 and Non-Patent Document 1 teach that a peptide containing an amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro Phe-Leu-Gln-Pro-Glu (NIPPLTQTPVVVPPFLQPE) (SEQ ID NO: 1) (this peptide is referred to as lactononadecapeptide or LNDP) has a brain function improving activity and disclose the Y-maze tests and the novel object recognition tests as grounds for the above teaching. Patent Document 2 describes a method for producing LNDP. Non-Patent Document 2 discloses that continuous ingestion of a casein hydrolysate containing LNDP for 12 weeks improved cognitive functions including attentiveness, capacity for concentration, and arithmetic processing ability. Non-Patent Document 3 discloses that continuous ingestion of a fermented milk beverage containing LNDP for 8 weeks was observed to exert functions of improving attentiveness and short-term memory.

References Patent Documents Patent Document 1: Japanese Patent Application Publication No. 2012-031139 Patent Document 2: Japanese Patent Application Publication No. 2015-154773

Non-Patent Documents

Non-Patent Document 1: Ohsawa, K., Uchida, N., Ohki, K., and Yokogoshi, H. (2018a), Int. i Food. Sci. Nutr., 69, 33-45 Non-Patent Document 2: Fumiya Nakamura, Kazuhito Osawa, Yasunori Nakamura, Akiyoshi Sawabe, Naoki Miura, and Jiro Okuda (2017) Jpn PharmacolTher, 45, 1303 1314 Non-Patent Document 3: Ohsawa, K., Nakamura, F., Uchida, N., Mizuno S., Yokogoshi, H. (2018b), Int. J Food. Sci. Nutr., 69, 369-376 Non-Patent Document 4: Yakushiji, Y., Horikawa, E., Eriguchi, M., Nanri, Y., Nishihara, M., Hirotsu, T. and Hara, H. (2014), Intern. Med., 53, 2447-2453 Non-Patent Document 5: Wechsler, D. (1997), "Wechsler Adult Intelligence Scale-Third Edition", NCS Pearson, Inc, Indiana. "Japanese version of WAIS-III, titled Theoretical Manual of Wechsler Adult Intelligence Scale" (2006), translated by Kazuhiro Fujita, Hisao Maekawa, Hitoshi Dairoku, and Katsuko Yamanaka, Nihon Bunka Kagakusha Co., Ltd., Tokyo Non-Patent Document 6: Fukuhara, S., Bito, S., Green, J., Hsiao, A. and Kurokawa, K. (1998a), J. Clin. Epidemiol., 51, 1037-1044 Non-Patent Document 7: Fukuhara, S., Ware, JE., Kosinski, M., Wada, S. and Gandek, B. (1998b), J Clin. Epidemiol., 51, 1045-1053 Non-Patent Document 8: Yoshihiro Murakami and Chieko Murakami (2008) "Revised Clinical Psychology Assessment Handbook", Kitaoji Shobo, Kyoto

Summary of Invention Problems to be solved by the present invention The present invention provides a composition and a method for improving verbal ability, reasoning, logical thinking, insight, visualization and/or information processing (verbal ability and others). The present invention provides a composition and a method for improving a test result in at least one item among "Information", "Block Design", "Object Assembly" or "Verbal Comprehension Index" in Wechsler Adult Intelligence Scale 3rd Edition (WAIS III) (Non-Patent Document 5).

Means for solving the problems The present invention includes the following compositions and methods. (1) A composition comprising a peptide comprising an amino acid sequence Asn-Ile-Pro Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving verbal ability, reasoning, logical thinking, insight, visualization, and/or information processing. (2) The composition according to (1), comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the verbal ability. (3) The composition according to (1), comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the reasoning. (4) The composition according to (1), comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the logical thinking. (5) The composition according to (1), comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the insight. (6) The composition according to (1), comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the visualization. (7) The composition according to (1), comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the information processing. (8) The composition according to (1), comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving a test result in at least one item among "Verbal Comprehension", "Information", "Block Design", and "Object Assembly" of WAIS-III. (9) The composition according to any one of (1) to (8), wherein the composition is for oral administration or oral ingestion. (10) The composition according to any one of (1) to (8), wherein the composition is a food, a beverage, a food composition, a beverage composition, or a supplement. (11) The composition according to any one of (1) to (9), wherein the composition is a pharmaceutical composition. (12) A method comprising administrating a peptide comprising an amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving verbal ability, reasoning, logical thinking, insight, visualization, and/or information processing of the target. (13) The method according to (12), comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the verbal ability. (14) The method according to (12), comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the reasoning. (15) The method according to (12), comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the logical thinking. (16) The method according to (12), comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the insight. (17) The method according to (12), comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the visualization. (18) The method according to (12), comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the information processing. (19) The method according to (12), comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving a test result in at least one item among "Verbal Comprehension", "Information", "Block Design", and "Object Assembly" of WAIS-III. (20) The method according to any one of (12) to (19), wherein the administration or the ingestion is oral administration or oral ingestion. In the present specification, a peptide comprising the amino acid sequence Asn Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) is also referred to as "lactononadecapeptide" or abbreviated as "LNDP" in some cases.

Detailed Description of Embodiments In an embodiment, the present invention provides a composition for improving verbal ability, reasoning, logical thinking, insight, visualization, and/or information processing, the composition comprising a peptide (lactononadecapeptide or LNDP) comprising an amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof. In an embodiment, the present invention provides a method for improving verbal ability, reasoning, logical thinking, insight, visualization, and/or information processing, the method comprising administering LNDP or a salt thereof to a target or causing the target to ingest the LNDP or the salt thereof. The LNDP can be administered to or ingested by human as a medical practice or a non-medical practice. When the present specification refers to a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (LNDP), the peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (LNDP) includes a salt of the peptide unless the context clearly indicates that the salt is excluded or the salt is explicitly excluded. Such salts include salts that may exist under physiological conditions, for example, including, but not limited to, sodium salts, potassium salts, and hydrochlorides. Compositions of the present invention include, for example, pharmaceutical compositions, foods, beverages, food compositions, beverage compositions, food additives, beverage additives, and supplements (the supplements are also referred to as dietary supplements or health supplements). In an embodiment, the composition of the present invention is a pharmaceutical composition. In an embodiment, the composition of the present invention is a food, a beverage, a food composition, a beverage composition, or a supplement. The LNDP or the composition of the present invention may be used as a food and/or beverage material for humans. For example, the LNDP or the composition of the present invention may be added to a food, a beverage, or raw materials thereof to produce a food, a beverage, a food composition, a beverage composition, or a supplement having a desired biological effect such as an effect of improving verbal ability, reasoning, logical thinking, insight, visualization, and/or information processing. The food, beverage, food composition, beverage composition, or supplement having such an effect may be also referred to as a functional food or a functional beverage in some cases. The LNDP (lactononadecapeptide) can be produced by hydrolyzing casein, and, for example, can be obtained by enzymatically hydrolyzing casein with a protease derived from Bacillus licheniformis (Patent Document 2). The LNDP can be also synthesized in an organic chemical scheme. As an organic chemical method for synthesizing the peptide, any of general methods such as solid phase methods (t-Boc method and Fmoc method) and liquid phase methods can be used. For example, the peptide may be synthesized by using an automatic peptide synthesizer such as a peptide synthesizer (PSSM-8) manufactured by Shimadzu Corporation. As the reaction conditions and the like for the peptide synthesis, any synthesis method, appropriate reaction conditions, and the like selected based on the common general technical knowledge of those skilled in the art may be set. Methods for purifying a peptide chemically synthesized are also well known to those skilled in the art. The composition of the present invention may contain substances other than the active ingredient LNDP such as proteins, peptides other than the LNDP, free amino acids or salts thereof, carriers, excipients, fillers, antiseptics, stabilizers, binders, pH adjusters, buffers, thickeners, gelling agents, preservatives, and antioxidants. In the context of the present invention, the three-letter and one-letter notations of amino acids and the notation of the peptide follow general rules well known to those skilled in the art. Therefore, Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) is also described as NIPPLTQTPVVVPPFLQPE, and the left end is an amino terminus (N terminus). The biological effects of the LNDP and the composition of the present invention can typically be confirmed by performing the Wechsler Adult Intelligence Scale 3rd Edition (WAIS-III) (Non-Patent Document 5). For example, functions of the LNDP can be confirmed by causing each of subjects to ingest a LNDP-containing composition or a placebo (negative control) for a certain period (for example, 24 weeks), conducting the WAIS-II during and/or after the certain period, and comparing the test results (scores) of a group ingesting the LNDP-containing composition and a group ingesting the placebo. The functions of the composition of the present invention can be confirmed by checking the test results in, in particular, "Information", "Block Design", "Object Assembly" and/or "Verbal Comprehension Index" among the items in the WAIS-III. More specifically, it can be confirmed that the LNDP has statistically significant effects by appropriately statistically processing the test results and using any of various verification methods well known in the technical field. Description will be given of how to interpret a statistically significant increase in the score of the test result of "Information", "Block Design", "Object Assembly", or "Verbal Comprehension Index" among the items in the WAIS-III (Non-Patent Document 8).

[Verbal Comprehension] The verbal comprehension includes three subtest problems named Vocabulary, Similarities, and Information. This index comprehensively indicates how much one understands the meanings of words, how much one has an ability to abstract reality and make logical reasoning, and how much one absorbs general information in the daily life. This index focuses on intellectual curiosity or urge to collect knowledge, linguistic competence, general intelligence, verbal concept formation and conceptual thinking, a logical abstract reasoning ability, an ability to distinguish essential from non essential details, a range of knowledge about general facts, cultural environments at home and school, reading, long-term memory, and so on. The high scores is interpreted as "one has strong intellectual curiosity, a wide range of knowledge about general facts, high verbal intelligence, and superior verbal concept formation and conceptual thinking abilities". More specifically, when the LNDP or the composition of the present invention is administered to or ingested by a target, the target may demonstrate effects of, for example, enhancing the ability to abstract reality and make logical reasoning, enhancing the intellectual curiosity or urge to collect knowledge, enhancing the linguistic competence, the general intelligence, and the verbal concept formation and conceptual thinking, enhancing the logical abstract reasoning ability, and enhancing the ability to distinguish essential from non-essential details.

The terms "Verbal Ability", "Reasoning", "Insight" and/or "Logical Thinking" described herein are concepts that simply represent the above-mentioned abilities from several points of view. For example, "intellectual curiosity or urge to collect knowledge and linguistic competence", "ability to understand words", "ability to abstract reality and make logical reasoning", "ability to absorb general information in the daily life" and so on generally involve a language and therefore can be comprehensively interpreted as "Verbal Ability", "general intelligence and verbal concept formation" can be interpreted as "Verbal Ability" or "Reasoning", "ability to abstract reality and make logical reasoning" and "logical abstract reasoning ability" can be comprehensively interpreted as "Logical Thinking", and "ability to abstract reality and make logical reasoning" and "ability to distinguish essential from non-essential details" can be comprehensively interpreted as "Logical Thinking" or "Insight". Therefore, in relation to the present invention, in the case where the score of "Verbal Comprehension" in the WAIS-II statistically significantly increases after the ingestion of a LNDP food as compared with that before the ingestion whereas the score does not statistically significantly increase before and after the ingestion of a placebo food, or in the case where the LNDP group shows a statistically significant increase in the score as compared with the placebo group, it is possible to determine that the "Verbal Ability", "Reasoning", "Insight" and/or "Logical Thinking" of the target are improved.

[Information] In the WAIS-III, "Information" is a subtest of "Verbal Comprehension". The Information relates to a verbal comprehension factor. This test is composed of questions concerning facts such as persons, places, and common phenomena. This measures how much average persons absorb general information available in schools, books, televisions, and the neighborhood. Most of them are things overlearned and habituated in the case of older children and adults. Although the test score involves remote memory and alertness to day-to-day world, it is influenced only to a small extent by conscious effort and is only minimally affected by an intensity of anxiety. The high score can be achieved if one has a lot of experience in the past, retains long-term memory well, and possesses a wide range of interests. This subtest focuses on the range of knowledge about general facts, cultural environment at home, learning at school, intellectual curiosity or urge to collect knowledge, reading, alertness to the day-to-day world, long-term memory, and so on.

The high score is interpreted as "one has strong intellectual curiosity and a wide range of knowledge about general facts, shows positive attitude toward school educations, absorbs knowledge well, memorizes well what was learned in the past, and is good at daily alertness". More specifically, when the LNDP or the composition of the present invention is administered to or ingested by a target, the target may demonstrate effects of, for example, enhancing the verbal comprehension, enhancing the alertness to the day-to-day world, enhancing experience, widening the range of interests, widening the range of knowledge about general facts, and enhancing the intellectual curiosity or urge to collect knowledge. Since "Information" falls under "Verbal Comprehension" in the WAIS-III test, "Verbal Ability" described herein is a concept comprehensively representing the aforementioned abilities in addition to the items explained in the section of [Verbal Comprehension]. For example, "ability to absorb knowledge from the daily life," and "range of knowledge about general facts, cultural environment at home, learning at school, and intellectual curiosity or urge to collect knowledge" involve a language in most cases, and therefore "has strong intellectual curiosity and a wide range of knowledge about general facts, shows positive attitude toward school educations, absorbs knowledge well, memorizes well what was learned in the past " also generally involve the language. In consideration of this, these abilities can be comprehensively interpreted as "Verbal Ability". Therefore, in relation to the present invention, in the case where the score of "Information" in the WAIS-II statistically significantly increases after the ingestion of a LNDP food as compared with that before the ingestion whereas the score does not statistically significantly increase before and after the ingestion of a placebo food, or in the case where the LNDP group shows a statistically significant increase in the score as compared with the placebo group, it is possible to determine that "Verbal Ability" of the target is improved.

[Block Design] In the WAIS-III, "Block Design" is a subtest of "Perceptual Organization". Block Design is related to a perceptual organization factor. The first problem can be solved by trial-and-error, but most problems require considerable visual-logical reasoning ability. This subtest is closely related to the perceptual organization ability, and is an index of ability to visualize an invisible thing in the mind and ability of abstract conceptualization. This subtest focuses on ability to analyze a whole into component parts, spatial visualization, nonverbal concept formation, perceptual organization, concentration, visual-motor-spatial coordination, and so on. The high score is interpreted as "one has superior perceptual organization ability, good visual-spatial reasoning ability, and ability to analyze a whole into component parts, is able to visualize an invisible thing in the mind and make abstract conceptualization, is good at visual-motor-spatial coordination, and has a capacity for concentration". More specifically, when the LNDP or the composition of the present invention is administered to or ingested by a target, the target may demonstrate effects of, for example, enhancing the perceptual organization ability, enhancing the visual or logical reasoning ability, enhancing the ability to visualize an invisible thing in the mind, enhancing the ability of abstract conceptualization, enhancing the ability to analyze a whole into component parts, improving the spatial visualization, enhancing nonverbal concept formation ability, and enhancing the visual-motor-spatial coordination. The "Visualization" described herein is a concept comprehensively representing the above abilities. For example, the above statement "one has superior perceptual organization ability, good visual-spatial reasoning ability, and ability to analyze a whole into component parts, is able to visualize an invisible thing in the mind and make abstract conceptualization, is good at visual-motor-spatial coordination, and has a capacity for concentration" can be interpreted, as it is, to rephrase "Visualization". Therefore, in relation to the present invention, in the case where the score of "Block Design" in the WAIS-II statistically significantly increases after the ingestion of a LNDP food as compared with that before the ingestion whereas the score does not statistically significantly increase before and after the ingestion of a placebo food, or in the case where the LNDP group shows a statistically significant increase in the score as compared with the placebo group, it is possible to determine that "Visualization" of the target is improved.

[Object Assembly] Object Assembly is related to a perceptual organization factor. This subtest is composed of a question in which a line drawing of a familiar object is separated into several pieces, and a subject is asked to correctly combine the several pieces. This test measures the ability of quick visual conceptualization and manual rearrangement. The test score is an index of the ability to perceive a whole from its parts and the speed of visual-motor coordination. This subset focuses on visual-motor coordination, ability to perceive a whole from its parts, holistic simultaneous processing, ability to differentiate relative configurations, and so on. The high score is interpreted as "one has superior visual motor coordination, is endowed with the abilities to perform holistic simultaneous processing and perceive a whole from its parts, also has superior visual conceptualization ability, and achieves high speed manipulation". More specifically, when the LNDP or the composition of the present invention is administered to or ingested by a target, the target may demonstrate effects of, for example, enhancing the perceptual organization ability, increasing the speed of visual conceptualization, enhancing the ability to perceive a whole from its parts, increasing the speed of visual-motor coordination, and enhancing the abilities to conduct holistic simultaneous processing and differentiate relative configurations. "Information Processing" described herein is a concept simply and comprehensively representing the above abilities from several points of view. For example, "ability to perceive a whole from its parts" "abilities to perform holistic simultaneous processing and differentiate relative configurations", and "(ability related to) the speed of visual-motor coordination" can be comprehensively interpreted as "Information Processing". Therefore, in the context of the present invention, when the score of "Object Assembly" in the WAIS-II statistically significantly increases after the ingestion of a LNDP food as compared with that before the ingestion whereas the score does not statistically significantly increase before and after the ingestion of a placebo food, or in the case where the LNDP group shows a statistically significant increase in the score as compared with the placebo group, "Information Processing" of the target can be considered to be improved. The composition of the present invention or the LNDP can achieve the above described effects when orally administrated to or ingested by a target. In the present invention, the "target" includes human. The dose or ingestion amount of the composition of the present invention and the administration or ingestion period thereof can be adjusted in consideration of the age of the target for the administration or ingestion, the health conditions of the target, and so on. The composition of the present invention can be expected to produce continuous biological effects when administered or ingested continuously at least once a day. The LNDP is a peptide that can also be obtained as a hydrolysate of casein, so it is highly safe and can be administered or ingested routinely every day. Even after the desired biological effects are observed, the administration or ingestion of the LNDP can be continued. The composition of the present invention to be used as a pharmaceutical composition may be in the form of formulations for oral administration. Such forms include, for example, tablets, pills, hard capsules, soft capsules, microcapsules, powders, granules, liquids, and so on. When the composition of the present invention is used as a pharmaceutical composition, the composition may contain any of pharmaceutically acceptable carriers, excipients, fillers, antiseptics, stabilizers, binders, pH adjusters, buffers, thickeners, gelling agents, preservatives, antioxidants, and the like, and may be in any unit dosage form required for generally accepted drug administration. The LNDP is highly safe as mentioned above and a prescription is unnecessary to obtain the LNDP or the composition of the present invention. For this reason, it can also be administered to or ingested by humans as a non-medical practice by a person who does not have a medical license. For example, the LNDP or the composition of the present invention may be provided as an aid to enhancing the effectiveness of learning or training in various schools or cultural centers for learning or training of children, adults, or the elderly. For example, the LNDP or the composition of the present invention may be provided in tutoring schools to enhance the learning effects. For example, the LNDP or the composition of the present invention may be provided to enhance the training effects during exercise and improve athletic performance. In such a case, the composition of the present invention or the LNDP is typically provided in the form contained in a food, beverage, or supplement. Regarding the dose or ingestion amount of the composition of the invention or the LNDP to obtain the desired biological effects, the total amount of the LNDP as an active ingredient per administration or ingestion is 1 g/kg body weight to 1 mg/kg body weight, preferably 10 g/kg body weight to 0.4 mg/kg body weight, and more preferably 20 g/kg body weight to 0.2 mg/kg body weight. In the case of preparing a composition containing the LNDP of the present invention, for example, a food, a beverage, a beverage composition, a food composition, or a supplement, the composition can be prepared such that the content of the active ingredient LNDP per 100 g of the final preparation is 0.1 mg to 1 g, preferably 0.2 mg to 500 mg, and more preferably 0.5 mg to 200 mg, which depends on the form of the composition. The content of the LNDP in a food, a beverage, a beverage composition, a food composition, or a supplement can be even lower than the above-specified content, depending on the number of ingestions per day. In some cases, the composition of the present invention may contain other ingredients, for example, ingredients for balancing nutrition and ingredients for adjusting flavor and taste. These ingredients include those usable in foods, beverages, and the like including sugars, proteins, lipids, vitamins, minerals, and flavors, such as, for example, various carbohydrates, lipids, vitamins, minerals, sweeteners, fragrances, pigments, texture improvers, or mixtures thereof. The composition of the present invention may be in any form of solid, gel or liquid. Examples thereof include various processed foods, beverages, dried powders, tablets, capsules, granules, and the like, and further the composition may be in the form of, but not limited to, various beverages, yogurts, liquid foods, jellies, candies, retort foods, tablets, cookies, castella, bread, biscuits, chocolates, and so on. The present invention will be described specifically by using the following Examples, but the scope of the present invention should not be limited to Examples

[Example 1] 1. Selection of Subjects 140 healthy Japanese males and females aged 35 or over and under 55, who were aware of the decline in reading comprehension, arithmetic ability, and comprehension were gathered, and were provided with sufficient explanations on the research details and the test method, and submitted the written consents. Pre-tests and pre-ingestion tests were conducted including background survey, interview with subjects, body measurement (height, body weight, body fat percentage, and body mass index (BMI)), physical examinations (blood pressure and pulse), Mini-Mental State Examination (MMSE) (Non-Patent Document 4), Wechsler Adult Intelligence Scale 3rd Edition (WAIS-II) (Non-Patent Document 5), and Short-Form 36-Item Health Survey version 2 (SF-36v2) Japanese Version (Non-Patent Documents 6 and 7). From among those who met the selection criteria and did not fall into the exclusion criteria in the pre-tests and pre-ingestion tests and were judged to be appropriate for participation in the trial according to the judgment by a doctor in charge of the trial, 100 subjects were selected by excluding those having cognitive dysfunction with a MMSE score less than 24 and those whose scores in the WAIS-III were outliers.

2. Preparation of LNDP-containing Food A LNDP-containing food was prepared in the following method. A protease derived from Bacillus licheniformis was added to an aqueous sodium caseinate solution, and the obtained mixture was reacted for 10 hours at 50± 2C and pH 7.0 1.0, and the enzymatic reaction was stopped by heating. The reaction product was powdered by a spraydryer. An excipient and a lubricant were added to the powered reaction product (enzymatic hydrolysate of casein) and the resultant product was filled into hard capsules to produce LNDP-containing capsules (LNDP food). Placebo capsules (placebo food) were produced by replacing the enzymatic hydrolysate of casein with cellulose. For each kind of capsules, four capsules were set as an ingestion amount per day. As a result of an LC-MS/MS analysis (Non-Patent Document 3), the LNDP food contained 4.2 mg of LNDP per 4 capsules, but no LNDP was detected in the placebo food. The ingredient compositions of the LNDP food and the placebo food are shown in Table 1.

Table 1. Compositions of Trial Capsules (4 Capsules) LNDP Capsules Placebo Capsules Calorie 5.7 kcal 4.3 kcal Moisture 0.08 g 0.04 g Protein 0.815 g 0.001 g Lipid 0.030 g 0.008 g Carbohydrate 0.54 g 1.06 g Na 12.2 mg 0.3 mg LNDP 4.2 mg Not Detected

3. Trial Design In accordance with the Declaration of Helsinki and ethical guidelines for medical and health research involving human subjects, a randomized, double-blind, placebo controlled, parallel-group comparative trial was conducted after being approved by the Ethics Committee of the Oriental Ueno Detection Center (approved on December 5, 2017, approval number: Orin No. 2017-36) and pre-registered (UMIN trial ID: UMIN000031094) in the clinical trial registration system of the University hospital Medical Information Network. The 100 subjects who entered the trial were randomly divided into two groups (LNDP group and placebo group) in a stratified block randomization method by an allocation manager who was not directly involved in the trial so that the two groups had no bias in terms of the age, gender, and WAIS-III index scores in the pre-ingestion tests, and then it was finally confirmed that there was no significant difference between the allocation groups. Four capsules of the LNDP food or the placebo food were ingested for 24 weeks once a day before breakfast with water or lukewarm water without chewing. The subjects were instructed to avoid irregular lifestyles during the trial period and to keep lifestyle habits before participating in the trial such as dietary habits, alcohol drinking, exercising, sleeping, and smoking unchanged as much as possible. The tests were conducted before ingestion and 24 weeks after the start of ingestion.

4. Evaluation Method The WAIS-II (Non-Patent Document 5) was employed as efficacy evaluation items. Before and 24 weeks after the ingestion of the LNDP food or the placebo food, the tests were conducted in the form of an oral question by a psychiatrist or clinical psychologist using the WAIS-II (test set purchased from Nihon Bunka Kagakusha Co., Ltd.). Using the aggregated raw scores of 14 subtests, the WAIS-III enables calculation of three IQs including verbal IQ, performance IQ, and full scale IQ, and scores for four secondary indices including verbal comprehension, perceptual organization, working memory, and processing speed, and thereby allows more multifaceted understanding and interpretation of intelligence. The IQs include the verbal IQ, the performance IQ, and the full scale IQ. The verbal IQ is calculated from the total score of vocabulary, similarities, arithmetic, digit span, information, and comprehension, the performance IQ is calculated from the total score of picture completion, coding, block design, matrix reasoning, and picture arrangement, and the full scale IQ is calculated from the total score of the subtests constituting the vocabulary IQ and the performance IQ. The calculation of the verbal IQ makes it possible to evaluate "acquired knowledge, verbal reasoning, and attention to verbal stimulus," the calculation of the performance IQ makes it possible to evaluate "fluid reasoning, spatial processing, attention to details, and visual-motor integration", and the calculation of the full scale IQ makes it possible to evaluate "the overall level of intellectual functions of an individual". The secondary indices include the verbal comprehension, the perceptual organization, the working memory, and the processing speed. The verbal comprehension is calculated from the total score of vocabulary, similarities, and information, the perceptual organization is calculated from the total score of picture completion, block design, and matrix reasoning, the working memory is calculated from the total score of arithmetic, digit span, and letter-number sequencing, and the processing speed is calculated from the total score of coding and symbol search. The calculation of the verbal comprehension makes it possible to evaluate "acquired verbal knowledge and verbal reasoning", the calculation of the perceptual organization makes it possible to evaluate "non-verbal fluid reasoning, attention to details, and visual-motor integration", the calculation of the working memory makes it possible to evaluate "ability to pay attention to information, hold it for a short time, process the information in memory, and derive an answer", and the calculation of the processing speed makes it possible to evaluate "ability to quickly process visual information" (Non-Patent Document 5).

5. Results i) Background Factors of Subjects The LNDP group of 46 subjects (19 males and 27 females aged; 45.2 5.2 years old) and the placebo group of 43 subjects (15 males and 28 females aged; 45.2 5.3 years old) were set as subjects for efficacy analysis. Table 2 shows background factors of the 89 subjects. In all the factors, no significant difference was observed between the two groups. Table 2. Values for Subjects before Ingestion LNDP Group Placebo Group Number of Subjects (males/females) 19/27 15/28 Age 45.2 5.2 years old 45.2 5.3 years old Height 164.2 8.3 cm 163.7 8.3 cm Body Weight 60.6 10.4 kg 58.6 10.2 kg MMSE 28.8 1.3 29.1 1.0 Data are presented as average standard deviation. MMSE: mini-mental state test

ii) WAIS-II Table 3 shows the scores of the IQs and the secondary indices of the WAIS-II. There was no significant difference between the LNDP group and the placebo group. Only the LNDP group demonstrated a significant improvement of "Verbal Comprehension" after the ingestion as compared with that before the ingestion.

Table 3. Scores of IQs and Secondary Indices of WAIS-II LNDP Group Placebo Group

(n=46) (n=43) Before 24 Weeks Before 24 Weeks after Ingestion after Ingestion Ingestion Ingestion IQ Verbal IQ 97.9 9.5 100.2 10.2* 99.7 9.3 101.3 10.0* Performance IQ 96.2 11.7 101.4 12.2** 95.3 10.7 100.3 12.4** Full Scale IQ 96.9 9.7 100.7 10.0** 97.5 9.4 101.0 10.7**

Secondary Index Verbal 98.1 8.8 100.2 10.4** 100.6 9.2 101.2 8.2 Comprehension Perceptual 95.2 12.1 99.0 13.4* 93.5 10.5 97.2 11.7* Organization Working Memory 92.8 12.4 94.5 11.7 94.9 11.0 96.7 12.5 Processing Speed 99.7 12.4 106.3 13.0** 100.0 13.7 105.8 13.1** Data are presented as average standard deviation. Comparison with the score before the ingestion in the same group (Wilcoxon signed-rank test): * P < 0.05, ** P < 0.01. WAIS-III: Wechsler Adult Intelligence Scale 3rd Edition, IQ: Intelligence Quotient

Table 4 shows the raw scores of the subtests without taking the ages into consideration. Only the LNDP group demonstrated significant improvements in the items "Information" and "Block Design" after the ingestion as compared with those before the ingestion. In the item "Object Assembly", both the LNDP group and the placebo group demonstrated significant improvements after the ingestion as compared with those before the ingestion, and further the LNDP group also demonstrated a significant improvement as compared with the placebo group.

Table 4. Raw Scores of Subtests of WAIS-II LNDP Group Placebo Group (n=46) (n=43) Before 24 Weeks Before 24 Weeks Ingestion after Ingestion after Ingestion Ingestion

Verbal Tests Vocabulary 29.9 7.2 30.3 7.8 32.1 7.2 31.1 6.4 Similarities 22.1 3.1 22.3 4.6 22.4 3.7 23.0 2.9 Arithmetic 13.8 3.2 13.9 3.1 13.6 3.4 13.4 3.5 Digit Span 16.6 3.2 17.6 3.8* 16.9 2.8 17.9 3.6 Information 15.6 3.6 16.5 3.7** 16.0 3.2 16.8 3.7 Comprehension 19.5 4.1 19.7 3.9 19.6 4.3 20.4 3.2 Letter-Number 11.8 2.5 11.8 2.3 12.6 2.1 12.7 2.5 Sequencing

Performance Tests Picture Completion 15.8 2.0 16.5 2.2* 15.1 1.9 15.9 2.0* Coding 83.0 12.7 89.4 83.1 88.5 13.4** 12.1** 15.5 Block Design 46.2 9.9 49.0 9.6* 46.2 9.2 48.0 10.7 Matrix Reasoning 17.1 4.1 16.9 4.1 17.0 4.0 17.1 3.7 Picture Arrangement 14.4 4.4 15.1 3.9 14.5 3.9 15.3 3.6 Symbol Search 40.3 6.9 42.5 6.4** 39.7 7.6 42.3 7.1** ObjectAssembly 31.9 9.1 36.0 28.9 8.3 32.2 7.9** 9.3 **'" Data are presented as average standard deviation. Comparison between the scores before and after the ingestion in the same group (Wilcoxon signed-rank test): * P < 0.05, ** P < 0.01. Comparison with the placebo group for the same item (Mann-Whitney U test):#P<0.05. WAIS-III: Wechsler Adult Intelligence Scale 3rd Edition.

As shown in Tables 3 and 4, as a result of giving the LNDP food or the placebo food to each of the 89 healthy Japanese males and females aged 35 or over and under 55 for 24 weeks, only the group that ingested the LNDP food was observed to achieve improvements in the items of "Information", "Block Design", and "Verbal Comprehension Index" as compared with those before the ingestion. In addition, the group that ingested the LNDP food was observed to achieve a significant improvement in the item of "Object Assembly" as compared with the group that ingested the placebo food. These results prove that the LNDP has the effects of improving the verbal ability, reasoning, logical thinking, insight, visualization, and/or information processing.

Claims (20)

1. What is claimed is: 1. A composition comprising a peptide comprising an amino acid sequence Asn-Ile-Pro Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving verbal ability, reasoning, logical thinking, insight, visualization, and/or information processing.
2. 2. The composition according to claim 1, comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the verbal ability.
3. 3. The composition according to claim 1, comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the reasoning.
4. 4. The composition according to claim 1, comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the logical thinking.
5. 5. The composition according to claim 1, comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the insight.
6. 6. The composition according to claim 1, comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the visualization.
7. 7. The composition according to claim 1, comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving the information processing.
8. 8. The composition according to claim 1, comprising a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro Glu (SEQ ID NO: 1) or a salt thereof, wherein the composition is for improving a test result in at least one item among "Verbal Comprehension", "Information", "Block Design", and "Object Assembly" of WAIS-III.
9. 9. The composition according to any one of claims 1 to 8, wherein the composition is for oral administration or oral ingestion.
10. 10. The composition according to any one of claims I to 8, wherein the composition is a food, a beverage, a food composition, a beverage composition, or a supplement.
11. 11. The composition according to any one of claims 1 to 9, wherein the composition is a pharmaceutical composition.
12. 12. A method comprising administrating a peptide comprising an amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro-Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving verbal ability, reasoning, logical thinking, insight, visualization, and/or information processing of the target.
13. 13. The method according to claim 12, comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the verbal ability.
14. 14. The method according to claim 12, comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the reasoning.
15. 15. The method according to claim 12, comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the logical thinking.
16. 16. The method according to claim 12, comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the insight.
17. 17. The method according to claim 12, comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving visualization processing ability.
18. 18. The method according to claim 12, comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving the information processing.
19. 19. The method according to claim 12, comprising administrating a peptide comprising the amino acid sequence Asn-Ile-Pro-Pro-Leu-Thr-Gln-Thr-Pro-Val-Val-Val-Pro-Pro Phe-Leu-Gln-Pro-Glu (SEQ ID NO: 1) or a salt thereof to a target or causing the target to ingest the peptide or the salt thereof, wherein the method is for improving a test result in at least one item among "Verbal Comprehension", "Information", "Block Design", and "Object Assembly" of WAIS-III.
20. 20. The method according to any one of claims 12 to 19, wherein the administration or the ingestion is oral administration or oral ingestion.

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