Composition for maintaining or improving life expectancy, and method for detecting individual to which said composition is applicable

Abstract

One problem to be solved by the present invention is to provide a composition for maintaining or improving life expectancy. The problem is solved by a composition for maintaining or improving life expectancy, which contains α-amino-n-butyric acid or a salt thereof that is pharmaceutically acceptable or is acceptable for a food.

Description

Title of Invention: COMPOSITION FOR MAINTAINING OR IMPROVING LIFE EXPECTANCY, AND METHOD FOR DETECTING INDIVIDUAL TO WHICH SAID COMPOSITION IS APPLICABLE Technical Field

[0001] The present description discloses a composition for maintaining or improving life expectancy and a method for detecting an individual in need of application of said composition. Background Art

[0002] Non Patent Literature 1 describes that depressive symptoms in older communitydwelling individuals correlate with blood a-aminobutyric acid concentrations, and that a-aminobutyric acid concentrations can be a marker of the depressive symptoms. Patent Literature 1 exemplifies a-aminobutyric acid as one of the amino acids effective for glycemic control.

[0003] Non Patent Literature 2 describes that a-aminobutyric acid increases a synthesis of glutathione in cells and that oral administration of the a-aminobutyric acid increases glutathione concentrations in a heart and reduces myocardial damage caused by doxorubicin. Patent Literature 2 describes an antioxidant inducer containing 2-aminobutyric acid as an active ingredient, a therapeutic agent for diseases caused by oxidative stress. Non Patent Literature 3 describes an effect of methionine on life expectancy and fecundity of Drosophila. Citation List Patent Literature

[0004] [Patent Literature 1] WO2021156181A1 [Patent Literature 2] IP2018008884A Non Patent Literature

[0005] [Non Patent Literature 1] Geriatr Gerontol Int. 2019 Mar; 19(3):254-258. [Non Patent Literature 2] Sci Rep. 2016 Nov 9;6:36749. [Non Patent Literature 3] Nature 2009 Dec 24;462(7276): 1061-4. Summary of Invention Technical Problem

[0006] According to the Basic Resident Registration as of lanuary 1, 2022, the Kyotango region (Kyotango City, Miyazu City, Yosano Town, and Ine Town), located in the northern part of Kyoto Prefecture, has about three times as many centenarians as the national average (FIG. 1A and FIG IB). This area also has one of the highest numbers of healthy elderly people.

[0007] However, it is not yet known what factors contribute to longevity of people living in the Kyotango region. Moreover, factors that maintain healthy life expectancy, the period during which people can live without being restricted by health problems, have not yet been identified.

[0008] An object of the present invention is to provide a composition for maintaining or improving life expectancy. In addition, another object is to provide a method for detecting an individual in need of application of said composition. Solution to Problem

[0009] The present invention may include the following embodiments. Item 1. A composition for maintaining or improving life expectancy, containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof. Item 2. The composition according to item 1, wherein the life expectancy is healthy life expectancy and / or average life expectancy. Item 3. The composition according to item 2, wherein a parameter indicative of the healthy life expectancy is at least one selected from the group consisting of motor function, cardiac function, pulmonary function, and cognitive function. Item 4. The composition according to item 3, wherein, when an individual in need of application of said composition is a human, an indicator of the motor function is at least one selected from the group consisting of leg extension strength, walking speed, and grip strength, an indicator of the cardiac function is a blood brain natriuretic peptide concentration, and an indicator of the pulmonary function is a tricuspid regurgitation pressure gradient. Item 5. The composition according to item 1, wherein, when an individual in need of application of said composition is a human, the individual in need of application of said composition is 60 years or older. Item 6. A composition for suppressing a decrease in motor function caused by Parkinson's disease, containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof. Item 7. A composition for enhancing mitochondrial function, containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof. Item 8. A method for detecting an individual to which a composition for maintaining or improving life expectancy containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof is applicable, including acquiring a measured value indicative of a content of the a-amino-n-butyric acid in a specimen taken from a subject individual, and comparing said measured value with a predetermined reference value to suggest that the subject individual is the individual in need of application of said composition when the measured value is lower than the predetermined reference value. Item 9. A detection device for detecting an individual to which a composition for maintaining or improving life expectancy containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof is applicable, wherein the detection device includes a processing unit, the processing unit acquires a measured value indicative of a content of the a-amino-n-butyric acid in a specimen taken from a subject individual, compares the measured value with a predetermined reference value, and outputs a label indicating that the subject individual is the individual in need of application of said composition when the measured value is lower than the predetermined reference value. Item 10. A computer program for detecting an individual to which a composition containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof is applicable, when executed by a computer, causing the computer to perform steps of: acquiring a measured value indicative of a content of the a-amino-n-butyric acid in a specimen taken from a subject individual, and comparing the measured value with a predetermined reference value, and outputting a label indicating that the subject individual is the individual to which said composition for maintaining or improving life expectancy is applicable when the measured value is lower than the predetermined reference value. Advantageous Effects of Invention

[0010] The present invention can provide the composition for maintaining or improving life expectancy. In addition, the method for detecting the individual in need of application of said composition can be provided. Brief Description of Drawings

[0011] FIG. 1 shows the population of centenarians in the Kyotango region as of January 1, 2022. FIG. 1A shows a breakdown of the population of centenarians in each city and town in the Kyotango region. FIG. IB is a graph showing a comparison among the population of centenarians in the Kyotango region, Kyoto City, and Japan. FIG. 2 is a diagram showing an exemplary overview of a detection system 3000. FIG. 3 is a flowchart showing a process flow of a detection program 3042a. FIG. 4 shows 30 items that correlated with age in a Kyotango cohort. FIG. 4A shows items that correlated negatively with age. FIG. 4B shows items that correlated positively with age. FIG. 5 shows correlations between blood concentrations of a-amino-n-butyric acid (FIG. 5A), which correlated negatively with age, cystine (FIG. 5B), total homocysteine (FIG. 5C), 3-methylhistidine (FIG. 5D), citrulline (FIG. 5E), asparagine (FIG. 5F), and phenylalanine (FIG. 5G), whichcorrelated positively with age, and the age on study date of study subjects in a Kyotango cohort. FIG. 6 shows 30 items that correlated with age in an Iwaki-machi cohort in 2020. FIG. 6A shows items that correlated negatively with age. FIG. 6B shows items that correlated positively with age. FIG. 7 shows 30 items that correlated with renal function (eGFR) in the Kyotango cohort. FIG. 7A shows the items that correlated negatively with age. FIG. 7B shows the items that correlated positively with age. FIG. 8 shows 30 items that correlated with renal function (eGFR) in the Iwaki-machi cohort. FIG. 8A shows the items that correlated negatively with age. FIG. 8B shows the items that correlated positively with age. FIG. 9 shows results of multivariate analysis of urinary a-amino-n-butyric acid concentration (corrected for urinary Cr concentration), blood a-amino-n-butyric acid concentration, urinary sodium ion (Na) concentration, and eGFR. FIG. 9A shows a correlation between the urinary a-amino-n-butyric acid concentration and the blood a-amino-n-butyric acid concentration. FIG. 9B shows a correlation between the blood a-amino-n-butyric acid concentration and the urinary Na concentration. FIG. 9C shows a correlation between the urinary a-amino-n-butyric acid concentration and the eGFR. FIG. 10 shows comparison results of life expectancy of four groups. FIG. 10A shows survival curves of the four groups. FIG. 10B shows the number of days that 50% lethality is reached for the four groups. FIG. 10C shows results of a significance test by Wilcoxon test. FIG. 11A shows means and standard deviations of Climbing Assay scores for each group at 3, 10, 18, 30, 39, 50, and 60 days after eclosion. FIGS. 11B to HE show significant differences (p values) in the scores of a group fed calorie-restricted feed supplemented with the a-amino n-butyric acid and a group fed standard feed supplemented with the a-amino n-butyric acid compared to a group fed the calorie-restricted feed and significant differences (p values) in the scores of a group fed calorie-restricted feed supplemented with the a-amino n-butyric acid and the group fed the standard feed supplemented with the a-amino n-butyric acid compared to the group fed standard-restricted feed. FIG. 1 IB shows the significant difference at 10 days after eclosion, FIG. 1 IC shows the significant difference at 18 days after eclosion, FIG. 1 ID shows the significant difference at 30 days after eclosion, and FIG. 1 IE shows the significant difference at 39 days after eclosion. FIG. 12 shows contents of the a-amino-n-butyric acid in plasma and various organs of mice. FIG. 12A shows the content of the a-amino-n-butyric acid in the plasma, FIG. 12B shows the content of the a-amino-n-butyric acid in heart, FIG. 12C shows the content of the a-amino-n-butyric acid in liver, FIG. 12D shows the content of the a-amino-n-butyric acid in kidney, FIG. 12F shows the content of the a-amino-n-butyric acid in soleus muscle, and FIG. 12G shows the content of the a-amino-n-butyric acid in gastrocnemius muscle. FIG. 13 shows results of a suspension test using the Inverted Screen Test. FIG. 13A shows suspension times at a start of an experiment. FIG. 13B shows suspension times at three months after the start of the experiment. FIG. 14 shows results of a treadmill test at 3 months after the start of the experiment. FIG. 15 shows results of examination on a preventive effect of the a-amino-n-butyric acid on muscle atrophy. FIG. 15A shows a measurement image for a minor diameter of myotube cells. FIG. 15B shows mean myotube cell minor diameters in a cont. group and a Dex. group. FIG. 15C shows mean myotube cell minor diameters of the Dex. group and a 2AB+Dex. group. FIG. 16 shows results of statistical analysis of a relationship between 10-m walking speed, serum a-amino-n-butyric acid concentration, and age. FIG. 16A shows a correlation between the serum a-amino-n-butyric acid concentration (pg / pL) and the age. FIG. 16B shows a correlation between mean 10-m walking speed (m / sec.) and the age. FIG. 16C shows a correlation between the mean 10-m walking speed (m / sec.) and the serum a-amino-n-butyric acid concentration (pg / pL). FIG. 17 shows results of statistical analysis of a relationship between mean leg extension strength, serum a-amino-n-butyric acid concentration, and age. FIG. 17A shows a correlation between the serum a-amino-n-butyric acid concentration (pg / pL) and the age. FIG. 17B shows a correlation between the mean leg extension strength (kgw) and the age. FIG. 17C shows a correlation between the mean leg extension strength (kgw) and the serum a-amino-n-butyric acid concentration (pg / pL). FIG. 18A shows a correlation between blood BNP concentration and blood a-amino-n-butyric acid concentration. FIG. 18B shows a correlation between TRPG and the blood a-amino-n-butyric acid concentration. FIG. 19 shows a correlation between MMSE score and blood a-amino-n-butyric acid concentration. FIG. 20A shows a correlation between blood a-amino-n-butyric acid concentration and MMSE total score on a reference health examination day (first time). FIG. 2B shows a correlation between blood a-amino-n-butyric acid concentration and MMSE total score after 3 years (second time). FIG. 21 shows survival curves for groups fed with (2AB, n=20) and without (Cont., n=20) a-amino-n-butyric acid. FIG. 22 shows a Climbing efficiency in standard feed group and standard feed + a-amino-n-butyric acid group in a Drosophila model of Parkinson's disease. FIG. 23 shows an effect of addition of a-amino-n-butyric acid on mitochondrial function in C2C12 cells. FIG. 23A shows Basal Respiration and Spare Capacity. FIG. 23B shows Proton Leak and ATP production. FIG. 24 shows an effect of addition of a-amino-n-butyric acid on mitochondrial function in HUVEC cells. FIG. 24A shows Basal Respiration and Spare Capacity. FIG. 24B shows Proton Leak and ATP production. Description of Embodiments

[0012] 1. Composition 1-1. Composition for maintaining or improving life expectancy One embodiment of the present invention relates to a composition for maintaining or improving life expectancy (hereinafter also referred to simply as “composition”).

[0013] The composition contains, as an active ingredient, a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof The a-amino-n-butyric acid is also referred to as a-aminobutyric acid, or 2-aminobutyric acid. It is also sometimes abbreviated as 2-AB, 2-ABA, or ABAA.

[0014] The a-amino-n-butyric acid may include enantiomers and diastereomers. The enantiomer may be any of L-isomers, D-isomers, and racemates. The racemate is preferred.

[0015] The pharmaceutically or food-acceptable salts of the a-amino-n-butyric acid may include, salts with inorganic acids such as hydrohalic acid (Hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like), sulfuric acid, nitric acid, and phosphoric acid; salts with alkali metals such as sodium, potassium and lithium; salts with alkaline earth metals such as calcium and magnesium; salts with ammonium; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid and citric acid; salts with organic bases such as ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, and triethanolamine. Here, the pharmaceutically or food-acceptable salts include salts that are acceptable to be added to veterinary drugs or animal or insect feeds.

[0016] The above composition may be the active ingredient as it is, or may contain a carrier or the like depending on an application of the composition. The application of the composition may include medicine, veterinary medicine, food, animal or insect feed and the like.

[0017] For the medicine, veterinary medicine, or food, the composition may be formulated as a medicine, veterinary medicine, or supplement by methods known per se, incorporating appropriate pharmaceutically or food-acceptable carriers as needed for formulation. The pharmaceutically or food-acceptable carrier includes, for example, excipients, binders, lubricants, solvents, disintegrants, dissolution aids, suspending agents, emulsifiers, tonicity agents, stabilizing agents, soothing agents, preservatives, antioxidants, corrigent / flavoring agents, coloring agents, and the like.

[0018] The excipients include organic excipients such as saccharides (e.g., lactose, glucose, and D-mannitol), starches, and (e.g., cellulose such as crystalline cellulose); and inorganic excipients such as calcium carbonate and kaolin, and the like.

[0019] The binders include pregelatinized starch, gelatin, gum arabic, methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and the like.

[0020] The lubricants include stearic acid, fatty acid salts such as stearate, talc, silicates, and the like.

[0021] The solvents include purified water, physiological saline, and the like.

[0022] The disintegrants include low-substituted hydroxypropyl cellulose, chemically modified cellulose, starches, and the like.

[0023] The dissolution aids include polyethylene glycol, propylene glycol, trehalose, benzyl benzoate, ethanol, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and the like.

[0024] The suspending agents or emulsifiers include sodium lauryl sulfate, gum arabic, gelatin, lecithin, glyceryl monostearate, polyvinyl alcohol, polyvinylpyrrolidone, cellulose such as sodium carboxymethyl cellulose, polysorbates, polyoxyethylene hydrogenated castor oil, and the like.

[0025] The tonicity agents include sodium chloride, potassium chloride, saccharides, glycerin, urea, and the like, and the stabilizing agents include polyethylene glycol, dextran sulfate sodium, other amino acids, and the like.

[0026] The soothing agents include glucose, calcium gluconate, procaine hydrochloride, and the like.

[0027] The preservatives include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.

[0028] The antioxidants include sulfite, ascorbic acid, and the like.

[0029] The corrigent / flavoring agents include sweeteners, flavors, and the like, which are commonly used in the field of the medicine, veterinary medicine, or food.

[0030] The colorants include coloring agents which are commonly used in the field of the medicine, veterinary medicine, or food.

[0031] In addition, the food-acceptable carriers include, for example, ingredients for processing, seasonings, flavors, sweeteners and the like.

[0032] Further, vitamins and other nutritional supplement additives may be incorporated into the composition.

[0033] A dosage form of the composition may be, but not particularly limited, for example, solid dosage forms such as powders, granules, capsules, tablets and chewables, and liquid dosage forms such as solutions and syrups, and the like for oral administration. The above dosage form may also be, for example, injections, infusions, nasal and pulmonary sprays, and the like for parenteral administration.

[0034] As used herein, the term “food” refers to foods in general for human use (including beverages), and includes foods with health claims (foods for specified health uses (including food for specified health uses with conditions), foods with nutrient function claims, foods with function claims) as specified in the Food with Health Claims System of the Consumer Affairs Agency, general foods (including health foods), and foods for special dietary uses (foods for medical uses, powdered formulas for pregnant or lactating women, infant formulas and foods for people with dysphagia) as specified in the Foods for Special Dietary Uses System.

[0035] The feed includes feed for non-human animals or insects and beverages for the animals or insects.

[0036] The composition may include, for example, one in which the active ingredient is added to a food or feed.

[0037] The content of the active ingredient in the composition is not particularly limited and may be adjusted accordingly to contain the amount necessary to achieve an effect of the present invention. The content of the active ingredient varies depending on the type of dosage form and the type of carrier used, but is for example 0.015 to 100wt%, preferably 0.02 to 99wt%, more preferably 0.025 to 98.5wt%, and even more preferably 0.03 to 98wt% based on the total weight of the formulation. When the active ingredient is a salt, the content shall be calculated after conversion to the a-amino-n-butyric acid.

[0038] An individual in need of application of said composition may include animals such as humans, dogs, cats, rabbits, hamsters, guinea pigs, rabbits, ferrets, prairie dogs, cattle, horses, donkeys, goats, sheep, deer, bears, birds, and the like. Insects such as bees (preferably honeybees), beetles, stag beetles, butterflies and the like may also be included.

[0039] When the individual in need of application of said composition is a human, an applicable age for the composition is preferably, for example, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older, or 95 years or older.

[0040] When the individual in need of application of said composition is other than a human, an applicable age, applicable month age, or applicable week age for the composition is preferably 6 / 10 or more, 6.5 / 10 or more, 7 / 10 or more, 7.5 / 10 or more, 8 / 10 or more, 8.5 / 10 or more, 9 / 10 or more, or 9.5 / 10 or more of an average life expectancy.

[0041] When the individual in need of application of said composition is a human, a daily dose (intake) of the composition for an adult varies depending on an age, body weight, symptoms, method of administration and the like of the individual in need of application of said composition, but is usually 0.000625 to 5.0 g / kg / day (daily intake per 1 kg body weight), preferably 0.0007 to 3.0 g / kg / day, more preferably 0.00075 to 2.0 g / kg / day, and even more preferably 0.0008 to 1.5 g / kg / day, as a mass of the active ingredient. When the active ingredient is a salt, the content shall be calculated after conversion to the a-amino-n-butyric acid.

[0042] When the individual in need of application of said composition is other than a human, a daily dose (intake) of the composition varies depending on an age, body weight, symptoms, method of administration and the like of the individual in need of application of said composition, but is usually 0.000625 to 5.0 g / kg / day (daily intake per 1 kg body weight), preferably 0.0007 to 3.0 g / kg / day, more preferably 0.00075 to 2.0 g / kg / day, and even more preferably 0.0008 to 1.5 g / kg / day, as a mass of the active ingredient. When the active ingredient is a salt, the content shall be calculated after conversion to the a-amino-n-butyric acid. When the individual in need of application of said composition is an insect, a daily dose (intake) of the composition varies depending on an age, body weight, symptoms, method of administration and the like of the individual in need of application of said composition, but is usually 0.000625 to 5.0 mg / g / day (daily intake per 1 g body weight), preferably 0.0007 to 3.0 mg / g / day, more preferably 0.00075 to 2.0 mg / g / day, and even more preferably 0.0008 to 1 mg / g / day, as a mass of the active ingredient. When the active ingredient is a salt, the content shall be calculated after conversion to the a-amino-n-butyric acid.

[0044] The composition is, for example, when the individual in need of application of said composition is an animal, preferably applied to the same individual for 3 months, 6 months, 1 year or more, 2 years or more, 3 years or more, 4 years or more, 5 years or more, 6 years or more, 7 years or more, 8 years or more, 10 years or more, 11 years or more, 12 years or more, 13 years or more, 14 years or more, 15 years or more, 16 years or more, 17 years or more, 18 years or more, 19 years or more, or 20 years or more depending on life expectancy of each animal. The composition is preferably ingested or administered daily. It is preferably ingested or administered during old age in each animal.

[0045] The composition is, for example, when the individual in need of application of said composition is an insect, preferably ingested daily after becoming an adult.

[0046] The “life expectancy” may include “average life expectancy” and / or “healthy life expectancy”.

[0047] The average life expectancy is defined by the Ministry of Health, Labour and Welfare as “life expectancy at age 0.” For humans, the average life expectancy in 2019 was 81.41 years for men and 87.45 years for women.

[0048] Maintaining the life expectancy is intended, for example, that an average life expectancy of an organism that has ingested the composition is in the range of [(average life expectancy) - 1SD] to [(average life expectancy) + 2SD], preferably [(average life expectancy) -2SD] to [(average life expectancy) + 2SD], Improving the life expectancy is intended to further extend the life expectancy. Extending the life expectancy is intended, for example, that the life expectancy of each organism exceeds the average life expectancy, preferably exceeds [(average life expectancy) + 2SD], The “SD” indicates standard deviation or variance, the “-’’is intended to subtract, and the “+” is intended to add.

[0049] The healthy life expectancy is defined by the Ministry of Health, Labour and Welfare as “the period during which a person can conduct daily life activities without being constrained by health problems.” For humans, the healthy life expectancy in 2019 was 72.68 years for men and 75.38 years for women.

[0050] In the present description, maintaining the healthy life expectancy is intended that the average healthy life expectancy of the organism that has ingested the composition is in the range of [(average healthy life expectancy) - 1SD] to [(average healthy life expectancy) + 2SD], preferably [(average healthy life expectancy) - 2SD] to [(average healthy life expectancy) + 2SD], Improving the healthy life expectancy is intended to further extend the period during which a person can conduct daily life activities without being constrained by health problems. Extending the healthy life expectancy is intended, for example, that the healthy life expectancy of each organism exceeds the average healthy life expectancy of the biological species of each organism, preferably exceeds [(average healthy life expectancy) + 2SD], The “SD” indicates standard deviation or variance, the “-’’is intended to subtract, and the “+” is intended to add.

[0051] In order to maintain or improve the healthy life expectancy, it is necessary to maintain or improve, for example, motor function, cardiac function, pulmonary function, cognitive function, and the like. Therefore, when evaluating whether the healthy life expectancy is maintained or not, it is preferable to evaluate at least one selected from the group consisting of the motor function, cardiac function, pulmonary function, and cognitive function as a parameter.

[0052] When the individual in need of application of said composition is a human, at least one selected from the group consisting of, for example, leg extension strength, walking speed, and grip strength may be used as an indicator of the motor function.

[0053] The leg extension strength may be measured, for example, using a Hand-Held Dynamometer (HHD) pTas F-l or the like. For example, it can be determined that the leg extension strength is maintained when the decrease in the leg extension strength after the lapse of a predetermined period from a start of application of the composition is less than 20%, less than 15%, less than 12%, less than 10%, less than 5%, or less than 3% in comparison with a measured value of leg extension strength on a reference day before the application of the composition in the same individual. In addition, it can be determined that the leg extension strength was improved when the increase in the leg extension strength after the lapse of the predetermined period from the start of application of the composition is 3% or more, 5% or more, 10% or more, 12% or more, 15% or more, or 20% or more in comparison with the measured value of the leg extension strength on the reference day.

[0054] The walking speed may be, for example, 10-m walking speed. For example, it can be determined that the 10-m walking speed is maintained when the decrease in the 10-m walking speed after the lapse of the predetermined period from the start of application of the composition is less than 20%, less than 15%, less than 12%, less than 10%, less than 5%, or less than 3% in comparison with a measured value of the 10-m walking speed on the reference day before the application of the composition in the same individual. A method for measuring walking speed is known. In addition, it can be determined that the 10-m walking speed was improved when the increase in the 10-m walking speed after the lapse of the predetermined period from the start of application of the composition is 3% or more, 5% or more, 10% or more, 12% or more, 15% or more, or 20% or more in comparison with the measured value of the 10-m walking speed on the reference day.

[0055] A method for measuring grip strength is known. For example, it can be determined that the grip strength is maintained when the decrease in the grip strength after the lapse of the predetermined period from the start of application of the composition is less than 20%, less than 15%, less than 12%, less than 10%, less than 5%, or less than 3% in comparison with a measured value of the grip strength on the reference day before the application of the composition in the same individual. In addition, it can be determined that the 10-m walking speed was improved when the increase in the grip strength after the lapse of the predetermined period from the start of application of the composition is 3% or more, 5% or more, 10% or more, 12% or more, 15% or more, or 20% or more in comparison with the measured value of the grip strength on the reference day. When the individual in need of application of said composition is a human, for example, a blood brain natriuretic peptide (BNP) concentration, a blood N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration, and the like may be used as an indicator of the cardiac function. For example, it can be determined that the cardiac function is maintained when the increase in the blood BNP concentration or blood NT-proBNP concentration after the lapse of the predetermined period from the start of application of the composition is less than 20%, less than 15%, less than 12%, less than 10%, less than 5%, or less than 3% in comparison with the blood BNP concentration or blood NT-proBNP concentration on the reference day before the application of the composition in the same individual. In addition, it can be determined that the cardiac function was improved when the decrease in the blood BNP concentration or blood NT-proBNP concentration after the lapse of the predetermined period from the start of application of the composition is 3% or more, 5% or more, 10% or more, 12% or more, 15% or more, or 20% or more in comparison with the blood BNP concentration or blood NT-proBNP concentration on the reference day. A method for measuring the blood brain natriuretic peptide (BNP) concentration or blood N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration is known.

[0057] When the individual in need of application of said composition is a human, for example, a tricuspid regurgitation pressure gradient may be used as an indicator of the pulmonary function. For example, it can be determined that the pulmonary function is maintained when the increase in the tricuspid regurgitation pressure gradient after the lapse of the predetermined period from the start of application of the composition is less than 20%, less than 15%, less than 12%, less than 10%, less than 5%, or less than 3% in comparison with the tricuspid regurgitation pressure gradient on the reference day before the application of the composition in the same individual. In addition, it can be determined that the pulmonary function was improved when the decrease in the tricuspid regurgitation pressure gradient after the lapse of the predetermined period from the start of application of the composition is 3% or more, 5% or more, 10% or more, 12% or more, 15% or more, or 20% or more in comparison with the tricuspid regurgitation pressure gradient on the reference day. A method for measuring the tricuspid regurgitation pressure gradient is known.

[0058] When the individual in need of application of said composition is a human, for example, the Mini-Mental State Examination (MMSE) may be used as an indicator of the cognitive function. When the individual is Japanese, the MMSE is preferably the Japanese version, MMSE-J. For example, it can be determined that the cognitive function is maintained when the decrease in a total score of the MMSE after the lapse of the predetermined period from the start of application of the composition is less than 3 points, less than 2 points, or less than 1 point, in comparison with a total score of the MMSE on the reference day before the application of the composition in the same individual. In addition, it can be determined that the cognitive function is improved when the increase in the total score of the MMSE after the lapse of the predetermined period from the start of application of the composition is 1 point or more, 2 points or more, or 3 points or more in comparison with the total score of the MMSE on the reference day before the application of the composition. The MMSE is known.

[0059] Alternatively, whether healthy life expectancy is maintained or not, and whether healthy life expectancy is improved or not, may be determined by comparing a value of each indicator with a reference range established for each generation. As for the reference range, for example, if the above indicator is an item whose value decreases when the healthy life expectancy is not maintained, a range higher than a threshold may be set as being within the reference range. In addition, if the above indicator is an item whose value is high when the healthy life expectancy is not maintained, a range lower than the threshold may be set as being within the reference range. The threshold may be determined by an ROC (receiver operating characteristic curve), discriminant analysis method, mode method, Kittier method, 3o method, p-tile method, or the like. Examples of the threshold may include sensitivity, specificity, negative predictive value, positive predictive value, the first quartile, and the like.

[0060] When the individual in need of application of said composition is a non-human animal, for example, the motor function can be evaluated by a treadmill test, suspension strength or the like depending on a biological species. For insects, the motor function can be evaluated by the Climbing Assay or the like shown in the Examples. It can be determined that the motor function is maintained when the decrease in the motor function after the lapse of the predetermined period from the start of application of the composition is less than 20%, less than 15%, less than 12%, less than 10%, less than 5%, or less than 3% in comparison with a measured value of the motor function on the reference day before the application of the composition in the same individual. In addition, it can be determined that the motor function was improved when the increase in the motor function after the lapse of the predetermined period from the start of application of the composition is 3% or more, 5% or more, 10% or more, 12% or more, 15% or more, or 20% or more in comparison with the measured value of the motor function on the reference day.

[0061] Alternatively, whether the healthy life expectancy is maintained or not, and whether the healthy life expectancy is improved or not, may be determined by comparing each indicator with a reference range established for each generation. For the reference ranges established for each generation, the above description is incorporated herein. The threshold, measured values of each item, scores, and the like are preferably obtained from the same type of specimens of the same species of organisms.

[0062] The reference date is intended to be a date on which observation of the individual in need of application of said composition starts. The reference date is preferably before the application of the composition.

[0063] The predetermined period from the start of application of the composition is intended to be, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years or 20 years when the individual in need of application of said composition is a human.

[0064] 1-2. Composition for suppressing decrease in motor function caused by Parkinson's disease One embodiment of the present invention relates to a composition for suppressing decrease in the motor function caused by Parkinson’s disease. For the active ingredients, formulation, dose, and the like of the composition, the description in the above section 1-1. is incorporated herein. Said composition is applicable to individuals diagnosed with Parkinson's disease or suspected to have Parkinson's disease. For the evaluation of the motor function, the description in the above section 1-1. is incorporated herein. Decreased motor function is intended to mean a case where the motor function of an individual is decreased by 10% or more, 20% or more, or 50% or more in comparison with the most recent previous value of motor function of the same individual, or in comparison with an individual of the same age without Parkinson's disease. In addition, suppression of the decrease in the motor function is intended to suppress the decrease in the motor function by less than 10%, less than 20%, or less than 50% in comparison with the most recent previous value of motor function of the same individual, or in comparison with an individual of the same age without Parkinson's disease.

[0065] 1-3. Composition for enhancing mitochondrial function One embodiment of the present invention relates to a composition for enhancing mitochondrial function. For the active ingredients, formulation, dose, and the like of the composition, the description in the above section 1-1. is incorporated herein. The composition for enhancing mitochondrial function may be administered to an individual or to a cell or tissue in vitro. Enhancing the mitochondrial function is intended to enhance aerobic respiratory function of mitochondria. The mitochondrial function can be evaluated by measuring Oxygen Consumption Rate (OCR: pmol / min) using the Extracellular Flux Analyzer series (manufactured by Seahorse Bioscience, Inc.; sold by Primetech Corporation). For example, when the OCR of a group to which the composition is applied is compared with a negative control group to which the composition is not applied, if the OCR of the group to which the composition is applied is increased by 5% or more, 10% or more, or 20% or more of that of the negative control group, it can be determined that the mitochondrial function is enhanced.

[0066] 2. Detection of individual to which composition is applicable One embodiment of the present invention relates to detecting the individual to which the composition for maintaining or improving life expectancy (hereinafter also referred to simply as “composition”) containing the a-amino-n-butyric acid, or pharmaceutically or food-acceptable salt thereof is applicable.

[0067] 2-1. Overview A method for detecting the individual in need of application of said composition includes obtaining a measured value indicating the content of the a-amino-n-butyric acid in a specimen taken from a subject individual. The measured value is compared to a predetermined reference value, and when the measured value is lower than the predetermined reference value, it is suggested that the subject individual is the individual in need of application of said composition.

[0068] The specimen includes, for example, blood samples, cells of biological origin, tissues (adrenal gland, aorta, brain, lung, pancreas, pituitary gland, skin, skull, skeletal muscle, spleen, testis, thyroid, kidney, large intestine, eyeball, heart, liver, salivary gland, thymus, adipose tissue, stomachjejunum, ileum, and the like), body fluids (sweat, secretory fluid from skin, tear fluid, saliva, spinal fluid, ascites and pleural fluid), and the like. The specimen is preferably the blood sample and urine. The blood sample may include plasma and whole blood, but the plasma, especially plasma separated from whole blood collected using ethylenediaminetetraacetic acid (EDTA) salt as an anticoagulant is preferred.

[0069] A method for measuring the a-amino-n-butyric acid is known. For example, it can be measured by mass spectrometry such as gas chromatography-mass spectrometry (GC / MS analysis) or liquid chromatography-mass spectrometry (LC / MS). The measured value may be the content of the a-amino-n-butyric acid in the specimen obtained by comparison with a standard, or it may be a peak area of a mass spectrum.

[0070] The predetermined reference value may be determined by, for example, the ROC (receiver operating characteristic curve), discriminant analysis method, mode method, Kittier method, 3 g method, p-tile method, or the like based on the measured values of the a-amino n-butyric acid in the specimens collected from a group in which at least one of the indicators described in the above section 1. is within the reference range (a group in which healthy life expectancy is maintained) and another group in which all of the indicators described in the above section 1 are outside the reference range (a group in which healthy life expectancy is not maintained) for a control population of the same generation. The threshold may be calculated by the sensitivity, specificity, negative predictive value, positive predictive value, first quartile, and the like, and the obtained threshold may be used as the predetermined reference value.

[0071] A previous value of the same subject individual may also be used as the reference value. For example, it can be determined that the measured value of the a-amino-n-butyric acid is decreased when the measured value of the a-amino-n-butyric acid in the specimen after the lapse of the predetermined period from the reference date is decreased by 1% or more, 2% or more, 5% or more, or 8% or more, in comparison with the measured value of the a-amino-n-butyric acid in the specimen on the reference date.

[0072] The reference date is intended to be the date on which observation of the individual in need of application of said composition starts. The reference date is preferably before the application of the composition.

[0073] The predetermined period from the start of application of the composition is intended to be, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years or 20 years when the individual in need of application of said composition is a human.

[0074] The individual in need of application of said composition may include animals such as humans, dogs, cats, hamsters, guinea pigs, rabbits, ferrets, prairie dogs, cattle, horses, donkeys, goats, sheep, deer, bears, birds, and the like. Insects such as bees (preferably honeybees), beetles, stag beetles, butterflies and the like may also be included.

[0075] When the individual in need of application of said composition is a human, the applicable age for the composition is preferably, for example, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older, or 95 years or older.

[0076] When the individual in need of application of said composition is other than a human, an applicable age, applicable month age, or applicable week age for the composition is preferably 6 / 10 or more, 6.5 / 10 or more, 7 / 10 or more, 7.5 / 10 or more, 8 / 10 or more, 8.5 / 10 or more, 9 / 10 or more, or 9.5 / 10 or more of the average life expectancy.

[0077] 2-2. Detection device for detecting individual to which composition is applicable One embodiment of the present invention relates to a detection device 30 for detecting the individual in need of application of said composition (hereinafter also referred to simply as “detection device 30”). A hardware configuration of the detection device 30 will be described with reference to FIG. 2.

[0078] The detection device 30 may be connected to an input device 311, an output device 312, and a media drive 313. In addition, the detection device 30 may be communicatively connected to an analysis device 90 by a wired or wireless network to constitute a detection system 3000 for detecting the individual in need of application of said composition. The analysis device 90 may be a mass spectrometer or the like.

[0079] In the detection device 30, a processing unit 301, a memory 302, a read only memory (ROM) 303, a storage device 304, a communication interface (I / F) 305, an input interface (I / F) 306, an output interface (I / F) 307 and a media interface (I / F) 308 are connected to each other by a bus 309 to enable data communication. The memory 302 and the storage device 304 may be collectively referred to simply as a storage unit. The storage unit stores the measured value or the reference value in a volatile or non-volatile manner.

[0080] The processing unit 301 is a CPU of the detection device 30 and is also referred to as an arithmetic unit. The processing unit 301 may cooperate with a GPU. The processing unit 301 cooperates with an operating system (OS) 3041 stored in the storage device 304 or ROM 303 to execute a detection program 3042a for detecting the individual in need of application of said composition (hereinafter simply referred to as “detection program 3042a”), which is described below, and processes data to be acquired, whereby a computer functions as the detection device 30.

[0081] In the ROM 303, the detection program 3042a to be executed by the processing unit 301 and data to be used therefor are stored. The processing unit 301 may be an MPU101. The ROM 303 stores a boot program to be executed by the processing unit 301 at startup of the detection device 30, as well as programs and settings related to the operation of a hardware of the detection device 30.

[0082] The memory 302 is used for readout of the detection program 3042a stored in the ROM303 and the storage device 304. The memory 302 is also used as a working area when the processing unit 301 executes these detection programs 3042a.

[0083] The storage device 304 is composed of a hard disk and others. The storage device 304 stores the operating system and the various detection programs 3042a such as an application program to be executed by the processing unit 301, as well as various setting data used to execute the detection programs 3042a. Specifically, a reference value database DB2 is stored in a non-volatile manner.

[0084] The communication I / F 305 receives data from the analysis device 90 or other external device under the control of the processing unit 301, and transmits or displays information stored in or generated by the detection device 30 to the analysis device 90 or external device as required. The communication I / F 305 may communicate with the analysis device 90 or other external device via the network.

[0085] The input I / F 306 accepts text input, clicks, voice input, and the like from the input device 311. Accepted input contents are stored in the memory 302 or the storage device 304.

[0086] The input device 311 is composed of a touch panel, keyboard, mouse, pen tablet, microphone, and the like, and provides the text or voice input to detection device 30. The input device 311 may be connected externally to the detection device 30 or may be integrated with the detection device 30.

[0087] The output I / F 307 outputs the information generated by the processing unit 301 to the output device 312. The output I / F 307 outputs the information generated by the processing unit 301 and stored in the storage device 304 to the output device 312.

[0088] The output device 312 is composed of. for example, a display, printer, and the like, and displays measurement results transmitted from the analysis device 90, various operation windows in the detection device 30, analysis results, and the like.

[0089] The media I / F 308 reads out, for example, application software, and the like stored in the media drive 313. The read out application software and the like is stored in the memory 302 or in the storage device 304. The media I / F 308 also writes the information generated by the processing unit 301 to the media drive 313. The media I / F 308 writes the information generated by the processing unit 301 and stored in the storage device 304 to the media drive 313. The media drive 313 is composed of a flexible disk, CD-ROM, DVD-ROM, or the like. The media drive 313 is connected to the media I / F 308 by a flexible disk drive, CD-ROM drive, DVD-ROM drive, or the like. The media drive 313 may store the application program and the like for the computer to execute the operations.

[0090] The processing unit 301 may acquire the application software and various settings necessary for controlling the detection device 30 through the network instead of reading them out from the ROM303 or the storage device 304. The application program is stored in a storage device of a server computer on the network, and the detection device 30 can access the server computer to download the detection program 3042a and store it in the ROM303 or the storage device 304.

[0091] In addition, an operating system that provides a graphical user interface environment, such as Windows® manufactured and sold by Microsoft Corporation of the United States, for example, is installed in the ROM 303 or storage device 304. The application program below operates on the operating system. That is, the detection device 30 may be a personal computer or the like.

[0092] The detection system 3000 need not be installed in one location, and the detection device 30 and the analysis device 90 may be located in separate locations and connected via the network. The detection device 30 may be a device that does not require an operator, omitting the input device 311 and output device 312.

[0093] 2-3. Processing of detection program of individual to which composition is applicable Processing of the detection program 3042a will be described with reference to FIG. 3. The processing unit 301 accepts a detection process start command input by the operator from the input device 311 and starts a detection process.

[0094] In step S31, the processing unit 301 acquires the measured value of the a-amino-n-butyric acid in the specimen taken from the subject individual input by the operator from the input device 311. Alternatively, in step S31, the processing unit 301 acquires the measured value of the a-amino-n-butyric acid in the specimen taken from the subject individual transmitted by the analysis device 90.

[0095] In step S32, the processing unit 301 reads out the pre-determined reference value from the reference value database DB2, and compares the measured value acquired in step S31 with the pre-determined reference value. When the measured value is lower than the pre-determined reference value as a result of the comparison (“YES” in step S32), the detection process proceeds to step S33, where a label indicating that the subject individual is the individual in need of application of said composition is output, and the process is terminated. The label may be a symbol such as an exclamation mark, asterisk, and the like, or may be text such as “Please consider applying the composition” and the like. When the measured value is equal to or greater than the pre-determined reference value as a result of the comparison (“NO” in step S32), the detection process proceeds to step S34, where a label indicating that the subject individual is not the individual in need of application of said composition is output, or the process is terminated without any output.

[0096] 2-4. Storage medium storing program One embodiment of the present invention relates to a program product, such as a media drive, that stores the detection program 3042a. That is, the detection program 3042a may be stored in the media drive, such as a hard disk, a semiconductor memory element such as a flash memory, or an optical disk. The media drive may also be a computer, such as a server device. A storing format of the program to the media drive is not limited as long as each device is capable of reading the program. The storing to the media drive is preferably non-volatile. Examples

[0097] Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention should not be construed as limited to the examples.

[0098] 1. Cohort study The Kyotango region (Kyotango City, Miyazu City, Yosano Town, and Ine Town), located in the northern part of Kyoto Prefecture, has about three times as many centenarians as the national average (FIG. 1A and FIG IB), is one of the areas with the highest number of healthy elderly people. Therefore, health examination of people aged 65 years or older was conducted in this region, and 352 items including blood test items were examined in 533 subjects who had received the health examination by March 2020 in the Kyotango region in order to search for factors of longevity. The cohort in the Kyotango region is hereinafter also referred to as the “Kyotango cohort”. This study was conducted in conjunction with a cohort study of 2000 items which is currently being conducted in Iwaki-machi by Hirosaki University, which aims at getting Aomori prefecture out of the short-lived prefecture. The cohort in the Iwaki-machi is hereinafter also referred to as the “Iwaki-machi cohort”.

[0099] 2. Correlation with age and renal function Factors correlated with age were examined by multivariate correlation analysis for the Kyotango cohort and the Iwaki-machi cohort.

[0100] FIG. 4 shows 30 items that correlated with age in the Kyotango cohort. FIG. 4A shows items that correlated negatively with age. FIG. 4B shows items that correlated positively with age. Blood a-amino-n-butyric acid concentration was negatively correlated with age (FIG. 4A). On the other hand, many blood amino acids were positively correlated with age (FIG. 4B).

[0101] FIG. 5 shows correlations between blood concentrations of the a-amino-n-butyric acid (FIG. 5A), which was correlated negatively with age, cystine (FIG. 5B), total homocysteine (FIG. 5C), 3-methylhistidine (FIG. 5D), citrulline (FIG. 5E), asparagine (FIG. 5F), and phenylalanine (FIG. 5G), which were correlated positively with age, and the age on study date of study subjects in the Kyotango cohort. The blood a-amino-n-butyric acid concentration decreased with increasing age. On the other hand, the blood concentrations of many other amino acids increased with increasing age.

[0102] FIG. 6 shows 30 items that correlated with age in the Iwaki-machi cohort in 2020. FIG. 6A shows the items that correlated negatively with age. FIG. 6B shows the items that correlated positively with age. The tendency of the items that correlated with age was similar to that of the Kyotango cohort. This suggests that the decrease in the blood a-amino-n-butyric acid concentration with increasing age is not regional. Next, the factors correlated with the renal function in the Kyotango cohort and the Iwaki-machi cohort were examined by the multivariate correlation analysis.

[0103] FIG. 7 shows 30 items that correlated with the renal function (eGFR) in the Kyotango cohort. FIG. 7A shows the items that correlated negatively with age. FIG. 7B shows the items that correlated positively with age. The blood concentrations of many amino acids were negatively correlated with the eGFR (FIG. 7A). On the other hand, the blood a-amino-n-butyric acid concentration was positively correlated with the eGFR (FIG. 7B). These results indicate that the higher the renal function, that is, the more normal the kidney function, the higher the blood a-amino-n-butyric acid concentration.

[0104] FIG. 8 shows 30 items that correlated with the renal function (eGFR) by multivariate analysis in the Iwaki-machi cohort. FIG. 8A shows the items that correlated negatively with age. FIG. 8B shows the items that correlated positively with age. Similar to the Kyotango cohort, the blood concentrations of many amino acids were negatively correlated with the eGFR (FIG. 8A). On the other hand, the blood a-amino-n-butyric acid concentration was positively correlated with the eGFR (FIG. 8B).

[0105] FIG. 9 shows results of multivariate analysis of urinary a-amino-n-butyric acid concentration (corrected for urinary Cr concentration), blood a-amino-n-butyric acid concentration, urinary sodium ion (Na) concentration, and eGFR in the Kyotango cohort of 45 subjects conducted in 2021. The multivariate analysis was performed by the REML method. Significance was defined as p<0.05. FIG. 9A shows a correlation between the urinary a-amino-n-butyric acid concentration and the blood a-amino-n-butyric acid concentration. A good correlation was observed with a correlation coefficient of 0.437 and a p value of 0.0008. FIG. 9B shows a correlation between the blood a-amino-n-butyric acid concentration and the urinary Na concentration. No correlation was observed with a correlation coefficient of 0.2335 and a p value of 0.2335. FIG. 9C shows a correlation between the urinary a-amino-n-butyric acid concentration and the eGFR. A correlation was observed with a correlation coefficient of 0.3239 and a p value of 0.0158. These results suggest that serum a-amino-n-butyric acid concentration is influenced by dietary and by synthesis and metabolism in a body.

[0106] 3. Verification of effect of a-amino-n-butyric acid in Drosophila As described in Non Patent Literature 2 and Patent Literature 2, an association between serum concentration and antioxidant effect of the a-amino-n-butyric acid has been reported. However, there have been no reports to date on effects related to life expectancy or motor ability. Furthermore, it is known that reduced dietary caloric intake prolongs life expectancy in C. elegans, Drosophila, mice, and chimpanzees, but there have been no reports that amino acid administration prolongs life expectancy. Therefore, in order to verify the effect of a-amino-n- butyric acid intake, an experiment was first conducted in Drosophila melanogaster (hereinafter simply referred to as “Drosophila”). The experiment using Drosophila was contracted to Laboratory of Kansai Science City (Seika-cho, Souraku-gun, Kyoto Prefecture) of KANKYO EISEI YAKUHIN CO., LTD.

[0107] 3-1. Methods (1) Drosophila Drosophila was a wild-type standard strain Canton S, commonly used in Drosophila experiments.

[0108] Eggs laid on an egg-collecting plate were collected and transferred to respective rearing feeds prepared. There, they were reared until they reached adult. Adults after eclosion were anesthetized with CO2 and only males were collected and used for tests.

[0109] (2)Feed The Drosophila were reared under the same conditions except for feed. The Drosophila were reared in four groups: standard feed, calorie-restricted feed, standard feed supplemented with 0.7mM a-amino-n-butyric acid (standard feed + a-amino-n-butyric acid), and calorie-restricted feed supplemented with 0.7mM a-amino-n-butyric acid (calorie-restricted feed + a-amino-n-butyric acid).

[0110] The calorie-restricted feed was prepared following the standard recipe used in Drosophila experiments. Per 1 L of water, 100 g of dried yeast (EBIOS), 50 g of glucose, and 8.0 g of agarose were added and brought to a boil while stirring and heating. After the heating was stopped and the temperature dropped to about 65°C, 5.0 mL of 10% methyl parahydroxybenzoatein 70% ethanol and 5.0 mL of propionic acid were added per 1 L of feed and dispensed into rearing bottles to solidify. The standard feed was prepared in the same way as the calorie-restricted feed, with 200 g of dried yeast (EBOIS), 50 g of glucose, and 8.0 g of agarose per 1 L of water. The a-amino-n-butyric acid was added to the standard feed and calorie-restricted feed, respectively, at a final concentration of 0.7 mM (0.07 g / 1 L of feed). [OHl] (3) Measurement of life expectancy Comparisons of the life expectancy of Drosophila adults were performed in the following method. For Drosophila to be used in the test, four rearing bottles (22 mm in diameter x 96 mm in height) containing each feed were prepared, and 10 adults were placed in each rearing bottle and reared (n = 40 per feed). The temperature was maintained at 25 ± 2°C and the adults were transferred to rearing bottles with new feed every 2 or 3 days. Survival was observed at least once every 3 days and the number of deaths was recorded. The observations were continued until the last individual died. After termination of the observation, survival curves were generated using the Kaplan-Meier method, and the survival curves were statistically tested using the Wilcoxon test using analysis software R.

[0112] (4) Measurement of motor ability The motor ability of the Drosophila was evaluated using Climbing Assay. Specifically, test vials were prepared by connecting two rearing bottles (22 mm in diameter x 96 mm in height) to form a container, with a mark placed at 2 cm intervals from the bottom of the container. 10 adult male individuals from each group were placed into the test vial. The 10 individuals were collected in one direction of the test vial, and then the vial was stood with the collected side down, and after 30 seconds, the location of the individuals was recorded and scored. Scores were as follows: 0 points for less than 2 cm, 1 point for 2 cm or more and less than 4 cm, 2 points for 4 cm or more and less than 6 cm, 3 points for 6 cm or more and less than 8 cm, 4 points for 8 cm or more and less than 10 cm, and 5 points for 10 cm or more from the bottom of the rearing bottle. The rearing feed was exchanged once every 2 or 3 days, and the tests were performed at 3, 10, 18, 30, 39, 50, and 60 days after eclosion. Tests were repeated 5 times per vial on each test day. Obtained results were evaluated by Welch's t-test using Excel.

[0113] 3-2. results (1) Effect of a-amino-n-butyric acid on life expectancy FIG. 10 shows comparison results of life expectancy of the four groups. FIG. 10A shows survival curves of the four groups. FIG. 10B shows the number of days that 50% lethality is reached for the four groups. The number of days that 50% lethality is reached was the shortest in the group fed the standard feed, at 42 days. The next shortest was 49 days in the group fed calorie-restricted feed. The number of days that 50% lethality is reached was 56 days in the group fed standard feed supplemented with the a-amino-n-butyric acid and in the group fed calorie-restricted feed supplemented with the a-amino-n-butyric acid. FIG. 10C shows results of a significance test by Wilcoxon test. Significance was defined as p<0.05. There was no significant difference between the group fed the calorie-restricted feed and the group fed the standard feed. The group fed the calorie-restricted feed supplemented with the a-amino-n-butyric acid and the group fed the standard feed supplemented with the a-amino-n-butyric acid group had significantly prolonged life expectancy compared to the group fed the calorie-restricted feed. The group fed the calorie-restricted feed supplemented with the a-amino-n-butyric acid and the group fed the standard feed supplemented with the a-amino-n-butyric acid had significantly prolonged life expectancy compared to the group fed the standard feed. These results indicate that intake of the a-amino-n-butyric acid significantly prolongs life expectancy even when compared to simply restricting calories.

[0114] (2) Effect of a-amino-n-butyric acid on motor ability FIG. 11 shows results of the Climbing Assay. FIG. 11A shows means and standard deviations of the Climbing Assay scores for each group at 3, 10, 18, 30, 39, 50, and 60 days after eclosion. FIGS. 1 IB to 1 IE show significant differences (p values) in the scores of the group fed the calorie-restricted feed supplemented with the a-amino n-butyric acid and the group fed the standard feed supplemented with the a-amino n-butyric acid compared to the group fed the calorie-restricted feed and significant differences (p values) in the scores of the group fed the calorie-restricted feed supplemented with the a-amino n-butyric acid and the group fed the standard feed supplemented with the a-amino n-butyric acid compared to the group fed the calorie-restricted feed. FIG. 1 IB shows the significant difference at 10 days after eclosion, FIG. 1 IC shows the significant difference at 18 days after eclosion, FIG. 1 ID shows the significant difference at 30 days after eclosion, and FIG. 1 IE shows the significant difference at 39 days after eclosion. Significance was defined as p<0.05.

[0115] At 3 days after eclosion, there were no differences in the scores between the groups. However, differences were observed after the 10th day after eclosion. At 10 days after eclosion, there was no difference between the groups fed the standard feed and the calorie-restricted feed, but at 18 and 30 days after eclosion, the group fed the calorie-restricted feed had significantly higher scores compared to the group fed the standard feed, however this was reversed after 39 days from eclosion (FIGS. 11A to 1 IE). At 10 days after eclosion, the group fed the calorie- restricted feed supplemented with the a-amino-n-butyric acid and the group fed the standard feed supplemented with the a-amino-n-butyric acid had significantly higher scores compared to the group fed the calorie-restricted feed or the group fed the standard feed (FIGS. 11A and 1 IC). At 18 days after eclosion, the group fed the calorie-restricted feed supplemented with the a-amino-n-butyric acid had significantly higher score compared to the group fed the calorie-restricted feed or the group fed the standard feed, whereas the group fed the standard feed supplemented with the a-amino-n-butyric acid had significantly higher score only compared to the group fed the standard feed (FIGS. HA and 1 IC). At 30 days after eclosion, only the group fed the standard feed supplemented with the a-amino-n-butyric acid had significantly higher scores compared to the group fed the standard feed (FIGS. 11A and 1 ID). At 39 days after eclosion, the group fed the calorie-restricted feed supplemented with the a-amino-n-butyric acid and the group fed the standard feed supplemented with the a-amino-n-butyric acid had significantly higher score compared to the group fed the calorie-restricted feed. Only the group fed the standard feed supplemented with the a-amino-n-butyric acid had significantly higher score compared to the group fed the standard feed (FIGS. 11A and 1 IE). These results indicate that the a-amino-n-butyric acid has the effect of maintaining the motor ability of Drosophila.

[0116] 4. Verification of effect of a-amino-n-butyric acid in mice 4-1. Measurement of a-amino-n-butyric acid in serum and various organs of mice (1) Methods The a-amino-n-butyric acid content in serum, heart, liver, kidney, soleus muscle, and gastrocnemius muscle of young (10 weeks old: 10 wks) and old (77 weeks old: 77 wks) C57BL6 mice was measured. After feeding L-a-amino-n-butyric acid and DL-a-amino-n-butyric acid to young C57BL6 mice, the serum, heart, liver, kidney, soleus muscle, and gastrocnemius muscle were collected from each mouse, and the a-amino-n-butyric acid content in each organ was measured. There were five mice in each group. L-a-amino-n-butyric acid and DL-a-amino-n-butyric acid were mixed with drinking water at a concentration of 10 mM and fed for 2 weeks.

[0117] The a-amino-n-butyric acid contents in the heart, liver, kidney, soleus muscle, and gastrocnemius muscle were measured by GC-MS method. The a-amino-n-butyric acid content was measured according to a method described by Yasuhiro Irino et al., (Sci Rep. 2016 Nov 9;6:36749. doi: 10.1038 / srep36749.).

[0118] (2) Results FIG. 12 shows results. FIG. 12A shows the content of the a-amino-n-butyric acid in the plasma, FIG. 12B shows the content of the a-amino-n-butyric acid in the heart, FIG. 12C shows the content of the a-amino-n-butyric acid in the liver, FIG. 12D shows the content of the a-amino-n-butyric acid in the kidney, FIG. 12F shows the content of the a-amino-n-butyric acid in the soleus muscle, FIG. 12G shows the content of the a-amino-n-butyric acid in the gastrocnemius muscle. When comparing between young and aged individuals, the content of the a-amino-n-butyric acid in the soleus muscle was significantly lower in the aged individuals (p<0.0001). No differences were observed in serum or organs other than the soleus muscle between the young and aged individuals.

[0119] In mice fed the L-a-amino-n-butyric acid or DL-a-amino-n-butyric acid, increased a-amino-n-butyric acid content was observed in the serum, heart, liver, kidney, soleus muscle, and gastrocnemius muscle.

[0120] 4-2. Verification of effect of a-amino-n-butyric acid on muscle strength of mice by suspension test using Inverted Screen Test To verify effect of the a-amino-n-butyric acid on maintaining muscle strength, a suspension test using the Inverted Screen Test was performed.

[0121] (1) Methods The muscle strength was evaluated by the suspension test using the Inverted Screen Test between a group of aged C57BL6 mice (77 weeks old) fed with the a-amino-n-butyric acid (2AB group) and a group of aged C57BL6 mice (77 weeks old) not treated with the a-amino-n-butyric acid (Cont. group). The 2AB group was treated with the 10 mM a-amino-n-butyric acid solution prepared in tap water instead of drinking water. The treatment period was 12 weeks (3 months) and the L-a-amino-n-butyric acid solution was exchanged approximately every 10 days. The Cont. group was treated with tap water. There were 12 mice in each group.

[0122] The suspension test using the Inverted Screen Test was performed according to Kondziela's method (Literature: J Vis Exp. 2013 Jun 2; (76): 2610. doi: 10.3791 / 2610.). Statistical analysis was performed by one-way ANOVA. Significance was defined as p<0.05.

[0123] (2) Results FIG. 13 shows results. FIG. 13 A shows suspension times at a start of an experiment (63 weeks old). FIG. 13B shows suspension times at three months after the start of the experiment (74 weeks old). At the start of the experiment, the 2AB group had a suspension time of 120 ± 15.6 seconds (median 107 seconds) and the Cont. group had a suspension time of 108.3 ± 9.4 seconds (median 104.5 seconds), showing no difference in suspension time between the 2AB and Cont. groups (p = 0.8542). However, after 3 months, the 2AB group had a suspension time of 139.6 ± 12.9 seconds (median 123 seconds) and the Cont. group had a suspension time of 100.6 ±15.5 seconds (median 93 seconds), indicating that the 2AB group had a significantly longer suspension time than the Cont. group (p=0.0229). In addition, for the 2AB group, the suspension time was prolonged after 3 months than at the start of the experiment. The suspension time in the Cont. group was slightly shorter than that at the start of the experiment. These results indicate that the a-amino-n-butyric acid has the effect of improving the muscle strength in aged mice.

[0124] 4-3. Verification of effect of a-amino-n-butyric acid on muscle strength of mice by treadmill test To verify effect of the a-amino-n-butyric acid on maintaining muscle strength, a treadmill test was performed.

[0125] (1) Methods A group of aged C57BL6 mice (74 weeks old) treated with the a-amino-n-butyric acid (2AB group) and a group of aged C57BL6 mice (74 weeks old) not treated with the a-amino-n-butyric acid (Cont. group) were prepared as described in the above section 4-2.(1), and the treadmill test was performed at 3 months after the start of the experiment. There were 9 mice in each group.

[0126] The treadmill test was performed at 15 m / min according to a method described in the literature: Aoi etal., (Nutrition). 2011 Jun;27(6):687-92. doi: 10.1016 / j.nut.2010.06.004. Statistical analysis comparing the two groups was performed by one-way ANOVA. Significance was defined as p<0.05.

[0127] (2) Results FIG. 14 shows results of the treadmill test at 3 months after the start of the experiment. Running time on the treadmill was 1036 ± 147.3 seconds in the 2AB group and 653.7 ± 147.3 seconds in the Cont. group, indicating that the running time on the treadmill in the 2AB group was significantly longer than that in the Cont. group (p = 0.0414). These results indicate that the a-amino-n-butyric acid has an effect on improving the motor ability in aged mice.

[0128] 5. Verification of effect of a-amino-n-butyric acid on preventing muscle atrophy Since the a-amino-n-butyric acid content in the soleus muscle was significantly lower in the aged individuals in the investigation described in the above section 4-1., the following experiment was performed on an assumption that the a-amino-n-butyric acid has an effect to suppress the atrophy of striated muscle seen in the aged individuals.

[0129] (1) Methods C2C12 cells, which are undifferentiated mesenchymal cells of mice and can differentiate into striated muscle cells in vitro, were passaged into a 12-well plate in a medium of D-MEM supplemented with fetal bovine serum (10%). The day of passaging was set as day 0, and the cells were cultured until day 2. On day 2, the medium was replaced with a medium of D-MEM supplemented with 2% horse serum, and the C2C12 cells were cultured for 4 days to differentiate into striated muscle cells. On day 6, counting from day 0, dexamethasone (DEX), a muscle atrophy agent, was added at a final concentration of 1 OuM for a dexamethasone addition group. The a-amino-n-butyric acid was added at lOOpM for the a-amino-n-butyric acid (2AB) addition group. The investigation was performed on a cont. group without dexamethasone and a-amino-n-butyric acid, a Dex. group with dexamethasone only, and a 2AB + Dex. group with dexamethasone and a-amino-n-butyric acid.

[0130] On day 2 after the addition of each agent (day 8, counting from day 0), the cells were immunostained with MyHC antibody and a minor diameter was measured at the center of each myotube cell (>100 pm in length, with one or more nuclei visible). FIG. 15A shows an actual measurement image for the minor diameter of the myotube cells. In this case, those having a large diameter (cell minor diameter >70 pm) due to immediately after cell fusion were excluded. Observations were made at 3 fields of view / 1 well, and approximately 250 cells / 3 fields of view / well were counted and compared at 500 cells / 2 wells in each group.

[0131] (2) Results FIG. 15B shows mean myotube cell minor diameters in the cont. group and the Dex. group. The mean myotube cell minor diameter in the cont. group was 26.0 pm, and the mean myotube cell minor diameter in the Dex. group was 24.7, indicating that the Dex. group had significantly shorter mean myotube cell minor diameter than the cont. group (p = 0.044, t-test).

[0132] FIG. 15C shows mean myotube cell minor diameters of the Dex. group and the 2AB+Dex. group. The mean myotube cell minor diameter in the Dex. group was 24.7, and the mean myotube cell minor diameter in the 2AB + DEX. group was 26.7 pm, indicating that the mean myotube cell minor diameter was significantly maintained in the 2AB + DEX. group compared to the Dex. group (p=0.0030, t-test). These results indicate that the a-amino-n-butyric acid has a preventive effect on myocyte atrophy.

[0133] 6. Re-evaluation of serum a-amino-n-butyric acid concentration in Kyotango cohort Reinvestigation of serum a-amino-n-butyric acid concentrations was conducted in the Kyotango cohort of 820 subjects aged 65 years or older who had received health examinations by March 2022. First, a relationship between 10-m walking speed, blood a-amino-n-butyric acid concentration, and age was statistically analyzed. FIG. 16 shows results.

[0134] As shown in FIG. 16A, the blood a-amino-n-butyric acid concentration (pg / pL) was negatively correlated with age (p<0.0001). Also, as shown in FIG. 16B, mean 10-m walking speed (m / sec.) was negatively correlated with age (p<0.0001). On the other hand, as shown in FIG. 16C, the mean walking speed of 10 m (m / sec.) was positively correlated with the blood a-amino-n-butyric acid concentration (pg / pL) (p<0.0001).

[0135] Multiple regression analysis was used to adjust for age in terms of the blood a-amino-n-butyric acid concentration, age, and mean 10-m walking speed. As a result, an estimated value between the a-amino-n-butyric acid concentration and mean 10-m walking speed was 0.0057604, standard error was 0.002556, t value was 2.25, and p value (Prob>|t|) was 0.0245. An estimated value between the age and mean 10-m walking speed was -0.032567, standard error was 0.002253, t value was -14.45, and p value (Prob>|t|) was p<0.0001. The age and a-amino-n-butyric acid concentration were independently and significantly correlated with the mean 10-m walking speed. This suggests that the change in the 10-m walking speed correlated with the a-amino-n-butyric acid concentration was not due to confounding by age.

[0136] Next, the relationship between the leg extension strength measured using a Hand-Held Dynamometer (HHD) pTas F-l (Anima Co., Ltd.), blood a-amino-n-butyric acid concentration, and age was statistically analyzed for the same 820 subjects of the Kyotango cohort as above. FIG. 17 shows results.

[0137] As shown in FIG. 17A, the blood a-amino-n-butyric acid concentration (pg / pL) was negatively correlated with age (p<0.001). Also, as shown in FIG. 17B, mean leg extension strength (kgw) was negatively correlated with age (p<0.001). On the other hand, as shown in FIG. 17C, the mean leg extension strength (kgw) was positively correlated with the blood a-amino-n-butyric acid concentration (pg / pL) (p=0.0021).

[0138] Multiple regression analysis was used to adjust for age in terms of the blood a-amino-n-butyric acid concentration, age, and mean leg extension strength. As a result, an estimated value between the a-amino-n-butyric acid concentration and mean leg extension strength was 0.129179, standard error was 0.060726, t value was 1.99, and p value (Prob>|t|) was 0.0468. An estimated value between the age and mean leg extension strength was -0.367954, standard error was 0.053119, t value was -6.93, and p value (Prob>|t|) was p<0.0001. The age and a-amino-n-butyric acid concentration were independently and significantly correlated with the mean leg extension strength. This suggests that the change in the leg extension strength correlated with the a-amino-n-butyric acid concentration was not due to confounding by age.

[0139] 7. Correlation of other biomarkers with blood a-amino-n-butyric acid concentrations A correlation between the blood a-amino-n-butyric acid concentration and blood brain natriuretic peptide (BNP) concentration (pg / mL), a marker for heart failure, or tricuspid regurgitation pressure gradient (TRPG), a marker for pulmonary hypertension, was statistically analyzed for the same 820 subjects of the Kyotango cohort as in the above section 6. FIG. 18 shows results. FIG. 18A shows the correlation between the blood BNP concentration and blood a-amino-n-butyric acid concentration. The subjects with lower blood BNP concentration showed higher blood a-amino-n-butyric acid concentration (p=0.0012). FIG. 18B shows the correlation between the TRPG and the blood a-amino-n-butyric acid concentration. The subjects with lower TRPG showed higher blood a-amino n-butyric acid concentration (p=0.0011). These results indicate that aged subjects with high a-amino-n-butyric acid concentrations also have high cardiac function or pulmonary function.

[0140] Next, the correlation between the total score on the Mini-Mental State Examination (MMSE), known as a dementia test, and blood a-amino-n-butyric acid concentration was statistically analyzed.

[0141] The MMSE total score was investigated for 186 subjects with 2 health examination history among the 820 subjects of the Kyotango cohort described in the above section 6. In the MMSE, a total score of 30 is the perfect score, and a score of 27 or less is considered suspicious for mild cognitive impairment (MCI), and a score of 23 or less is considered suspicious for dementia.

[0142] FIG. 19 shows the correlation between the MMSE total score and the blood a-amino-n-butyric acid concentration. A positive correlation was found between the MMSE total score and the blood a-amino-n-butyric acid concentration (p value = 0.0030).

[0143] Next, among the subjects who was subjected to measurement of blood a-amino-n-butyric acid concentration and received MMSE on the reference health examination day (first time), 89 subjects who received the health examination again 3 years later (second time) were subjected to measurement of blood a-amino-n-butyric acid concentration and MMSE again, and the correlation between the blood a-amino-n-butyric acid concentration and the MMSE total score was statistically analyzed.

[0144] FIG. 20 shows results. FIG. 20A shows the correlation between the blood a-amino-n-butyric acid concentration and MMSE total score on the reference health examination day (first time). At this time point, no correlation was found between the blood a-amino-n-butyric acid concentration and the MMSE total score (p value = 0.8445). FIG. 20B shows the correlation between the blood a-amino-n-butyric acid concentration and the MMSE total score after 3 years (second time). At this time point, a positive correlation was found between the blood a-amino-n-butyric acid concentration and the MMSE total score (p=0.0258). These results indicate that blood a-amino-n-butyric acid concentration is also high in subjects whose brain cognitive function is maintained.

[0145] The results indicate that the muscle strength, cardiac function, pulmonary function, and brain cognitive function are maintained and the healthy life expectancy is maintained in aged subjects with high blood a-amino-n-butyric acid concentrations.

[0146] 8. Effect of a-amino-n-butyric acid intake on life expectancy Effect of intake of the a-amino-n-butyric acid on the life expectancy of mice was evaluated. Survival curves were compared between groups fed with (2AB, n=20) and without (Cont., n=20) a-amino-n-butyric acid. Male C57BLJ mice were used. The 2AB was fed daily drinking water (tap water) containing 10 mmol of a-amino-n-butyric acid from 68 weeks of age. The Cont. was fed drinking water only. FIG. 21 shows results. The results show that 50% lethality was reached at 93 weeks of age in the Cont., whereas it was at 101 weeks of age in the 2AB. In addition, the maximum age was 106 weeks (median 93 weeks) in the Cont., whereas it was 127 weeks (median 101.5 weeks) in the 2AB. A comparison of the 50% lethality between the two groups by the log-rank test showed a significantly longer life expectancy (p=0.0047).

[0147] 9. Effect of a-amino-n-butyric acid intake on motor function Effect of the a-amino-n-butyric acid on the motor function was evaluated using a Climbing efficiency of Drosophila model of Parkinson's disease, as an indicator.

[0148] For Drosophila, Fl males obtained by crossing w; nSyb-Gal4; tub-gal80ts line with yw; UAS-a-synS126D; UAS-a-synWT / CyO :: TM6B were used. The Fl males were reared at 29°C to express a-synuclein in a neuron-specific and synchronous manner. The temperature was maintained at 29°C during rearing.

[0149] The Drosophila were divided into two groups, after reaching adulthood, one group was fed a standard feed as a rearing feed and the other group was fed a rearing feed containing 0.07 mg of a-amino-n-butyric acid (final concentration 0.7mM) per liter of standard feed. The group fed only the standard feed is referred to as “standard feed group” and the group fed a rearing feed containing the a-amino-n-butyric acid is referred to as “standard feed + a-aminobutyric acid intake group”. 20 individuals in each group were reared in separate vials, and a total of 80 individuals were used for evaluation. The rearing feed was exchanged once every 3 days, and the motor ability of the control and the test-fed groups was tested every 2 to 4 days after the initial event. In the test, individuals climbing more than 5 cm within 10 seconds were counted. The test was performed 2 times with an interval of 15 seconds, and the mean value was taken as a measurement result. Comparisons between the two groups were performed by Welch's t-test. FIG. 22 shows results.

[0150] The climbing efficiency was higher in the standard sample + a-aminobutyric acid intake group than in the standard feed group from the 10th day after the start of a-aminobutyric acid intake. The difference was especially significant at 17 days after the start of intake, P=0.0002.

[0151] These results confirm that the intake of the a-amino-n-butyric acid ameliorates the a-synuclein-induced decrease in the motor ability. It was also shown that the suppression by the a-amino-n-butyric acid was high at the time when a-synuclein toxicity appeared rapidly.

[0152] 10. Effect of a-amino-n-butyric acid intake on mitochondrial function Myoblasts derived from the mesenchymal stem cell line C2C12 cells and HUVEC cells, cultured vascular endothelial cells, were used to investigate effect of the a-amino-n-butyric acid on mitochondrial function.

[0153] The C2C12 cells were seeded in 10-cm dishes and, as myoblasts, on day 3 after seeding, the a-amino-n-butyric acid was added to a medium at a final concentration of 30 pM or 100 pM. 24 hours after the addition of the a-amino-n-butyric acid, Oxygen Consumption Rate (OCR: pmol / min) was measured using the Extracellular Flux Analyzer XFe96 (manufactured by Seahorse Bioscience, Inc.; sold by Primetech Corporation) according to the protocol provided by the manufacturer. FIG. 23 shows results. FIG. 23A shows Basal Respiration and Spare Capacity FIG. 23B shows Proton Leak and ATP production.

[0154] The HUVEC cells were seeded in 10-cm dishes. On day 3 after seeding, the a-amino-n-butyric acid was added to a medium at a final concentration of 30 pM or 100 pM. 24 hours after the addition of the a-amino-n-butyric acid. Oxygen Consumption Rate (OCR: pmol / min) was measured using the Extracellular Flux Analyzer XFe96 (manufactured by Seahorse Bioscience, Inc.; sold by Primetech Corporation) according to the protocol provided by the manufacturer. FIG. 24 shows results. FIG. 24A shows Basal Respiration and Spare Capacity. FIG. 24B shows Proton Leak and ATP production.

[0155] It was shown that the addition of the a-amino-n-butyric acid increased the Basal Respiration, Spare Capacity, and ATP production in both the C2C12 cells and the HUVEC cells.

[0156] These results indicate that the a-amino-n-butyric acid enhances the mitochondrial function.

Claims

1. A composition for maintaining or improving life expectancy containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof.

2. The composition according to claim 1, wherein the life expectancy is healthy life expectancy and / or average life expectancy.

3. The composition according to claim 2, wherein a parameter indicative of the healthy life expectancy is at least one selected from the group consisting of motor function, cardiac function, pulmonary function, and cognitive function.

4. The composition according to claim 3, wherein,when an individual in need of application of said composition is human,an indicator of the motor function is at least one selected from the group consisting of leg extension strength, walking speed, and grip strength,an indicator of the cardiac function is a blood brain natriuretic peptide concentration, andan indicator of the pulmonary function is a tricuspid regurgitation pressure gradient.

5. The composition according to claim 1, wherein, when the individual in need of application of said composition is human, the individual in need of application of said composition is 60 years or older.

6. A composition for suppressing a decrease in motor function caused by Parkinson's disease, containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof.

7. A composition for enhancing mitochondrial function, containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof.

8. A method for detecting an individual to which a composition for maintaining or improving life expectancy containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof is applicable, includingacquiring a measured value indicative of a content of the a-amino-n-butyric acid in a specimen taken from a subject individual, andcomparing said measured value with a predetermined reference value to suggest that said subject individual is the individual in need of application of said composition when the measured value is lower than the predetermined reference value.

9. A detection device for detecting an individual to which a composition for maintaining or improving life expectancy containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof is applicable, whereinthe detection device includes a processing unit,the processing unitacquires a measured value indicative of a content of the a-amino n-butyric acid in a specimen taken from a subject individual, andcompares the measured value with a predetermined reference value, and outputs a label indicating that the subject individual is the individual in need of application of said composition when the measured value is lower than the predetermined reference value.

10. A computer program for detecting an individual to which said composition containing a-amino-n-butyric acid, or a pharmaceutically or food-acceptable salt thereof is applicable, when executed by a computer, causing the computer to perform steps of:acquiring a measured value indicative of a content of the a-amino-n-butyric acid in a specimen taken from a subject individual, andcomparing the measured value with a predetermined reference value, and outputting a label indicating that the subject individual is the individual to which said composition for maintaining or improving life expectancy is applicable when the measured value is lower than the predetermined reference value.INTERNATIONAL SEARCH REPORT International application No. PCT / JP2024 / 004398A. CLASSIFICATION OF SUBJECT MATTER 46 / if3 / / / P5(2006.01)i;423Z / 33 / / 75(2016.01)i;45 / PP / <W(2006.01)i;46 / P / lW(2006.01)i;46 / P2 / / (W(2006.01)i; 4 61P 25 / 25(2006.01)i FI: A61K31 / 198; A61P9 / 00; A61P11 / 00; A61P21 / 00: A61P25 / 28; A23L33 / 175 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K31 / 198; A23L33 / 175; A61P9 / 00; A61P11 / 00; A61P21 / 00; A61P25 / 28 Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Published examined utility model applications of Japan 1922-1996 Published unexamined utility model applications of Japan 1971-2024 Registered utility model specifications of Japan 1996-2024 Published registered utility model applications of Japan 1994-2024 Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) JSTPlus / JMEDPlus / JST7580 (JDreamlll); CAplus / REGISTRY / MEDLINE / EMBASE / BIOSIS (STN) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X 1 X JP 2018-008884 A (NATIONAL UNIVERSITY CORPORATION KOBE UNIVERSITY) 18 January 2018 (2018-01-18) entire text IRINO, Y. et al, 2-Aminobutyric acid modulates glutathione homeostasis in the myocardium, SCIENTIFIC REPORTS, 2016, 6:36749, p. 10 entire text 1-6 1-5 X WO 2021 / 156181 Al (SOCIETE DES PRODUITS NESTLE S.A.) 12 August 2021 (2021-08-12) entire text, in particular, claims 1-20, p. 7, lines 10-15, 25-31, examples 1-5, 8-10 A BOHMER, T., The formation of Propionylcarnitine in Isolated Rat Liver Mitochondria, BIOCHIMICA ET BIOPHYSICA ACTA, 1968, 164, pp. 487-497 entire text 7 | | Further documents are listed in the continuation of Box C. | Z | See patent family annex. * Special categories of cited documents: “T” later document published after the international filing date or priority “A” document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand the to be of particular relevance principle or theory underlying the invention “D” document cited by the applicant in die international application “X” document of particular relevance; the claimed invention cannot be ■SE” earlier application orpatent but published on or after the international considered novel or cannot be considered to involve an inventive step filing date when the document is taken alone •SL” document which may throw doubts on priority claim(s) or which is “Y” document of particular relevance; the claimed invention cannot be cited to establish the publication date of another citation or other considered to involve an inventive step when the document is special reason (as specified) combined with one or more other such documents, such combination “O” document referring to an oral disclosure, use, exhibition or other being obvious to a person skilled in the art means document member of the same patent family “P” document published prior to the international filing date but later than the priority date claimed Date of the actual completion of the international search 02 April 2024 Date of mailing of the international search report 16 April 2024 Name and mailing address of the ISA / JP Japan Patent Office (ISA / JP) 3-4-3 Kasumigaseki, Chiyoda-ku, Tokyo 100-8915 Japan Authorized officer Telephone No.

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