Composition for preventing, treating or ameliorating sarcopenia and method for diagnosing sarcopenia

Abstract

The present invention relates to a pharmaceutical composition, a health-care functional food composition or a health-care functional food for preventing, treating or ameliorating sarcopenia, comprising at least one of one or more short-chain or medium-chain fatty acids, esters thereof or triglyceride forms thereof. Furthermore, the present invention relates to a composition for diagnosing a possible group of sarcopenia or a group of sarcopenia, comprising, as an active ingredient, an agent for measuring the content of one or more short-chain or medium-chain fatty acids in blood, and to a method of providing information for determining a possible group of sarcopenia or a group of sarcopenia comprising the step of measuring the content of one or more short-chain or medium-chain fatty acids from the blood of a subject.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition, a health functional food composition, a health functional food and a diagnostic composition for sarcopenia, comprising one or more short-chain fatty acids or medium-chain fatty acids, and to a method for diagnosing a possible sarcopenia group or a sarcopenia group, the method comprising measuring the content of one or more short-chain fatty acids or medium-chain fatty acids in blood from a subject. Background Art

[0002] Loss of muscle mass and strength is one of the main characteristics of human aging, and it is a factor that significantly affects all physical activities, lifestyle, and appearance of an individual. Loss of muscle mass and strength due to aging is one of the symptoms of sarcopenia, a disease accompanied by symptoms of decreased muscle mass and muscle function due to a decrease in the number and size of muscle fibers that make up muscle.

[0003] Patients with sarcopenia have a reduced ability to perform daily physical activities (such as walking speed or the ability to sit and stand) due to a lack of muscle mass, making them more likely to fall frequently and therefore at risk for fall-related accidents. In addition, because muscle also serves as an energy source for the body by storing glucose in the form of glycogen, it is known that a loss of muscle mass can lead to greater fatigue and may worsen chronic diseases.

[0004] The United Nations (UN) classifies countries where the proportion of people aged 65 and over exceeds 14% of the total population as aging societies, and countries where the proportion exceeds 20% as super-aging societies. According to UN population projections, the proportion of elderly people in developed countries is expected to increase from 13.0% in 1990 to 23.3% in 2030, and the elderly population in developing countries is expected to more than double, from 4.6% in 1990 to 9.7% in 2030. As the elderly population increases, the number of patients suffering from or at risk of sarcopenia is rapidly increasing.

[0005] Therefore, techniques for diagnosing sarcopenia have been investigated and are currently diagnosed by directly measuring muscle mass using imaging techniques such as dual-energy x-ray absorptiometry (DEXA) or computed tomography (CT), while simultaneously assessing muscle strength (e.g., grip strength) and physical activity performance (e.g., walking speed, chair stand test, and Short Physical Status Board (SPPB)), and then interpreting the scores obtained from these assessments according to European (EWGSOP) or Asian (AWGS) guidelines.

[0006] However, the above tests are not only cumbersome and uneconomical as they require expensive medical equipment, but also carry the risk of radiation exposure during these tests. Therefore, there is a growing need to develop accurate, safe, and cost-effective diagnostic tools for sarcopenia as an alternative.

[0007] While exercise and nutrition are known to help slow sarcopenia, there are currently no treatments approved by regulatory agencies such as the FDA or its global counterparts. Summary of the Invention

[0008] Technical issues

[0009] The present invention aims to solve the technical challenges of simply and safely diagnosing, preventing, treating or improving sarcopenia by providing a method for providing information for determining possible sarcopenia groups and sarcopenia groups by measuring the content of one or more short-chain fatty acids or medium-chain fatty acids in the blood, and a composition for preventing, treating or improving sarcopenia comprising the fatty acids.

[0010] Solution to the problem

[0011] In order to solve the above problems, the present invention provides a pharmaceutical composition, a health functional food composition and a health functional food for preventing, treating or improving sarcopenia, which contain one or more short-chain fatty acids or medium-chain fatty acids; or their alkyl esters as active ingredients.

[0012] Another aspect of the present invention provides a composition for diagnosing a possible sarcopenia group or a sarcopenia group, the composition comprising as an active ingredient a reagent capable of measuring the content of one or more short-chain fatty acids or medium-chain fatty acids in the blood.

[0013] Another aspect of the present invention provides a method for providing information for determining a possible sarcopenia group or a sarcopenia group, the method comprising (i) collecting blood from a subject and measuring the content of one or more short-chain fatty acids or medium-chain fatty acids; (ii) dividing the measured value in the above step (i) by the content value of the one or more short-chain fatty acids or medium-chain fatty acids in the plasma of a normal control group; and (iii) when the value obtained by the above division is less than 1, determining that the subject is in a state of the possible sarcopenia group or the sarcopenia group.

[0014] Yet another aspect of the present invention provides a method for treating sarcopenia, comprising administering to a subject one or more short-chain fatty acids or medium-chain fatty acids; or one or more esters or salts of these fatty acids.

[0015] Another aspect of the present invention provides use of one or more short-chain fatty acids or medium-chain fatty acids, or esters or salts of these fatty acids, in preparing a pharmaceutical composition for preventing, treating or improving sarcopenia.

[0016] Another aspect of the present invention provides use of one or more short-chain fatty acids or medium-chain fatty acids, or esters or salts of these fatty acids for preventing or treating sarcopenia.

[0017] Beneficial technical effects of the present invention

[0018] The composition containing short-chain fatty acids or medium-chain fatty acids of the present invention has the effect of preventing, treating or improving sarcopenia and can be effectively used as a sarcopenia therapeutic agent or health supplement, and has the following advantages: it allows accurate and easy diagnosis of sarcopenia by providing a method for determining possible sarcopenia groups or information on sarcopenia groups.

[0019] However, the technical effects of the present invention are not limited to the above-mentioned technical effects, and those skilled in the art will clearly understand other technical effects that are not mentioned from the following description. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The figure shows the diagnostic algorithm for sarcopenia according to the Asian Working Group on Sarcopenia (AWGS) in 2019. There are various diagnostic criteria for sarcopenia worldwide, but in Asia, sarcopenia is diagnosed according to the diagnostic algorithm for sarcopenia established by the AWGS.

[0021] Figure 2 The following table shows the plasma levels of butyrate / isobutyrate, valeric acid, hexanoic acid, and heptanoic acid in the probable sarcopenia group and the sarcopenia group compared with the normal control group. The levels were converted to logarithms (ln) and subjected to the Welch t-test. * indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.005, and # indicates p < 0.0001.

[0022] Figure 3 Receiver operating characteristic (ROC) curves and area under the curve (AUC) values ​​of butyrate / isobutyrate, valeric acid, hexanoic acid, and heptanoic acid in the possible sarcopenia group and the sarcopenia group are shown.

[0023] Figure 4Shown are changes in grip strength in aged mice fed ethyl valerate, ethyl hexanoate, ethyl heptanoate, ethyl octanoate, ethyl palmitate, tripalanin, trihexanoin, and triheptanoin over a four-week period, as measured by the Mann-Whitney U test. *, # indicate p < 0.05; **, $$ indicate p < 0.01; **, $$$ indicate p < 0.001; and **** indicate p < 0.0001.

[0024] Figure 5 Shows the Figure 4 The changes in running time after feeding in the same manner as in the previous figure are shown in the Mann-Whitney U test. * indicates p < 0.05; $$ indicates p < 0.01.

[0025] Figure 6 Shown are changes in grip strength over a four-week period in aged mice fed a diet containing inositol or inositol-diheptanoate, as determined by the Mann-Whitney U test. *** indicates p = 0.0003. DETAILED DESCRIPTION

[0026] Hereinafter, the present invention will be described in detail.

[0027] 1. Pharmaceutical compositions, methods of treatment, and uses for preventing or treating sarcopenia

[0028] One aspect of the present invention provides a pharmaceutical composition for preventing or treating sarcopenia, comprising one or more short-chain fatty acids or medium-chain fatty acids as active ingredients.

[0029] The term "short-chain fatty acid or medium-chain fatty acid" as used herein may refer to any one selected from the group consisting of fatty acids having a chain of 1 to 12, 1 to 10, 1 to 8, 5 to 8, or 5 to 7 carbon atoms. For example, a short-chain fatty acid may refer to one or more selected from fatty acids containing 1, 2, 3, 4, or 5 carbon atoms, and a medium-chain fatty acid may refer to one or more selected from fatty acids containing 6, 7, 8, 9, 10, 11, or 12 carbon atoms. In addition, a short-chain fatty acid or medium-chain fatty acid may refer to any saturated, unsaturated, or branched fatty acid having a chain of the aforementioned number of carbon atoms.

[0030] More specifically, the short-chain fatty acid or the medium-chain fatty acid may be one or more selected from the group consisting of fatty acids having chains of 5, 6, and 7 carbon atoms.

[0031] According to one embodiment of the present invention, the short-chain fatty acid or medium-chain fatty acid can be one or more fatty acids selected from the group consisting of valeric acid, hexanoic acid and heptanoic acid. The pharmaceutical composition of the present invention can include one or more, two or more, three or more, or four or more short-chain fatty acids or medium-chain fatty acids.

[0032] The "fatty acid ester" of the present invention can improve the inherent odor of fatty acids, thereby improving the convenience of intake compared to when the composition of the present invention is taken in the form of fatty acids.

[0033] The "fatty acid ester" of the present invention may be any one selected from the group consisting of glycerol fatty acid esters, alkyl fatty acid esters, sugar fatty acid esters, and sugar alcohol fatty acid esters.

[0034] In addition, the ester of fatty acid may be selected from the group consisting of methyl fatty acid ester, ethyl fatty acid ester, propyl fatty acid ester, butyl fatty acid ester, inositol fatty acid ester and triglyceride, but other than these, any ester may be used without limitation as long as the convenience of intake can be increased.

[0035] In addition, the "sugar alcohol" in the "sugar alcohol fatty acid ester" can be any one selected from the group consisting of erythritol, threitol, xylitol, arabitol, ribitol, mannitol, sorbitol, galactitol, fusitol, iditol, inositol, bolemitol, isomalt, maltitol, lactitol and polyglycitol, but is not limited thereto.

[0036] In the present invention, a triglyceride of a short-chain fatty acid or a medium-chain fatty acid may refer to a triglyceride in which three fatty acid molecules of the same type are bound to glycerol. For example, the triglyceride form of valeric acid, or "tripalkenylglycerol," refers to a triglyceride in which three molecules of valeric acid are bound to a glycerol molecule. Additionally, a triglyceride of a short-chain fatty acid or a medium-chain fatty acid may refer to a triglyceride in which three different fatty acid molecules are bound to glycerol. For example, fatty acids having chains of 5, 6, or 7 carbon atoms may be bound one after the other to a single glycerol molecule.

[0037] In the present invention, the ester form of fatty acids can be hydrolyzed in vivo by esterase or lipase into fatty acid residues and alcohol residues, fatty acid residues and sugar or sugar alcohol residues, or fatty acid residues and glycerol residues, and then absorbed into the body. In this way, fatty acid esters can be understood as a means of improving the inherent bad smell of fatty acids, thereby increasing the convenience of intake and smoothly delivering fatty acids into the body.

[0038] “Sarcopenia”, that is, the pharmaceutical composition of the present invention is expected to have a preventive or therapeutic effect on it, may refer to one or more symptoms exhibited by a group selected from a “possible sarcopenia group” (according to the AWGS2019 sarcopenia diagnostic algorithm, one or more of muscle strength and physical activity decreased compared with the normal group) and a “sarcopenia group” (muscle mass decreased and muscle strength or physical activity worsened). That is to say, the pharmaceutical composition of the present invention can be achieved by improving one or more of the group consisting of muscle mass, muscle strength and physical activity of a subject who needs to prevent or treat sarcopenia. In addition, the improvement effect of the pharmaceutical composition of the present invention is not limited to Asians, and the excellent effect of the present invention is not affected by factors such as race, physical characteristics and gender.

[0039] In the present invention, the term "prevent" is used to encompass, but is not limited to, any and all actions that inhibit or delay the symptoms of loss of muscle mass, decreased muscle strength, and impaired physical activity associated with sarcopenia. In the present invention, the term "treat" is used to encompass, but is not limited to, any and all actions that ameliorate or beneficially alter the above symptoms associated with sarcopenia.

[0040] The short-chain fatty acids or medium-chain fatty acids of the present invention, or esters or salts of these fatty acids, can be administered at a concentration level of 0.1 wt% to 100 wt% based on the total weight of the pharmaceutical composition, or even if administered at a concentration level outside the above range, can be administered without restriction, as long as the amount is sufficient to achieve the desired effect. For example, relative to the total weight of the pharmaceutical composition, the short-chain fatty acids or medium-chain fatty acids of the present invention can be present in an amount of 0.1 wt% to 100 wt%, 0.1 wt% to 90 wt%, 0.1 wt% to 80 wt%, 0.1 wt% to 70 wt%, 0.1 wt% to 60 wt%, 0.1 wt% to 50 wt%, 0.1 wt% to 40 wt%, 0.1 wt% to 30 wt%, 0.1 wt% to 20 wt%, 0.1 wt% to 10 wt%, 1 wt% to 100 wt%, 1 wt% to 90 wt%, 1 wt% to 8 0wt%, 1wt% to 70wt%, 1wt% to 60wt%, 1wt% to 50wt%, 1wt% to 40wt%, 1wt% to 30wt%, 1wt% to 20wt%, 1wt% to 10wt%, 10wt% to 100wt%, 20wt% to 100wt%, 30wt% to 100wt%, 40wt% to 100wt%, 50wt% to 100wt%, 60wt% to 100wt%, 70wt% to 100wt%, 80wt% to 100wt% or 90wt% to 100wt%.

[0041] Specifically, the amount of fatty acid used varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, disease severity, etc. The pharmaceutical composition of the present invention can be administered once a day or several times a day, and the administration cycle can be 1 day to 12 months, but can be administered without restriction until the preventive or therapeutic effect of sarcopenia occurs. For example, short chain or medium chain fatty acids, or esters or salts of these fatty acids can be taken at 500 mg to 9000 mg, 500 mg to 8000 mg, 500 mg to 7000 mg, 500 mg to 6000 mg, 500 mg to 5000 mg, 500 mg to 4000 mg, 500 mg to 3000 mg, 500 mg to 2000 mg, 500 mg to 1000 mg, 1000 mg to 9000 mg, 1000 mg to 8000 mg, 1000 mg to 7000 mg, 1000 mg to 6000 mg, 1000 mg to 5000 mg, 500 mg to 4000 mg, 500 mg to 3000 mg, 500 mg to 2000 mg, The dosage of the drug may be 5000 mg to 5000 mg, 1000 mg to 4000 mg, 1000 mg to 3000 mg, 1000 mg to 2000 mg, 2000 mg to 9000 mg, 2000 mg to 8000 mg, 2000 mg to 7000 mg, 2000 mg to 6000 mg, 2000 mg to 5000 mg, 2000 mg to 4000 mg or 2000 mg to 3000 mg to adult males, but is not limited thereto. Even when administered in an amount greater than or less than the above range, it may be administered without limitation as long as the amount is sufficient to achieve the desired effect.

[0042] The pharmaceutical composition containing the short-chain fatty acids or medium-chain fatty acids of the present invention as an active ingredient can be formulated and used in the form of oral dosage forms (e.g., powders, granules, tablets, capsules, tablets, suspensions, emulsions, syrups, aerosols, etc.), external preparations, suppositories or sterile injection solutions according to conventional methods.

[0043] According to conventional methods, the pharmaceutical composition of the present invention containing short-chain fatty acids or medium-chain fatty acids as active ingredients may also include suitable carriers, excipients, or diluents. Specifically, the pharmaceutical composition may be prepared using diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants commonly used in formulation preparation. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which can be prepared by mixing one or more excipients with the compound, such as starch, calcium carbonate, sucrose, lactose, gelatin, and the like. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration may include suspensions, liquid preparations for internal use, emulsions, syrups, and the like. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, spices, and preservatives may also be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. As non-aqueous solvents and suspending agents, propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil) and injectable esters (e.g., ethyl oleate) can be used. As suppository bases, Wetepsol, polyethylene glycol, Tween 61, cocoa butter, trilaurin, glyceryl gelatin, etc. can be used.

[0044] The pharmaceutical composition of the present invention comprising a short-chain fatty acid or a medium-chain fatty acid as an active ingredient can be administered to mammals, such as rats, mice, livestock, and humans, via various routes. The administration route can be any route, such as intradermal, oral, rectal, intravenous, intraperitoneal, intramuscular, subcutaneous, endometrial injection, or intracerebroventricular injection, preferably via oral or intravenous routes, but not limited thereto.

[0045] Administration can also include one or more active components that show identical or similar functions.For administration, one or more additional pharmaceutically acceptable carriers can be included.As pharmaceutically acceptable carrier, one or more mixtures in physiological saline solution, sterile water, Ringer's solution, buffered saline solution, glucose solution, maltodextrin solution, glycerol, ethanol and these compositions can be mixed and used, and if necessary, other common additives, such as antioxidants, buffer solutions, antibacterial agents can be added.In addition, the compound according to the present invention can be easily formulated into various preparations, such as, by additionally adding diluent, dispersant, surfactant, adhesive and lubricant, forming injectable preparations (such as, aqueous solution, suspension, emulsion etc.), powder, tablet, capsule, pill, granule or injection solution.

[0046] According to an embodiment of the present invention, when measuring muscle strength at the time point after 4 weeks of feeding short-chain, medium-chain or long-chain fatty acids to elderly mice, compared with the muscle strength of mice fed with fatty acids whose content is not reduced in the plasma of sarcopenia patients, it is observed that the muscle strength and motor function of mice fed with short-chain fatty acids or medium-chain fatty acids (which are the fatty acid types whose content in sarcopenia patients' plasma is reduced) are improved. When short-chain fatty acids or medium-chain fatty acids of the present invention are applied, the effect of treating or improving sarcopenia is observed (see Example 2). Therefore, the composition of the present invention can be used as a therapeutic agent for preventing or treating sarcopenia by enhancing muscle strength and motor function.

[0047] Another aspect of the present invention provides a method for treating sarcopenia, comprising administering to a subject one or more short-chain fatty acids or medium-chain fatty acids, or one or more esters or salts of these fatty acids.

[0048] Another aspect of the present invention provides use of one or more short-chain fatty acids or medium-chain fatty acids, or esters or salts of these fatty acids, in preparing a pharmaceutical composition for preventing, treating or improving sarcopenia.

[0049] Another aspect of the present invention provides the use of one or more short-chain fatty acids or medium-chain fatty acids, or esters or salts of these fatty acids, for treating or preventing sarcopenia. All terms related to the methods and uses herein are understood to have the same definitions as those related to the above-mentioned compositions.

[0050] 2. Health functional food compositions and health functional foods for preventing or improving sarcopenia

[0051] One aspect of the present invention provides a health functional food composition for preventing or improving sarcopenia, which comprises short-chain fatty acids or medium-chain fatty acids as active ingredients.

[0052] The health functional food composition and health functional food of the present invention contain one or more short-chain fatty acids or medium-chain fatty acids, or esters or salts of these fatty acids as active ingredients.

[0053] In this regard, the descriptions regarding “short-chain fatty acids or medium-chain fatty acids,” “esters of fatty acids,” “sarcopenia,” and “prevention” are as described in the above-mentioned section “1. Pharmaceutical compositions, treatment methods, and uses for preventing or treating sarcopenia.”

[0054] The "health functional food" of the present invention refers to a food prepared by adding short-chain fatty acids or medium-chain fatty acids to food materials (e.g., beverages, teas, spices, chewing gum, candies, etc.), or by encapsulating, powdering, or entering a suspension, and consuming the food produces a specific effect on health. However, unlike general medicines, since the health functional food is made from food, it has the advantage of not producing any side effects that may occur when taking medicine for a long time. Since the health functional food of the present invention obtained in this way can be eaten every day, it can be easily and conveniently ingested, and is therefore very useful because it is expected to prevent or improve sarcopenia.

[0055] The "food composition" of the present invention may refer to a composition that can be used to produce the above-mentioned health functional food.

[0056] There is no particular limitation on the type of "food" of the present invention, as long as the short-chain fatty acids or medium-chain fatty acids of the present invention can be added thereto. Examples of foods to which the fatty acids of the present invention can be added include meat, sausages, bread, chocolate, candy, snacks, preserves, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, wine, alcoholic beverages, vitamin complexes, and the like.

[0057] The food or health functional food of the present invention may contain various aromatics or natural carbohydrates, various nutritional supplements, vitamins, electrolytes, flavorings, colorants, pectin acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. as additional ingredients.

[0058] In the present invention, "improvement" is used to refer to, but not limited to, all actions that improve parameters related to sarcopenia treatment, and may refer to, for example, actions that at least alleviate the degree of symptoms.

[0059] Therefore, the food or health functional food composition of the present invention comprises one or more short-chain fatty acids or medium-chain fatty acids, esters or salts of these fatty acids as active ingredients.

[0060] The short-chain fatty acid or medium-chain fatty acid can be selected from the group consisting of fatty acids having chains of 5, 6 and 7 carbon atoms. For example, the short-chain fatty acid or medium-chain fatty acid can be any one selected from the group consisting of valeric acid, hexanoic acid and heptanoic acid.

[0061] In addition, the ester of fatty acid can be any one selected from the group consisting of glycerol fatty acid ester, alkyl fatty acid ester, sugar fatty acid ester and sugar alcohol fatty acid ester. In addition, the ester can be selected from the group consisting of methyl fatty acid ester, ethyl fatty acid ester, propyl fatty acid ester, butyl fatty acid ester, inositol fatty acid ester and triglyceride.

[0062] 3. Composition for diagnosing a possible sarcopenia group or a sarcopenia group

[0063] One aspect of the present invention provides a composition for diagnosing a possible sarcopenia group or a sarcopenia group, comprising as an active ingredient a reagent capable of measuring the content of short-chain fatty acids or medium-chain fatty acids in blood.

[0064] The reagents included in the diagnostic composition of the present invention can measure the levels of one or more short-chain fatty acids or medium-chain fatty acids in the blood.

[0065] In the present invention, the one or more short-chain fatty acids or medium-chain fatty acids in the blood whose content is to be measured may be one or more fatty acids selected from the group consisting of fatty acids having chains of 5, 6, and 7 carbon atoms.

[0066] In this regard, the description of “short-chain fatty acids or medium-chain fatty acids” is as described in the above section “1. Pharmaceutical compositions, treatment methods, and uses for preventing or treating sarcopenia”.

[0067] In the present invention, "measuring" the "content" of short-chain fatty acids or medium-chain fatty acids in the blood refers to measuring the content of short-chain fatty acids or medium-chain fatty acids contained in the blood, which can be an absolute content or a relative content. For example, in the present invention, mass spectrometry can be used as a method for measuring the content of short-chain fatty acids or medium-chain fatty acids. In addition, "agents capable of measuring the content" may refer to reagents capable of measuring the absolute content or relative content of short-chain fatty acids or medium-chain fatty acids contained in the blood, but are not limited thereto. The advantage of measuring the content of short-chain fatty acids or medium-chain fatty acids in the blood in the present invention is that it can reflect various information about the biochemical changes in the body that occurred immediately before blood collection, thereby enabling early diagnosis of sarcopenia.

[0068] The "possible sarcopenia group" and "sarcopenia group" of the present invention may refer to groups classified according to the AWGS 2019 sarcopenia diagnostic algorithm. Specifically, the "possible sarcopenia group" refers to a group in which one or more of muscle strength and physical activity are reduced compared to the normal group, and refers to a patient group in which the symptoms of sarcopenia have begun to progress. In addition, the "sarcopenia group" refers to a group that shows a decrease in muscle mass, as well as a deterioration in muscle strength and physical activity compared to the normal group, and refers to a patient group that clearly shows symptoms of sarcopenia (see Figure 1 ).

[0069] In the present invention, the term "diagnosis" refers to confirmation of the presence or characteristics of a pathological condition, and for the purpose of the present invention, it refers not only to classification into a normal group, a possible sarcopenia group, and a sarcopenia group according to the degree of progression of sarcopenia, but also to comprehensive determination of the degree of treatment or improvement of sarcopenia in the corresponding subjects after treatment of sarcopenia, responsiveness and resistance to drugs, etc.

[0070] 4. Methods for providing information for determining possible sarcopenia groups or sarcopenia groups

[0071] One aspect of the present invention provides a method for providing information for determining that a subject belongs to a possible sarcopenia group or a sarcopenia group by measuring the content of short-chain fatty acids or medium-chain fatty acids in the blood of the subject.

[0072] In the information providing method of the present invention, the descriptions of "short-chain fatty acids or medium-chain fatty acids", "content measurement", "possible sarcopenia group" and "sarcopenia group" are as described in the above-mentioned "1. Pharmaceutical compositions, treatment methods and uses for preventing or treating sarcopenia" and "3. Compositions for diagnosing possible sarcopenia groups or sarcopenia groups".

[0073] The method of the present invention for providing information for determining a possible sarcopenia group, a possible sarcopenia group, or a sarcopenia group includes: (i) collecting blood from a subject and measuring the content of one or more short-chain fatty acids or medium-chain fatty acids in the plasma; (ii) dividing the measured value in the above step (i) by the content value of the one or more short-chain fatty acids or medium-chain fatty acids in the plasma of a normal control group; and (iii) when the value obtained by the division is less than 1, determining that the subject is in a state of the possible sarcopenia group or the sarcopenia group.

[0074] In an embodiment, it is observed that the content of short-chain fatty acids or medium-chain fatty acids in the plasma of the subject is lower than the content of short-chain fatty acids or medium-chain fatty acids in the plasma of the normal control group. Therefore, the method of providing information in the present invention includes comparing the content of short-chain fatty acids or medium-chain fatty acids in the plasma of the subject and the normal control group. The case where the value obtained by division in the above step (iii) is less than 1 refers to the case where the value is 0.90 or less, 0.85 or less, 0.80 or less, 0.75 or less, 0.70 or less, 0.65 or less, 0.60 or less, 0.55 or less, 0.50 or less or 0.45 or less.

[0075] More specifically, according to one embodiment of the present invention, compared with the normal control group, in the possible sarcopenia group, the content of valeric acid may be 0.50 or less, 0.47 or less, or 0.45 or less, and in the sarcopenia group, the content of valeric acid may be 0.45 or less, 0.42 or less, or 0.40 or less. Compared with the normal control group, in the possible sarcopenia group, the content of caproic acid may be 0.83 or less, 0.80 or less, or 0.77 or less, and in the sarcopenia group, the content of caproic acid may be 0.87 or less, 0.85 or less, or 0.82 or less. Compared with the normal control group, in the possible sarcopenia group, the content of heptanoic acid may be 0.55 or less, 0.53 or less, or 0.50 or less, and in the sarcopenia group, the content of heptanoic acid may be 0.57 or less, 0.55 or less, or 0.54 or less (see Example 1-1).

[0076] More specifically, according to one embodiment of the present invention, when a patient is diagnosed as one of a normal control group, a possible sarcopenia group, and a sarcopenia group based on the content of short-chain or medium-chain fatty acids in plasma, the AUC value of the ROC curve is calculated to determine whether the patient's classification is consistent with the classification according to the AWGS2019 sarcopenia diagnostic algorithm. Specifically, the value of butyrate or isobutyrate in the possible sarcopenia group can be 0.77 or less, 0.75 or less, or 0.73 or less, and the value of butyrate or isobutyrate in the sarcopenia group can be 0.75 or less, 0.73 or less, or 0.71 or less. The value of valeric acid in the possible sarcopenia group can be 0.85 or less, 0.83 or less, or 0.81 or less, and the value of valeric acid in the sarcopenia group can be 0.87 or less, 0.85 or less, or 0.84 or less. The value of hexanoic acid in the possible sarcopenia group may be 0.85 or less, 0.83 or less, or 0.82 or less, and the value of hexanoic acid in the sarcopenia group may be 0.85 or less, 0.80 or less, or 0.78 or less. The value of heptanoic acid in the possible sarcopenia group may be 0.97 or less, 0.95 or less, or 0.94 or less, and the value of heptanoic acid in the sarcopenia group may be 0.95 or less, 0.93 or less, or 0.92 or less (see Examples 1-2).

[0077] [Example]

[0078] Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are provided to facilitate a better understanding of the present invention, and the content of the present invention is not limited to these examples.

[0079] Example 1. Diagnosis of sarcopenia using short-chain fatty acid or medium-chain fatty acid content

[0080] Example 1-1. Determination of the content of short-chain fatty acids or medium-chain fatty acids in the blood of patients with sarcopenia

[0081] In order to diagnose sarcopenia by measuring the content of short-chain fatty acids or medium-chain fatty acids in the blood, plasma was separated from the blood of the normal control group and the sarcopenia group, and the content of short-chain fatty acids and medium-chain fatty acids was measured.

[0082] Based on the 2019 Asian Working Group on Sarcopenia (AWGS) sarcopenia diagnostic algorithm, the sarcopenia group was divided into two groups (i.e., possible sarcopenia group and sarcopenia group), and the experiment was conducted on 90 men aged 70 years and older in each group. The symptom descriptions of each group classified according to the AWGS sarcopenia diagnostic algorithm are shown in the table below.

[0083] [Table 1]

[0084]

[0085] The AWGS2019 diagnostic algorithm for sarcopenia and the criteria for the symptoms listed in Table 1 above are as follows Figure 1 As shown, and this experiment is for men, according to Figure 1 The experimental groups were divided according to the reference values ​​of limb skeletal muscle mass and hand grip strength of males shown in . Specifically, muscle mass was measured as limb skeletal muscle mass (ASM), and when ASM (kg) / (height (m)) 2 <7.0kg / m 2 When the muscle mass is reduced, it is determined that the muscle mass is reduced. Muscle strength is measured by hand grip strength, and when the hand grip strength is <28kg, the muscle strength is determined to be reduced. Finally, physical activity is determined by walking speed (6-meter walk), the time required to sit down and stand up 5 times (5 chair stand tests) or the physical function index. Physical activity is determined to be reduced when the walking speed is <1.0m / s, the time required to sit down and stand up 5 times is ≥12s or the physical function index (Simple Physical Status Scale; SPPB) is ≤9. SPPB is a test standard developed by the National Institutes of Health, which can determine sarcopenia by comprehensively testing walking speed, sit down and stand up, grip strength, etc.

[0086] First, a total of four fatty acids, i.e., butyric / isobutyric acid and valeric acid (short-chain fatty acids) and hexanoic acid and heptanoic acid (medium-chain fatty acids), were analyzed by mass spectrometry in the plasma of the normal control group, the probable sarcopenia group, and the sarcopenia group.

[0087] The content of each fatty acid in the plasma of the possible sarcopenia group and the sarcopenia group was measured by mass spectrometry. The median of the measured raw data was set to 1, and based on this, the scaled imp data, i.e. the value corrected for the remaining content, was calculated. These corrected content values ​​were then divided by the level of each fatty acid found in the plasma of the normal control group, and the values ​​obtained from this division made it possible to calculate the relative levels of fatty acids in the plasma of both the possible sarcopenia group and the sarcopenia group compared to the normal control group (see Tables 2 and Figure 2 ).

[0088] [Table 2]

[0089]

[0090] As a result, as shown in Table 2 above, it was observed that the fatty acid content in the plasma of the possible sarcopenia group and the sarcopenia group was generally decreased to 0.85 or less compared with the normal control group.

[0091] In particular, in the case of the medium-chain fatty acid heptanoic acid, it was confirmed that the plasma levels of heptanoic acid in the possible sarcopenia group and the sarcopenia group were reduced to approximately half compared to the normal control group. Meanwhile, in the case of the short-chain fatty acid valeric acid, it was confirmed that the plasma levels of valeric acid in the possible sarcopenia group and the sarcopenia group were reduced to less than half compared to the normal control group. Finally, in the case of hexanoic acid, it was observed that the plasma levels of hexanoic acid in both the possible sarcopenia group and the sarcopenia group were reduced to approximately 80% of the normal control group level.

[0092] Example 1-2. Confirmation of the accuracy of short-chain fatty acids or medium-chain fatty acids as diagnostic markers for sarcopenia

[0093] To determine the accuracy of short-chain fatty acids or medium-chain fatty acids as diagnostic markers for sarcopenia, receiver operating characteristic (ROC) curves were drawn, and the area under the curve (AUC) values ​​were calculated.

[0094] ROC curve analysis is a method used to determine the diagnostic accuracy of a specific indicator, where the x-axis is "1-specificity", which represents the false positive rate, specificity is a value defined as true positive / (false positive + true positive), and the y-axis is "sensitivity", which represents the true positive rate.

[0095] That is, in the experiment of the present invention, when the patient was diagnosed as belonging to one of the normal control group, the possible sarcopenia group and the sarcopenia group based on the content of short-chain fatty acids or medium-chain fatty acids in the patient's plasma, when it met the patient classification according to the AWGS2019 sarcopenia diagnostic algorithm, it was determined to be a true positive, and when it did not meet the requirements, it was determined to be a false positive.

[0096] The area under the curve of the ROC curve is called AUC. The closer the AUC value is to 1, the higher the diagnostic accuracy of the specific indicator, and values ​​of 0.7 or higher are generally considered to be useful as diagnostic indicators (Table 3; Source: Muller et al., (2005)). Can routine laboratory tests discriminate between severe acute respiratory syndrome and other causes of community-acquired pneumonia? Clinical Infectious Diseases 40(8):1079-1086).

[0097] [Table 3]

[0098] AUC Accuracy determination 0.9≤AUC<1.0 excellent 0.8≤AUC<0.9 good 0.7≤AUC<0.8 generally AUC<0.7 Difference

[0099] The results of calculating the AUC values ​​of short-chain fatty acids and medium-chain fatty acids according to the above method are shown in Table 4 and Figure 3 shown.

[0100] [Table 4]

[0101]

[0102] As described above, all fatty acid markers showed effective AUC values ​​of 0.7 or higher in the possible sarcopenia group and the sarcopenia group, confirming high diagnostic accuracy. Among them, heptanoic acid showed a particularly high AUC value of 0.9 or higher for the possible sarcopenia group and the sarcopenia group, confirming that its diagnostic accuracy was the best as a diagnostic marker for the possible sarcopenia group and the sarcopenia group.

[0103] Example 2. Confirmation of the therapeutic effect of sarcopenia by taking short-chain fatty acids or medium-chain fatty acids

[0104] To confirm the effectiveness of treating sarcopenia by ingesting short-chain fatty acids or medium-chain fatty acids, 5 to 10 male mice aged 18-20 months were fed with short-chain fatty acids or medium-chain fatty acids ad libitum, corresponding to 5% by weight of the feed.

[0105] Example 2-1. Intake of short-chain fatty acids or medium-chain fatty acids in ester form

[0106] Specifically, due to the unpleasant smell of short-chain fatty acids and medium-chain fatty acids themselves, they are difficult to ingest, so fatty acids are fed as flavorings. Fatty acids are provided in the form of ethyl esters or triglycerides through the feed and are degraded by esterase or lipase in the mouse body. After feeding as described above, the grip strength of the mice was measured using a digital dynamometer (source: SHIMPO digital dynamometer) 4 weeks after the start of feeding (see Table 5 and Figure 4 ). In addition, a running test was performed to confirm the changes in motor function, and the change values ​​(%) of the running time that the mice could run without interruption were compared (see Tables 6 and Figure 5 ).

[0107] As described in Table 5 below, "ethyl valerate," "ethyl hexanoate," "ethyl heptanoate," "ethyl octanoate," and "ethyl palmitate" refer to the ethyl ester forms of fatty acids; and "tripalkanol," "tricaproin," and "triheptanoin" are tri(acyl)glyceride forms of fatty acids, in which three fatty acids of the same type are bound to a glycerol molecule.

[0108] [Table 5]

[0109]

[0110] As described in Table 5 above, it was confirmed that the muscle strength of mice fed with ethyl caprylate and ethyl palmitate, which are ester forms of caprylic acid and palmitic acid (i.e., long-chain fatty acids) (the levels of which are not reduced in the plasma of sarcopenic patients), decreased by 5.5% and 2.6%, respectively, compared to the muscle strength before the experiment, while the muscle strength of mice fed with valeric acid (i.e., short-chain fatty acid), ethyl valerate, tripvaleric acid, ethyl caproate, tricaproic acid, ethyl heptanoate, and triheptanoin (ester forms of caproic acid and heptanoic acid (i.e., medium-chain fatty acids) (the levels of which are reduced in the plasma of sarcopenic patients)) increased by about 10.1% to 15.5%.

[0111] [Table 6]

[0112]

[0113] In addition, as described in Table 6 above, regarding the changes in running time of mice fed with ethyl caprylate and ethyl palmitate, which are ester forms of caprylic acid and palmitic acid (i.e., long-chain fatty acids) whose levels are not reduced in the plasma of sarcopenic patients, small changes were confirmed, which increased by 22.5% or decreased by 24.4%, while the changes in running time of mice fed with valeric acid (i.e., short-chain fatty acid), ethyl valeric acid, tripalanin, ethyl caproate, tricaprylic acid, ethyl heptanoate, and triheptanoin (ester forms of caproic acid and heptanoic acid (i.e., medium-chain fatty acids) whose levels are reduced in the plasma of sarcopenic patients) were significantly improved to 74.0% to 94.1%, thereby indicating improvement in motor function.

[0114] Example 2-2. Intake of sugar alcohols in the form of short-chain fatty acids or medium-chain fatty acids

[0115] To investigate the therapeutic effects of sarcopenia by ingesting fatty acids in the form of sugar alcohols, seven to eight 18-month-old male mice were fed a diet containing either myo-inositol or myo-inositol-diheptanoate (5% by weight of the diet) ad libitum. Mice fed only myo-inositol served as a control group.

[0116] The grip strength of mice was measured in the same manner as in Example 2-1 (see Tables 7 and Figure 6 ).

[0117] [Table 7]

[0118]

[0119] As shown in Table 7 above, when inositol-diheptanoate fatty acid was fed, the change in grip strength over four weeks was confirmed to be approximately 12% higher than when inositol alone was fed. This demonstrates that muscle strength was improved and increased even in mice fed fatty acids in the form of sugar alcohols. In this manner, the composition of the present invention can be used as a therapeutic agent for preventing or treating sarcopenia by improving and enhancing muscle strength in patients with sarcopenia.

Claims

1. A pharmaceutical composition for preventing or treating sarcopenia, comprising one or more short-chain fatty acids or medium-chain fatty acids, or esters or salts of these fatty acids as active ingredients.

2. The pharmaceutical composition according to claim 1, wherein The short-chain fatty acid or medium-chain fatty acid is any one selected from the group consisting of fatty acids having a chain of 5, 6 or 7 carbon atoms.

3. The pharmaceutical composition according to claim 1, wherein The fatty acid ester is any one selected from the group consisting of glycerol fatty acid ester, alkyl fatty acid ester, sugar fatty acid ester and sugar alcohol fatty acid ester.

4. The pharmaceutical composition according to claim 1, wherein The short-chain fatty acid or medium-chain fatty acid is any one selected from the group consisting of valeric acid, hexanoic acid and heptanoic acid.

5. The pharmaceutical composition according to claim 1, wherein The ester of short-chain fatty acid or medium-chain fatty acid is selected from the group consisting of methyl fatty acid ester, ethyl fatty acid ester, propyl fatty acid ester, butyl fatty acid ester, inositol fatty acid ester and triglyceride.

6. A health functional food composition for preventing or improving sarcopenia, comprising one or more short-chain fatty acids or medium-chain fatty acids, or esters or salts of these fatty acids as active ingredients.

7. The health functional food composition according to claim 6, wherein The short-chain fatty acid or medium-chain fatty acid is any one selected from the group consisting of fatty acids having a chain of 5, 6 or 7 carbon atoms.

8. The health functional food composition according to claim 6, wherein The fatty acid ester is any one selected from the group consisting of glycerol fatty acid ester, alkyl fatty acid ester, sugar fatty acid ester and sugar alcohol fatty acid ester.

9. The health functional food composition according to claim 6, wherein The short-chain fatty acid or medium-chain fatty acid is any one selected from the group consisting of valeric acid, hexanoic acid and heptanoic acid.

10. The health functional food composition according to claim 6, wherein The ester of short-chain fatty acid or medium-chain fatty acid is selected from the group consisting of methyl fatty acid ester, ethyl fatty acid ester, propyl fatty acid ester, butyl fatty acid ester, inositol fatty acid ester and triglyceride.

11. A health functional food for preventing or improving sarcopenia, comprising one or more short-chain fatty acids or medium-chain fatty acids, or esters or salts of these fatty acids.

12. The health functional food according to claim 11, wherein The short-chain fatty acid or medium-chain fatty acid is any one selected from the group consisting of fatty acids having a chain of 5, 6 or 7 carbon atoms.

13. The health functional food according to claim 11, wherein The fatty acid ester is any one selected from the group consisting of glycerol fatty acid ester, alkyl fatty acid ester, sugar fatty acid ester and sugar alcohol fatty acid ester.

14. The health functional food according to claim 11, wherein The short-chain fatty acid or medium-chain fatty acid is any one selected from the group consisting of valeric acid, hexanoic acid and heptanoic acid.

15. The health functional food according to claim 11, wherein The ester of short-chain fatty acid or medium-chain fatty acid is selected from the group consisting of methyl fatty acid ester, ethyl fatty acid ester, propyl fatty acid ester, butyl fatty acid ester, inositol fatty acid ester and triglyceride.

16. A diagnostic composition for a possible sarcopenia group or a sarcopenia group, comprising as an active ingredient a reagent capable of measuring the content of one or more short-chain fatty acids or medium-chain fatty acids in blood.

17. The diagnostic composition according to claim 16, wherein The short-chain fatty acid or medium-chain fatty acid is one or more fatty acids selected from the group consisting of fatty acids having a chain of 5, 6 or 7 carbon atoms.

18. A method of providing information for determining a possible sarcopenia group or a sarcopenia group, comprising: (i) collecting blood from a subject and measuring the content of one or more short-chain fatty acids or medium-chain fatty acids in the plasma; (ii) dividing the measured value in step (i) by the content of one or more short-chain fatty acids or medium-chain fatty acids in the plasma of a normal control group; and (iii) When the value obtained by the above division is less than 1, the subject is determined to be in the state of the possible sarcopenia group or the sarcopenia group.

19. The method according to claim 18, wherein The short-chain fatty acid or medium-chain fatty acid is one or more fatty acids selected from the group consisting of fatty acids having a chain of 5, 6 or 7 carbon atoms.

20. The method according to claim 18, wherein If the value obtained by the division in step (iii) is less than 0.85, the subject is determined to be in the possible sarcopenia group or the sarcopenia group.

21. A method for treating sarcopenia comprising administering to a subject one or more short-chain fatty acids or medium-chain fatty acids, or one or more esters or salts of these fatty acids.

22. Use of one or more short-chain fatty acids or medium-chain fatty acids, or esters or salts of these fatty acids, in the preparation of a pharmaceutical composition for preventing, treating or improving sarcopenia.

23. Use of one or more short-chain fatty acids or medium-chain fatty acids, or esters or salts of these fatty acids, for preventing or treating sarcopenia.

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