Preventive and ameliorating agent of frailty

Abstract

To provide a pharmaceutical and food compositions that appropriately ameliorate reduction of a blood albumin value, anemia symptom or the like which is a symptom of frailty.SOLUTION: A frailty preventive and ameliorating agent has geraniol as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for preventing and improving frailty. [Background technology]

[0002] A report by the Ministry of Health, Labor and Welfare (Non-Patent Document 1) defines frailty as "a state in which physical and mental vitality (motor function, cognitive function, etc.) declines with age, and daily living functions are impaired due to the influence of factors such as the coexistence of multiple chronic diseases, resulting in the appearance of physical and mental fragility; however, with appropriate intervention and support, daily living functions can be maintained and improved." According to the revised J-CHS criteria (2020) used to assess frailty, a person is diagnosed as frail if they meet three or more of the following criteria: (1) weight loss, (2) fatigue, (3) decreased walking speed, (4) decreased muscle strength, and (5) decreased physical activity (Non-patent document 2). Furthermore, known symptoms of frailty include decreased blood albumin levels and anemia (Non-Patent Documents 3, 4, and 5).

[0003] Sesamin-related compounds (Patent Document 1) and agarooligosaccharides (Patent Document 2) are known as ingredients that prevent or improve such frailty. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2021 / 065661 [Patent Document 2] Patent No. 7236712 [Non-patent literature]

[0005] [Non-Patent Document 1] Ministry of Health, Labour and Welfare Science Research Grant (General Research Project on Longevity Science) Comprehensive Research Report Research on the Ideal Health Care Program for the Late Elderly [Non-patent document 2] Healthy Longevity Class Textbook 2nd Edition [Non-patent document 3] Environ Health Prev Med(2012)17:164-168 [Non-patent document 4] Clin Geriatr Med. 2011 February;27(1):67-78 [Non-Patent Document 5] J Am Geriatr Sci 56:529-535,2008 Summary of the Invention [Problem to be solved by the invention]

[0006] However, no component has yet been found that can effectively improve the symptoms of frailty, such as decreased blood albumin levels and anemia. Therefore, an object of the present invention is to provide pharmaceutical and food compositions that accurately improve symptoms of frailty such as decreased blood albumin levels and anemia symptoms. [Means for solving the problem]

[0007] Therefore, the present inventors have searched for components derived from various plants that improve the symptoms of frailty, and have found that geraniol, which is mainly found in rose oil, palmarosa oil, and citronella oil, improves the decrease in blood albumin levels and the symptoms of anemia in aged mice, and is useful as an agent for preventing and improving frailty and as a food composition for preventing and improving frailty, thereby completing the present invention.

[0008] That is, the present invention provides the following inventions [1] to [8]. [1] A drug for preventing and improving frailty, containing geraniol as its active ingredient. [2] An albumin synthesis promoter containing geraniol as its active ingredient. [3] An albumin gene transcription promoter containing geraniol as its active ingredient. [4] An agent for improving anemia symptoms, containing geraniol as an active ingredient. [5] A food composition containing geraniol for preventing and improving frailty. [6] A food composition containing geraniol for promoting albumin synthesis. [7] A food composition containing geraniol for promoting albumin gene transcription. [8] A food composition containing geraniol for improving anemia symptoms. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide pharmaceutical and food compositions that improve decreased blood albumin levels and anemic symptoms in elderly people, and prevent and / or improve frailty. [Brief explanation of the drawings]

[0010] [Figure 1] 1 shows a test outline for evaluating the effect of oral administration of geraniol to aged mice in Test Example 1. [Figure 2] Graphs showing the measured concentrations of albumin (ALB), total cholesterol (TCHO), and triglyceride (TG) in plasma are shown. [Figure 3] 1 shows a graph measuring albumin gene expression levels in the liver. [Figure 4] 1 shows graphs evaluating the effects of oral administration of geraniol on blood parameters. [Figure 5] 1 shows a test outline for evaluating the effect of adding geraniol on albumin expression using a human hepatoma-derived cell line in Test Example 2. [Figure 6] 1 shows a graph measuring albumin gene expression levels in cells. [Figure 7] 1 shows a graph measuring albumin concentration in the culture medium. DETAILED DESCRIPTION OF THE INVENTION

[0011] Terms used in this specification are used in the sense commonly used in the art unless otherwise specified.

[0012] As used herein, the terms "contain" or "comprise" include "consist" of "consist essentially of" and "may further contain other components." In this specification, the term "containing an active ingredient" includes all cases in which the ingredient described herein is contained as an active ingredient, and also includes cases in which other ingredients are contained as further active ingredients.

[0013] In this specification, "frailty" is defined in accordance with the definition in Non-Patent Document 1 as "a state in which physical and mental vitality (motor function, cognitive function, etc.) declines with age, and daily living functions are impaired due to the influence of factors such as the coexistence of multiple chronic diseases, resulting in the appearance of physical and mental fragility, but at the same time, daily living functions can be maintained and improved with appropriate intervention and support." According to the revised J-CHS criteria (2020) used to assess frailty, a person is diagnosed as frail if they meet three or more of the following criteria: (1) weight loss, (2) fatigue, (3) decreased walking speed, (4) decreased muscle strength, and (5) decreased physical activity. Here, frailty is clearly distinguished from neurodegenerative diseases such as Alzheimer's disease.

[0014] As used herein, "blood albumin level" refers to the concentration of albumin in plasma, and the blood albumin concentration (standard value) of a healthy person is 4.1 to 5.1 g / dL. In frailty, this blood albumin level is lower than the standard value. "Anemia" or "anemic symptoms" refers to when the hemoglobin concentration in the blood falls below the standard value. This standard value is approximately 13.0 g / dL for men and 12.0 (or 11.5) g / dL for women. In frailty, this hemoglobin concentration falls below the standard value.

[0015] As used herein, "prevention" refers to suppressing the onset of the disease or suppressing the onset of symptoms. "Amelioration" refers to alleviating the symptoms of the disease. "Prevention / Amelioration" refers to prevention and / or amelioration. "Synthesis promotion" refers to promoting the synthesis of a substance in a living body. "Gene transcription promotion" refers to promoting the transcription of a gene in a living body.

[0016] One aspect of the present invention is an agent for preventing or ameliorating frailty, an agent for promoting albumin synthesis, an agent for promoting albumin gene transcription, or an agent for ameliorating anemia symptoms, which contains geraniol as an active ingredient. Another aspect of the present invention is a food composition containing geraniol for preventing or improving frailty, a food composition for promoting albumin synthesis, a food composition for promoting albumin gene transcription, or a food composition for improving anemia symptoms.

[0017] The active ingredient of the pharmaceutical or food composition of the present invention is geraniol. Geraniol is a linear monoterpenoid found mainly in rose oil, palmarosa oil, and citronella oil. Its pharmacological effects include promoting blood circulation, improving skin quality, antibacterial properties, and reducing body odor. However, its effects of promoting albumin synthesis, promoting albumin gene transcription, improving anemia symptoms, and preventing and improving frailty are unknown.

[0018] Geraniol can be produced by chemical synthesis, but essential oils containing geraniol, such as rose oil, palmarosa oil, citronella oil, geranium essential oil, and lemon essential oil, and compositions containing these essential oils can also be used. Examples of compositions containing essential oils include aqueous solutions containing essential oils, such as rose water containing rose oil. Also, fractions rich in geraniol can be obtained and used from the essential oils. In the present invention, it is preferable to use essential oils selected from rose oil, palmarosa oil, citronella oil, geranium essential oil, lemon essential oil, rose water, bergamot essential oil, jamarosa essential oil, thyme essential oil, lemongrass essential oil, coriander seed essential oil, lemon basil essential oil, neroli essential oil, myrtle essential oil, lychee essential oil, gewurztraminer essential oil, and Japanese pepper essential oil, and it is preferable to use essential oils selected from rose oil, palmarosa oil, citronella oil, geranium essential oil, lemon essential oil, rose water, bergamot essential oil, jamarosa essential oil, thyme essential oil, lemongrass essential oil, coriander seed essential oil, lemon basil essential oil, neroli essential oil, myrtle essential oil, lychee essential oil, gewurztraminer essential oil, and Japanese pepper essential oil. It is more preferable to use essential oils selected from rose oil, palmarosa oil, citronella oil, geranium essential oil, lemon essential oil, rose water, bergamot essential oil, jamarosa essential oil, and thyme essential oil, and it is even more preferable to use essential oils selected from rose oil and rose water.

[0019] As described in the Examples below, geraniol has the effect of reducing blood albumin levels and improving anemia symptoms in aged mice. This blood albumin level improving effect is due to the albumin synthesis promoting effect based on the albumin gene transcription promoting effect. Furthermore, as shown in the Examples below, geraniol has the effect of increasing blood total cholesterol levels in aged mice. On the other hand, as mentioned above, the main symptoms of frailty are known to be decreased blood albumin levels and anemia. Therefore, geraniol is useful as an active ingredient in agents for preventing and improving frailty, and compositions containing geraniol are useful as food compositions for preventing and improving frailty. Here, the food composition is used as a health food, a health functional food, a food with functional claims, a nutritional functional food, or a food for specified health uses for the purpose of preventing or improving the above-mentioned symptoms.

[0020] Examples of the pharmaceutical or food composition of the present invention include solid compositions such as tablets, coated tablets, powders, granules, capsules, etc.; and beverage compositions such as drinks, etc. To produce a solid composition, a pharmaceutically acceptable carrier such as an excipient, binder, disintegrant, lubricant, diluent, stabilizer, adsorbent, colorant, flavoring agent, odorant, etc. may be added.

[0021] Examples of excipients include lactose, sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, fine silicon dioxide, silicic acid, methylcellulose, cellulose, glycerin, sodium alginate, gum arabic, sucrose, reduced maltose syrup, trehalose, and mixtures thereof. Examples of lubricants include talc, stearates, borax, polyethylene glycol, sucrose fatty acid esters, glycerin fatty acid esters, hydrogenated oils, and mixtures thereof. Examples of binders include simple syrup, glucose solution, starch solution, gelatin, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, potassium phosphate, hydroxypropylcellulose, hydroxypropylmethylcellulose, pregelatinized starch, pullulan, and mixtures thereof.

[0022] Examples of disintegrants include dry starch, sodium alginate, powdered agar, powdered laminaran, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, corn starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and mixtures thereof. Examples of diluents include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and mixtures thereof. Examples of stabilizers include sodium metabisulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, ascorbic acid, erythorbic acid, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, calcium stearate, guar gum, and mixtures thereof. Examples of the adsorbent include light anhydrous silicic acid, crospovidone, hydrous silicon dioxide, magnesium aluminometasilicate, aluminum silicate, calcium silicate, carmellose calcium, magnesium silicate, magnesium carbonate, and mixtures thereof.

[0023] Examples of the form of the beverage composition include non-alcoholic beverages such as soft drinks, carbonated drinks, fruit juices, vegetable juices, isotonic drinks, enhanced water, bottled water, near-water, coffee drinks, nutritional drinks, beauty drinks, jelly drinks, tea drinks, processed milk, dairy drinks, and lactic acid bacteria drinks.

[0024] The amount of geraniol blended in the pharmaceutical or food composition of the present invention is preferably 1% by mass to 100% by mass. The dosage of the pharmaceutical or food composition of the present invention for adults is preferably 1 mg to 240 mg per day in terms of geraniol. [Example]

[0025] The present invention will be described below with reference to examples, but the scope of the present invention is not limited thereto. Unless otherwise specified, numerical values ​​such as "%" and "parts" represent numerical values ​​based on mass.

[0026] Test Example 1 (Effect of oral administration of geraniol on albumin expression) Young (5-month-old) and old (24-29-month-old) mice (C57BL / 6NCrSlc, Japan SLC Co., Ltd.) were orally administered geraniol at 200 mg / kg / day. Geraniol (Fujifilm Wako Pure Chemical Industries, Ltd.) was diluted 50-fold with corn oil and orally administered via a disposable oral probe (Catalog No. 5202, Fuchigami Instruments Co., Ltd.). The negative control (vehicle) group received the same amount of corn oil. The administration was continued once daily, five times a week, for four weeks. The day after administration ended, the mice were dissected, and blood and liver samples were collected. An outline of the study is shown in Figure 1.

[0027] (Experiment 1: Measurement of plasma biochemical markers) Albumin (ALB), total cholesterol (TCHO), and triglycerides (TG) in plasma separated from blood were measured using a Fuji Dry-Chem NX700 (Fujifilm Corporation) according to the prescribed manual. The results are shown in Figure 2. The number of samples was 6 for the young negative control group, 12 for the old negative control group, and 10 for the old geraniol group. The graph shows the mean ± standard deviation for each group. * indicates p<0.05, and ** indicates p<0.01.

[0028] In the young negative control group, plasma ALB, TCHO, and TG levels were 2.60 g / dL, 70.3 mg / dL, and 66.0 mg / dL, respectively. In the old negative control group, plasma ALB, TCHO, and TG levels were 2.06 g / dL, 58.6 mg / dL, and 44.5 mg / dL, respectively. In the old geraniol group, plasma ALB, TCHO, and TG levels were 2.43 g / dL, 94.9 mg / dL, and 33.9 mg / dL, respectively. These results demonstrate that oral administration of geraniol increases blood ALB and TCHO levels, which decrease with aging.

[0029] (Experiment 2: Measurement of Alb mRNA expression level) The collected livers were minced with dissecting scissors in Sepasol-RNA I Super G Reagent (Cat. No. 09379-55, Nacalai Tesque, Inc.) and total RNA was extracted according to the manufacturer's instructions. cDNA was obtained from 1 mg of total RNA using ReverTra Ace qPCR RT Master Mix (Model No. FSQ-301, Toyobo Co., Ltd.). Alb mRNA expression levels were measured by real-time PCR in a CFX Opus 96 (Bio-Rad Laboratories, Inc.) using Sso Advanced SYBR Green Supermix (Cat. No. 1725271, Bio-Rad Laboratories, Inc.) according to the manufacturer's instructions. The results are shown in Figure 3. The number of samples was four for the young negative control group, 12 for the aged negative control group, and 10 for the aged geraniol group. The graph represents the mean ± standard deviation for each group. * indicates p<0.05.

[0030] The vertical axis shows the fold increase in Alb mRNA expression in the liver of each group, relative to the Alb mRNA expression level in the liver of the young negative control group, which was set to 1. As shown in Figure 3, when the young negative control group was set to 1, the fold increase in Alb mRNA expression in the old negative control group and the old geraniol group was 1.05 and 1.53, respectively. These results demonstrate that oral administration of geraniol to old mice significantly increases Alb mRNA expression in the liver.

[0031] (Experiment 3: Measurement of blood parameters) Blood red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular hemoglobin (MCH), white blood cell count (WBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and platelets (PLT) were measured using a pocH-100iV (Sysmex) according to the prescribed manual. The results are shown in Figure 4. The number of samples was 6 for the young negative control group, 12 for the old negative control group, and 11 for the old geraniol group. The graph shows the mean ± standard deviation for each group. * indicates p<0.05, and ** indicates p<0.01.

[0032] The RBC, HGB, HCT, and MCH in the young negative control group were 1045 × 10 4 / μL, 15.1 g / dL, 46.8%, and 14.5 pg, respectively. In the elderly negative control group, the RBC, HGB, HCT, and MCH were 675 × 10 4 / μL, 10.7 g / dL, 34.8%, and 16.4 pg, respectively. RBC, HGB, HCT, and MCH in the aged geraniol group were 896 × 10 4 The results were: / μL, 13.0 g / dL, 42.5%, and 14.5 pg. These results indicated that oral administration of geraniol increased RBC, HGB, and HCT levels, which decrease with age. Furthermore, oral administration of geraniol was shown to decrease MCH, which increases with age. On the other hand, no significant changes were observed in WBC, MCV, MCHC, or PLT levels among the three groups.

[0033] Test Example 2 (Effect on albumin expression in cells treated with geraniol) A suspension of DMEM medium (Nacalai Tesque, Inc.) and human hepatoma cell line (HepG2 cells) was placed in a 12-well plate (Thermo Fisher Scientific Co., Ltd.) at a concentration of 2.4 × 10 5 Cells were seeded at 1000 cells / well. The geraniol added to the cells was prepared in DMSO (dimethyl sulfoxide) as a solvent to a final concentration of 7.5 μM. Geraniol and DMSO (a negative control) were added to the wells to a solution volume of 0.1% (v / v), and the plate was incubated at 37°C in 5% CO2. An overview of the experiment is shown in Figure 5.

[0034] (Experiment 1: Measurement of Alb mRNA expression level) The expression level of Alb mRNA in cells collected 6 hours after the addition of geraniol was measured by real-time PCR in the same manner as in Experiment 2 of Test Example 1 above. The results are shown in Figure 6. The number of samples was 12 for the negative control group and 11 for the geraniol group, and the graph shows the mean ± standard deviation for each group. * indicates p<0.05.

[0035] The vertical axis shows the fold increase in Alb mRNA expression in the geraniol group, relative to the Alb mRNA expression level in the negative control group, which was set to 1. As shown in Figure 6, when the negative control group was set to 1, the geraniol group's expression was 1.17. These results demonstrate that geraniol treatment of human hepatocellular carcinoma-derived cell lines significantly increases Alb mRNA expression.

[0036] (Experiment 2: Measurement of albumin concentration in culture medium) The albumin concentration in the medium collected 24 hours after the addition of geraniol was measured using a Human Albumin ELISA kit (model number: KE00076, Proteintech Japan, Inc.) according to the manufacturer's instructions. The results are shown in Figure 7. There were three samples in each group, and the graph shows the mean ± standard deviation for each group. * indicates p<0.05.

[0037] The albumin concentration in the medium was 10.6 mg / mL in the negative control group, but 12.6 mg / mL in the geraniol group, demonstrating that geraniol treatment of the cell line promoted albumin production.

Claims

1. A frailty prevention and improvement agent with geraniol as its active ingredient.

2. An albumin synthesis promoter whose active ingredient is geraniol.

3. An albumin gene transcription promoter containing geraniol as its active ingredient.

4. An agent for improving anemia symptoms, containing geraniol as an active ingredient.

5. A food composition containing geraniol for preventing and improving frailty.

6. A food composition containing geraniol for promoting albumin synthesis.

7. A food composition containing geraniol for promoting albumin gene transcription.

8. A food composition containing geraniol for improving anemia symptoms.

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