QOL improvement agent

Abstract

Provided is a quality-of-life improving agent that is capable of improving a wide range of qualities of life related to emotions / behaviors, aging symptoms, digestive symptoms, chronic fatigue, chronic inflammation, metabolic diseases, and so forth, the agent being characterized by containing, as an active ingredient, a plant fermented product that is a mixture of the following substances (a) to (g): (a) an Aspergillus-oryzae fermented product of at least one type of bean / grain selected from the group consisting of barley, black soybean, red rice, black rice, red bean, adlay, Japanese barnyard millet, foxtail millet, and proso millet; (b) a yeast and / or lactic-acid-bacteria fermented product of at least one type of fruit selected from the group consisting of mandarin orange, grape, apple, crimson glory vine, peach, persimmon, papaya, pear, watermelon, Prunus mume, fig, Chinese quince, pumpkin, kumquat, yuzu, loquat, apricot, jujube, chestnut, silver vine, and Prunus salicina; (c) a yeast and / or lactic-acid-bacteria fermented product of at least one type of root vegetable / tuber selected from the group consisting of purple sweet potato, Jerusalem artichoke, carrot, onion, sweet potato, taro, wild yam, daikon, red turnip, burdock, lotus root, yacon, lily bulb, threeleaf arrowhead, ginger, garlic, and turmeric; (d) a yeast and / or lactic-acid-bacteria fermented product of at least one type of flower / leafy vegetable selected from the group consisting of cabbage, shiso, mulberry leaf, fish mint, mugwort, Sasa veitchii, and dandelion; (e) a yeast and / or lactic-acid-bacteria fermented product of at least one type of seaweed selected from the group consisting of kombu, wakame, and mozuku; (f) a yeast and / or lactic-acid-bacteria fermented product of at least one type of seed selected from the group consisting of black sesame, walnut, and ginkgo nut; and (g) a yeast and / or lactic-acid-bacteria fermented product of at least one type of mushroom selected from the group consisting of hen-of-the-woods and shiitake.

Description

[Technical field]

[0001] The present invention relates to a QOL improving agent that utilizes a fermented plant product. [Background technology]

[0002] QOL (quality of life) has been emphasized in the medical field for a long time, and for example, Shimotsuma has explained the history of QOL (Non-Patent Document 1). According to this, the idea of ​​QOL originated from cancer treatment, and its purpose is to eliminate various side effects and discomfort caused by various cancer treatments aimed at medical cure.

[0003] Thus, the scope of QOL is broad, but it also includes the avoidance and elimination of discomfort, and covers a wide range of complex symptoms from pre-illness to actual illness.

[0004] In addition to the above QOL, with the rapid progression of aging, there is also a growing need to improve the decline in QOL caused by the aging of the body's organs, tissues, and cells themselves, as well as regulatory functions.

[0005] However, medicines based on science developed in the West are required to explain the cause of a disease and symptoms in a 1:1 relationship, and the medical system in Japan also has Western science as its main origin. The basis of Western medicine is to confirm the diagnosis of a disease and then determine a prescription for it. Therefore, it was impossible for such medicines to provide comprehensive improvements to a wide range of QOL. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 6013670 [Patent Document 2] International Publication No. 2019 / 009437 Brochure [Patent Document 3] International Publication No. 2019 / 009438 Brochure [Non-patent literature]

[0007] [Non-Patent Document 1] "History and Prospects of QOL Assessment Research", Kojiro Shimotsuma, Behavioral Medicine Research, Vol. 21, (1) 4-7 (2015) Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, an object of the present invention is to provide a QOL improving agent that can comprehensively improve a wide range of QOL. [Means for solving the problem]

[0009] The inventors have conducted intensive research to solve the above problems and have discovered that plant fermentation products, which the inventors have developed and have been shown to have anti-aging effects (Patent Document 1), spontaneous cancer prevention effects (Patent Document 2), and immune checkpoint inhibitory effects (Patent Document 3), can improve a wide range of QOL, thereby completing the present invention.

[0010] That is, the present invention provides the following (a) to (g): (a) Aspergillus oryzae fermentation products of one or more kinds of beans or grains selected from the group consisting of barley, black soybeans, red rice, black rice, adzuki beans, pearl oats, barnyard millet, foxtail millet, and millet. (b) yeast and / or lactic acid bacteria fermentation products of one or more fruits selected from the group consisting of mandarin oranges, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, quince, pumpkins, kumquats, yuzu, loquats, apricots, jujubes, chestnuts, silver vines, and plums (c) A yeast and / or lactic acid bacteria fermentation product of one or more root vegetables or tubers selected from the group consisting of purple sweet potato, Jerusalem artichoke, carrot, onion, sweet potato, taro, wild yam, radish, red turnip, burdock, lotus root, yacon, lily root, water chestnut, ginger, garlic and turmeric. (d) yeast and / or lactic acid bacteria fermentation products of one or more kinds of flower or leaf vegetables selected from the group consisting of cabbage, shiso, mulberry leaves, dokudami, mugwort, kumazasa, and dandelion (e) A yeast and / or lactic acid bacteria fermentation product of one or more kinds of seaweed selected from the group consisting of kombu, wakame and mozuku. (f) yeast and / or lactic acid bacteria fermentation products of one or more seeds selected from the group consisting of black sesame, walnuts, and ginkgo nuts (g) A yeast and / or lactic acid bacteria fermentation product of one or two kinds of mushrooms selected from the group consisting of Maitake and Shiitake mushrooms. The QOL improving agent is characterized by containing as an active ingredient a plant fermentation product which is a mixture of the above.

[0011] The present invention also relates to a food or drink for improving QOL, which contains the above-mentioned QOL improving agent. Effect of the Invention

[0012] The QOL-improving agent of the present invention is suitable as a food or drink since it contains as an active ingredient a specific fermented plant product that has been widely consumed up until now.

[0013] Furthermore, unlike conventional QOL improving agents, the QOL improving agent of the present invention can comprehensively improve a wide range of QOL, for example, QOL based on emotions / behavior, aging symptoms, digestive symptoms, chronic fatigue, chronic inflammation, metabolic diseases, dementia, etc. [Brief description of the drawings]

[0014] [Figure 1] Figure 1 shows heat maps of DNA microarray analysis of the thymus and kidney. [Diagram 2] FIG. 2 shows the abundance ratio of intestinal bacteria at the genus level in senescence-accelerated mice. [Diagram 3] FIG. 3 shows the increase or decrease in the Lactobacillus genus in senescence-accelerated mice. [Figure 4] FIG. 4 shows the number of Lactobacillus species in each test group of senescence-accelerated mice. [Diagram 5]FIG. 5 shows the increase or decrease of the genus Bacteroides in senescence-accelerated mice. [Figure 6] FIG. 6 shows the increase or decrease in the Clostridium genus in senescence-accelerated mice. [Figure 7] FIG. 7 shows the results of α-diversity using Unifrac analysis. [Figure 8] FIG. 8 shows the results of β-diversity using Unifrac analysis. [Figure 9] FIG. 9 shows the results of Weighted Unifrac analysis taking into account the number of reads (composition ratio) between bacterial flora. [Figure 10] FIG. 10 shows the age of T lymphocytes in the subjects immediately before intake. [Figure 11] FIG. 11 shows the T lymphocyte age of subjects after four weeks of intake. [Figure 12] FIG. 12 shows the age of T lymphocytes in the subjects two weeks after the end of intake. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The QOL-improving agent of the present invention contains the following fermented plant product as an active ingredient. This fermented plant product is a mixture of the following fermented plant products (a) to (g):

[0016] (a) A fermented product obtained by allowing Aspergillus oryzae to act on one or more kinds of beans or grains selected from the group consisting of barley, black soybeans, red rice, black rice, adzuki beans, pearl oats, barnyard millet, foxtail millet, and millet.

[0017] (b) A fermented product obtained by allowing yeast and / or lactic acid bacteria to act on one or more fruits selected from the group consisting of mandarin oranges, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, quince, pumpkins, kumquats, yuzu, loquats, apricots, jujubes, chestnuts, silver vines, and plums.

[0018] (c) A fermented product obtained by allowing yeast and / or lactic acid bacteria to act on one or more root vegetables or tubers selected from the group consisting of purple sweet potato, Jerusalem artichoke, carrot, onion, sweet potato, taro, wild yam, radish, red turnip, burdock, lotus root, yacon, lily root, arrowhead, ginger, garlic and turmeric.

[0019] (d) A fermented product obtained by allowing yeast and / or lactic acid bacteria to act on one or more kinds of flower or leaf vegetables selected from the group consisting of cabbage, shiso, mulberry leaves, dokudami, mugwort, kumazasa, and dandelion.

[0020] (e) A fermented product obtained by allowing yeast and / or lactic acid bacteria to act on one or more types of seaweed selected from the group consisting of kombu, wakame, and mozuku.

[0021] (f) A fermented product obtained by fermenting one or more seeds selected from the group consisting of black sesame, walnuts, and ginkgo nuts with yeast and / or lactic acid bacteria.

[0022] (g) A fermented product obtained by allowing yeast and / or lactic acid bacteria to act on one or two kinds of mushrooms selected from the group consisting of Maitake mushroom and Shiitake mushroom.

[0023] The QOL improving agent of the present invention may contain as an active ingredient the plant fermented product obtained by mixing the fermentation products (a) to (g) above, but the taste and formulation properties can be improved by further subjecting the product to multi-stage fermentation.

[0024] Examples of yeast include yeasts belonging to the genus Saccharomyces and Zygosaccharomyces, and among these, Saccharomyces cerevisiae (S. cervisiae), Zygosaccharomyces rouxii, Saccharomyces exiguus, and the like are preferably used. Examples of lactic acid bacteria include lactic acid bacteria belonging to the genera Pediococcus, Leuconostoc, Lactobacillus, Lactococcus, etc., and among these, Pediococcus acidilacti (P. acidilacti), Lactobacillus brevis (L. brevis), Leuconostoc mesenteroides (L. mesenteroides), Lactobacillus plantarum (L. plantarum), Lactococcus lactis (L. lactis), Lactobacillus sakei (L. sakei), Pediococcus pentosaceus (P. pentosaceus), Lactobacillus casei (L. casei), Lactobacillus reuteri (L. reuteri), and Lactobacillus curvatus (L. Aspergillus curvatus and the like are preferably used, and one or more of these may be used. Aspergillus oryzae, Aspergillus niger, Aspergillus kawachii and the like are exemplified, and one or more of these may be used. Commercially available products may also be used.

[0025] Plants such as beans, grains, and fruits to be fermented may be used as they are, or may be pretreated by crushing, drying, etc., as necessary. In addition, water may be added to dilute the plant materials as necessary.

[0026] The fermented products (a) to (g) above can be obtained by inoculating a plant material with lactic acid bacteria, yeast or koji mold and culturing it. The culturing can be carried out by a conventional method, for example, by adding about 0.001 to 1 mass % of lactic acid bacteria, yeast or koji mold to a mixture of one or more plants and fermenting it at 20 to 50° C. for about 70 to 140 hours.

[0027] The fermented products (a) to (g) thus obtained can be mixed and used as an active ingredient as it is, but it is preferable to further culture them at 20 to 40°C for about 200 to 300 hours as necessary. It is preferable to further ferment (maturity) this mixture. In the post-fermentation, acetic acid bacteria may be acted on as necessary. For example, the above-mentioned yeast may be acted on one or more of the plants included in the above (a) to (g) and an acetic acid fermentation product obtained by acting on acetic acid bacteria such as Acetobacter aceti (A.aceti) may be added. The post-fermentation may be performed at 25 to 35°C for about 70 hours to about one year. By undergoing the maturation process by the post-fermentation, the taste and formulation properties can be improved, and the antioxidant activity can also be increased.

[0028] A suitable example of a method for producing the above-mentioned plant fermentation product is a multi-stage complex fermentation method. In this method, a complex lactic acid bacteria fermentation product made mainly from fruits, vegetables, and seaweed is mixed with a yeast fermentation product made mainly from vegetables, root vegetables, seeds, mushrooms, and fruits, to which is added a koji mold fermentation product made mainly from grains and beans, and then an acetic acid fermentation product is added and mixed, followed by filtering and concentrating, and then post-fermentation for about one year. It is believed that this type of multi-stage complex fermentation improves the flavor and enhances the effects of antioxidant activity and the like by further assimilating and converting each fermentation product with a different type of fungus.

[0029] The fermented plant product as an active ingredient used in the present invention has the following properties (1) to (4). (1) Taste It has the sweetness of koji in addition to the organic acids and sweetness derived from fruits and vegetables. Although it contains polyphenols derived from the raw materials, it has little bitterness. (2) Solubility in water It dissolves easily in water. (3) Stability It is stable against heat and acid, and the paste can be stored at room temperature for one year without spoilage or change in taste. (4) Safety The vegetables, fruits, herbs, etc. used as ingredients are commonly consumed, and the yeast, lactic acid bacteria, and koji mold used for fermentation are all species derived from food brewing and pickling, so they are widely consumed.

[0030] The fermented plant product used in the present invention has the following properties (A) to (D).

[0031] (A) General ingredients (per 100g) Water 15~35g Protein: 5-20g Fat 1~8g Ash content 1~5g Carbohydrates: 30-70g Sodium 40-150mg Vitamin B6 0.1-0.5mg Energy 200~500kcal

[0032] (a) Amino acid composition (per 100g) Arginine 0.2~0.6g Lysine 0.1-0.7g Histidine 0.1-0.4g Phenylalanine 0.2~0.8g Tyrosine 0.1-0.6g Leucine 0.3~1.2g Isoleucine 0.2~0.8g Methionine 0.05~0.3g Valine 0.2~0.9g Alanine 0.2~0.9g Glycine 0.2~0.7g Proline 0.4~1.2g Glutamic acid 1.2~3.0g Serine 0.2~0.8g Threonine 0.2~0.7g Aspartic acid 0.4~1.5g Tryptophan 0.03~0.15g Cystine 0.05~0.40g

[0033] (c) Organic acid composition (per 100g) Citric acid 0.5~1.2g Malic acid 0.05~0.5g Succinic acid 0.04~0.3g Lactic acid 0.5-6.0g Formic acid 0.01-0.1g Pyruvic acid 0.005~0.05g Free γ-aminobutyric acid 0.01-0.05g

[0034] (D) Mineral composition (per 100g) Phosphorus 100-400mg Iron 1-5mg Calcium 500-900mg Potassium 600-1000mg Magnesium 70-120mg Zinc 0.8-1.6mg Iodine 1.0-2.5mg

[0035] This QOL improving agent, which contains the fermented plant product as an active ingredient, can improve various QOLs, such as QOLs based on emotions and behaviors, aging symptoms, digestive symptoms, chronic fatigue, chronic inflammation, metabolic diseases, dementia, etc. In addition, by taking this QOL improving agent, it is possible to reduce or stop taking medicines currently being used in various fields.

[0036] The QOL improving agent of the present invention can be obtained by adding pharmacologically acceptable carriers, excipients, water activity regulators, etc. to the thus obtained plant fermentation product in accordance with known pharmaceutical manufacturing methods, and formulating the product. The plant fermentation product may be concentrated to adjust the concentration, or may be powdered by spraying or freeze-drying, etc., as necessary. Examples of carriers and excipients used in formulation include lactose, glucose, sucrose, starch, and sugar mixtures. The final form may be a solution, paste, soft capsule, chewable tablet, or capsule. As for the dosage and method of use, for example, 0.1 g or more, preferably 0.1 to 12 g, and more preferably 0.6 to 10 g (in terms of solid content) of the plant fermentation product as the active ingredient may be orally taken by an adult per day.

[0037] In addition, the QOL improving agent of the present invention can be used as a medicine, a quasi-drug, etc., and can also be made into a food or drink form by mixing with a known food material. The above-mentioned plant fermentation product can be ingested as it is, but it may be filtered and concentrated after sterilization to improve shelf life, or it may be sprayed or freeze-dried into a powder form after adding an excipient as necessary. Furthermore, in order to improve shelf life during distribution, it is desirable to concentrate it to reduce water activity. Examples of the form of such food or drink include paste, soft capsule, tablet, drink, etc. By orally ingesting 0.1 g or more, preferably 0.1 to 12 g, more preferably 0.6 to 10 g (in terms of solid content) of the plant fermentation product per day for adults, excellent QOL improvement effects, etc. can be obtained. Examples of commercially available products in which such plant fermentation products are formulated and made into food forms include Tensei Koso Kinjirushi, Tensei Koso Capsule, and Amou Koso (manufactured by Nihon Shizen Hakko Co., Ltd.).

[0038] In addition to the above, foods and beverages containing the QOL improving agent of the present invention may also include foods and beverages in which the active ingredient, the fermented plant product, is used as a type of seasoning, etc., and is contained in seasonings such as miso, breads such as white bread, confectioneries such as rice crackers, cookies, chocolate, candy, buns, and cakes, dairy products such as yogurt and cheese, pickles such as takuan (pickled radish), noodles such as ramen, soba, and udon, soups such as corn potage and wakame seaweed soup, soft drinks, health drinks, carbonated drinks, fruit juice drinks, and the like.

[0039] Furthermore, the QOL improving agent of the present invention can improve the QOL based on dementia such as Alzheimer's, and in this case, it is preferable to combine it with a substance that is known to have an improved effect on dementia. Examples of such substances include anserine derived from fish. Specifically, when combining the QOL improving agent of the present invention with anserine, 500 to 1500 mg, preferably 700 to 1000 mg of anserine per adult per day may be orally ingested at the same time as the daily dose of the QOL improving agent of the present invention. It should be noted that the QOL improving agent of the present invention can improve the QOL based on dementia such as Alzheimer's, but it goes without saying that it can also prevent dementia if taken before the onset of dementia such as Alzheimer's.

[0040] Furthermore, the plant fermentation product, which is an active ingredient of the QOL improving agent of the present invention, can improve QOL based on chronic inflammation. Unlike pharmaceuticals, this plant fermentation product is shown in the present specification to broadly suppress the expression of inflammatory cytokines and chemokines, particularly suppressing the expression of IL-6. Therefore, the plant fermentation product can also be used to prevent and treat various diseases associated with chronic inflammation, particularly those caused by excessive or sustained expression of IL-6. Examples of such diseases include rheumatoid arthritis, juvenile idiopathic arthritis, Castleman's disease, adult-onset Still's disease, cytokine storm, etc., and in particular may suppress cytokine storm (rapid aggravation of multiple organ failure, etc.) caused by COVID-19 infection, Kawasaki disease-like symptoms, sepsis, Behcet's disease, psoriasis, etc. In order to use the plant fermentation product to suppress the expression of IL-6, it is sufficient to administer the same daily amount as the QOL improving agent of the present invention. EXAMPLES

[0041] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0042] Manufacturing Example 1 Production of plant fermentation products: The following plants were used as raw materials: (a) Beans and grains (barley, black soybeans, red rice, black rice, adzuki beans, pearl barley, barnyard millet, foxtail millet, millet) (b) Fruits (tangerines, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, quince, pumpkins, kumquats, yuzu, loquats, apricots, jujubes, chestnuts, silver vines, and plums) (c) Root vegetables (purple sweet potato, Jerusalem artichoke, carrot, onion, sweet potato, taro, wild yam, radish, red turnip, burdock, lotus root, yacon, lily root, water chestnut, ginger, garlic, turmeric) (d) Flowers and leafy vegetables (cabbage, shiso, mulberry leaves, dokudami, mugwort, kumazasa, dandelion) (e) Seaweed (kelp, wakame, mozuku) (f) Seeds (black sesame, walnuts, ginkgo nuts) (g) Mushrooms (maitake, shiitake)

[0043] The above raw materials (c), (d), and (g) (730 g) contained approximately 1.0 × 10 lactic acid bacteria (P. acidilacti, L. brevis, L. mesenteroides, L. plantarum, L. lactis, L. sakei, L. casei). 5 The culture solution was inoculated at 0.2% by mass so that the bacterial concentration was cfu / g, and cultured at 30°C for 50 hours. In addition, yeasts (5 species of S. cervisiae, 2 species of Z. rouxii) were inoculated at approximately 1.0 × 10 5 A culture solution prepared to give a bacterial concentration of cfu / g was inoculated at 0.4% by mass and cultured at 30°C for 50 hours. (a) Bean and cereal raw materials (1000 kg) were inoculated with 0.1% by mass of koji fungi (yellow koji fungus, black koji fungus, white koji fungus) and cultured at 35°C for 70 hours. The cultures were then mixed and cultured at 30°C for 200 hours. The fermented moromi was subjected to solid-liquid separation, and the resulting filtrate was concentrated into a paste, which was dispensed into containers and further fermented (aged) for one year to obtain a plant fermentation product.

[0044] The fermented plant product obtained in Production Example 1 had the following properties. (A) General analysis value (per 100g) Water 25.2g Protein: 11.8g Fat 3.6g Ash content 2.1g Carbohydrates 57.3g Sodium 54.0mg Vitamin B6 0.20mg Energy 309kcal

[0045] (a) Amino acid composition (per 100g) The samples were hydrolyzed with 6N hydrochloric acid and analyzed by an automatic amino acid analyzer. Cystine was analyzed by hydrolysis with hydrochloric acid after oxidation with performic acid. Tryptophan was analyzed by high performance liquid chromatography. Arginine 0.33g Lysine 0.34g Histidine 0.22g Phenylalanine 0.51g Tyrosine 0.32g Leucine 0.74g Isoleucine 0.42g Methionine 0.13g Valine 0.54g Alanine 0.48g Glycine 0.42g Proline 0.92g Glutamic acid 2.25g Serine 0.4g Threonine 0.36g Aspartic acid 0.84g Tryptophan 0.06g Cystine 0.15g

[0046] (c) Organic acid composition (per 100g) Citric acid 0.81g Malic acid 0.31g Succinic acid 0.12g Lactic acid 1.17g Formic acid 0.03g Pyruvic acid 0.01g Free γ-aminobutyric acid 24mg

[0047] (D) Mineral composition (per 100g) Phosphorus 262mg Iron 2.65mg Calcium 72.1mg Potassium 798mg Magnesium 97.8mg Zinc 1.19mg Iodine 1.7mg

[0048] This plant fermentation product is the same as Tensei Koso Kinjirushi (manufactured by Nihon Shizen Hakko Co., Ltd.), and was used in the following examples. When administering to humans, a predetermined amount of the plant fermentation product was sealed in an aluminum sheet and stored at room temperature until use.

[0049] Example 1 Administration test and questionnaire compilation A voluntary questionnaire survey (permission was obtained for use of the questionnaire) was conducted on purchasers who regularly purchase the plant fermentation product (Tensei Koso Kinjirushi) and on factory tours where the plant fermentation product (Tensei Koso Kinjirushi) produced in Production Example 1 was distributed (a total of about 3,000 people). Without providing any preliminary information about the efficacy, participants were asked to freely write down the subjective symptoms and other experience information along with the intake status, and from the approximately 3,100 responses, responses that simply contained thank-you notes were excluded and responses that contained some symptoms were extracted for each major category related to QOL (emotions / behavior, aging symptoms, digestive symptoms, chronic fatigue, chronic inflammation, metabolic diseases, etc.) (Table 1 below shows the extraction status of the questionnaire). 1,679 responses were adopted, and multiple responses were used for classification according to symptoms. The total number of valid cases, sorted by the total number of cases, was 2,268. In addition, the intake amount (g / day) in the examples was estimated from the sales records and distribution records of each person. Furthermore, the percentage in the table indicates the improvement rate.

[0050] Furthermore, this was not a randomized comparative study, and although the answers were mainly qualitative, they also included records of changes in test values. These are raw records of subjective and objective symptoms, and as the sample size is large, it is possible to grasp the effects of fermented plant products, making this valuable data. Classification was carried out according to the following criteria. The Ministry of Health, Labour and Welfare's diagnostic criteria for chronic fatigue syndrome also focus on records of subjective symptoms, and do not include the effects on objective symptoms such as cytokines, so a comparative study would be difficult.

[0051] [Table 1] *Symptoms not stated: Excluded were cases where the effect could not be evaluated (e.g., simple thank you letter), cases where the person took the drug in hopes of receiving health benefits despite not having any current symptoms, and cases where the period of intake was short.

[0052] From the above results, it was found that the fermented plant product (Tensei Koso Kinjirushi) produced in Production Example 1 has a QOL improving effect. The QOL improving effect will be explained in detail below for each major category.

[0053] <Emotions and Behavior> In this broad category of "feeling energetic" the subjective symptom of "feeling energetic" is a subjective, subjective response, and the corresponding questionnaire responses were diverse. If we were to classify them, they would be as shown in Table 2 below. The number of cases for each subcategory, including gender, improvement, no change, and indeterminable (the effect cannot be determined as the intake period was short), is shown in Table 3.

[0054] [Table 2]

[0055] [Table 3] ?: Gender unknown

[0056] A number of cases were identified that were consistent with the prior consumer feedback that "eating fermented plant products somehow makes me feel better." Although these were vague expressions, when classified by symptoms, there was also an objective evaluation that the patient looked younger than their age, based on a general subjective mental state. Depressive symptoms are objectively detected through the overall impression. In patients with chronic lymphoma and memory disorders, improvement in depressive symptoms has been observed objectively in response to the fermented plant products.

[0057] When the overall improvement rate for vitality, physical condition, and sense of health is considered, 80% of the responses in this category show improvement, and we receive not only subjective impressions, but also objective comments from family and friends. Not only has the mood improved, but the appetite of those underweight at 30kg has returned, and the patient is no longer in the dangerous range of low body weight. There were no cases of deterioration.

[0058] <Aging symptoms> The questionnaire responses corresponding to subjective symptoms in these broad categories were diverse. If we were to categorize them, they would be as shown in Table 4 below. The number of cases for each subcategory, including gender, improvement, no change, and indeterminable (effect cannot be determined due to short intake period), is shown in Table 5.

[0059] [Table 4]

[0060] [Table 5] ?: Gender unknown

[0061] As we age, our ability to recover decreases. There was a subjective effect that suggests an enhanced healing ability. Also noteworthy were responses that mentioned faster recovery after surgery for cancer, improved test results, and reduced medication. There were responses that the lustrous, firm skin, hair, facial expression, etc. made others see them as younger. This is consistent with the inhibitory effect on aging symptoms seen in SAM mice. It was pointed out that the subjects were able to become aware of their increased physical strength, and that this contributes not only to exercise but also to farm work and transportation. It appears that the "frailty" (tendency to become weak), which has become a problem in an aging society, appears to be improving. Of note are the descriptions of post-operative recovery. Most of the post-operative periods were for stomach cancer, liver cancer, lung cancer, etc., and there were many responses that mentioned faster recovery after surgery or a sense of health. Not only did subjects feel healthier, but this was also confirmed objectively, with doctors suggesting improved test results and reduced medication.

[0062] As aging progresses, the healing power gradually declines. In a long-term breeding test of SAM accelerated aging model mice, the intake of fermented plant products showed inhibition of aging in all items of the aging index specified by the SAM Society and also extended lifespan. As the population ages, the number of cases of sarcopenia increases, and the number of cases of people becoming dependent on care due to falls, etc. is on the rise. Measures to prevent this are required, and the Ministry of Health, Labor and Welfare also needs measures. There are a number of health foods for locomotor disorders, but most of them are branched amino acids, proteins, and joint strengthening effects, and it is noteworthy that fermented plant products make people aware of their frailty-suppressing effect. In the major category of "energy and physical condition," the improvement rate of "energy and sense of health" was high at 60%, and it is possible that mental aspects contribute to the frailty-improving effect. In the field of Chinese medicine, emphasis is placed on improving healing power, and the mental effects are also attracting attention in this field. It seems that the healing power is a new effect that is recognized by the reduction in the dosage of medicine along with the improvement of symptoms and test values. The content of the function was based on the scoring system used to evaluate the aging of SAM mice in four areas: behavior, skin symptoms, eye inflammation, and spinal curvature. The improvement rate was 50%, demonstrating that the drug can also be applied to the anti-aging effect in humans.

[0063] <Gastrointestinal symptoms> In this broad category, there were many comments about bowel movements (especially constipation). The elderly make up a high proportion of consumers. This is because the digestive organs also age as people age. It has become clear that the digestive system is not only responsible for the functions of food digestion and defecation, but is also deeply related to the immune system and directly connected to brain function. It is becoming recognized as an important area of ​​QOL. When classified, they are as shown in Table 6 below. The number of cases for each subcategory, by gender, improvement, no change, and indeterminable (effect cannot be determined as the period of intake was short), are shown in Table 7.

[0064] [Table 6]

[0065] [Table 7] ?: Gender unknown

[0066] The majority of the QOL improvement effects in this category were improvements in constipation. Constipation is becoming recognized in Japan as an important aspect of QOL. The number of cases shows that the effect of relieving constipation is strongly desired by consumers. Comments about stomach symptoms were diverse, including "increased appetite" and "stomach feels refreshed." For those with a weak constitution, it also leads to weight gain, which is thought to have an effect on improving QOL. Although the number of cases regarding diarrhea symptoms was small, the responses regarding the effect on ulcerative colitis, for which there are few effective treatments, are of interest.

[0067] Bowel movements are recognized as an important area of ​​QOL, as they cause discomfort and limit range of movement. In the questionnaire responses, constipation was frequently improved. Constipation and diarrhea are closely related to digestive activity and the state of the central nervous system and intestinal bacteria, and are increasingly being recognized as an area of ​​QOL. Bowel movement problems involve the lower digestive tract, but gastric symptoms such as "feeling nauseous" and mental symptoms such as increased appetite were classified. Gastric reflux and stomach pain were classified as chronic inflammation. 1) Among the responses regarding improvement in bowel movements, the most common response was improvement in constipation. There were particularly many improvement cases among women. 2) In Japan, the only treatment for constipation is to encourage people to consume dietary fiber such as vegetables, and it seems that QOL is not as important as it is in the West, where constipation is considered an important factor in QOL and is the subject of vigorous scientific research. 3) The proportion of patients who reported that the fermented plant product improved bowel movements reached 166 out of the total number of patients evaluated, and the subjective effects were highly reproducible. A regular user (5g / day) who had constipation and could not expect any effect from medicines discontinued administration for three weeks, but recovered within three days of resuming intake. The dietary fiber content (enzyme weight method) of this fermented plant product is about 5g / 100g, which is only a moderate amount compared to edamame. Elderly people are particularly prone to constipation due to intestinal aging. Constipation improvement drugs are prescribed, but the downside is that it is impossible to predict when you will have to defecate, and it is especially difficult to find a toilet when traveling. The fermented plant product is appreciated for its mild effect. In terms of bowel movements, the pleasant feeling of having banana-shaped stools come out smoothly was commented to be a real improvement in QOL. 4) It has also been noted to be effective against stomatitis, but this is classified as chronic inflammation.

[0068] <Chronic fatigue> The targets in this broad category include general fatigue, such as resistance to fatigue and regaining energy, as well as mental fatigue, muscular fatigue, and metabolic fatigue. If we were to classify them, we would get Table 8 below. Table 9 shows the number of cases for each subcategory, by gender, improvement, no change, and indeterminable (effect cannot be determined as the intake period was short). Complaints of chronic fatigue are on the rise, making it an important target for improving QOL. The mechanism is gradually becoming clearer, and there are an increasing number of cases where pinpointed therapeutic effects are being aimed at. Chronic inflammation is at the base of this, but chronic fatigue is mainly a subjective evaluation such as physical sensation, and was tallied separately from chronic inflammation, the cause of which is easier to grasp.

[0069] [Table 8]

[0070] [Table 9] ?: Gender unknown

[0071] Chronic fatigue is an extremely difficult field, but there is a high demand for the alleviation of vague symptoms. In fact, the responses covered a wide range of areas. One response stated that "eating makes me less tired." Skin firmness and lustre were described both as subjective and objective symptoms. In addition to physical fatigue, it is known that fatigue involving the central nervous system and the autonomic nervous system are involved in fatigue. It is difficult to detect autonomic nervous activity, so we attempted to classify the symptoms from the responses. Skin symptoms included lustrous, firm skin, and the expression "looking younger." An overall impression of exhaustion was also included. In the area of ​​exercise and muscle fatigue, expressions of fatigue were classified as "I don't get tired easily even when exercising" and "I have more stamina." Stomach symptoms were a state in which one felt like one had no appetite. However, this seems to be different from simple appetite. Many people suffer from insomnia when it comes to sleep. The issue is quantity and quality, and the expression does not involve measuring REM and non-REM sleep. Rather, expressions of improved QOL include having slept well and waking up refreshed. There is a feeling of fatigue, although the reason is unclear. This may be due to a wasting metabolic disease, but this refers to cases where the cause cannot be identified. Autonomic nervous regulation has recently been elucidated as one of the important causes of fatigue. It is not possible to measure autonomic nervous activity by oneself except with special equipment, but rather symptoms such as palpitations due to blood pressure fluctuations, dizziness, poor circulation, sweating, and a feeling of heat in the body are classified here. This is an area in which improvement in QOL can be felt.

[0072] <Chronic inflammation> Acute inflammatory reactions are a series of biological reactions of repair action against emergency conditions such as wounds and infections. When a series of reactions such as recognition of the defect, pain, and redness ends, a series of termination reactions toward healing occur. This is a normal biological reaction. On the other hand, in the process of ending acute inflammation, there are often cases where the inflammatory reaction is weak but the inflammatory state continues, which becomes chronic inflammation and becomes the basis of many chronic diseases. It has been found that this chronic inflammation is the basis of various malfunctions in the body, such as lifestyle-related diseases such as diabetes, obesity, cancer (development, metastasis, etc.), aging, and autoimmunity. For example, it has been found that some kind of stress causes inflammation in microglial cells of the brain and nervous system, and inflammatory factors are carried throughout the body through the bloodstream, triggering other inflammatory symptoms. It is presumed that this may occur in the early stages of dementia, and a search for new therapeutic and preventive drugs has begun. So-called allergies and inflammation of various organs were classified into this field. Chronic inflammation is important as an alarm function, and many symptoms such as pain and redness can be felt. The answers were also a wide range of symptoms. The questionnaire answers corresponding to subjective symptoms in this large field were diverse. If we were to classify them, we would get the results shown in Table 10 below. The number of cases for each subcategory, including gender, improvement, no change, and indeterminable (the effect cannot be determined because the intake period was short), are shown in Table 11. Note that obesity is classified here because it is inflammation of fat cells, while insulin resistance and diabetes are chronic inflammation. Simple weight gain and loss were also classified here.

[0073] [Table 10]

[0074] [Table 11] ?: Gender unknown

[0075] Some respondents reported that applying it directly to inflamed areas of the skin improved symptoms. Many respondents reported that stomatitis improved. Others reported that inflammatory reactions such as stomach pain, heartburn, reflux gastritis, and nausea improved. In terms of liver function, there was a decrease in GOT and GPT test values, and there was also an effect on fatty liver. Weight gain and loss related to fatty liver was also included in this category. Nephritis was seen as an accompanying symptom of worsening diabetes, and cystitis was also included in this category. In the circulatory system, many responses were made about blood pressure, but blood pressure fluctuations are due to various regulatory mechanisms, so they were not included in this category and were counted in the "Other QOL-related category." Hyperlipidemia and thrombosis-related were adopted. Diabetes is based on chronic inflammation, and as the condition progresses, it can lead to systemic inflammation such as nephritis and vasculitis, so it is summarized here. Cancer is set as a medium category because chronic inflammation is generally involved in carcinogenesis, proliferation, metastasis, recurrence, etc. There were many responses that fermented plant products gave them energy after cancer surgery, but this was not categorized in this category, but rather in the medium category of healing power within the broad category of energy. There was also a response that it had been cured of malignant lymphoma, and although this could be the result of drug treatment, it was categorized as such. It is not easy to confirm the effectiveness of suppressing metastasis and recurrence, and this has not been confirmed. In the respiratory system and allergies field, bronchial asthma, coughs, etc. were occasionally observed. There were responses that various symptoms of chronic rheumatoid arthritis, cataracts, and glaucoma had improved slightly. There were also responses that it had cured sinusitis, and responses that, although their heads had been heavy after surgery for sinusitis, their bodies felt lighter and they were able to continue working.

[0076] <Metabolic diseases, etc.> The physiological responses related to improvement in QOL are summarized here. The corresponding questionnaire responses were diverse. If we were to classify them, they would be as shown in Table 12 below. The number of cases for each subcategory, including gender, improvement, no change, and indeterminable (effect cannot be determined as intake period was short), are shown in Table 13. It should be noted that diabetes, hyperlipidemia, and obesity are accompanied by chronic inflammation as underlying diseases, but here they are classified as metabolic diseases.

[0077] [Table 12]

[0078] [Table 13] ?: Gender unknown

[0079] There were many cases of improvement in blood pressure. Interestingly, not only was blood pressure normalized, but there were also cases where the amount of antihypertensive medication taken was reduced or even eliminated. Blood pressure is the result of cardiac output x vascular resistance, but there are many factors that affect this. As many of the survey respondents were elderly, this could be due to a decrease in peripheral vascular flexibility or mental influences.

[0080] <Reduction or cessation of medication> In the questionnaire responses, there were scattered cases in various fields where the dosage of medicines being used had been reduced or discontinued, so these were extracted and compiled into a table. As shown in Table 14, the cases covered a wide range of fields, but there were also cases where the medicine was removed from the prescription based on the doctor's decision rather than the patient's. The efficacy of the medicine as an auxiliary in treatment was also estimated.

[0081] [Table 14]

[0082] <Pain relief> Because the questionnaire was categorized from the viewpoint of OQL based on pathology, "improvement of pain" tended to be scattered across many areas. Therefore, we tried to extract the keyword "pain" from the questionnaire results. The results are shown in Table 15.

[0083] [Table 15]

[0084] There were 115 responses containing the keyword "pain," of which 10 were deemed "unevaluable" because not enough time had passed since the start of consuming the fermented plant products and no evaluation had been performed. 105 responses stated that they felt some kind of effectiveness, and this was in a wide range of areas. There were no cases of worsening pain. Thus, the effectiveness of the product in improving pain was also confirmed.

[0085] <Summary> From the above results, it was found that fermented plant products improved QOL in broad areas (emotions / behavior, aging symptoms, digestive symptoms, chronic fatigue, chronic inflammation, metabolic diseases, etc.). These are summarized in Table 16.

[0086] [Table 16] TIFF0007602812000017.tif109170?:Unknown gender

[0087] In the overall list of cases, the areas of note are the medium area of ​​"energy, health, and mood," which had a total of 389 cases of improvement, accounting for 14.9% of the total improvement. The QOL area is diverse, so 14.9% of the improvement is a large number. This area and the number of cases of improved healing power (68 cases = 3.0%) seem to be based on improvements in "energy, health, and mood." While this concept is not important in modern Western medicine, it is emphasized in Kampo and is classified as a "superior medicine." In Western medicine, a 1:1 relationship between etiology (diagnosis) and treatment is required. Treatment of infections with antibiotics is a typical example. However, antibiotics simply act on pathogenic microorganisms and reduce their numbers. The number of pathogenic bacteria is reduced, and the body's defenses, such as the immune system, lead to recovery. Although bowel dysfunction was not previously considered to be part of QOL, it has come to occupy an important position in QOL in Europe and the United States. The number of improvements in both men and women was high, at 194, with an improvement rate of 8.6%. The fermented plant products have been shown to have a wide range of beneficial effects in various areas, and in some cases doctors have even suggested reducing the amount of medicine used. This type of QOL improvement agent is a new one.

[0088] Example 2 Evidence for improved quality of life based on chronic inflammation: (1) Mouse Six SAM-P1 (female) mice were purchased from Sankyo Labo Service Co., Ltd. and were 8 weeks old. Mice were kept in an SPF mouse breeding facility (23±2°C, humidity 50±10%, light / dark cycle of 20:00-8:00) with six mice per sample per group, and kept singly under SPF conditions in polycarbonate cages manufactured by CLEA Japan. The mice were allowed to freely consume 500N (sterilized by gamma rays) purchased from Sankyo Labo Service. High-temperature sterilized bedding manufactured by CLEA Japan was used for the bedding. Cages were changed once a week. The mice did not decrease their food intake during breeding.

[0089] (2) Sample The plant fermentation product produced in Production Example 1 was used as a sample. The plant fermentation product was dissolved in ion-exchanged water to a concentration of 2.0% or 0% (control), dispensed into 500 ml medium bottles, and all were sterilized by autoclave (121°C, 20 minutes). The resulting precipitate was transferred aseptically to a water bottle (sterilized) so as not to clog the nozzle of the water bottle. The dose of the plant fermentation product was calculated by converting a 30-fold amount of plant fermentation product into a value per kg of body weight based on a case in which a large amount of plant fermentation product was ingested on a daily basis (77 g / week = 11 g / day). This conversion rate is a value empirically used when applying herbal medicines to mice at the Toyama University Institute of Japanese and Chinese Medicine. (Kinzo Matsumoto, Personal Information, 28th SAM Research Meeting, "The Ameliorative Effects of the Kampo Medicine Chotosan and the Traditional Chinese Medicine Kangen Granules on Cognitive Behavioral Disorders in the Aging Model Animal SAMP8 and Their Neural Mechanisms," 5 July (2013), Aichi Gakuin University). If a mouse drinks about 30 ml of a 2.0% concentration sample per day, this is equivalent to about 10 g / day in humans. The fermented plant products diluted with ion-exchanged water as described above were freely ingested as drinking water.

[0090] (3) Collection of samples Six SAMP-1 (male) mice in each group were given the above samples as drinking water and were raised for a long period of time until they reached 10 and 56 weeks of age (test groups are shown below). After somnopentyl anesthesia, the mice were opened and the thymus and kidneys were collected, immersed in ice-cold RNA Later solution, and transported refrigerated to a measurement facility (Filgen Co., Ltd.). RNA extraction and DNA microarray measurements were also performed by the measurement facility.

[0091] [Table 17]

[0092] (4) DNA microarray From the analytical data obtained from the above institutions (41,354 genes), we analyzed the expression of the following genes.

[0093] (a) Inflammation-related genes The analysis data obtained from the above institutions was filtered for the keyword "inflammation," resulting in 566 results. In order to narrow down genes with clear expression, we narrowed down the number of genes to 68 by setting an increase ratio of 1.5 times or more and a decrease ratio of 0.66 times or less. Clustering analysis was performed using these genes. The test groups compared in clustering and their purposes are as follows. In addition, in the DNA microarray analysis of the kidney, the number of genes was overwhelmingly smaller than that of the thymus, and the degree of increase or decrease was also small. In the explanation of each lineage of the SAM Society, it is stated that SAM-P1 is prone to renal atrophy, but in the kidneys collected in this study, there were no histological abnormalities in the capillaries or renal pelvis, so they do not need to be subject to inflammation evaluation.

[0094] [Table 18]

[0095] The gene descriptions of the 68 entries include genes for major inflammation-related mediators, receptors, enzymes, etc., indicating that inflammatory responses in this test system can be analyzed with little bias.

[0096] A heat map was created reflecting the degree of increase or decrease in expression, and it was found that in the 0% sample, the effect of advanced age was that the degree of aging progressed (patent: aging inhibitor) and the degree of inflammation increased, but when plant fermentation products (2%) were consumed (total aging score was significantly lower), there was a tendency for the degree of inflammation to be suppressed.

[0097] A literature search was conducted on all 68 narrowed-down genes. In the case of inflammation, the same gene may act in both an up- and down-direction manner, so individual confirmation is necessary. A search was conducted by inputting "Gene Symbol" and "Inflammation" into Pub-Med to investigate inflammatory symptoms in mammals. When there were an extremely large number of hits, a Google search was also conducted, and when there were no hits in Pub-Med, "Gene Description" was also used. References in the Gene Database were also referred to.

[0098] [Table 19] JPEG0007602812000021.jpg210170

[0099] In 11 out of 68 cases, increased gene expression suppressed inflammatory symptoms. Five cases showed both an increase and a decrease. The rightmost column shows an overall evaluation of the effects of consuming fermented plant products. In 36 out of 68 cases, there was an inflammation suppressing effect, and in 27 cases there was a tendency for suppression, resulting in an increase in inflammatory symptoms. Many of these included genes related to chronic inflammation. Heat maps of DNA microarray analysis of the thymus and kidney are shown in Figure 1.

[0100] When we extracted 15 cases in which the intake of fermented plant products showed a clear tendency to suppress inflammation, as shown in the patent application (published) "Spontaneous Cancer Inhibitor," the spontaneous cancer incidence rate in older mice was 50%, but there was a significant decrease in spontaneous cancer (17%) in the group that consumed fermented plant products, which revealed that the suppression of chronic inflammation is presumed to be related to the suppression of spontaneous cancer.

[0101] In most cases, the increase in gene expression leads to the worsening of inflammatory symptoms, but in some cases, the increase in gene expression has been shown to have a tissue-protecting effect, demonstrating the multifaceted nature of inflammation. For example, the gene Ly86, also known as MD1 (Myeloid differentiation protein 1), has been reported to worsen cardiac allergies and to alleviate symptoms in ulcerative colitis when it is deficient, demonstrating its dual nature.

[0102] DNA microarray testing was also conducted on the kidneys. There were 10 hits in the range of a 1.5-fold increase to a 0.66-fold decrease (under the same conditions as the thymus), which means that inflammation due to aging is milder than the 68 hits in the thymus. Materials from the SAM Research Society state that renal atrophy occurs with age in SAMP1 (male), but kidney weight was unchanged at 56 weeks of age, and tissue examination results showed that the structure of the glomeruli was normal. The highest value among these 10 was a 1.66-fold increase in IL1-β, but this was slight, and there was no change in the group that consumed fermented plant products, and even slight tendencies towards inflammation in the kidneys were suppressed.

[0103] (b) IL1-β-related genes As shown in the survey results, fermented plant products are effective in alleviating a wide variety of chronic inflammatory symptoms. It is believed that these diverse effects are achieved by suppressing inflammatory factors that are located upstream in the chain reaction of chronic inflammation. The following paper makes it clear that IL-1β is an important factor in many inflammations. For this reason, an analysis of IL1-β gene expression was carried out. The increase in IL1-β expression in 56-week-old mice (sample = 0%) was 5.5 times that of 10-week-old mice (sample = 0%), the highest, but it was significantly reduced to 1.9 times in the group that consumed fermented plant products. When comparing 56-week-old mice with and without fermented plant products, the rate of decrease was 0.34, the largest.

[0104] IL1-β is a central inflammatory mediator that mediates many inflammatory responses and is involved in the expression of inflammatory molecules such as TNF-α and IL-6 via NF-κB, an important factor in inflammatory responses, and is positioned upstream of these molecules.

[0105] The clearest example of IL1-β's involvement in inflammation is the specific antibody canakinumab (development code ACZ885), an antibody drug developed by Novartis. Its effectiveness against atherothrombosis, the main cause of acute coronary syndrome and cardiovascular death, was proven in a large-scale clinical trial involving more than 10,000 cases over a period of approximately six years (CANTOS: Canakinumab Anti-inflammatory Thrombosis Outcomes Study, The Lancet 2017) (https: / / www.novartis.com). This is an example where pinpointing the inflammatory effects of IL1-β proved effective.

[0106] Reports relating IL1-β to inflammatory diseases are as follows: High expression in epithelial cells of inflammatory chronic obstructive pulmonary disease (Pub-Med) · Report on evidence of proinflammatory genes (Pub-Med) Report that this gene is related to inflammation in bronchitis (Pub-Med)

[0107] IL1-β measurement kits are commercially available as diagnostic agents. Diseases in which IL1-β shows abnormal values ​​when measured in peripheral monocyte culture supernatant include many inflammatory diseases and "chronic fatigue syndrome." (Listed in the catalog of Falco Biosystems Research Institute, Inc.) In other words, it is clear that chronic fatigue syndrome and chronic inflammation are overlapping areas.

[0108] (c) Aim2-related genes Increased expression of the Aim2 gene indicates both reduced and decreased inflammation. - Inflammasomes suppress microbial infections ·Psoriasis, dermatitis, arthritis, autoimmune suppression · Inflammation caused by excess cholesterol increases Aim2 · Reduce inflammation in pancreatitis by lowering Aim2

[0109] (d)Pathway analysis Genes displayed in the pathway analysis results are those with an increase of 1.5-fold or more and a decrease of 0.66-fold or less. This limit on the range of increase or decrease is the same as in the clustering analysis. However, because the range is limited by the keyword "inflammation" in the clustering analysis, the number of genes in the display range of the two is different, with the pathway analysis displaying a greater number of genes. For this reason, it is possible to observe changes in genes that were not displayed in the inflammation clustering analysis.

[0110] The genetic changes in the test groups shown in Table 16 are displayed by decrease and increase for each pathway. In the 0% sample at 56 weeks of age, there was a significant increase in inflammation-related genes, and it was possible to estimate from the comparison of this increase and decrease that the intake of 2% sample suppresses inflammation.

[0111] [Table 20]

[0112] The phenomenon found in the inflammation cluster analysis, where long-term rearing without samples increased inflammation-related gene groups in the thymus and where ingestion of fermented plant products tended to suppress inflammation, was also observed in the pathway analysis. In addition, IL-6, IL-7, TNF-α, and other important inflammation-related factors not extracted by inflammation clustering, were also observed to have an inflammation-suppressing effect by fermented plant products, and suppression of lung fibrosis, which frequently occurs with inflammation, was also observed. Type II interferon, an inflammation mediator that showed little change in the inflammation clustering analysis, also showed a similar tendency (Table 21).

[0113] [Table 21] JPEG0007602812000024.jpg246170JPEG0007602812000025.jpg244170JPEG0007602812000026.jpg243170JPEG0007602812000027.jpg250147

[0114] (1.IL-6) 1) The IL-6 pathway was significantly increased (P=0.033) in the 56-week-old aging group with accelerated aging compared to the 10-week-old young mice. Seven genes were found to be involved. Most of them were found in the Pathway Map. 2) In the group that consumed 2% fermented plant products, the increases in six of the seven genes disappeared. The gene symbol Elf2a did not decrease. 3) Fermented plant products suppressed the IL-6 pathway, a pro-inflammatory cytokine. 4) In inflammation-related reviews, the IL-6-related genes Jak1, Jak2, Stat1, and Stat3 have been attracting attention as targets for drug development, but they were not found in this table. However, because fermented plant products have been shown to be highly effective in patients with rheumatoid arthritis, in which IL-6 is strongly involved, it is possible that another pathway exists. 5) In severe cases of COVID-19, there are no approved drugs for severe cases caused by cytokine storm in acute respiratory distress syndrome (ADRS). 6) Tocilimab, an IL-6 inhibitor, has shown some effectiveness and clinical trials are ongoing.

[0115] (2. Lung fibrosis) 1) Pathway analysis was performed on pulmonary fibrosis resulting from pulmonary inflammation. 2) Fibrosis is caused by tissue fibrosis after inflammation (tissue damaged by inflammation is repaired by cell proliferation). 3) Gene expression was significantly higher (P=0.01) and was suppressed by 2% plant fermentation product. IL-1β showed the most significant increase and significant suppression.

[0116] (3.TNF-α) 1) TNF-α is a representative inflammatory substance and is directly involved in many inflammations. However, it is not deeply involved in the aging of SAM mice, as the P value of this pathway was not significant. It is known that TNF-α is not deeply involved in rheumatoid arthritis, in which fermented plant products showed remarkable efficacy. IL-6 is located upstream of TNF-α in the inflammatory response and has a more diverse regulatory effect on the response.

[0117] (4.IL-1) 1) IL-1 is also an important cytokine that causes inflammation. In pathway analysis, the P value was P=0.007 and P=0.01 in both test systems, and it is one of the main players in the inflammatory response in this study. Plant fermentation products have the effect of suppressing the expression of most of the genes involved in this pathway. This was in good agreement with the data from keyword searches. However, in inflammatory responses, it often acts downstream of IL-6.

[0118] (5.Chemokaine) 1) Chemokines are basic proteins that exert their effects via G protein-coupled receptors, and are a group of cytokines. They cause migration of white blood cells and are involved in the formation of inflammation. They refer to chemotactic cytokines. They cause various inflammatory reactions at the site of inflammation and are located downstream of IL-6. 2) Many chemokines were detected in this pathway, with a significance level of P=0.02. They increased in test system 1 (aging), and all were reduced by the ingestion of fermented plant products.

[0119] (6. Overall findings) 1) IL-6 attracted the most attention. 2) The P value was 0.03, and the increase was observed in test system 1 (aging), but was suppressed by the intake of fermented plant products as shown in test systems 2 and 3. 3) Janus kinase (JAK) inhibitors are attracting attention as targets for anti-rheumatic drugs. In the course of treatment trials, it was shown that the suppression of IL-6, one of the inflammation-causing factors, by this inhibitor can suppress severe viral pneumonia in COVID-19 (novel coronavirus infection). It is expected that this will lead to prevention of the disease becoming severe, and clinical trials are currently being conducted. A questionnaire survey showed that this fermented plant product was highly effective in patients with rheumatoid arthritis, and a doctor's diagnosis showed that it is also effective in patients with Behçet's disease, a similar disease. It is known that in both of these diseases, the blood concentration of IL-6 increases as the condition worsens and decreases as the condition calms down. 4) Currently, two types of genetically modified drugs against the IL-6 receptor have been approved. However, both are highly specific and do not target a wide range of inflammatory reactions. Moreover, they are injectable (infusion) drugs and are very expensive, so they are only recommended for use in severely ill patients. 5) On the other hand, this fermented plant product is a food product that is widely sold on the commercial market and has almost no reports of side effects or cases of discontinuation. Moreover, it is less expensive than pharmaceuticals. As shown in the list of inflammation-related pathways, it not only suppresses IL-6, which is the main player in chronic inflammation, but also IL-1, chemokine, and pulmonary fibrosis that occurs as a result of inflammation, making it a diverse product. Inflammatory responses, especially chronic inflammatory responses, are diverse and can suppress many inflammatory factors that also control normal host defense responses. Conventional pharmaceuticals that suppress inflammation with a 1:1 effect may in some cases suppress normal host defense responses as well. Fermented plant products work to normalize the body while maintaining overall balance like herbal medicine, with fewer side effects. Moreover, they are orally administered and inexpensive.

[0120] It is clear that a wide range of inflammatory symptoms occur in parallel with various aging symptoms due to aging, and that the ingestion of fermented plant products suppresses various inflammatory symptoms in parallel with suppressing aging symptoms. Many people fear carcinogenesis and metastasis, which affects their psychological quality of life. Diabetes, obesity, hyperlipidemia, and other so-called lifestyle-related diseases, as well as aging, all have chronic inflammation as their roots, and suppressing chronic inflammation is effective in extending healthy lifespan.

[0121] These findings support the idea that fermented plant products improve inflammation-related QOL.

[0122] Example 3 Evidence for improving QOL based on chronic fatigue: (1) Mouse The same materials as those used in Example 2 were used. (2) Sample The same materials as those used in Example 2 were used. (3) Collection of samples The same procedure as in Example 2 was followed. (4) DNA microarray From the analytical data obtained from the above institutions (566 genes), the expression of the following genes was analyzed.

[0123] (a) Interferon-related genes Frequent side effects of interferon in humans include fatigue, weakness, and fever. Inflammation clustering analysis data also showed that Type II interferon genes increase with age, and that expression is suppressed by the intake of fermented plant products. Inflammation clustering analysis showed similar results, although the number of target genes was small. This suggests a relationship between inflammation and chronic fatigue.

[0124] (b) Pathway analysis Regarding chronic fatigue, when searching for keywords (fatigue, tired, exhaust, anxiety) in the clustering analysis, the number of hits was zero. Therefore, WIKI-Pathway analysis was used. Because a different database was used than for the clustering analysis, there may be differences in the degree of increase or decrease and the genes that were hit.

[0125] [Table 22] JPEG0007602812000029.jpg246157

[0126] Pathway analysis showed the involvement of genes related to Alzheimer's disease, and the decline of the gene "Atp2a1 = ATPase, Ca membrane permeability" was involved in the Ca 2+ It causes apoptosis due to a decrease in IL-1, and has recently been suspected to be related to Alzheimer's disease. The inhibitory effect of fermented plant products is not significant, and it may be a phenomenon associated with aging. The increase in expression of the caspase 12 gene, one of the markers involved in inflammation, disappears when fermented plant products are consumed. Of note is interleukin 1-β. The expression level in the 56-week-old mice is 5.5 times that of young mice, but no increase or decrease was observed in the group that consumed fermented plant products. In inflammation clustering, the expression level decreases by about 2 times when fermented plant products are consumed. IL1-β is secreted when microglia in the brain are activated by infection or stress, and it is known to migrate throughout the body, causing inflammation and symptoms of chronic fatigue syndrome.

[0127] Serotonin and its precursor tryptophan have been known to be associated with chronic fatigue, but this has been changing recently. Pathway analysis showed that the genes for both were increased 2-3 times in the aging group, but both were decreased in the group that consumed fermented plant products. This suggests a relationship with the alleviation of chronic fatigue symptoms. Two types of microglial genes showed a similar trend. As with inflammation, gene expression levels of genes involved in chronic fatigue symptoms were also reduced in the group that consumed fermented plant products.

[0128] These findings support the idea that fermented plant products improve quality of life in patients with dementia such as Alzheimer's disease and chronic fatigue.

[0129] Example 4 Proof of gut bacteria regulation: (1) Analysis of the intestinal bacteria of senescence-accelerated mice The test groups of SAM mice used are shown in Table 17. Therefore, the results of the DNA microarray can be compared at the individual level. For the microarray analysis, stool samples stored from the thymus test of six mice in each group were used. Analysis of the intestinal flora was entrusted to Techno Suruga Lab Co., Ltd. (Shimizu City) based on the individual feces collected, and analysis was performed down to the species level using the TFLP method (human and mouse types) and a next-generation sequencer using 16sRNA (human type).

[0130] The abundance ratio at the genus level is shown in Figure 2. Note that some were judged to be "rejected" because human genes were used as templates. The increase or decrease in the top three microorganisms, Lactobacillus, Bacteroides, and Clostridium, in each test group is shown in Figures 3 to 6. The maximum value of each bar graph indicates those classified as "rejected." Among the intestinal bacteria excluding these, the Lactobacilli genus showed lower values ​​at 56 weeks of age compared to 10 weeks of age when ingesting water samples, but in the group that ingested 2% plant fermentation products, the Lactobacilli genus did not decrease even at 56 weeks of age and was close to the value at 10 weeks of age. This is consistent with the results of the literature ("The Influence of the Intestinal Microflora and Immune System on Emotions," by Tomoo Miyajima, "Experimental Medicine Vol. 37 (2) 140-147 (2019)"). Ingestion of plant fermentation products suppresses intestinal aging. Feces samples were also collected by dissection, and the elasticity of the intestinal tract itself, peritoneum, arteries, veins, etc. was higher in the sample-fed group, approaching that of young 10-week-old mice. Mice do not have Bifidobacterium, but the genus Lactobacillus is the major intestinal bacterium, and this was reduced in older mice compared to 10-week-old mice, and the fact that this did not decrease with the intake of fermented plant foods suggests that this also works to suppress intestinal aging.

[0131] Young mice had many Lactobacillus species, but the number dropped dramatically in the 0% 56-week-old sample, but the decrease was suppressed in the 2% administration group. Figure 3 shows that the Lactobacillus genus, which was most frequently detected, was analyzed to the species level. In the species level analysis of Lactobacillus, three species were found to be predominant, L. reuteri and L. intestinalis, and the numbers were lower in the 0% 56-week-old sample than in the 10-week-old sample, decreasing with age, while the decrease was suppressed even in the older group in the plant fermentation intake group. This coincides with the results of a human survey, which showed a high rate of improvement in bowel movements in those who consumed plant fermentation products. L. reuteri is widely sold commercially as a useful lactic acid bacterium, and its usefulness is described in detail on Wikipedia.

[0132] As shown in FIG. 5, there was almost no increase or decrease in Bacteroides.

[0133] As shown in Figure 6, the Clostridium subclass showed less change than the Lactobacillus genus.

[0134] (2) Analysis of the diversity of changes in the intestinal flora during aging in SAM mice Arai et al. have explained the relationship between aging and the intestinal microbiota ("Intestinal Flora and Aging", Japanese Journal of Geriatrics, Vol. 53, 318-325, 2016). According to this paper, it is known that immune function, especially adaptive immune response, declines with age, and this is called immunosenescence. Immunosenescence causes "inflamaging", a mild chronic immune response. Compared to adults, the intestinal microbiota of elderly people has greater individual differences and is less diverse and stable. In a long-term breeding test of SAM mice, the detection number of Lactobacillus was high in young mice, but decreased to about 50% in older mice, but the detection number remained at about 82% in the group that consumed 2% plant fermentation products. This was particularly noticeable in L. reuteri, which is known to have an immune-enhancing effect. Here, we focused on the change in the diversity of the microbiota during aging and analyzed it.

[0135] The diversity was examined using Unifrac analysis for both α- and β-diversity, and the results are shown in Figures 7 and 8.

[0136] In the α-diversity analysis, the 10-week-old group (0%) had more diversity than the 56-week-old group (0% / 2%), which is consistent with the results in the literature, but the difference was not significant at p=0.05. In other words, the 3 groups used in the α-diversity analysis showed similar diversity.

[0137] In the analysis of β-diversity, there are two methods: Unweighted, which does not take into account the number of reads (composition ratio) included in the OUT, and Weighted, which does. The former only reflects the presence or absence of bacterial species, while the latter reflects the difference in the composition ratio of the same bacterial species in the distance of similarity between the two bacterial flora ("Latest Technology for Human Intestinal Microbiome Analysis," Shohei Hattori, Jpn. J. Clin. Immunol., Vol. 37, (5) 412-422 (2014)).

[0138] As shown in Figure 8, in the unweighted-unifrac analysis, in the test group 10wk 0% (●), the six points of the six mice were distributed compactly on the left side, but in the 56-week-old group, all were vertically clustered on the right side, clearly different from the 10-week-old group. In addition, in the 56-week-old group, the 2% group was distributed compactly in the first quadrant, while the 0% group was somewhat dispersed and distributed in the second quadrant. This shows that there is a difference in diversity between the two groups, but the composition ratio of OUT is not taken into account. Figure 9 shows the weighted unifrac analysis taking into account the number of reads (composition ratio) between the bacterial flora.

[0139] The 0% 10-week-old young mice (●) showed a linear distribution with a downward sloping slope, but the 0% 56-week-old mice were widely dispersed, indicating a large difference in the microbiota between each mouse. In contrast, the distribution of the microbiota of the 56-week-old mice that had consumed the 2% sample (▲) was cohesive, showing a similar distribution gradient to that of the 10-week-old mice. The 2% plant fermentation product in the older SAM mice showed a similar trend to the young mice in terms of the β-diversity of intestinal bacteria. The relationship between these three showed a similar trend to other indicators of chronic inflammation and chronic fatigue.

[0140] The distribution of the 56-week-old mice is on the right side for both 0% and 2% sample concentrations, which is different from the distribution of the young mice (10 weeks old). The 2% group has a smaller variation between mice.

[0141] Thus, the in vivo effects of fermented plant products were suppression of aging in SAM mice, extension of lifespan, suppression of spontaneous cancer, and suppression of immune checkpoints. Overall, this is thought to be a rare fermentation product that leads to an overall extension of healthy lifespan and has an overall effect of improving QOL. Changes in the intestinal bacteria of aged mice included a decrease in the Lactobacillus genus compared to young mice, and this was also supported by the fact that intake of fermented plant products prevented the decrease in Lactobacillus. It was also revealed that they have a so-called prebiotic effect.

[0142] From the above, it has been confirmed that plant fermentation products significantly increase the number of Lactobacillus bacteria, especially Lactobacillus reuteri, and therefore can be widely used for the purposes of regulating the intestinal environment, treating functional gastrointestinal disorders including diarrhea and constipation, and inhibiting the growth of Helicobacter pylori, dental caries bacteria, and periodontal disease bacteria.

[0143] Example 5 Human studies: (1) Method A 69-year-old man (n=1) was administered 5g / day of fermented plant products (Tensei Koso Kinjirushi). Two weeks prior to administration, the patient was ordered to stop consuming foods related to immunity, such as yogurt and bananas, and administration was then started. The administration was continued for four weeks, and peripheral blood samples were collected at three points in time, at the end of the administration and two weeks after the end of the administration, and used for lymphocyte testing. Analysis was outsourced to Ortho Medico Co., Ltd. An outline of the method is described on the Ortho Medico Co., Ltd. website (https: / / www.orthomedico.jp / clinical-trials / case / immunity.html). At the same time, feces were collected and used for intestinal bacteria analysis, which was outsourced to Ortho Medico Co., Ltd. The TFLP method was used for analysis. The results are shown in Figures 10 to 12.

[0144] Immediately before ingestion, T cells were present in sufficient numbers, but the CD4+ / CD8+ cell ratio and CD8CD28+ T cell count were low. The T lymphocyte age was evaluated to be 78-81 years (Figure 10). After 4 weeks of intake, the CD4+ / CD8+ cell ratio and CD8CD28+ T cell count increased. The T lymphocyte age was estimated to be 66-69 years (Figure 11). Two weeks after the end of intake, the lymphocyte pattern was maintained, and the T lymphocyte age was estimated to be 66-69 years (Figure 12).

[0145] Based on the above, we tried to have a human (69-year-old male) ingest fermented plant products. According to a method for estimating immune age from the trends of peripheral blood lymphocytes before, immediately after, and after 4 weeks of daily ingestion for 4 weeks, the value, which was equivalent to 71-81 years old (80 years old) before ingestion, dropped to 66-69 years old after ingestion, and this value was maintained even 2 weeks after cessation of ingestion. Yamakoshi explains the relationship between SASP generated by cellular senescence, chronic inflammation, and carcinogenesis ("Cellular senescence and chronic inflammation," Japanese Journal of Geriatrics, Vol. 53, p. 88-94 (2016)). When an analysis of intestinal bacteria was carried out at this time, an increase in Clostridium subcluster IXa was observed, suggesting immune enhancement.

[0146] From the above, fermented plant products have been shown to reverse the aging of peripheral blood lymphocytes and suppress immunosenescence. This is also supported by an increase in Clostridium cluster Xa, which is involved in immune enhancement in intestinal bacteria. Immunosenescence is deeply involved in antigen-antibody reactions, such as infection defense capabilities, and is one of the indicators of immunosenescence that has been adopted as an axis for evaluating QOL.

[0147] Example 6 Improving dementia-based quality of life: A patient who was diagnosed with Alzheimer's disease based on MRI imaging etc., took 5g of fermented plant extract (Tensei Koso Kinjirushi) every day. After one month, the family and friends noticed a change in the patient's facial expression. The patient's eyes became more focused, his facial expression became brighter, and he was able to actively participate in conversations. The improvement continued for another month.

[0148] A little over two months after taking the drug, he was re-evaluated and the MRI showed that he had right-brain atrophy but did not have Alzheimer's or hydrocephalus (there was no mention of the hippocampus).

[0149] Furthermore, the improvement continued even several months after taking the supplement.

[0150] Example 7 Miso-like food for improving QOL: The paste-like plant fermented product produced in Production Example 1 was mixed with miso, and the taste was adjusted with seasonings to produce a miso-like food for improving QOL.

[0151] Example 8 Beverages for improving QOL: The paste-like plant fermentation product produced in Production Example 1 was dissolved in water, and then mixed with fructose glucose liquid and fruit juice, and the taste was adjusted to produce a beverage for improving QOL.

[0152] Example 9 Softgel: The paste-like plant fermented product produced in Production Example 1 was mixed with vegetable oil and lecithin and filled into soft capsules in the usual manner to produce soft capsules for use in improving QOL.

[0153] Example 10 Chewable tablets: The paste-like plant fermentation product produced in Production Example 1 was mixed with crystalline cellulose and sucrose and compressed into tablets in the usual manner to produce chewable tablets for use in improving QOL.

[0154] Example 11 Softgel: The paste-like plant fermented product produced in Production Example 1 (daily amount) was mixed with vegetable oil, lecithin and 900 mg of anserine and filled into soft capsules in the usual manner to produce soft capsules for use in improving QOL.

[0155] Example 12 Prevention and treatment of IL-6-related diseases: In the administration test of Example 1 and the results of the questionnaire survey, there were cases in which the following diseases were improved.

[0156] [Table 23]

[0157] [Table 24]

[0158] As described above, the plant fermentation product, which is an active ingredient of the QOL improving agent of the present invention, is expected to be effective against rheumatoid arthritis and Behçet's disease, which are autoimmune diseases in which the concentration of IL-6 in the blood rises in parallel with the deterioration of the condition. Both of these are intractable diseases, and the QOL decline is significant due to pain and the condition, causing great mental damage, so the QOL improvement effect is great. In addition, it has been shown in Example 2 that the plant fermentation product, which is an active ingredient of the QOL improving agent of the present invention, suppresses the expression of IL-6. There has been no substance that suppresses the expression of IL-6 in this way, so this is a novel invention. Since the mechanism is different from that of existing antibody drugs, it can be used in combination with antibody drugs.

[0159] In addition, as described above, the fermented plant product, which is an active ingredient of the QOL improving agent of the present invention, is expected to be effective against pulmonary inflammation-related diseases. Such pulmonary inflammation-related diseases are also caused by the rapid aggravation of the novel coronavirus (COVID-19) infection. Therefore, the fermented plant product, which is an active ingredient of the QOL improving agent of the present invention, is highly likely to suppress the rapid aggravation of the novel coronavirus infection, and it is believed that ingestion from an early stage of infection is effective. [Industrial Applicability]

[0160] The QOL improving agent of the present invention can be used to improve a wide range of QOL, for example, QOL based on emotions / behavior, aging symptoms, digestive symptoms, chronic fatigue, chronic inflammation, metabolic diseases, dementia, and the like.

Claims

1. The following (a) to (g): (a) Barley, black soybeans, red rice, black rice, adzuki beans, pearl barley, barnyard millet, foxtail millet and millet fermented with Aspergillus oryzae (b) yeast and / or lactic acid bacteria fermentation products of mandarin oranges, grapes, apples, wild grapes, peaches, persimmons, papayas, pears, watermelons, plums, figs, quince, pumpkins, kumquats, yuzu, loquats, apricots, jujubes, chestnuts, silver vines, and plums (c) Yeast and / or lactic acid bacteria fermentation products of purple sweet potato, Jerusalem artichoke, carrot, onion, sweet potato, taro, wild yam, radish, red turnip, burdock, lotus root, yacon, lily root, water chestnut, ginger, garlic and turmeric (d) yeast and / or lactic acid bacteria fermentation products of cabbage, shiso, mulberry leaves, dokudami, mugwort, kumazasa, and dandelion (e) Fermentation products of kelp, wakame and mozuku with yeast and / or lactic acid bacteria (f) Yeast and / or lactic acid bacteria fermentation products of black sesame, walnuts and ginkgo nuts (g) Maitake and shiitake mushrooms fermented with yeast and / or lactic acid bacteria A QOL improving agent comprising, as an active ingredient, a fermented plant product which is a mixture of QOL is based on emotional / behavioral or metabolic disorders; Improvements in QOL based on emotions and behavior include improved vitality, physical condition, mood, and eating behavior. Improvement of QOL due to metabolic disease includes improvement of blood pressure, improvement of diabetes, improvement of obesity, and improvement of menopause. A QOL improving agent.

2. 2. The QOL improving agent according to claim 1, wherein the plant fermentation product contains amino acids of the following composition per 100 g of the plant fermentation product. Arginine 0.2-0.6g Lysine 0.1-0.7g Histidine 0.1-0.4g Phenylalanine 0.2-0.8g Tyrosine 0.1-0.6g Leucine 0.3-1.2g Isoleucine 0.2-0.8g Methionine 0.05-0.30g Valine 0.2-0.9g Alanine 0.2-0.9g Glycine 0.2-0.7g Proline 0.4-1.2g Glutamic acid 1.2-3.0g Serine 0.2-0.8g Threonine 0.2-0.7g Aspartic acid 0.4-1.5g Tryptophan 0.03-0.15g Cystine 0.05-0.40g

3. 3. The QOL improving agent according to claim 1 or 2, wherein the plant fermentation product contains organic acids having the following composition per 100 g of the plant fermentation product. Citric acid: 0.5 to 1.2 g Malic acid 0.05-0.5g Succinic acid 0.04-0.3g Lactic acid 0.5-6.0g Formic acid 0.01-0.1 g Pyruvic acid 0.005-0.05g Free γ-aminobutyric acid 0.01-0.05g

4. 4. The QOL improving agent according to any one of claims 1 to 3, wherein the lactic acid bacteria is one or more species selected from the group consisting of Pediococcus acidilacti (P. acidilacti), Lactobacillus brevis (L. brevis), Leuconostoc mesenteroides (L. mesenteroides), Lactobacillus plantarum (L. plantarum), Lactococcus lactis (L. lactis), Lactobacillus sakei (L. sakei), Pediococcus pentosaceus (P. pentosaceus), Lactobacillus casei (L. casei) and Lactobacillus curvatus (L. curvatus).

5. 5. The QOL improving agent according to any one of claims 1 to 4, wherein the yeast is Saccharomyces cerevisiae (S. cervisiae) and / or Zygosaccharomyces rouxii (Z. rouxii).

6. A food or drink for improving QOL, comprising the QOL improving agent according to any one of claims 1 to 5.

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