Preventing or ameliorating agent for age-related cognitive dysfunction, enhancer for neurotrophin 3, preventing or ameliorating agent for age-related decline in eagerness, and method for producing them

Abstract

To provide a preventing or ameliorating agent for age-related cognitive dysfunction and to provide an enhancer for neurotrophin 3.SOLUTION: The preventing or ameliorating agent for age-related cognitive dysfunction includes tea leaf or a tea leaf extract being an extract extracted from the tea leaf. In the preventing or ameliorating agent, the tea leaf and the tea leaf extract include non-gallate-type catechin and theogallin and have a ratio of a molar concentration (μmol / L) of theogallin to a molar concentration (μmol / L) of non-gallate-type catechin of 0.3 or more. The enhancer for neurotrophin 3 includes tea leaf and a tea leaf extract being an extract extracted from the tea leaf. In the enhancer for neurotrophin 3, the tea leaf and the tea leaf extract include non-gallate-type catechin and theogallin and have a ratio of a molar concentration (μmol / L) of theogallin to a molar concentration (μmol / L) of non-gallate-type catechin of 0.3 or more.SELECTED DRAWING: Figure 3

Description

Technical Field

[0001] The present invention relates to a preventive or ameliorating agent for cognitive dysfunction associated with aging, an enhancer of neurotrophin 3, a preventive or ameliorating agent for decreased motivation associated with aging, and methods for producing these agents.

Background Art

[0002] The decline in cognitive function associated with aging has been regarded as a problem, and components that can suppress the decline in cognitive function have been studied. For example, caffeine has been reported to suppress the decline in brain function associated with aging by animal experiments (see Non-Patent Documents 1 to 3). In addition, it has been reported that the cognitive function of experimental animals is improved by administration of L-theanine (see Patent Document 1 and Non-Patent Document 4). And the most actively studied are gallate-type catechins such as epigallocatechin gallate (EGCG), and it has been reported that catechins centered on EGCG exhibit a preventive effect against the decline in cognitive function observed in aging-accelerated model animals and the like (see Non-Patent Documents 5 to 9). Also, in Alzheimer's disease model animals, it has been reported that catechins suppress the decline in cognitive function (Patent Document 2).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Summary of the Invention

Problems to be Solved by the Invention

[0005] However, since caffeine induces excitation of the sympathetic nervous system, continuous intake at high concentrations is avoided. In addition, catechins (especially gallate-type catechins such as EGCG) have a strong bitter taste and are difficult to continuously ingest. And theanine has no problems in terms of safety and palatability, but since the effective concentration is very high, for example, with the usual consumption amount of green tea, the effect of improving cognitive function cannot be obtained. Also, although it is possible to cultivate tea with an increased theanine content, it is laborious to cultivate, and tea with a high theanine content also contains a large amount of caffeine and gallate-type catechins at the same time, which is not preferable.

[0006] Therefore, it is desirable to suppress cognitive impairment or the like by using components other than the above components. Theogallin, strictinin, and G-strictinin are not known to have preventive or ameliorative effects on cognitive impairment associated with aging. Also, from the viewpoint of ease of intake, it is desirable to be ingestible as a food.

[0007] In addition, as a symptom associated with aging, in addition to the above-described decline in cognitive function associated with aging, from the results of a behavioral test for observing anxiety-like behavior, it has been reported that the exploratory desire also declines with aging in experimental animals (Non-Patent Document 10). Therefore, it is also desired to suppress the decline in motivation associated with aging. Theogallin, strictinin, and G-strictinin are not known to have preventive or ameliorative effects on the decline in motivation associated with aging.

[0008] Here, neurotrophin-3 (NT-3), which is a type of neurotrophic factor, has been reported to have the potential to improve memory and learning ability. For example, when NT-3 is administered, memory and learning ability are restored. In addition, NT-3 has also been reported to have the potential for an antidepressant effect. Therefore, by enhancing NT-3, in addition to preventing or ameliorating cognitive impairment, an antidepressant effect, for example, suppression of a decline in motivation, can also be expected.

[0009] As described above, since gallate-type catechins such as EGCG have a strong bitter and astringent taste, from the viewpoint of palatability, it is desirable to be able to manufacture them by a method in which the content of EGCG is reduced. Also, as described above, it is also desirable to be able to manufacture them by a method in which the caffeine content is reduced.

[0010] The present invention has been made in view of the above circumstances, and an object thereof is to provide a preventive or ameliorative agent for cognitive impairment associated with aging, an enhancer of neurotrophin 3, a preventive or ameliorative agent for a decline in motivation associated with aging, and methods for producing these.

Means for Solving the Problems

[0011] The inventors of the present invention have found that continuous intake of tea leaves containing theogallin or an extract of the tea leaves can prevent or improve cognitive dysfunction associated with aging, prevent or improve decreased motivation associated with aging, enhance neurotrophin-3, and that when the tea leaves are extracted with water at -5°C or higher and 40°C or lower, theogallin leaches out well and the leaching of gallate-type catechins such as epigallocatechin gallate (EGCG) can be suppressed, leading to the completion of the present invention. More specifically, the present invention provides the following.

[0012] (1) A preventive or ameliorative agent for cognitive dysfunction associated with aging, comprising tea leaves or a tea leaf extract which is an extract of the tea leaves, wherein the tea leaves and the tea leaf extract contain non-gallate catechins and theogallin, and the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of the non-gallate catechins is 0.3 or more.

[0013] (2) A preventive or ameliorative agent for cognitive dysfunction associated with aging, comprising tea leaves or a tea leaf extract which is an extract of the tea leaves, wherein the tea leaves contain at least one selected from tea leaves containing 1% by mass or more of theogallin, "MK5601", and descendants of "MK5601".

[0014] (3) The preventive or ameliorative agent for cognitive dysfunction associated with aging according to (1) or (2), wherein the tea leaves and the tea leaf extract contain at least one of strictinin and G-strictinin.

[0015] (4) The preventive or ameliorative agent for cognitive dysfunction associated with aging according to (3), wherein the tea leaves and the tea leaf extract contain strictinin, and the ratio of the molar concentration (μmol / L) of strictinin to the molar concentration (μmol / L) of the non-gallate catechins is 0.002 or more.

[0016] (5) The tea leaves and the tea leaf extract contain G-strictinin, and the ratio of the molar concentration (μmol / L) of G-strictinin to the molar concentration (μmol / L) of non-gallate catechin is 0.001 or more, and it is a preventive or ameliorating agent for cognitive dysfunction associated with aging according to (3) or (4).

[0017] (6) An enhancer of neurotrophin-3, comprising a tea leaf or a tea leaf extract which is an extract of the tea leaf, The tea leaves and the tea leaf extract contain non-gallate catechin and theogallin, and the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechin is 0.3 or more, and it is an enhancer of neurotrophin-3.

[0018] (7) An enhancer of neurotrophin-3, comprising a tea leaf or a tea leaf extract which is an extract of the tea leaf, The tea leaf contains at least one selected from tea leaves containing 1% by mass or more of theogallin, "MK5601", and descendants of "MK5601", and it is an enhancer of neurotrophin-3.

[0019] (8) The tea leaves and the tea leaf extract contain at least one of strictinin and G-strictinin, and it is an enhancer of neurotrophin-3 according to (6) or (7).

[0020] (9) The tea leaves and the tea leaf extract contain strictinin, and the ratio of the molar concentration (μmol / L) of strictinin to the molar concentration (μmol / L) of non-gallate catechin is 0.002 or more, and it is an enhancer of neurotrophin-3 according to (8).

[0021] (10) The tea leaves and the tea leaf extract contain G-strictinin, and the ratio of the molar concentration (μmol / L) of G-strictinin to the molar concentration (μmol / L) of non-gallate catechin is 0.001 or more, and it is an enhancer of neurotrophin-3 according to (8) or (9).

[0022] (11) A preventive or ameliorating agent for decreased motivation associated with aging, comprising tea leaves or a tea leaf extract which is an extract of the tea leaves, wherein the tea leaves and the tea leaf extract contain non-gallate catechins and theogallin, and a ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins is 0.3 or more, the preventive or ameliorating agent for decreased motivation associated with aging.

[0023] (12) A preventive or ameliorating agent for decreased motivation associated with aging, comprising tea leaves or a tea leaf extract which is an extract of the tea leaves, wherein the tea leaves include at least one selected from tea leaves containing 1% by mass or more of theogallin, "MK5601", and descendants of "MK5601", the preventive or ameliorating agent for decreased motivation associated with aging.

[0024] (13) The preventive or ameliorating agent for decreased motivation associated with aging according to (11) or (12), wherein the tea leaves and the tea leaf extract contain at least one of strictinin and G-strictinin.

[0025] (14) The preventive or ameliorating agent for decreased motivation associated with aging according to (13), wherein the tea leaves and the tea leaf extract contain strictinin, and a ratio of the molar concentration (μmol / L) of strictinin to the molar concentration (μmol / L) of non-gallate catechins is 0.002 or more.

[0026] (15) The preventive or ameliorating agent for decreased motivation associated with aging according to (13) or (14), wherein the tea leaves and the tea leaf extract contain G-strictinin, and a ratio of the molar concentration (μmol / L) of G-strictinin to the molar concentration (μmol / L) of non-gallate catechins is 0.001 or more.

[0027] (16) A method for producing a preventive or ameliorating agent for cognitive dysfunction according to any one of (1) to (5), comprising a step of producing the tea leaf extract by extracting the tea leaves with water at -5°C or higher and 40°C or lower, the method for producing a preventive or ameliorating agent for cognitive dysfunction.

[0028] (17) A method for producing an enhancer for neurotrophin 3 according to any one of items (6) to (7), The method for producing an enhancer for neurotrophin 3 having a step of producing the tea leaf extract by extracting the tea leaves with water at -5°C or higher and 40°C or lower.

[0029] (18) A method for producing a preventive or ameliorating agent for decreased motivation associated with aging according to any one of items (11) to (15), The method for producing a preventive or ameliorating agent for decreased motivation associated with aging having a step of producing the tea leaf extract by extracting the tea leaves with water at -5°C or higher and 40°C or lower.

Advantages of the Invention

[0030] According to the present invention, it is possible to provide a preventive or ameliorating agent for cognitive dysfunction associated with aging, an enhancer for neurotrophin 3, and a preventive or ameliorating agent for decreased motivation associated with aging. And since these contain tea leaves or a tea leaf extract which is an extract of the tea leaves, they can be ingested as food and drink. Further, these can also be produced by a production method in which the extraction of theogallin is good and the extraction of gallate-type catechins such as epigallocatechin gallate (EGCG) can be suppressed.

Brief Description of the Drawings

[0031]

Figure 1

Figure 2

Figure 3

Figure 4

Embodiments for Carrying Out the Invention

[0032] Hereinafter, embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments and can be implemented with appropriate modifications within the scope of the object of the present invention. In this specification, the "tea leaves" are tea leaves (green tea leaves, black tea leaves, semi-fermented tea leaves) of Camellia sinensis, preferably dried tea leaves. In this specification, the "tea leaf extract" is an extract obtained by roasting raw tea leaves, which are the raw materials of the tea leaf extract, as necessary, and then extracting with an extraction solvent, or a concentrate of the extract (liquid concentrate, powder concentrate).

[0033] (Embodiment 1) Preventive or ameliorating agent for cognitive dysfunction associated with aging, and method for producing the same The preventive or ameliorating agent for cognitive dysfunction associated with aging according to Embodiment 1 contains tea leaves or a tea leaf extract which is an extract of the tea leaves. In Embodiment 1, the tea leaves and the tea leaf extract contain non-gallate catechins and theogallin, and the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins in the preventive or ameliorating agent for cognitive dysfunction associated with aging (molar concentration of theogallin / molar concentration of non-gallate catechins) is 0.3 or more. Theogallin is a compound represented by the following formula (1). In this specification, the non-gallate catechins are catechin (C), gallocatechin (GC), epicatechin (EC) and epigallocatechin (EGC), and the molar concentration of the non-gallate catechins is the total value of these concentrations.

[0034] [Chemical formula]

[0035] Thus, by setting the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins in a preventive or ameliorating agent for cognitive dysfunction associated with aging, which contains tea leaves or a tea leaf extract, to 0.3 or more, as shown in the examples described later, it is possible to prevent or ameliorate cognitive dysfunction associated with aging by continuous intake, for example, intake for 16 weeks or more, and a preventive or ameliorating agent for cognitive dysfunction associated with aging can be obtained. Since the preventive or ameliorating agent for cognitive dysfunction associated with aging of the present embodiment contains tea leaves or a tea leaf extract, it can be ingested as a food or drink. The ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins in a preventive or ameliorating agent for cognitive dysfunction associated with aging may be 0.3 or more, preferably 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more. The concentration of theogallin in a preventive or ameliorating agent for cognitive dysfunction associated with aging is preferably 700 μmol / L or more, and more preferably 900 μmol / L or more. The upper limit value of the concentration of theogallin in a preventive or ameliorating agent for cognitive dysfunction associated with aging is, for example, 3000 μmol / L.

[0036] The theogallin has a structural feature that its metabolite may pass through the blood-brain barrier, but no behavioral verification from a macroscopic perspective has been conducted, and the preventive or ameliorating effect of cognitive dysfunction associated with aging by continuous intake has not been known conventionally. Now, the present inventors have found that it is possible to prevent or ameliorate cognitive dysfunction associated with aging by continuous intake of tea leaves or a tea leaf extract containing theogallin. The mice used in the examples described later are not special mice such as Alzheimer's disease models, but natural aging models of wild-type mice. In the former Alzheimer's disease, cognitive dysfunction associated with aging and other disorders / diseases are caused by specific pathogenic factors such as the neurotoxicity of amyloid-β, while in the aging of the latter wild-type mice, neurotrophin 3 (NT-3) in the brain is insufficient due to other complex factors rather than amyloid-β, causing cognitive dysfunction. Therefore, the two are different dysfunctions.

[0037] In the present embodiment, the tea leaves and the raw tea leaves of the tea leaf extract preferably contain 1% by mass or more of theogallin, are the tea variety "MK5601", or are descendants of the tea variety "MK5601". "MK5601" is a tea leaf belonging to Camellia sinensis (L.) Kuntze. "MK5601" is a theogallin-rich variety that can be obtained at the National Agriculture and Food Research Organization. The variety registration application number of "MK5601" is No. 33550. The tea leaves of "MK5601" are a variety that contains 1% by mass or more of theogallin in the dry tea leaves. Also, the tea leaves of "MK5601" are a variety that can contain a total of 1.5% by mass or more of strictinin and G-strictinin in the dry tea leaves. And "MK5601" is a variety that has more components other than caffeine, theanine, and catechins compared to other tea leaves. Note that for "Yabukita", the most common tea variety in Japan, the content of theogallin in the dry tea leaves is about 0.3% by mass, the content of strictinin is 1% by mass or less, and it does not contain G-strictinin.

[0038] In the present embodiment, the tea leaves and the raw tea leaves of the tea leaf extract preferably contain strictinin and G-strictinin (1,2-di-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl-β-D-glucose). Strictinin is a compound represented by the following formula (2), and G-strictinin is a compound represented by the following formula (3).

[0039]

Chemical formula

[0040]

Chemical formula

[0041] When tea leaves or tea extracts contain strictinin, the ratio of the molar concentration (μmol / L) of strictinin to the molar concentration (μmol / L) of non-gallate catechins in a preventive or ameliorating agent for cognitive dysfunction associated with aging (molar concentration of strictinin / molar concentration of non-gallate catechins) is, for example, 0.002 or more, preferably 0.02 or more, more preferably 0.03 or more, and even more preferably 0.04 or more. The concentration of strictinin in a preventive or ameliorating agent for cognitive dysfunction associated with aging is, for example, 5 μmol / L or more, preferably 40 μmol / L or more, more preferably 50 μmol / L or more, and even more preferably 60 μmol / L or more. The upper limit of the concentration of strictinin in a preventive or ameliorating agent for cognitive dysfunction associated with aging is, for example, 600 μmol / L.

[0042] When tea leaves or tea extracts contain G-strictinin, the ratio of the molar concentration (μmol / L) of G-strictinin to the molar concentration (μmol / L) of non-gallate catechins in a preventive or ameliorating agent for cognitive dysfunction associated with aging (molar concentration of G-strictinin / molar concentration of non-gallate catechins) is, for example, 0.001 or more, preferably 0.01 or more, more preferably 0.05 or more, and even more preferably 0.06 or more. The concentration of G-strictinin in a preventive or ameliorating agent for cognitive dysfunction associated with aging is, for example, 3 μmol / L or more, preferably 30 μmol / L or more, more preferably 50 μmol / L or more, even more preferably 70 μmol / L or more, and even more preferably 90 μmol / L or more. The upper limit of the concentration of G-strictinin in a preventive or ameliorating agent for cognitive dysfunction associated with aging is, for example, 700 μmol / L.

[0043] In addition, the tea leaves and tea leaf extracts may contain theogallin, strictinin, and other components other than G-strictinin. Examples of other components include caffeine, theanine, and catechins other than non-gallate catechins (gallate catechins). However, in the present invention, since theogallin, which is a component other than these, can prevent or improve cognitive dysfunction associated with aging, these components may be contained in a small amount or may not be contained at all. For example, the preventive or ameliorating agent for cognitive dysfunction associated with aging may be caffeine-free, and the caffeine concentration in the preventive or ameliorating agent for cognitive dysfunction associated with aging in the case of being caffeine-free is, for example, 10 mg / L or less. The caffeine concentration in the preventive or ameliorating agent for cognitive dysfunction associated with aging is, for example, 4000 μmol / L or less, the theanine concentration is, for example, 2000 μmol / L or less, and the concentration of catechins other than non-gallate catechins is, for example, 5000 μmol / L or less and may be 3000 μmol / L or less. In the case of using a preventive or ameliorating agent for cognitive dysfunction associated with aging with a low caffeine concentration, as the tea leaves, it is preferable to use tea leaves in which the amount of caffeine in the tea leaves has been reduced (for example, reduced by 60% or more) by hot water treatment using a hot water treatment device or the like, or a tea leaf extract obtained by a specific extraction method described in detail later.

[0044] The form of the preventive or ameliorative agent for cognitive dysfunction associated with aging in the present embodiment may be any form, for example, it may be in the form of food or drink. The preventive or ameliorative agent for cognitive dysfunction associated with aging in the present embodiment may be the above-mentioned tea leaves or tea leaf extract itself, may be a dilution of the tea leaf extract with a solvent such as water, or may be a product obtained by adding other components according to the purpose. For example, when applying the preventive or ameliorative agent for cognitive dysfunction associated with aging in the present embodiment as food or drink, the above-mentioned tea leaf extract or a dilution of the tea leaf extract with a solvent such as water may be directly ingested as a tea beverage, or may be ingested as various beverage ingredients or food ingredients, such as confectionery, health food, and supplements. The property of the preventive or ameliorative agent for cognitive dysfunction associated with aging in the present embodiment is in a solid state or a liquid state. When it is in a solid state, for example, tea leaves, tea leaf extracts, or a dilution of the tea leaf extract with a solvent such as water may be processed into dosage forms such as tablets, capsules, granules, syrups, and lozenges. Further, when applying the preventive or ameliorative agent for cognitive dysfunction associated with aging in the present embodiment as food or drink, a gelling agent, saccharides, flavors, sweeteners, fats and oils, substrates, excipients, food additives, auxiliary materials, bulking agents, etc. may be appropriately blended.

[0045] Note that the tea leaf extract can be obtained by subjecting tea leaves to an extraction treatment with a solvent, and a conventionally known method can be adopted. From the viewpoint of extracting active ingredients such as theogallin, it is preferable to pulverize the tea leaves for extraction. Since the pulverized product (powder) of the tea leaves is preferably of uniform size, the pulverized product may be sieved.

[0046] The extraction solvent may be any non-toxic one, and examples thereof include water, a hydrophilic solvent, or a mixture thereof. Examples of water include tap water, distilled water, pure water, ion-exchanged water, etc. Examples of the hydrophilic solvent include lower alcohols such as methanol, ethanol, propyl alcohol, and isopropyl alcohol, lower aliphatic ketones such as acetone and methyl ethyl ketone, and polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin.

[0047] Also, the extraction temperature (temperature of the extraction solvent) is preferably 40°C or lower, more preferably 30°C or lower, and even more preferably 10°C or lower. Regarding the lower limit of the extraction temperature, it is, for example, -5°C or higher. It has not been conventionally known that the extraction rate of theogallin is high even at a low temperature (40°C or lower) and it can be extremely well extracted (eluted). Also, in the extraction at a low temperature of 40°C or lower, not only theogallin but also strictinin and G-strictinin can be extracted.

[0048] By extracting tea leaves with water at -5°C or higher and 40°C or lower, theogallin can be extremely well extracted while reducing the elution amount of gallate-type catechins such as epigallocatechin gallate (EGCG). Therefore, in the production of a preventive or ameliorating agent for age-related cognitive impairment containing a tea leaf extract, when the step of producing the tea leaf extract by extracting tea leaves with water at -5°C or higher and 40°C or lower is included, while exhibiting the preventive or ameliorating effect of age-related cognitive impairment by theogallin, the astringency due to EGCG is suppressed, so that a preventive or ameliorating agent for age-related cognitive impairment with excellent palatability can be produced. Note that by extracting with water at 30°C or lower, the elution amount of EGCG can be suppressed to 1 / 5 or more and 1 / 2 or less compared to hot water (for example, water at 70°C or higher). Also, by extracting tea leaves with water at -5°C or higher and 10°C or lower, not only the elution amount of gallate-type catechins such as EGCG but also the elution amount of caffeine can be reduced, and theogallin with a high extraction rate can be specifically extracted even with water at a low temperature of -5°C or higher and 10°C or lower. Therefore, in the production of a preventive or ameliorating agent for age-related cognitive impairment containing a tea leaf extract, when the step of producing the tea leaf extract by extracting tea leaves with water at -5°C or higher and 10°C or lower is included, a preventive or ameliorating agent for age-related cognitive impairment with a reduced amount of caffeine can be produced. Note that by extracting with water at -5°C or higher and 10°C or lower, the elution amount of caffeine can be suppressed to 1 / 5 or more and 1 / 2 or less compared to hot water (for example, water at 70°C or higher). Also, in the extraction at a low temperature of 10°C or lower, strictinin and G-strictinin can be extracted.

[0049] Alternatively, a treatment may be performed to convert EGCG into epigallocatechin (EGC) and gallic acid by allowing tannase, which hydrolyzes the depside bond within the gallate molecule of EGCG, to act on the extract obtained by extracting tea leaves with a solvent.

[0050] The extraction may be performed multiple times by recovering the residue after the first extraction. Also, the extraction may use a method generally used as a chemical separation and purification technique. For example, liquid-liquid partitioning, thin layer chromatography, adsorption column chromatography, partition column chromatography, gel filtration column chromatography, ion exchange column chromatography, electrophoresis, high performance liquid chromatography, etc. can be used. Further, these separation and purification means may be combined as necessary.

[0051] (Embodiment 2) Preventive or ameliorating agent for cognitive dysfunction associated with aging, and method for producing the same The preventive or ameliorating agent for cognitive dysfunction associated with aging according to Embodiment 2 contains tea leaves or a tea leaf extract containing the tea leaf extract. And in Embodiment 2, the tea leaves contain at least one selected from tea leaves containing 1% by mass or more of theogallin, "MK5601", and the progeny of "MK5601". Hereinafter, Embodiment 2 will be described. Except as described below, it is the same as Embodiment 1, and some descriptions of the content overlapping with Embodiment 1 will be omitted.

[0052] In this way, by including tea leaves or a tea leaf extract and making the tea leaves contain at least one selected from tea leaves containing 1% by mass or more of theogallin, "MK5601", and the progeny of "MK5601", as shown in the examples described later, continuous ingestion, for example, ingestion for 16 weeks or more, can prevent or ameliorate cognitive dysfunction associated with aging, and a preventive or ameliorating agent for cognitive dysfunction associated with aging can be obtained. Since it contains tea leaves or a tea leaf extract, it can be ingested as a food or drink. The tea leaves of "MK5601" are the same as in Embodiment 1.

[0053] The tea leaves and tea leaf extract of the present embodiment contain non-gallate catechins and theogallin, and in the preventive or ameliorating agent for cognitive dysfunction associated with aging, the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins (the molar concentration of theogallin / the molar concentration of non-gallate catechins) is preferably 0.3 or more. In the preventive or ameliorating agent for cognitive dysfunction associated with aging, the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins is preferably 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more. The concentration of theogallin in the preventive or ameliorating agent for cognitive dysfunction associated with aging is preferably 700 μmol / L or more, and more preferably 900 μmol / L or more. The upper limit value of the concentration of theogallin in the preventive or ameliorating agent for cognitive dysfunction associated with aging is, for example, 3000 μmol / L.

[0054] In the present embodiment, the tea leaves and the raw tea leaves of the tea leaf extract preferably contain strictinin and G-strictinin. The ratio of the molar concentration (μmol / L) of strictinin to the molar concentration (μmol / L) of non-gallate catechins in the preventive or ameliorating agent for cognitive dysfunction associated with aging, the concentration of strictinin in the preventive or ameliorating agent for cognitive dysfunction associated with aging, the ratio of the molar concentration (μmol / L) of G-strictinin to the molar concentration (μmol / L) of non-gallate catechins in the preventive or ameliorating agent for cognitive dysfunction associated with aging, and the concentration of G-strictinin in the preventive or ameliorating agent for cognitive dysfunction associated with aging are the same as those in Embodiment 1.

[0055] Other components that the tea leaves and tea leaf extract of the present embodiment may contain, such as theogallin, strictinin, and G-strictinin, and the concentration of other components in the preventive or ameliorating agent for cognitive dysfunction associated with aging are the same as those in Embodiment 1.

[0056] Also, the form of the preventive or ameliorating agent for cognitive dysfunction associated with aging in the present embodiment, the method for obtaining the tea leaf extract, etc. are the same as those in Embodiment 1.

[0057] (Embodiment 3) Enhancer of neurotrophin 3 and method for producing the same The enhancer of neurotrophin 3 according to Embodiment 3 contains a tea leaf or a tea leaf extract which is an extract of the tea leaf. And in Embodiment 3, the tea leaf and the tea leaf extract contain non-gallate catechin and theogallin, and the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechin in the enhancer of neurotrophin 3 (molar concentration of theogallin / molar concentration of non-gallate catechin) is 0.3 or more.

[0058] Thus, by including a tea leaf or a tea leaf extract and making the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechin in the enhancer of neurotrophin 3 0.3 or more, as shown in the examples described later, an enhancer of neurotrophin 3 that can enhance neurotrophin 3 by continuous intake, for example, intake for 16 weeks or more, can be obtained. By enhancing neurotrophin 3, prevention and improvement of cognitive dysfunction can be achieved, and / or antidepressant effects (antidepressant effects) etc. can also be expected. Since the enhancer of neurotrophin 3 of the present embodiment contains a tea leaf or a tea leaf extract, it can be ingested as a food or drink. The ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechin in the enhancer of neurotrophin 3 may be 0.3 or more, preferably 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more. When the enhancer of neurotrophin 3 contains a tea leaf extract, the concentration of theogallin in the enhancer of neurotrophin 3 is preferably 700 μmol / L or more, and more preferably 900 μmol / L or more. The upper limit value of the concentration of theogallin in the enhancer of neurotrophin 3 is, for example, 3000 μmol / L.

[0059] Theogallin has the structural feature that its metabolite may pass through the blood-brain barrier of the brain, but no behavioral verification has been carried out from a macroscopic perspective, and the enhancing effect of neurotrophin 3 by continuous intake has not been known conventionally. This time, the inventors have found that continuous intake of tea leaves containing theogallin or an extract of the tea leaves can enhance neurotrophin 3.

[0060] In this embodiment, the tea leaves and the raw tea leaves of the tea leaf extract are preferably tea leaves containing 1% by mass or more of theogallin, the tea variety "MK5601", or a descendant of the tea variety "MK5601". "MK5601" (variety registration application number: No. 33550) is a tea leaf belonging to Camellia sinensis (L.) Kuntze, as described in Embodiment 1. The tea leaves of "MK5601" are a variety containing 1% by mass or more of theogallin in the dry tea leaves. Also, the tea leaves of "MK5601" are a variety that can contain a total of 1.5% by mass or more of strictinin and G-strictinin in the dry tea leaves. And "MK5601" is a variety with more components other than caffeine, theanine, and catechins compared to other tea leaves. Note that for "Yabukita", the most common tea variety in Japan, the content of theogallin in the dry tea leaves is about 0.3% by mass, the content of strictinin is 1% by mass or less, and G-strictinin is not contained.

[0061] In this embodiment, the tea leaves and the raw tea leaves of the tea leaf extract preferably contain strictinin and G-strictinin.

[0062] When the tea leaves or the tea leaf extract contains strictinin, the ratio of the molar concentration (μmol / L) of strictinin to the molar concentration (μmol / L) of non-gallate catechin in the enhancer of neurotrophin 3 (molar concentration of strictinin / molar concentration of non-gallate catechin) is, for example, 0.002 or more, preferably 0.02 or more, more preferably 0.03 or more, and even more preferably 0.04 or more. The concentration of strictinin in the enhancer of neurotrophin 3 is, for example, 5 μmol / L or more, preferably 40 μmol / L or more, more preferably 50 μmol / L or more, and even more preferably 60 μmol / L or more. The upper limit of the concentration of strictinin in the enhancer of neurotrophin 3 is, for example, 600 μmol / L.

[0063] When tea leaves or tea extracts contain G-strictinin, the ratio of the molar concentration (μmol / L) of G-strictinin to the molar concentration (μmol / L) of non-gallate catechins (molar concentration of G-strictinin / molar concentration of non-gallate catechins) in the enhancer of neurotrophin 3 is, for example, 0.001 or more, preferably 0.01 or more, more preferably 0.05 or more, and even more preferably 0.06 or more. The concentration of G-strictinin in the enhancer of neurotrophin 3 is, for example, 3 μmol / L or more, preferably 30 μmol / L or more, more preferably 50 μmol / L or more, even more preferably 70 μmol / L or more, and even more preferably 90 μmol / L or more. The upper limit of the concentration of G-strictinin in the enhancer of neurotrophin 3 is, for example, 700 μmol / L.

[0064] In addition, tea leaves or tea extracts may contain theogallin and other components other than strictinin and G-strictinin. Examples of other components include caffeine, theanine, and catechins other than non-gallate catechins (gallate catechins). However, the content of these components may be small or they may not be contained at all. For example, the enhancer of neurotrophin 3 may be caffeine-free, and the caffeine concentration in the caffeine-free enhancer of neurotrophin 3 is, for example, 10 mg / L or less. The caffeine concentration in the enhancer of neurotrophin 3 is, for example, 4000 μmol / L or less, the theanine concentration is, for example, 2000 μmol / L or less, and the concentration of catechins other than non-gallate catechins is, for example, 5000 μmol / L or less, and may be 3000 μmol / L or less. In the case of using it as an enhancer for neurotrophin 3 with a low caffeine concentration, as the tea leaves, it is preferable to use tea leaves with a reduced caffeine content (for example, reduced by 60% or more) in the tea leaves by hot water treatment using a hot water treatment device or the like, or specifically, a tea leaf extract obtained by a specific extraction method described later.

[0065] The form of the enhancer for neurotrophin 3 in this embodiment may be any form, for example, it may be in the form of a food or drink. The enhancer for neurotrophin 3 in this embodiment may be the above tea leaves or tea leaf extract itself, or may be a dilution of the tea leaf extract with a solvent such as water, or may be a mixture with other components added according to the purpose. For example, when applying the enhancer for neurotrophin 3 in this embodiment as a food or drink, the above tea leaf extract or a dilution of the tea leaf extract with a solvent such as water may be directly ingested as a tea beverage, or may be ingested as various beverage ingredients or food ingredients, such as confectionery, health foods, and supplements. The enhancer for neurotrophin 3 in this embodiment may be in a solid or liquid state. When it is in a solid state, for example, tea leaves, tea leaf extracts, or dilutions of tea leaf extracts with a solvent such as water may be processed into dosage forms such as tablets, capsules, granules, syrups, and troches. Also, when applying the enhancer for neurotrophin 3 in this embodiment as a food or drink, a gelling agent, saccharides, flavors, sweeteners, oils and fats, base materials, excipients, food additives, auxiliary materials, bulking agents, etc. may be appropriately blended.

[0066] The tea leaf extract can be obtained by extracting tea leaves with an extraction solvent, and a conventionally known method can be adopted. From the viewpoint of extracting the active ingredient, it is preferable to pulverize the tea leaves for extraction. Since the pulverized product (powder) of the tea leaves is preferably of uniform size, the pulverized product may be sieved.

[0067] The extraction solvent may be any non-toxic one, and examples thereof include water, hydrophilic solvents, or mixtures thereof. Examples of water include tap water, distilled water, pure water, ion-exchanged water, and the like. Examples of hydrophilic solvents include lower alcohols such as methanol, ethanol, propyl alcohol, and isopropyl alcohol, lower aliphatic ketones such as acetone and methyl ethyl ketone, and polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin.

[0068] Also, the extraction temperature is preferably 40°C or lower, more preferably 30°C or lower, and even more preferably 10°C or lower. The lower limit of the extraction temperature is, for example, -5°C or higher. It has not been previously known that the extraction rate of theogallin is extremely high and it can be leached (eluted) very well even at low temperatures (40°C or lower). Also, in the extraction at a low temperature of 40°C or lower, not only theogallin but also strictinine and G-strictinine can be leached.

[0069] By extracting tea leaves with water at -5°C or higher and 40°C or lower, theogallin can be leached very well while reducing the leaching amount of gallate-type catechins such as epigallocatechin gallate (EGCG). Therefore, in the production of an enhancer for nerve growth factor 3 containing a tea leaf extract, when the step of producing a tea leaf extract by extracting tea leaves with water at -5°C or higher and 40°C or lower is included, the enhancing effect of theogallin on nerve growth factor 3 is exhibited while the astringency due to EGCG is suppressed, so that an enhancer for nerve growth factor 3 with excellent palatability can be produced. In addition, by extracting with water at 30°C or lower, the leaching amount of EGCG can be suppressed to 1 / 5 or more and 1 / 2 or less compared with hot water (for example, water at 70°C or higher). Also, by extracting tea leaves with water at -5°C or higher and 10°C or lower, not only the extraction amount of gallate-type catechins such as EGCG but also the extraction amount of caffeine can be reduced, and theogallin with a high extraction rate can be specifically extracted even with water at a low temperature of -5°C or higher and 10°C or lower. Therefore, in the production of an enhancer for nerve growth factor 3 containing a tea leaf extract, when a step of producing a tea leaf extract by extracting tea leaves with water at -5°C or higher and 10°C or lower is included, an enhancer for nerve growth factor 3 with a reduced caffeine content can be produced. Note that by extracting with water at -5°C or higher and 10°C or lower, the extraction amount of caffeine can be suppressed to 1 / 5 or more and 1 / 2 or less compared to hot water (for example, water at 70°C or higher). Also, strictinin and G-strictinin can be extracted by extraction at a low temperature of 10°C or lower.

[0070] Further, a treatment may be performed to convert EGCG into epigallocatechin (EGC) and gallic acid by allowing tannase, which hydrolyzes the depside bond in the gallate molecule of EGCG, to act on the extract obtained by extracting tea leaves with a solvent. The extraction may be performed a plurality of times by recovering the residue after extraction once. Also, the extraction may use a method generally used as a chemical separation and purification technique. For example, liquid-liquid partitioning, thin layer chromatography, adsorption column chromatography, partition column chromatography, gel filtration column chromatography, ion exchange column chromatography, electrophoresis, high performance liquid chromatography, etc. can be used. Also, these separation and purification means may be combined as necessary.

[0071] (Embodiment 4) Enhancer for nerve growth factor 3 and method for producing the same The enhancer for nerve growth factor 3 according to Embodiment 4 contains a tea leaf extract which is tea leaves or an extract of the tea leaves. And in Embodiment 4, the tea leaves include at least one selected from tea leaves containing 1% by mass or more of theogallin, "MK5601", and the progeny of "MK5601". Next, Embodiment 4 will be described. Except as described below, it is the same as Embodiment 3, and the description of the content overlapping with Embodiment 3 will be partially omitted.

[0072] In this way, by including tea leaves or a tea leaf extract and making the tea leaves contain at least one selected from tea leaves containing 1% by mass or more of theogallin, "MK5601", and descendants of "MK5601", as shown in the examples described later, continuous ingestion, for example, ingestion for 16 weeks or more can enhance neurotrophin 3, and an enhancer for neurotrophin 3 can be obtained. By enhancing neurotrophin 3, it is possible to prevent and improve cognitive dysfunction and / or expect an antidepressant effect (antidepressant effect), etc. Since the enhancer for neurotrophin 3 of the present embodiment contains tea leaves or a tea leaf extract, it can be ingested as a food or drink. The tea leaves of "MK5601" are the same as those in Embodiment 3.

[0073] The tea leaves and the tea leaf extract of the present embodiment contain non-gallate catechins and theogallin, and the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins in the enhancer for neurotrophin 3 (the molar concentration of theogallin / the molar concentration of non-gallate catechins) is preferably 0.3 or more. The ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins in the enhancer for neurotrophin 3 is preferably 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more.

[0074] In the present embodiment, it is preferable that the tea leaves and the raw tea leaves of the tea leaf extract contain strictinin and G-strictinin. The ratio of the molar concentration (μmol / L) of strictinin to the molar concentration (μmol / L) of non-gallate catechin in the enhancer of neurotrophin 3, the concentration of strictinin in the enhancer of neurotrophin 3, the ratio of the molar concentration (μmol / L) of G-strictinin to the molar concentration (μmol / L) of non-gallate catechin in the enhancer of neurotrophin 3, and the concentration of G-strictinin in the enhancer of neurotrophin 3 are the same as those in Embodiment 3.

[0075] The theogallin, other components other than strictinin and G-strictinin, and the concentration thereof in the enhancer of neurotrophin 3 that may be contained in the tea leaves and tea leaf extract of the present embodiment are the same as those in Embodiment 3.

[0076] Also, the form of the enhancer of neurotrophin 3 and the method for obtaining the tea leaf extract in the present embodiment are the same as those in Embodiment 3.

[0077] (Embodiment 5) Agent for preventing or improving decline in motivation associated with aging, and method for producing the same The agent for preventing or improving decline in motivation associated with aging according to Embodiment 5 contains a tea leaf extract that is a tea leaf or an extract of the tea leaf. In Embodiment 5, the tea leaves and the tea leaf extract contain non-gallate catechin and theogallin, and the ratio (the molar concentration of theogallin / the molar concentration of non-gallate catechin) of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechin in the agent for preventing or improving decline in motivation associated with aging is 0.3 or more.

[0078] Thus, by setting the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins in a preventive or ameliorating agent for preventing or ameliorating decreased motivation associated with aging to 0.3 or more, as shown in the examples described later, it is possible to prevent or ameliorate decreased motivation associated with aging by continuous intake, for example, intake for 16 weeks or more, and a preventive or ameliorating agent for preventing or ameliorating decreased motivation associated with aging can be obtained. Since the preventive or ameliorating agent for preventing or ameliorating decreased motivation associated with aging in the present embodiment contains tea leaves or a tea leaf extract, it can be ingested as a food or drink. The ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins in a preventive or ameliorating agent for preventing or ameliorating decreased motivation associated with aging may be 0.3 or more, preferably 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more. When the preventive or ameliorating agent for preventing or ameliorating decreased motivation associated with aging contains a tea leaf extract, the concentration of theogallin in the preventive or ameliorating agent for preventing or ameliorating decreased motivation associated with aging is preferably 700 μmol / L or more, more preferably 900 μmol / L or more. The upper limit value of the concentration of theogallin in the preventive or ameliorating agent for preventing or ameliorating decreased motivation associated with aging is, for example, 3000 μmol / L.

[0079] Theogallin has a structural feature that its metabolite may pass through the blood-brain barrier in the brain, but no behavioral verification from a macroscopic perspective has been conducted, and the preventive or ameliorating effect of decreased motivation associated with aging by continuous intake has not been conventionally known. Now, the present inventors have found that it is possible to prevent or ameliorate decreased motivation associated with aging by continuous intake of tea leaves containing theogallin or an extract of the tea leaves.

[0080] In the present embodiment, the tea leaves and the raw tea leaves of the tea leaf extract are preferably tea leaves containing 1% by mass or more of theogallin, the tea variety "MK5601", or a descendant of the tea variety "MK5601". "MK5601" (variety registration application number: No. 33550) is a tea leaf belonging to Camellia sinensis (L.) Kuntze, as described in Embodiment 1. The tea leaves of "MK5601" are varieties containing 1% by mass or more of theogallin in the dry tea leaves. Also, the tea leaves of "MK5601" are varieties that can contain a total of 1.5% by mass or more of strictinin and G-strictinin in the dry tea leaves. And, "MK5601" is a variety with more components other than caffeine, theanine, and catechins compared to other tea leaves. Incidentally, for "Yabukita", the most common tea variety in Japan, the content of theogallin in the dry tea leaves is about 0.3% by mass, the content of strictinin is 1% by mass or less, and G-strictinin is not contained.

[0081] In the present embodiment, it is preferable that the tea leaves and the raw tea leaves of the tea leaf extract contain strictinin and G-strictinin.

[0082] When the tea leaves or the tea leaf extract contains strictinin, the ratio of the molar concentration (μmol / L) of strictinin to the molar concentration (μmol / L) of non-gallate catechin in the preventive or ameliorating agent for the decline in motivation associated with aging (molar concentration of strictinin / molar concentration of non-gallate catechin) is, for example, 0.002 or more, preferably 0.02 or more, more preferably 0.03 or more, and even more preferably 0.04 or more. The concentration of strictinin in the preventive or ameliorating agent for the decline in motivation associated with aging is, for example, 5 μmol / L or more, preferably 40 μmol / L or more, more preferably 50 μmol / L or more, and even more preferably 60 μmol / L or more. The upper limit value of the concentration of strictinin in the preventive or ameliorating agent for the decline in motivation associated with aging is, for example, 600 μmol / L.

[0083] When the tea leaves or the tea leaf extract contains G-strictinin, the ratio of the molar concentration (μmol / L) of G-strictinin to the molar concentration (μmol / L) of non-gallate catechin in the preventive or ameliorating agent for the decline in motivation associated with aging (molar concentration of G-strictinin / molar concentration of non-gallate catechin) is, for example, 0.001 or more, preferably 0.01 or more, more preferably 0.05 or more, and even more preferably 0.06 or more. The concentration of G-strictinin in the agent for preventing or improving decreased motivation associated with aging is, for example, 3 μmol / L or more, preferably 30 μmol / L or more, more preferably 50 μmol / L or more, still more preferably 70 μmol / L or more, and even more preferably 90 μmol / L or more. The upper limit of the concentration of G-strictinin in the agent for preventing or improving decreased motivation associated with aging is, for example, 700 μmol / L.

[0084] In addition, the tea leaves and tea leaf extracts may contain theogallin, strictinin, and other components other than G-strictinin. Examples of other components include caffeine, theanine, and catechins other than non-gallate catechins (gallate catechins). However, the content of these components may be small or they may not be contained at all. For example, the agent for preventing or improving decreased motivation associated with aging may be caffeine-free, and the caffeine concentration in the agent for preventing or improving decreased motivation associated with aging in the case of being caffeine-free is, for example, 10 mg / L or less. The caffeine concentration in the agent for preventing or improving decreased motivation associated with aging is, for example, 4000 μmol / L or less, the theanine concentration is, for example, 2000 μmol / L or less, and the concentration of catechins other than non-gallate catechins is, for example, 5000 μmol / L or less, and may be 3000 μmol / L or less. When the agent for preventing or improving decreased motivation associated with aging has a low caffeine concentration, it is preferable to use tea leaves in which the amount of caffeine in the tea leaves has been reduced (for example, reduced by 60% or more) by hot water treatment using a hot water treatment device or the like as the tea leaves, or more specifically, a tea leaf extract obtained by a specific extraction method described later.

[0085] The form of the agent for preventing or improving reduced motivation associated with aging in this embodiment may be any form, for example, it may be in the form of food or drink. The agent for preventing or improving reduced motivation associated with aging in this embodiment may be the above-mentioned tea leaves or tea leaf extract itself, may be a dilution of the tea leaf extract with a solvent such as water, or may be a product obtained by adding other components according to the purpose. For example, when applying the agent for preventing or improving reduced motivation associated with aging in this embodiment as food or drink, the above-mentioned tea leaf extract or a dilution of the tea leaf extract with a solvent such as water may be directly ingested as a tea beverage, or may be ingested as various beverage ingredients or food ingredients, such as confectionery, health foods, and supplements. The property of the agent for preventing or improving reduced motivation associated with aging in this embodiment may be solid or liquid. When it is solid, for example, tea leaves, tea leaf extracts, or a dilution of the tea leaf extract with a solvent such as water may be processed into dosage forms such as tablets, capsules, granules, syrups, and troches. Further, when applying the agent for preventing or improving reduced motivation associated with aging in this embodiment as food or drink, a gelling agent, saccharides, flavors, sweeteners, oils and fats, base materials, excipients, food additives, auxiliary materials, bulking agents, etc. may be appropriately blended.

[0086] The tea leaf extract can be obtained by subjecting tea leaves to an extraction treatment with an extraction solvent, and a conventionally known method can be adopted. From the viewpoint of extracting active ingredients, it is preferable to pulverize the tea leaves for extraction. Since the pulverized product (powder) of the tea leaves is preferably of uniform size, the pulverized product may be sieved.

[0087] The extraction solvent may be any non-toxic one, and examples thereof include water, hydrophilic solvents, or mixtures thereof. Examples of water include tap water, distilled water, pure water, ion-exchanged water, etc. Examples of hydrophilic solvents include lower alcohols such as methanol, ethanol, propyl alcohol, and isopropyl alcohol, lower aliphatic ketones such as acetone and methyl ethyl ketone, and polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin.

[0088] Moreover, the extraction temperature is preferably 40°C or lower, more preferably 30°C or lower, and even more preferably 10°C or lower. Regarding the lower limit of the extraction temperature, it is, for example, -5°C or higher. It should be noted that it has not been previously known that the extraction rate of theogallin is high even at low temperatures (40°C or lower) and it can be extremely well extracted (eluted). Also, in the extraction at a low temperature of 40°C or lower, not only theogallin but also strictinin and G-strictinin can be extracted.

[0089] By extracting tea leaves with water at -5°C or higher and 40°C or lower, while theogallin can be extremely well extracted, the extraction amount of gallate-type catechins such as epigallocatechin gallate (EGCG) can be reduced. Therefore, in the production of a preventive or ameliorating agent for age-related decrease in motivation containing a tea leaf extract, when there is a step of producing a tea leaf extract by extracting tea leaves with water at -5°C or higher and 40°C or lower, while the preventive or ameliorating effect of age-related decrease in motivation by theogallin is achieved, the astringency by EGCG is suppressed, and thus a preventive or ameliorating agent for age-related decrease in motivation with excellent palatability can be produced. It should be noted that by extracting with water at 30°C or lower, the extraction amount of EGCG can be suppressed to 1 / 5 or more and 1 / 2 or less compared to hot water (for example, water at 70°C or higher). Also, by extracting tea leaves with water at -5°C or higher and 10°C or lower, not only the extraction amount of gallate-type catechins such as EGCG but also the extraction amount of caffeine can be reduced, and theogallin with a high extraction rate can be specifically extracted even with water at a low temperature of -5°C or higher and 10°C or lower. Therefore, in the production of a preventive or ameliorating agent for age-related decrease in motivation containing a tea leaf extract, when there is a step of producing a tea leaf extract by extracting tea leaves with water at -5°C or higher and 10°C or lower, a preventive or ameliorating agent for age-related decrease in motivation with a reduced caffeine amount can be produced. It should be noted that by extracting with water at -5°C or higher and 10°C or lower, the extraction amount of caffeine can be suppressed to 1 / 5 or more and 1 / 2 or less compared to hot water (for example, water at 70°C or higher). Also, in the extraction at a low temperature of 10°C or lower, strictinin and G-strictinin can be extracted.

[0090] Alternatively, a treatment may be performed to convert EGCG into epigallocatechin (EGC) and gallic acid by allowing tannase, which hydrolyzes the depside bond within the gallate molecule of EGCG, to act on the extract obtained by extracting tea leaves with a solvent.

[0091] The extraction may be performed multiple times by recovering the residue after the first extraction. Also, the extraction may use a method commonly used as a chemical separation and purification technique. For example, liquid-liquid partitioning, thin-layer chromatography, adsorption column chromatography, partition column chromatography, gel filtration column chromatography, ion exchange column chromatography, electrophoresis, high-performance liquid chromatography, etc. can be used. Also, these separation and purification means may be combined as necessary.

[0092] (Embodiment 6) Agent for preventing or improving decreased motivation associated with aging, and method for producing the same The agent for preventing or improving decreased motivation associated with aging according to Embodiment 6 contains tea leaves or a tea leaf extract containing the tea leaf extract. And in Embodiment 6, the tea leaves include at least one selected from tea leaves containing 1% by mass or more of theogallin, "MK5601", and descendants of "MK5601". Hereinafter, Embodiment 6 will be described. Except as described below, it is the same as Embodiment 5, and some descriptions of the content overlapping with Embodiment 5 will be omitted.

[0093] In this way, by including tea leaves or a tea leaf extract and making the tea leaves contain at least one selected from tea leaves containing 1% by mass or more of theogallin, "MK5601", and descendants of "MK5601", as shown in the examples described later, it is possible to obtain an agent for preventing or improving decreased motivation associated with aging that can prevent or improve decreased motivation associated with aging by continuous intake, for example, intake for 16 weeks or more. Since the agent for preventing or improving decreased motivation associated with aging of the present embodiment contains tea leaves or a tea leaf extract, it can be ingested as a food or drink. The tea leaves of "MK5601" are the same as in Embodiment 5.

[0094] The tea leaves and the tea leaf extract of the present embodiment contain non-gallate catechins and theogallin, and in the preventive or ameliorating agent for decreased motivation associated with aging, the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins (the molar concentration of theogallin / the molar concentration of non-gallate catechins) is preferably 0.3 or more. In the preventive or ameliorating agent for decreased motivation associated with aging, the ratio of the molar concentration (μmol / L) of theogallin to the molar concentration (μmol / L) of non-gallate catechins is preferably 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more.

[0095] In the present embodiment, it is preferable that the tea leaves and the raw tea leaves of the tea leaf extract contain strictinin and G-strictinin. The ratio of the molar concentration (μmol / L) of strictinin to the molar concentration (μmol / L) of non-gallate catechins in the preventive or ameliorating agent for decreased motivation associated with aging, the concentration of strictinin in the preventive or ameliorating agent for decreased motivation associated with aging, the ratio of the molar concentration (μmol / L) of G-strictinin to the molar concentration (μmol / L) of non-gallate catechins in the preventive or ameliorating agent for decreased motivation associated with aging, and the concentration of G-strictinin in the preventive or ameliorating agent for decreased motivation associated with aging are the same as in Embodiment 5.

[0096] The concentrations of other components other than theogallin, strictinin, and G-strictinin that the tea leaves and tea leaf extract of the present embodiment may contain, and in the preventive or ameliorating agent for decreased motivation associated with aging are the same as in Embodiment 5.

[0097] Also, the form of the preventive or ameliorating agent for decreased motivation associated with aging and the method for obtaining the tea leaf extract of the present embodiment are the same as in Embodiment 5.

Examples

[0098] Hereinafter, the present invention will be described more specifically by way of examples, but the present invention is not limited thereto.

[0099] (Measurement of the Concentration of Each Component of Tea Leaves) Regarding the raw tea powder ("MK5601") (dry tea leaf powder) used in the examples, the contents of caffeine, gallate-type catechins, non-gallate-type catechins, theogallin, strictinin, and G-strictinin were measured by the following method. The measured gallate-type catechins are epigallocatechin gallate (EGCG), epicatechin gallate, gallocatechin gallate, and catechin gallate. First, 250 mg of the raw tea powder ("MK5601") (dry tea leaf powder) was extracted with 20 mL of a mixed solution of 2% (v / v) phosphoric acid aqueous solution: ethanol (1:1, v / v) at 30°C for 60 minutes, filled up to 25 mL with distilled water (DW), and then filtered. The contents of caffeine, gallate-type catechins, non-gallate-type catechins, theogallin, strictinin, and G-strictinin in the supernatant of the obtained filtrate were measured by high performance liquid chromatography under the following Condition 1. (Condition 1) LC-10ADvp, Shimadzu, Kyoto Column: Wakopak Navi C18-5 (i.d. 4.6×150 mm, particle size 5 μm, Fuji Film Wako Pure Chemical Industries, Ltd., Osaka) Guard column: Wakopak Navi C18-5 (i.d. 4.6×10 mm, particle size 5 μm, Fuji Film Wako Pure Chemical Industries, Ltd., Osaka) Column temperature: 40°C Detection wavelength: 242 nm and 272 nm Injection volume: 20 μL (DISMIC-13-HPPTFE, 0.45 μm filtered solution, Advantec Co., Ltd., Tokyo) Flow rate: 1 mL / min Mobile phase: Using mobile phase A (DW: acetonitrile: phosphoric acid (H3PO4) = 400:10:1 (v / v / v)) and mobile phase B (methanol: mobile phase A = 1:2 (v / v)), elution was carried out with A:B = 95:5 (v / v) for 0 - 2 minutes, a linear gradient with A:B = 20:80 (v / v) for 2 - 27 minutes, maintaining A:B = 20:80 (v / v) for 27 - 35 minutes, and then returning to A:B = 95:5 (v / v).

[0100] Also, regarding the crude tea powder (dried tea leaf powder) of "MK5601" used in the examples, the theanine content was measured by the following method. First, 100 mg of the crude tea powder (dried tea leaf powder) of "MK5601" was extracted with 10 mL of distilled water (DW) containing an internal standard substance at 80 °C for 30 minutes, and then filtered. The theanine content in the supernatant of the obtained filtrate was measured by high performance liquid chromatography under the following condition 2. (Condition 2) Using the o-phthalaldehyde automatic pre-column derivatization method with an autosampler SIL-30AC (Shimadzu, Kyoto) LC-20AD, Shimadzu, Kyoto Column: Inesrtsil ODS-4 (3 μm, 4.6 mm × 150 mm, GLSciences Inc., Tokyo) Mobile phase: Using mobile phase A (20 mM potassium phosphate buffer (pH 6.4)) and mobile phase B (DW: acetonitrile: methanol = 15:45:40 (V:V:V)), elution was carried out with A:B = 86:14 (v / v) for 0 - 3 minutes, linearly gradient with A:B = 65:35 (v / v) for 3 - 15 minutes, maintaining A:B = 60:40 (v / v) for 15 - 19 minutes, and then returning to A:B = 86:14 (v / v). Internal standard substance: Glycylglycine

[0101] As a result of these, in the crude tea powder (dried tea leaf powder) of "MK5601", the caffeine content was 2.8 mass%, the gallate-type catechin content was 11.9 mass%, the non-gallate-type catechin content was 4.3 mass%, the theogallin content was 2.4 mass%, the strictinin content was 0.8 mass%, and the G-strictinin content was 3.6 mass%.

[0102] [Example 1] "MK5601" The crude tea powder (dried tea leaf powder) of "MK5601" was added to cold water at 4 °C to prepare a leachate (tea leaf extract). Note that by extracting with cold water at 10°C or lower in this way, the leaching amounts of caffeine and gallate-type catechins were reduced, and theogallin, which has a high leaching efficiency even in cold water, was specifically leached, and strictinin and G-strictinin were also leached. This is shown by the results of <Measurement of Concentrations of Each Component> below. Next, the obtained leachate was diluted with water so that the caffeine concentration became about 950 μmol / L to obtain a diluted solution. The caffeine concentration of 950 μmol / L was about one-fifth compared to the caffeine concentrations in Non-Patent Documents 1 to 3, in which it has been reported that the decline in brain function associated with aging can be suppressed, and was a much lower concentration.

[0103] [Comparative Example 1] "Yabukita" A diluted solution was obtained in the same manner as in Example 1, except that the rough tea powder of "Yabukita" was used instead of the rough tea powder of "MK5601".

[0104] <Measurement of Concentrations of Each Component> Regarding the obtained diluted solution of Example 1 and the diluted solution of Comparative Example 1, the concentrations (μmol / L) of caffeine, gallate-type catechins, non-gallate-type catechins, theogallin, strictinin, and G-strictinin were measured by high-performance liquid chromatography under the above Condition 1, and the concentration of theanine was measured under the above Condition 2. The results are shown in Table 1. Note that the total catechins are the sum of gallate-type catechins and non-gallate-type catechins. Also, from the results in Table 1, the results of obtaining the ratio of the molar concentration of theogallin, strictinin, or G-strictinin to the molar concentration of non-gallate-type catechins (μmol / L) are shown in Table 2.

[0105] As shown in Table 1, the theanine concentration of the diluted solution of Example 1 was about 70% of that of the diluted solution of Comparative Example 1. Also, the theanine concentration of the diluted solution of Example 1 was about one-thirtieth compared to Non-Patent Document 4, in which it has been reported that the cognitive function of experimental animals is improved by the administration of theanine, and was a much lower concentration. The total catechin concentration of the dilution solution of Example 1 was about 1.2 times that of the dilution solution of Comparative Example 1, showing no significant difference. Also, the concentration of non-gallate catechins in the dilution solution of Example 1 was almost the same as that of the dilution solution of Comparative Example 1. In addition, the theogallin concentration of the dilution solution of Example 1 was about 10 times that of the dilution solution of Comparative Example 1. The strictinin concentration of the dilution solution of Example 1 was about 5.5 times that of the dilution solution of Comparative Example 1. G-strictinin was contained in the dilution solution of Example 1 but not in the dilution solution of Comparative Example 1.

[0106] From these results, by using the dilution solution of Example 1 and the dilution solution of Comparative Example 1, it can be said that the components involved in the following <<Evaluation by Neurotrophic Factor Concentration>>, <<Evaluation of Cognitive Dysfunction Associated with Aging by Kinetic Methods>>, and <<Evaluation of Decreased Motivation Associated with Aging by Kinetic Methods>> are not caffeine, theanine, catechins, but theogallin, strictinin, and G-strictinin.

[0107]

Table 1

[0108]

Table 2

[0109] <<Evaluation by Neurotrophic Factor Concentration>> The dilution solution of Example 1 and the dilution solution of Comparative Example 1 prepared above were allowed to be freely ingested by a group of middle-aged wild-type mice (C57 / BL6, ♂, 8 months old) for 16 weeks. Also, water was given to the control mouse group, which was set as Comparative Example 2. The mice used were not special mice such as Alzheimer's disease models, but natural aging models of wild-type mice, which are middle-aged wild-type mice in which brain function decline is considered to start.

[0110] <Measurement of the Concentration of Neurotrophic Factor (Neurotrophin-3 (NT-3)) in the Hippocampus> After 16 weeks of free intake, the hippocampus, which plays an important role in learning and memory, was excised from middle-aged wild-type mice, and an extract was prepared. After quantifying the total protein amount of the extract by the BCA (bicinchoninic acid) method, the concentration of neurotrophin-3 (NT-3), which is a type of neurotrophic factor, was measured by the ELISA method. The measurement results of the concentration of neurotrophic factor (neurotrophin-3 (NT-3)) in the hippocampus are shown in Figure 1. (Mean±SEM., n = 9, ANOVA (analysis of variance): p < 0.01, Tukey’s test: *p < 0.05)

[0111] In addition, the amount (intake amount) of each component ingested by the mice was determined from the reduction in the diluent. The results are shown in Table 3.

[0112] As shown in Table 3, the intake amount of caffeine, which is considered to have the greatest impact on the central nervous system, was comparable between the middle-aged mice that ingested the diluent of Example 1 and the middle-aged mice that ingested the diluent of Comparative Example 1. The intake amount of total catechins was comparable between the middle-aged mice that ingested the diluent of Example 1 and the middle-aged mice that ingested the diluent of Comparative Example 1. The theanine intake amount of the middle-aged mice that ingested the diluent of Example 1 was about 65% lower than that of the middle-aged mice that ingested the diluent of Comparative Example 1. However, compared with Non-Patent Document 4, which reports that the cognitive function of experimental animals is improved by the administration of theanine, the intake amounts of both Example 1 and Comparative Example 1 were less than one-tenth. On the other hand, the theogallin intake amount of the middle-aged mice that ingested the diluent of Example 1 was about 8 times higher than that of the middle-aged mice that ingested the diluent of Comparative Example 1. In addition, the intake amount of strictinin was small compared to other components, but the middle-aged mice that ingested the diluent of Example 1 were about 5 times that of the middle-aged mice that ingested the diluent of Comparative Example 1, and G-strictinin was contained only in the middle-aged mice that ingested the diluent of Example 1.

[0113] Also, as shown in Fig. 1, middle-aged mice that ingested the dilution solution of the example had a higher concentration of neurotrophin 3 (NT-3), a neurotrophic factor, in the hippocampus compared to middle-aged mice that ingested water (Comparative Example 2) or middle-aged mice that ingested the dilution solution of Comparative Example 1.

[0114] Therefore, it was confirmed that continuous ingestion of the extract of tea leaves containing theogallin increases the neurotrophic factor (NT-3) in the cerebral hippocampus. And since the mice used were not special mice such as Alzheimer's disease models but a natural aging model of wild-type mice, continuous ingestion of the extract of tea leaves containing theogallin does not target the neurotoxicity of amyloid-β, a factor related to Alzheimer's disease, but rather increases the neurotrophic factor (NT-3) involved in maintaining brain functions such as cognitive function in a more general situation. It can be said that this effect was confirmed.

[0115]

Table 3

[0116] <<Evaluation of Cognitive Dysfunction Associated with Aging by Behavioral Methods>> The dilution solution of Example 1 and the dilution solution of Comparative Example 1 prepared above were freely ingested by a group of middle-aged wild-type mice (C57 / BL6, ♂, 8 months old) for 16 weeks. Water was given to the control mice, which was used as Comparative Example 2. Also, water was given to mice aged 2 - 4 months as a young control, which was used as Comparative Example 3.

[0117] <Novel Location Recognition Test> After the above 16-week free ingestion, a novel location recognition test, which is a hippocampus-dependent behavioral test, was conducted to evaluate spatial cognitive function. Specifically, after 16 weeks of free ingestion, in the familiarization stage (Fig. 2(a)), the mice were allowed to freely explore two identical objects X1 and X2. Then, after a certain period (1 hour) elapsed, in the test stage (Fig. 2(b)), one of the objects X1 was moved, and the exploration time was measured. The results of the novel location recognition test are shown in Fig. 3. The results at the viewing stage are shown in Fig. 3(a), and the results at the test stage are shown in Fig. 3(b). If the mouse remembers the position of the object at the viewing stage, the search time for the newly moved object at the novel location will relatively increase. (Mean±SEM, n = 13 - 18, Unpaired t test: *p < 0.05)

[0118] At the viewing stage, as shown in Fig. 3(a), there was almost no difference in the search time between object X1 and object X2. On the other hand, at the test stage, as shown in Fig. 3(b), compared with the young mice that ingested water (Comparative Example 3), there was no significant bias in the search time for object X1 at the novel location and object X2 at the non-novel location in the middle-aged mice that ingested the dilution of Comparative Example 1 (Comparative Example 1) and the middle-aged control mice that ingested water (Comparative Example 2). Therefore, it cannot be said that Comparative Example 1 and Comparative Example 2 prevent or improve cognitive dysfunction associated with aging. In contrast, in the middle-aged mice that ingested the dilution of Example 1 (Example 1), at the test stage, there was a significant bias in the search time for object X1 at the novel location and object X2 at the non-novel location, which was comparable to that of the young mice that ingested water (Comparative Example 3). Therefore, it can be said that continuous ingestion of the extract of tea leaves containing theogallin can effectively prevent or improve cognitive dysfunction associated with aging.

[0119] From the above results, it can be said that continuous ingestion of the extract of tea leaves containing theogallin increases the concentration of neurotrophic factor (NT-3) in the hippocampus of the brain and prevents or improves cognitive dysfunction associated with aging.

[0120] <<Evaluation of Decline in Motivation Associated with Aging by Behavioral Methods>> The diluted solutions of Example 1 and Comparative Example 1 prepared above were allowed to be freely ingested by a group of middle-aged wild-type mice (C57 / BL6, ♂, 8 months old) for 16 weeks. Water was given to the control mice, which was set as Comparative Example 2. Also, water was given to mice at 2 - 4 months old as a young control, which was set as Comparative Example 3.

[0121] <Elevated plus maze test> After the above 16-week free ingestion, an elevated plus maze test, which is a behavioral test for observing anxiety-like behavior, was conducted to evaluate the decline in motivation associated with aging. The elevated plus maze test is a conflict model that utilizes the exploratory behavior based on the inherent curiosity of animals and the avoidance behavior motivated by anxiety and fear. An open passageway (open arm) without walls and a closed passageway (closed arm) with walls were crossed in a cross shape and installed at a high position from the floor. The results of the elevated plus maze test are shown in Figure 4. For experimental animals, the open arm is considered to be an area where they feel more anxiety compared to the closed arm, and the number of entries into the open arm decreases for animals with a higher anxiety level. On the other hand, animals with a high maintained exploratory motivation have a higher number of entries into the open arm. (Mean±SEM, n = 18 - 19, Kruskal - Wallis test: p < 0.001, Sheffe’s multiple comparison procedure: **p < 0.005, ***p < 0.001)

[0122] As shown in Figure 4, compared with the young mice that ingested water (Comparative Example 3), the middle-aged mice that ingested the diluted solution of Comparative Example 1 (Comparative Example 1) and the middle-aged control mice that ingested water (Comparative Example 2) showed a significantly decreased number of entries into the open arm, indicating a significant decline in exploratory motivation. Therefore, it cannot be said that Comparative Example 1 and Comparative Example 2 prevent or improve the decline in motivation associated with aging. On the other hand, in middle-aged mice (Example 1) that ingested the dilution solution of Example 1, no significant decrease in the number of entries into the open arms was observed. Therefore, it can be said that continuous ingestion of the extract of tea leaves containing theogallin partially suppresses the decline in motivation associated with aging.

[0123] From the above results, it can be said that continuous ingestion of the extract of tea leaves containing theogallin prevents and improves the decline in motivation associated with aging.

[0124] <Extraction Test 1> The green tea leaves (dried tea leaf powder) of "MK5601" were added to water at the temperature (extraction temperature) described in Table 4 to prepare a leachate (tea leaf extract). Note that 40 times the amount (by mass) of water was used with respect to the green tea leaves (dried tea leaf powder), and the extraction time described in Table 4 was used. For the green tea leaves and leachate used, the concentrations of each component (theogallin, EGCG, and caffeine) were measured, and the ratio of the content in the leachate to the content in the green tea leaves (content mass in the leachate / content mass in the green tea leaves) was determined. The results are shown in Table 4.

[0125] As shown in Table 4, when the temperature of the extraction solvent is 10°C or lower, it can be seen that the extraction ratios of EGCG and caffeine can be suppressed to about 1 / 3 and 1 / 2, respectively, compared to the case of extraction with hot water (70°C or higher). Therefore, by using the tea leaf extract extracted with water at 10°C or lower and concentrating it, for example, about 2 times, it is possible to increase the concentration of theogallin while having the same amount of caffeine and about 1 / 2 the amount of EGCG as in the case of using the tea leaf extract extracted with hot water.

[0126]

Table 4

[0127] <Extraction Test 2> Except for using dried tea leaves (leaf) as the green tea leaves of "MK5601" and setting the extraction temperature and extraction time as the values described in Tables 5 to 8, in the same manner as <Extraction Test 1>, the ratio of the content in the leachate to the content in the green tea leaves was determined. The results are shown in Tables 5 to 8. Since the extraction rates of caffeine and EGCG in the green tea leaves of "MK5601" are the same as those of green tea leaves such as "Yabukita", and it can be seen from the literature JARQ 52 (1): 1-6 (2018) that even if the extraction time exceeds 60 minutes, it is difficult to exceed the extraction rate at 60 minutes, the extraction time was set to 60 minutes or less.

[0128] As shown in Tables 5 to 8, it can be seen that by extracting with water at 40°C or lower, theogallin can be extremely well extracted while reducing the extraction amount of EGCG. Specifically, the theogallin can be maintained at about 100% by mass, within 15 minutes of elution time, and the EGCG can be suppressed to about 1 / 3 and the caffeine to about 1 / 2. Also, by extracting with water at 30°C or lower, the theogallin can be maintained at 100% by mass, and within 30 minutes of elution time, the EGCG can be suppressed to 1 / 5 and the caffeine to about 1 / 2.

[0129] [Table 5]

[0130] [Table 6]

[0131] [Table 7]

[0132] [Table 8] [Explanation of Signs]

[0133] X1, X2 Objects

Claims

1. An enhancer of neurotrophin-3, comprising tea leaves or a tea leaf extract which is an extract of the tea leaves, wherein the tea leaves include at least one selected from tea leaves containing 1% by mass or more of theogallin, "MK5601", and descendants of "MK5601", and is an enhancer of neurotrophin-3.

2. The enhancer of neurotrophin-3 according to Claim 1, wherein the tea leaves and the tea leaf extract contain at least one of strictinin and G-strictinin.

3. The enhancer of neurotrophin-3 according to Claim 2, wherein the tea leaves and the tea leaf extract contain strictinin, and the ratio of the molar concentration (μmol / L) of strictinin to the molar concentration (μmol / L) of non-gallate catechin is 0.002 or more.

4. The enhancer of neurotrophin-3 according to Claim 2 or 3, wherein the tea leaves and the tea leaf extract contain G-strictinin, and the ratio of the molar concentration (μmol / L) of G-strictinin to the molar concentration (μmol / L) of non-gallate catechin is 0.001 or more.

5. A method for producing an enhancer of neurotrophin-3 according to any one of Claims 1 to 4, comprising a step of producing the tea leaf extract by extracting the tea leaves with water at -5°C or higher and 40°C or lower, and is a method for producing an enhancer of neurotrophin-3.

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