JP6457497B2 - Delayed onset of physical symptoms associated with aging - Google Patents
Delayed onset of physical symptoms associated with aging Download PDFInfo
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- JP6457497B2 JP6457497B2 JP2016515219A JP2016515219A JP6457497B2 JP 6457497 B2 JP6457497 B2 JP 6457497B2 JP 2016515219 A JP2016515219 A JP 2016515219A JP 2016515219 A JP2016515219 A JP 2016515219A JP 6457497 B2 JP6457497 B2 JP 6457497B2
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- kale
- aging
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- gene
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- A—HUMAN NECESSITIES
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Description
本発明は、老化に伴って生じる種々の身体的症状の発現を遅延させる剤に関する。 The present invention relates to an agent that delays the onset of various physical symptoms that occur with aging.
老化に伴って生じる身体的症状としては、シワ、たるみ等の皮膚症状、老眼、眼瞼下垂などの眼の症状、薄毛等の頭髪症状、骨粗しょう症等の骨の症状等が知られている。これらの症状を改善するための薬剤としては、グアニジン誘導体が使用されている（特許文献１）。 Known physical symptoms associated with aging include skin symptoms such as wrinkles and sagging, eye symptoms such as presbyopia and eyelid droop, hair hair symptoms such as thinning hair, and bone symptoms such as osteoporosis. Guanidine derivatives have been used as drugs for improving these symptoms (Patent Document 1).
また、老化に伴って生じる身体的症状として背骨の湾曲があり、普段の姿勢が影響すると考えられている。 In addition, as a physical symptom caused by aging, there is a curvature of the spine, and it is considered that a normal posture is affected.
しかし、従来の薬剤は、既に発症した症状を改善するものであり、老化に伴う身体的症状の発現を遅延させるものではない。
本発明の課題は、老化に伴って生じる身体的症状の発現を遅延させる剤を提供することにある。However, conventional drugs improve symptoms already developed and do not delay the onset of physical symptoms associated with aging.
The subject of this invention is providing the agent which delays the onset of the physical symptom which arises with aging.
そこで本発明者は、老化促進マウスを用いて種々の成分を摂取させ、老化によって生じる身体的症状の発現を遅延させる作用を検討してきたところ、全く意外にも、ケール又はその加工物を摂取すると老化により生じる眼瞼下垂や背骨の湾曲等に代表される身体的症状の発現が遅延することを見出し、本発明を完成した。 Therefore, the present inventor has ingested various components using an aging-promoting mouse and has studied the action of delaying the onset of physical symptoms caused by aging. The present invention was completed by finding that the onset of physical symptoms represented by drooping eyelids and spinal curvature caused by aging is delayed.
すなわち、本発明は、次の〔１〕〜〔２４〕を提供するものである。 That is, the present invention provides the following [1] to [24].
〔１〕ケール又はその加工物を有効成分とする老化に伴う身体的症状の発現遅延剤。
〔２〕老化に伴う身体的症状が、眼及び／又は骨の症状である〔１〕記載の発現遅延剤。
〔３〕眼及び／又は骨の症状が、眼瞼下垂及び／又は背骨の湾曲である〔２〕記載の発現遅延剤。
〔４〕老化に伴う身体的症状の発現遅延が、ケール又はその加工物を摂取することによる、ＥＧＦ遺伝子、Ｓｉｒｔ２遺伝子及びＳｉｒｔ３遺伝子から選ばれる１種以上の遺伝子の発現上昇により生じるものである〔１〕〜〔３〕のいずれかに記載の発現遅延剤。
〔５〕ケールの加工物が、ケールをブランチング処理して得られ、ケール由来固形分１ｇあたりのグルコラファニン含量が１ｍｇ以上であるケール加工物である〔１〕〜〔４〕のいずれかに記載の発現遅延剤。
〔６〕ケールがハイパール（農林水産省品種登録第２０５５５号）である〔１〕〜〔５〕のいずれかに記載の発現遅延剤。
〔７〕老化に伴う身体的症状の発現遅延剤製造のための、ケール又はその加工物の使用。
〔８〕老化に伴う身体的症状が、眼及び／又は骨の症状である〔７〕記載の使用。
〔９〕眼及び／又は骨の症状が、眼瞼下垂及び／又は背骨の湾曲である〔８〕記載の使用。
〔10〕老化に伴う身体的症状の発現遅延が、ケール又はその加工物を摂取することによる、ＥＧＦ遺伝子、Ｓｉｒｔ２遺伝子及びＳｉｒｔ３遺伝子から選ばれる１種以上の遺伝子の発現上昇により生じるものである〔７〕〜〔９〕のいずれかに記載の使用。
〔11〕ケールの加工物が、ケールをブランチング処理して得られ、ケール由来固形分１ｇあたりのグルコラファニン含量が１ｍｇ以上であるケール加工物である〔７〕〜〔１０〕のいずれかに記載の使用。
〔12〕ケールがハイパール（農林水産省品種登録第２０５５５号）である〔７〕〜〔１１〕のいずれかに記載の使用。
〔13〕老化に伴う身体的症状の発現を遅延させるための、ケール又はその加工物。
〔14〕老化に伴う身体的症状が、眼及び／又は骨の症状である〔１３〕記載のケール又はその加工物。
〔15〕眼及び／又は骨の症状が、眼瞼下垂及び／又は背骨の湾曲である〔１４〕記載のケール又はその加工物。
〔16〕老化に伴う身体的症状の発現遅延が、ケール又はその加工物を摂取することによる、ＥＧＦ遺伝子、Ｓｉｒｔ２遺伝子及びＳｉｒｔ３遺伝子から選ばれる１種以上の遺伝子の発現上昇により生じるものである〔１３〕〜〔１５〕のいずれかに記載のケール又はその加工物。
〔17〕ケールの加工物が、ケールをブランチング処理して得られ、ケール由来固形分１ｇあたりのグルコラファニン含量が１ｍｇ以上であるケール加工物である〔１３〕〜〔１６〕のいずれかに記載のケール又はその加工物。
〔18〕ケールがハイパール（農林水産省品種登録第２０５５５号）である〔１３〕〜〔１７〕のいずれかに記載のケール又はその加工物。
〔19〕ケール又はその加工物の有効量を投与することを特徴とする老化に伴う身体的症状の発現遅延方法。
〔20〕老化に伴う身体的症状が、眼及び／又は骨の症状である〔１９〕記載の方法。
〔21〕眼及び／又は骨の症状が、眼瞼下垂及び／又は背骨の湾曲である〔２０〕記載の方法。
〔22〕老化に伴う身体的症状の発現遅延が、ケール又はその加工物を摂取することによる、ＥＧＦ遺伝子、Ｓｉｒｔ２遺伝子及びＳｉｒｔ３遺伝子から選ばれる１種以上の遺伝子の発現上昇により生じるものである〔１９〕〜〔２１〕のいずれかに記載の方法。
〔23〕ケールの加工物が、ケールをブランチング処理して得られ、ケール由来固形分１ｇあたりのグルコラファニン含量が１ｍｇ以上であるケール加工物である〔１９〕〜〔２２〕のいずれかに記載の方法。
〔24〕ケールがハイパール（農林水産省品種登録第２０５５５号）である〔１９〕〜〔２３〕のいずれかに記載の方法。[1] An agent for delaying onset of physical symptoms associated with aging, comprising kale or a processed product thereof as an active ingredient.
[2] The onset delay agent according to [1], wherein the physical symptoms associated with aging are eye and / or bone symptoms.
[3] The onset delay agent according to [2], wherein the eye and / or bone symptom is drooping eyelids and / or spine curvature.
[4] Delayed onset of physical symptoms accompanying aging is caused by increased expression of one or more genes selected from EGF gene, Sirt2 gene and Sirt3 gene by ingesting kale or processed product thereof [ The expression retarder according to any one of 1] to [3].
[5] Any one of [1] to [4], wherein the processed product of kale is a processed kale product obtained by blanching kale and having a glucoraphanin content of 1 mg or more per 1 g of kale-derived solid content. The expression retarder described in 1.
[6] The expression retarder according to any one of [1] to [5], wherein the kale is Hyperl (Ministry of Agriculture, Forestry and Fisheries Variety Registration No. 20555).
[7] Use of kale or a processed product thereof for producing an agent for delaying onset of physical symptoms associated with aging.
[8] The use according to [7], wherein the physical symptoms associated with aging are eye and / or bone symptoms.
[9] The use according to [8], wherein the eye and / or bone symptom is drooping eyelids and / or spine curvature.
[10] Delayed onset of physical symptoms accompanying aging is caused by increased expression of one or more genes selected from EGF gene, Sirt2 gene and Sirt3 gene by ingesting kale or processed product thereof [ Use of any one of [7] to [9].
[11] Any one of [7] to [10], wherein the processed product of kale is a processed kale product obtained by blanching kale and having a glucoraphanin content of 1 mg or more per 1 g of kale-derived solid content. Use as described in.
[12] The use according to any one of [7] to [11], wherein the kale is a hyperle (Ministry of Agriculture, Forestry and Fisheries Variety Registration No. 20555).
[13] Kale or a processed product thereof for delaying the onset of physical symptoms associated with aging.
[14] The kale according to [13] or a processed product thereof, wherein the physical symptoms associated with aging are eye and / or bone symptoms.
[15] The kale according to [14] or a processed product thereof, wherein the eye and / or bone symptom is drooping eyelid and / or spine curvature.
[16] Delayed onset of physical symptoms accompanying aging is caused by increased expression of one or more genes selected from EGF gene, Sirt2 gene and Sirt3 gene by ingesting kale or processed product thereof [ The kale according to any one of [13] to [15] or a processed product thereof.
[17] Any one of [13] to [16], wherein a processed kale product is obtained by blanching kale and has a glucoraphanin content of 1 mg or more per 1 g of kale-derived solid content. Or a processed product thereof.
[18] The kale according to any one of [13] to [17] or a processed product thereof, wherein the kale is hyperle (Ministry of Agriculture, Forestry and Fisheries, Variety Registration No. 20555).
[19] A method for delaying the onset of physical symptoms associated with aging, comprising administering an effective amount of kale or a processed product thereof.
[20] The method according to [19], wherein the physical symptoms associated with aging are eye and / or bone symptoms.
[21] The method of [20], wherein the eye and / or bone symptom is drooping eyelids and / or spine curvature.
[22] Delayed onset of physical symptoms accompanying aging is caused by increased expression of one or more genes selected from EGF gene, Sirt2 gene and Sirt3 gene by ingesting kale or processed product thereof [ [19] The method according to any one of [21] to [21].
[23] Any of [19] to [22], wherein the processed kale product is obtained by blanching kale and has a glucoraphanin content of 1 mg or more per 1 g of kale-derived solid content. The method described in 1.
[24] The method according to any one of [19] to [23], wherein the kale is a hyperle (Ministry of Agriculture, Forestry and Fisheries Variety Registration No. 20555).
本発明によれば、老化に伴って生じる身体的症状の発現を遅延させることができる。 According to the present invention, the onset of physical symptoms that occur with aging can be delayed.
本発明の老化に伴う身体的症状の発現遅延剤の有効成分は、ケール又はその加工物である。 The active ingredient of the agent for delaying the onset of physical symptoms accompanying aging according to the present invention is kale or a processed product thereof.
ケールはアブラナ科の植物であり、キャベツの一種であるが結球しない特性を有する。ケールには、グルコラファニン（スルフォラファングルコシノレート）が含まれており、当該グルコラファニンを摂取すると腸内細菌によってグルコラファニンはスルフォラファンに分解される。スルフォラファンには、発がん抑制作用、第二相解毒酵素誘導作用、ピロリ菌感染抑制作用等が報告されている。しかし、老化に伴う身体的症状の発現を遅延する作用は全く知られていない。 Kale is a cruciferous plant that is a kind of cabbage but has the property of not heading. Kale contains glucoraphanin (sulforaphane glucosinolate), and when ingested, glucoraphanin is decomposed into sulforaphane by intestinal bacteria. Sulforaphane has been reported to inhibit carcinogenesis, induce phase II detoxification enzyme, inhibit H. pylori infection, and the like. However, no action is known to delay the onset of physical symptoms associated with aging.
ケールには複数の品種が存在し、本発明においては、いずれの品種でもよいが、老化に伴う身体的症状の発現遅延作用の点から、ハイパール（農林水産省品種登録第２０５５５号）を用いるのが好ましい。ハイパールは、ケール変種（Brassica oleracea L.convar. acephala (DC.）Alef. var. sabellica L.）である。また、ケールの植物体全体を使用してもよいし、その一部分、例えば葉、茎、根、花蕾等を使用してもよいが、老化に伴う身体的症状の発現遅延作用の点から、茎及び／又は葉を使用することが好ましい。 There are a plurality of varieties of kale, and in the present invention, any varieties may be used, but Hyperl (Ministry of Agriculture, Forestry and Fisheries, Variety Registration No. 20555) is used from the viewpoint of the delayed action of physical symptoms accompanying aging. Is preferred. High pearl is a kale variety (Brassica oleracea L. convar. Acephala (DC.) Alef. Var. Sabellica L.). In addition, the whole plant of kale may be used, or a part thereof, such as leaves, stems, roots, flower buds, etc., may be used. From the viewpoint of the delayed action of physical symptoms accompanying aging, the stems And / or leaves are preferred.
ケール加工物の形態としては、細断組成物、破砕組成物、搾汁組成物等が挙げられるが、飲み易さの点から、搾汁組成物が好ましい。細断組成物、破砕組成物、搾汁組成物等は、そのままの形態でもよいが、熱風乾燥、噴霧乾燥、凍結乾燥等の手段により粉末化したものが保存性の点で好ましい。特に噴霧乾燥は、熱による変質が熱風乾燥に比べて小さく、また凍結乾燥に比べて乾燥処理時間が短いため、乾燥方法として好ましい。
ケール加工物のうち、老化に伴う身体的症状の発現遅延作用の点から、ブランチング処理（加熱処理）した加工物が好ましい。さらに、老化に伴う身体的症状の発現遅延作用の点から、ケールをブランチング処理して得られ、ケール由来固形分１ｇあたりのグルコラファニン含量が１ｍｇ以上であるケール加工物（以下、これをブランチングケール加工物という）を用いるのが好ましい。Examples of the form of the processed kale include shredded compositions, crushed compositions, juiced compositions, and the like, but juiced compositions are preferred from the viewpoint of ease of drinking. The shredded composition, crushed composition, squeezed composition, etc. may be in the form as they are, but those pulverized by means such as hot air drying, spray drying, freeze drying and the like are preferred in terms of storage stability. In particular, spray drying is preferable as a drying method because the alteration due to heat is smaller than that of hot air drying and the drying treatment time is shorter than that of freeze drying.
Among the kale processed products, a blanched processed (heated) processed product is preferable from the viewpoint of the delayed action of physical symptoms accompanying aging. Furthermore, in terms of delayed action of physical symptoms accompanying aging, kale is obtained by blanching treatment, and a processed kale product having a glucoraphanin content of 1 mg or more per 1 g of kale-derived solid content (hereinafter referred to as this) It is preferable to use a blanched kale product.
ブランチングケール加工物のケール由来固形分１ｇあたりのグルコラファニン含量は、１ｍｇ以上であり、老化に伴う身体的症状の発現遅延作用の点から、２ｍｇ以上が好ましく、３ｍｇ以上がより好ましく、７ｍｇ以上がさらに好ましい。通常のケール加工物のケール由来固形分１ｇあたりのグルコラファニン含量は０．１ｍｇ〜０．６ｍｇ程度であり、ブランチングケール加工物のグルコラファニン含量は通常のケール加工物に比べて高いものである。
ケール加工物中のグルコラファニン含量は、後述の実施例に記載の方法でＨＰＬＣにより測定したものである。The content of glucoraphanin per 1 g of kale-derived solid content of the blanched kale processed product is 1 mg or more, preferably 2 mg or more, more preferably 3 mg or more, 7 mg or more from the viewpoint of delayed action of physical symptoms accompanying aging. The above is more preferable. The content of glucoraphanin per gram of Kale-derived solid content of a normal kale processed product is about 0.1 mg to 0.6 mg, and the glucoraphanin content of a blanched kale processed product is higher than that of a normal kale processed product It is.
The content of glucoraphanin in the processed kale is measured by HPLC according to the method described in Examples below.
ブランチングケール加工物のケール由来固形分１ｇあたりのシニグリン含量は、特に限定されるものではないが、老化に伴う身体的症状の発現遅延作用の点から、１ｍｇ未満であることが好ましく、０．１ｍｇ未満であることがより好ましく、０．０２ｍｇ未満であることがさらに好ましい。通常のケール加工物のケール由来固形分１ｇあたりのシニグリン含量は２ｍｇ以上であり、ブランチングケール加工物のシニグリン含量は低いものである。
ケール加工物中のシニグリン含量は、後述の実施例に記載の方法でＨＰＬＣにより測定したものである。The content of sinigrin per gram of the kale-derived solid content of the blanched kale processed product is not particularly limited, but is preferably less than 1 mg from the viewpoint of the delayed action of physical symptoms accompanying aging. More preferably, it is less than 1 mg, and even more preferably less than 0.02 mg. The signiglin content per gram of the kale-derived solid content of a normal kale product is 2 mg or more, and the signiglin content of the blanched kale product is low.
The content of sinigrin in the processed kale is measured by HPLC according to the method described in Examples below.
また、ブランチングケール加工物のケール由来固形分１ｇあたりのプロゴイトリン含量は、特に限定されるものではないが、老化に伴う身体的症状の発現遅延作用の点から０．１ｍｇ未満であるのが好ましく、０．０２ｍｇ未満であることがより好ましい。通常のケール加工物のケール由来加工物１ｇあたりのプロゴイトリン含量は、０．２ｍｇ以上であり、ブランチングケール加工物中のプロゴイトリン含量は、通常のケール加工物に比べて低いものである。プロゴイトリンは、甲状腺肥大や甲状腺腫の発生と関係することが報告されており、含有量は少ないほうが望ましい。
ケール加工物中のプロゴイトリン含量は、後述の実施例に記載の方法でＨＰＬＣにより測定したものである。The progoitrin content per gram of the kale-derived solid content of the blanched kale processed product is not particularly limited, but is preferably less than 0.1 mg from the viewpoint of delayed action of physical symptoms associated with aging. More preferably, it is less than 0.02 mg. The progoitrin content per 1 g of the kale-derived processed product of the normal kale processed product is 0.2 mg or more, and the progoitrin content in the blanched kale processed product is lower than that of the normal kale processed product. Progoitrin has been reported to be associated with the development of thyroid hypertrophy and goiter, and a lower content is desirable.
The progoitrin content in the processed kale is measured by HPLC according to the method described in the examples below.
ブランチング処理は、ケールの状態で行ってもよく、ケール加工物の状態で行ってもよいが、ケールの状態で行うことが好ましい。ブランチング条件は、グルコラファニン含量の点から、６０〜１００℃で１〜１０分間行うのが好ましい。 The blanching process may be performed in a kale state or in a kale processed state, but is preferably performed in a kale state. The blanching conditions are preferably performed at 60 to 100 ° C. for 1 to 10 minutes from the viewpoint of glucoraphanin content.
ブランチング方法としては、特に限定されるものではなく、例えば、蒸し処理及び水中加熱処理（茹で処理）等を挙げることができるが、蒸し処理の場合、蒸気の流れが悪い状況では蒸気の当たり具合にばらつきが生じやすく、いわゆる「蒸しムラ」ができるため均一なブランチング処理が難しい場合があることから、水中加熱処理がより好ましい。ケールを水中で加熱する場合、水の重量に対するケールの投入量については特に制限はなく、均一に加熱できる条件であればどのような割合でもよい。水中加熱処理に際して、水にpH調整剤としてアルカリ剤、例えばクエン酸ナトリウム、アスコルビン酸ナトリウム、乳酸ナトリウム、水酸化カルシウム、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム等を添加することができる。また、水中加熱処理の水のｐＨについては、特に限定されるものではないが、強い酸性の条件下ではケール中のクロロフィルの分解が促進され、ケール加工物の色調が悪くなることから、ｐＨ６〜９であることが好ましい。 The blanching method is not particularly limited, and examples thereof include steaming and underwater heat treatment (boiled treatment). In water heating treatment is more preferable, since it is likely to cause variation and so-called “steaming unevenness” may occur and uniform blanching may be difficult. When heating the kale in water, the amount of kale to be added to the weight of water is not particularly limited, and any ratio may be used as long as it can be uniformly heated. In the heat treatment in water, an alkaline agent such as sodium citrate, sodium ascorbate, sodium lactate, calcium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like can be added to water as a pH adjuster. Further, the pH of the water for the heat treatment in water is not particularly limited, but the decomposition of chlorophyll in the kale is promoted under strongly acidic conditions, and the color tone of the processed kale deteriorates. 9 is preferred.
ブランチング処理後のケールは、速やかに冷却することが、色調の点で好ましい。冷却手段としては、自然放冷、氷、水等の冷媒を使用する方法などが挙げられる。 It is preferable in terms of color tone that the kale after the blanching treatment is cooled quickly. Examples of the cooling means include natural cooling, a method using a refrigerant such as ice and water, and the like.
ケール又はケール加工物は、後記実施例に示すように、老化に伴う身体的症状に対し、優れた発現遅延作用を有する。ここで、老化に伴う身体的症状としては、シワ、たるみ等の皮膚症状、老眼、眼瞼下垂などの眼の症状、薄毛等の頭髪症状、背骨の湾曲、骨粗しょう症、変形性関節症等の骨の症状等が挙げられる。背骨の湾曲とは、例えば、変形性脊椎症又は脊椎側弯症等が挙げられる。ケール又はケール加工物は、このうち、眼及び／又は骨の症状、特に、眼瞼下垂及び／又は背骨の湾曲に対して、優れた発現遅延作用を有する。老化に伴う身体的症状の発現遅延作用は、当該身体的症状の改善作用とは異なる作用である。即ち、発現遅延作用とは、当該身体的症状の発現の時期を遅らせる作用であるのに対し、改善作用とは当該身体的症状が既に発現しているものを、発現していない状態に戻す作用であるから、発現遅延作用と、改善作用は明確に相違するものである。ケール又はケール加工物が老化に伴う身体的症状の発現遅延作用を有することは、従来、全く知られてはいなかった。
また、ケール又はケール加工物は、ＥＧＦ（上皮細胞増殖因子）遺伝子、Ｓｉｒｔ２（Ｓｉｒｔｕｉｎ２）遺伝子及びＳｉｒｔ３（Ｓｉｒｔｕｉｎ３）遺伝子から選ばれる１種以上の遺伝子の発現を上昇させる作用を有する。これらの遺伝子は老化に関する遺伝子であるため、本願発明の老化に伴う身体的症状の発現遅延作用は、これらの遺伝子発現の上昇により生じると考えられる。The kale or the processed kale has an excellent onset delaying action on the physical symptoms associated with aging, as shown in Examples below. Here, physical symptoms associated with aging include skin symptoms such as wrinkles and sagging, presbyopia, eye symptoms such as eyelid drooping, hair symptoms such as thinning hair, spine curvature, osteoporosis, osteoarthritis, etc. Examples include bone symptoms. Examples of the curvature of the spine include degenerative spondylosis or scoliosis. Of these, the kale or the processed kale has an excellent onset delaying action on eye and / or bone symptoms, particularly on the drooping of the eyelids and / or the curvature of the spine. The action of delaying the onset of physical symptoms accompanying aging is an action different from the action of improving the physical symptoms. That is, the onset delaying action is an action that delays the onset of the physical symptom, whereas the improving action is an action that restores a state in which the physical symptom has already developed to a state in which it does not occur. Therefore, the expression delaying action and the improving action are clearly different. It has never been known at all that kale or a processed kale has a delayed action of physical symptoms associated with aging.
In addition, kale or processed kale has an action of increasing the expression of one or more genes selected from EGF (epidermal growth factor) gene, Sirt2 (Sirtuin2) gene, and Sirt3 (Sirtuin3) gene. Since these genes are genes related to aging, it is considered that the action of delaying the expression of physical symptoms accompanying aging according to the present invention is caused by an increase in the expression of these genes.
本発明の老化に伴う身体的症状の発現遅延剤の投与方法は、経口投与又は非経口投与のいずれも使用できるが、経口投与が好ましい。投与に際しては、有効成分を経口投与、直腸内投与、注射等の投与方法に適した固体又は液体の医薬用無毒性担体と混合して、慣用の医薬品製剤の形態で投与することができる。
このような製剤としては、例えば、錠剤、顆粒剤、散剤、カプセル剤等の固形剤、溶液剤、懸濁剤、乳剤等の液剤、凍結乾燥剤等が挙げられる。これらの製剤は製剤上の常套手段により調製することができる。上記の医薬用無毒性担体としては、例えば、グルコース、乳糖、ショ糖、澱粉、マンニトール、デキストリン、脂肪酸グリセリド、ポリエチレングリコール、ヒドロキシエチルデンプン、エチレングリコール、ポリオキシエチレンソルビタン脂肪酸エステル、アミノ酸、ゼラチン、アルブミン、水、生理食塩水等が挙げられる。また、必要に応じて、安定化剤、湿潤剤、乳化剤、結合剤、等張化剤、賦形剤等の慣用の添加剤を適宜添加することもできる。As the method for administering the agent for delaying the onset of physical symptoms accompanying aging according to the present invention, either oral administration or parenteral administration can be used, but oral administration is preferred. In administration, the active ingredient can be mixed with a solid or liquid non-toxic pharmaceutical carrier suitable for administration methods such as oral administration, rectal administration and injection, and administered in the form of a conventional pharmaceutical preparation.
Examples of such preparations include solid agents such as tablets, granules, powders and capsules, solutions such as solutions, suspensions and emulsions, and lyophilization agents. These preparations can be prepared by conventional means on the preparation. Examples of the non-toxic pharmaceutical carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, amino acid, gelatin, albumin , Water, physiological saline and the like. In addition, conventional additives such as stabilizers, wetting agents, emulsifiers, binders, isotonic agents, excipients and the like can be appropriately added as necessary.
本発明の老化に伴う身体的症状の発現遅延剤の有効成分であるケール又はその加工物は、従来より利用され、その安全性も確認されているものであることから、これを老化に伴う身体的症状の発現遅延剤として使用する場合の投与量に厳格な制限はないが、その好適な投与量はケール由来の固形分として１日当たり、体重７０ｋｇのヒトとして１ｇ〜５０ｇであり、特に１０ｇ〜４０ｇが好ましい。 The kale which is an active ingredient of the agent for delaying the onset of physical symptoms according to the present invention or a processed product thereof has been used conventionally and its safety has been confirmed. Although there is no strict restriction on the dosage when used as a symptom onset of symptomatic symptoms, the suitable dosage is 1 g to 50 g per day as a solid content derived from kale, 1 g to 50 g as a human having a body weight of 70 kg, particularly 10 g to 40 g is preferred.
以下、実施例を用いて本発明を具体的に説明するが、本発明はこれら実施例に限定されるものではない。
なお、本実施例におけるグルコシノレート類（以下、ＧＳＬと表記する場合があり、具体的にはグルコラファニン、プロゴイトリン、シニグリンである）の測定は、以下に示す方法により行った。
（グルコシノレート類の測定）
ＧＳＬの定量は、具体的には以下の通り行った。サンプル（ケール搾汁液、又はその乾燥物を水に溶解したもの）１ｍＬ（１０００ｍｇ前後）を正確に量り、ファルコンチューブ（１５ｍＬ）に分取する。０．１％ギ酸溶液（ギ酸１ｍＬを８０％メタノール水溶液に混和し、全量を１Ｌとしたもの）９ｍＬを加え、ボルテックスにより懸濁する。懸濁処理物を遠心分離して（２，１００ｇ、１５分）上清を分取し、試料を得た。
固相抽出カラム（ＯａｓｉｓTM ＷＡＸ １ｃｃ Ｃａｒｔｒｉｄｇｅ ３０ｍｇ Ｓｏｒｂｅｎｔ ｐｅｒ Ｃａｒｔｒｉｄｇｅ ３０μｍ Ｐａｒｔｉｃｌｅ ｓｉｚｅ、ウォーターズ株式会社）をメタノール１ｍＬで活性化し、０．１％ギ酸水（ギ酸１ｍＬを水に混和し、全量を１Ｌとしたもの）１ｍＬで平衡化し、先に調製した試料１００μＬを吸着させた後、０．１％ギ酸水１ｍＬ、次いでメタノール１ｍＬでカラム洗浄を行う。カラムに吸着している画分を５％アンモニア溶液（２８％アンモニア水をメタノールで希釈したもの）１ｍＬで溶出させ、エバポレーターで減圧濃縮した後、デシケーター内で減圧乾燥し乾固させる。乾固物に０．１％ギ酸水３００μＬを加えて再溶解し、フィルター付きバイアルに移し、ろ過したものを分析用サンプルとする。
分析はＨＰＬＣ−Ｐｒｏｍｉｎｅｎｃｅ（株式会社島津製作所）を用い、以下の条件で分析を行う。インジェクト量は１０μＬである。
なお、搾汁液のケール由来固形分は、搾汁液を乾燥し、水分を蒸発させた後、乾燥後の質量を測定することにより求めたものである。
＜分析条件＞
カラム：Ｄｅｖｅｌｏｓｉｌ ＲＰＡＱＵＥＯＵＳ ＡＲ−５（野村化学、φ４．６×２５０mm）
移動相Ａ：１０mMギ酸アンモニウム水（pH３．７５）
移動相Ｂ：１０mMギ酸アンモニウム水ｉｎ９０％（ｖ／ｖ）アセトニトリル／水（pH３．７５）
流 速：１ｍＬ／分
カラムオーブン温度：４０℃
移動相グラジエント：ｍｉｎ Ａ Ｂ
０ １００ ０
１０ １００ ０
１２ ０ １００
１７ ０ １００
１７．１ １００ ０
３０ １００ ０
検 出 器：ＵＶ検出器
検出器電圧：１００Ｖ
波 長：２２６ｎｍ
測定時間：３０分
なお、ＧＳＬの定量は、分析データのＧＳＬに対応するピークエリア面積を、標準品ＧＳＬのピークエリア面積と比較し行った。EXAMPLES Hereinafter, although this invention is demonstrated concretely using an Example, this invention is not limited to these Examples.
In addition, the measurement of the glucosinolates in this Example (hereinafter sometimes referred to as GSL, specifically, glucoraphanin, progoitrin, and synigrin) was performed by the following method.
(Measurement of glucosinolates)
Specifically, GSL was quantitatively determined as follows. 1 mL (around 1000 mg) of a sample (Kale juice or a dried product thereof dissolved in water) is accurately weighed and dispensed into a Falcon tube (15 mL). Add 9 mL of 0.1% formic acid solution (mixed with 1 mL of formic acid in 80% aqueous methanol solution to a total volume of 1 L) and suspend by vortexing. The suspension was centrifuged (2,100 g, 15 minutes), and the supernatant was collected to obtain a sample.
A solid phase extraction column (Oasis ™ WAX 1 cc Cartridge 30 mg Sorbent per Cartridge 30 μm Particle size, Waters Co., Ltd.) was activated with 1 mL of methanol, and 0.1% formic acid water (1 mL of formic acid was mixed with water to make the total volume 1 L) ) Equilibrate with 1 mL, adsorb 100 μL of the sample prepared above, and perform column washing with 1 mL of 0.1% formic acid and then 1 mL of methanol. The fraction adsorbed on the column is eluted with 1 mL of 5% ammonia solution (28% aqueous ammonia diluted with methanol), concentrated under reduced pressure with an evaporator, dried under reduced pressure in a desiccator and dried. Add 300 μL of 0.1% aqueous formic acid to the dried product, re-dissolve, transfer to a vial with a filter, and filter the sample for analysis.
Analysis is performed using HPLC-Prominence (Shimadzu Corporation) under the following conditions. The injection amount is 10 μL.
In addition, the kale origin solid content of squeezed liquid is calculated | required by measuring the mass after drying, after drying squeezed liquid and evaporating a water | moisture content.
<Analysis conditions>
Column: Develosil RPAQUEOUS AR-5 (Nomura Chemical, φ4.6 × 250 mm)
Mobile phase A: 10 mM ammonium formate water (pH 3.75)
Mobile phase B: 10 mM ammonium formate in 90% (v / v) acetonitrile / water (pH 3.75)
Flow rate: 1 mL / min Column oven temperature: 40 ° C
Mobile phase gradient: min AB
0 100 0
10 100 0
12 0 100
17 0 100
17.1 100 0
30 100 0
Detector: UV detector Detector voltage: 100V
Wavelength: 226nm
Measurement time: 30 minutes In addition, the quantitative determination of GSL was performed by comparing the peak area area corresponding to GSL in the analysis data with the peak area area of the standard product GSL.
製造例１
ケール（ハイパール：農林水産省品種登録第２０５５５号、３月播種、１１月収穫）の生の葉を水で洗浄し、９８℃の温浴中で２分間加熱処理後、水浴中にて冷却した。冷却したケールを破砕ポンプ（関口製作所：ＳＳ−００１）により粉砕した後に、スクリュープレス（ＶＥＴＴＥＲ社：ＤＶ）で搾汁し、搾汁液を得た。この搾汁液にプレート式熱交換機で１１７℃３５秒間の殺菌を行った。この搾汁液にデキストリンをケール由来固形分１重量部に対し１．５重量部加え、スプレードライヤー（株式会社三陽：ＳＣ−６００）で噴霧乾燥し、粉末サンプルとした。
得られた粉末サンプルを、その濃度が４％ｗ／ｗとなるようにイオン交換水に溶解したものについて、上記の方法により、そのグルコシノレート類の定量を行った。その結果を表１に示す。Production Example 1
The raw leaves of Kale (Hyperl: Ministry of Agriculture, Forestry and Fisheries, Variety Registration No. 20555, March sowing, harvested in November) were washed with water, heat-treated in a 98 ° C. warm bath for 2 minutes, and then cooled in the water bath. The cooled kale was pulverized with a crushing pump (Sekiguchi Seisakusho: SS-001) and then squeezed with a screw press (VETTER: DV) to obtain a squeezed liquid. This squeezed liquid was sterilized at 117 ° C. for 35 seconds using a plate heat exchanger. Dextrin was added to this squeezed liquid in an amount of 1.5 parts by weight with respect to 1 part by weight of the kale-derived solid, and spray dried with a spray dryer (Sanyo Co., Ltd .: SC-600) to obtain a powder sample.
The obtained powder sample was dissolved in ion-exchanged water so that its concentration was 4% w / w, and the glucosinolates were quantified by the above method. The results are shown in Table 1.
ハイパールは、グルコラファニン量が１４．５ｍｇであり、プロゴイトリンとシニグリンは未検出であった。 As for high pearl, the amount of glucoraphanin was 14.5 mg, and progoitrin and synigrin were not detected.
実施例１（ハイパール摂取がマウス外観に与える作用）
（動物）
雄のＳＡＭＰ８マウス（日本エスエルシー社）を使用した。
全てのマウスは温度２０−２３℃、湿度４０−７０％、明暗サイクルが１２ｈ／１２ｈで個別に飼育されている。Example 1 (Effect of hyperle intake on mouse appearance)
(animal)
Male SAMP8 mice (Japan SLC) were used.
All mice are individually housed at a temperature of 20-23 ° C, a humidity of 40-70%, and a light / dark cycle of 12h / 12h.
（実験計画）
１６週齢のマウスを１２匹ずつ２つの群に分けた。
コントロール群はＡＩＮ−９３Ｍ飼料（オリエンタル酵母工業）で飼育し、ハイパール摂取群は、製造例１で調製したハイパール粉末を１％（ｗ／ｗ）（ハイパール由来固形分に換算すると０．４％）含有するＡＩＮ−９３Ｍ飼料で飼育した。
飼料と水は自由摂取とした。飼料摂取量はコントロール群とハイパール摂取群で有意差はなかった。
２６週後、マウスの外観を評価した。（コントロール群は飼育中に３匹死亡したため、９匹のマウスについて外観を評価した。）(Experimental plan)
Sixteen-week-old mice were divided into two groups of 12 mice.
The control group is bred with AIN-93M feed (Oriental Yeast Co., Ltd.), and the hyperle intake group is 1% (w / w) of hyperl powder prepared in Production Example 1 (0.4% when converted to hyperl-derived solid content). The AIN-93M feed contained was raised.
Feed and water were ad libitum. There was no significant difference in feed intake between the control group and the hyperl intake group.
After 26 weeks, the appearance of the mice was evaluated. (In the control group, 3 mice died during breeding, so the appearance of 9 mice was evaluated.)
（結果）
コントロール群では、９匹中７匹（７８％）において、ハイパール摂取群と比較して目が小さく見え、老化による眼瞼下垂の症状が確認された（図１）。また、当該マウスにおいては背骨が湾曲しており、変形性脊椎症の症状が観察された（図１）。これらの症状が確認されたマウスは、２匹が重い症状であり、５匹が中程度の症状であった。一方、ハイパール摂取群においては、１２匹中３匹（２５％）において、コントロール群と同様に眼瞼下垂又は変形性脊椎症の症状が確認されたが、１２匹中９匹（７５％）においては、眼瞼下垂又は変形性脊椎症の症状が確認されなかった（図２）。ハイパール摂取群で症状が確認されたマウスは、全て中程度の症状であった。
これらのことから、ハイパール摂取群においては、眼瞼下垂や背骨の湾曲といった老化に伴う身体的症状の発現が、ハイパールの摂取によって遅延したものと考えられた。なお、重い症状とは、図１に示されている程度の症状をいい、中程度の症状とは、図１に示されている症状よりも背骨の湾曲又は眼瞼下垂の程度が軽いものをいう。(result)
In the control group, 7 out of 9 animals (78%) had smaller eyes compared to the hyperle intake group, and symptoms of eyelid droop due to aging were confirmed (FIG. 1). In addition, the spine was curved in the mouse, and symptoms of osteopathic spondylosis were observed (FIG. 1). Of the mice in which these symptoms were confirmed, 2 were severe symptoms and 5 were moderate symptoms. On the other hand, in the hyperl intake group, 3 of 12 animals (25%) were confirmed to have eyelid droop or spondylotic spondylosis as in the control group, but in 9 of 12 animals (75%) No symptoms of eyelid drooping or osteopathic spondylosis were observed (FIG. 2). All mice with symptoms confirmed in the high pearl intake group had moderate symptoms.
From these results, it was considered that in the hyperl intake group, the onset of physical symptoms associated with aging such as eyelid drooping and spine curvature was delayed by hyperl intake. Severe symptoms refer to the symptoms shown in FIG. 1, and moderate symptoms refer to those with less spinal curvature or eyelid drooping than the symptoms shown in FIG. .
実施例２（遺伝子発現解析）
実施例１のコントロール群、ハイパール摂取群のうち、無作為に選んだ４匹を解剖し、皮膚組織を採取した。Example 2 (Gene expression analysis)
Of the control group and hyperle intake group of Example 1, 4 randomly selected animals were dissected and the skin tissue was collected.
（皮膚からのＴｏｔａｌ ＲＮＡの抽出）
マウス背部を剃毛して表皮から真皮までを１cm角に採取し，ハサミにて細断した。ポリトロンホモジナイザーＰＴ３１００（KINEMATICA社）でホモジナイズし、TRI Reagent（Molecular Research Center社）でＴｏｔａｌ ＲＮＡを抽出した。(Extraction of Total RNA from skin)
The back of the mouse was shaved and the epidermis to the dermis were collected in 1 cm squares and cut into pieces with scissors. Homogenization was performed with polytron homogenizer PT3100 (KINEMATICA), and total RNA was extracted with TRI Reagent (Molecular Research Center).
（検体溶液の調製）
上記で得られたＴｏｔａｌ ＲＮＡからMessageAmpTMII-Biotin Enhanced Kit(Life technologies社)を用いてｃＤＮＡを合成し、MinElute PCR Purification Kit（Qiagen社）を用いてｃＤＮＡを精製した。
そして、MessageAmpTMII-Biotin Enhanced Kitを用いてビオチンで標識されたａＲＮＡ（amplified RNA）を合成し、RNeasy(R) MinEluteTMCleanup Kit(Qiagen社)を用いてａＲＮＡを精製した。
次いで、MessageAmpTMII-Biotin Enhanced Kitを用いてａＲＮＡを適切な鎖長に断片化し、自動ハイブリダイゼーション洗浄装置に供する検体溶液を作製した。(Preparation of sample solution)
CDNA was synthesized from the total RNA obtained above using MessageAmp ™ II-Biotin Enhanced Kit (Life technologies) and purified using MinElute PCR Purification Kit (Qiagen).
Then, aRNA (amplified RNA) labeled with biotin was synthesized using MessageAmp ™ II-Biotin Enhanced Kit, and aRNA was purified using RNeasy® MinElute ™ Cleanup Kit (Qiagen).
Next, aRNA was fragmented to an appropriate chain length using MessageAmp ™ II-Biotin Enhanced Kit, and a sample solution to be used in an automatic hybridization washing apparatus was prepared.
（ハイブリダイゼーション）
上記検体溶液を自動ハイブリダイゼーション洗浄装置（三菱レイヨン：ＡＨＦ−２００）に供し、ＤＮＡチップ「ジェノパール（登録商標）」の皮膚チップ（肌の形成やターンオーバーに関する遺伝子を搭載したＤＮＡチップ）を用いてハイブリダイゼーション及び洗浄を行った。(Hybridization)
The sample solution is subjected to an automatic hybridization washing apparatus (Mitsubishi Rayon: AHF-200), and a skin chip of a DNA chip “Genopal (registered trademark)” (a DNA chip carrying a gene relating to skin formation and turnover) is used. Hybridization and washing were performed.
（検出）
バイオチップ読取装置（横河電機：ＭＢ−Ｖ１）を用いて、ＤＮＡチップの蛍光シグナル強度を測定した。その結果は表２〜表５及び図３〜図５の通りである。(detection)
The fluorescence signal intensity of the DNA chip was measured using a biochip reader (Yokogawa: MB-V1). The results are as shown in Tables 2 to 5 and FIGS.
この結果から、ハイパール摂取群ではＥＧＦ遺伝子、Ｓｉｒｔ２遺伝子、Ｓｉｒｔ３遺伝子の発現量が、コントロール群に比べて１．２倍以上であり、Ｐ値が０．０５未満であることから、その発現量はコントロール群に対し統計的に有意に上昇していることが判明した。これらの遺伝子の発現上昇により、ハイパール摂取群では老化に伴う身体的症状の発現遅延が生じていると考えられる（ＥＧＦ：表４、図３、Ｓｉｒｔ２：表５、図４、Ｓｉｒｔ３：表５、図５）。
また、ハイパール摂取群では、Ａｃｅｒ２遺伝子（アルカリ性セラミド分解酵素）の発現が上昇していた（表４）。セラミドは皮膚の構成タンパク質の一種であり、皮膚のハリを保つ役割をもつ。したがって、ハイパール摂取群では、セラミドの分解が促進され、皮膚のハリがなくなり、眼瞼下垂の症状が発現する可能性が高まると考えられるが、意外なことにハイパール摂取群では、眼瞼下垂の症状の発現が遅延していた。
表２〜表５及び図３〜図５において、Ｃｏｎｔｒｏｌ：コントロール群、Ｓａｍｐｌｅ：ハイパール摂取群である。表では遺伝子発現のシグナル強度の平均値とｔ検定のＰ値を示し、グラフでは遺伝子発現のシグナル強度の平均値を示す。From this result, the expression level of EGF gene, Sirt2 gene, Sirt3 gene in the hyperle intake group is 1.2 times or more compared to the control group, and the P value is less than 0.05. It was found that there was a statistically significant increase relative to the control group. Due to the increased expression of these genes, it is considered that in the hyperl ingestion group, delayed onset of physical symptoms accompanying aging occurs (EGF: Table 4, FIG. 3, Sirt2: Table 5, FIG. 4, Sirt3: Table 5, FIG. 5).
In the hyperle intake group, the expression of Acer2 gene (alkaline ceramide degrading enzyme) was increased (Table 4). Ceramide is a kind of skin constituent protein and has the role of keeping the skin firm. Therefore, it is considered that the decomposition of ceramide is promoted in the hyperle intake group, the skin tension is eliminated, and the possibility of symptom of eyelid drooping increases. Onset was delayed.
In Tables 2 to 5 and FIGS. 3 to 5, Control is a control group, and Sample is a hyperle intake group. The table shows the average value of the signal intensity of gene expression and the P value of t test, and the graph shows the average value of the signal intensity of gene expression.
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